Crystalline forms of quinazoline derivatives, their preparation, compositions and uses

Abstract

The invention relates to a preparation method of (R)-N-(4-([1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy)-3-methylphenyl)-5-((3, 4, 5-triazolo [1, 5-c] pyrimidin-7-yloxy)-3-methylphenyl The present invention relates to crystalline forms of 2, 3-difluoro-1-methylpiperidin-4-yl) oxy)-6-methoxyquinazolin-4-amine, to processes for their preparation, to pharmaceutical compositions comprising one or more of the crystalline forms as an active ingredient and to the use of said crystalline forms in the treatment of hyperproliferative diseases.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of October 19, 2022, an application number of 202280070755.1, and an invention title of "Crystalline Forms of Quinazoline Derivatives, Their Preparation, Compositions, and Uses".

[0002] Cross - reference to related applications

[0003] This application claims the priority benefit of International Patent Application No. PCT / CN2021 / 125016, filed on October 20, 2021, the disclosure of which is incorporated herein by reference in its entirety. Technical field

[0004] This application relates to crystalline forms of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine, methods for their preparation, pharmaceutical compositions comprising one or more of the crystalline forms as active ingredients, and the use of the crystalline forms in the treatment of hyperproliferative diseases. Background art

[0005] The type I tyrosine kinase receptor family consists of four structurally related receptors: EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) (reviewed in: Riese and Stern, Bioessays , 1998, 20:41 - 48; Olayioye et al., EMBO Journal , 2000, 19:3159 - 3167; and Schlessinger, Cell , 2002, 110:669 - 672). The structures of all four family members are nearly identical, consisting of an extracellular or extracellular domain or ligand - binding domain, a single transmembrane domain, and an intracellular cytoplasmic tyrosine kinase domain.

[0006] It has been demonstrated that ErbB2 plays a role in the development of cancer. 20% to 25% of breast cancer (BC) patients have ErbB2 overexpression (Leyland - Jones B, J Clin Oncol. , 2009, 5278 - 86). Approximately 1.7 million new BC cases are diagnosed each year (Cardoso F et al., Breast , 2018, 131 - 138), and 80% of BC is invasive, which requires chemotherapy, radiotherapy, or targeted therapy in addition to surgery (Dai X. et al., Am J Cancer Res, 2015, 2929 - 2943). Brain metastases often occur in patients with metastatic breast cancer. The overall survival of patients with breast cancer brain metastases (BCBM) ranges from 2 months to 25.3 months (Leone J.P. Exp. Hematol. Oncol. , 2015, 4, 33). Surgery, whole - brain radiotherapy (WBRT), and stereotactic radiosurgery (SRS) are the three main treatment options for BCBM. Surgery is used to treat single or up to three brain metastases. SRS can be used in patients with four or fewer intracranial lesions. WBRT is used to manage multiple brain metastases but may cause significant neurocognitive decline (Venur V.A. et al., Int. J. Mol. Sci. , 2016, 1543).

[0007] Compared with other types of breast cancer, ErbB2 - positive tumors have a higher incidence of brain metastases, and up to 50% of ErbB2 - positive breast cancer patients develop intracranial metastases (Leyland - Jones B, J Clin Oncol. , 2009, 5278 - 86). The high incidence of BCBM in ErbB2 - positive patients is attributed to the intrinsic tropism of ErbB2 - positive breast cancer cells for the brain, the prolonged survival of patients treated with anti - ErbB2 therapies, and the limited intracranial activity of anti - ErbB2 therapies (Venur V.A. et al., Int. J. Mol. Sci. , 2016, 17, 1543).

[0008] Several anti - ErbB2 agents have been developed for clinical use, including monoclonal antibodies (such as trastuzumab), antibody - drug conjugates (ADCs) (such as T - DM1), and tyrosine kinase inhibitors (TKIs) (such as lapatinib, neratinib, afatinib, and tucatinib) (Kabraji S. et al., Clinical Cancer Research , 2018, 3351; Askoxylakis V. et al., JNCI J Natl Cancer Inst , 2015, 763 - 763; Tanaka, Y. et al., Scientific Reports , 2018, 343; Zhang, Shirong et al., Acta Pharmacologica Sinica , 2017, 233 - 240; Dinkel V et al., Cancer Research , 2012, 72). However, it is believed that none of these antibodies, ADCs, and TKIs have central nervous system (CNS) penetrability. When treating BCBM patients with non - brain - penetrant above - mentioned antibodies, ADCs, and TKIs, the observed clinical efficacy is limited.

[0009] International Patent Publication No. WO 2020 / 057511 A1 (which is incorporated herein by reference in its entirety) discloses quinazoline compounds that inhibit receptor tyrosine kinases of type I, exhibit good brain penetration in animals, and have a favorable toxicity profile (e.g., reduced activity against hERG), and are thus particularly useful for treating type I receptor tyrosine kinase-mediated diseases or disorders, especially ErbB2-related diseases or disorders (including cancer (e.g., metastatic cancer, such as brain metastases)). A specific compound, which was identified as (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine (also referred to herein as Compound (I)),

[0010]

[0011] has been regarded as a highly effective blood-brain barrier (BBB) penetrant ErbB2 (HER2) inhibitor, showing high selectivity for wild-type EGFR, which can minimize EGFR-mediated diarrhea and rash, and is thus useful for treating ErbB2-positive BC patients with or without brain metastases (see Examples 31 and biochemical assays in WO 2020 / 057511 A1).

[0012] Polymorphism is the phenomenon of a single compound occurring in different crystalline forms, and it is a property of some compounds and complexes. Thus, polymorphs are different solids with the same molecular formula, but each polymorph may have different solid-state physical properties. Therefore, a single compound can give rise to multiple polymorphic forms, each of which has different and unique solid-state physical properties, such as different solubility characteristics, melting point temperature, flowability, dissolution rate, and / or different X-ray diffraction peaks. These actual physical properties are influenced by the conformation and orientation of the molecules in the unit cell, which define the specific polymorphic form of the substance. Due to the possibility of variable solubility for each polymorph, the identification of the presence of drug polymorphs is crucial for providing predictable solubility characteristics for drugs. It is desirable to study all solid forms of a drug, including all polymorphic forms, and determine the stability, dissolution, and flow properties of each polymorphic form. The polymorphic forms of a compound can be distinguished in the laboratory by X-ray diffraction spectroscopy (such as X-ray powder diffraction (“XRPD”)) and by other methods (such as infrared spectroscopy). Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient can be administered alone or formulated into pharmaceutical drug compositions, and it is well known in the pharmaceutical field that they can affect, for example, the solubility, stability, flowability, handleability, and compressibility of the drug substance and the safety and efficacy of the pharmaceutical product. For more information, see Hilfiker, Rolf (ed),Polymorphism in the Pharmaceutical Industry , Weinheim, Germany: Wiley-VCH 2006。

[0013] The discovery of new polymorphic forms of pharmaceutically useful compounds provides new opportunities for improving the performance characteristics of pharmaceutical products. Accordingly, there is a continuing need to study the polymorphic forms of the above-mentioned quinazoline compounds that exhibit type I receptor tyrosine kinase inhibitory activity. It has now been found that there are new polymorphic forms of compound (I). SUMMARY OF THE INVENTION

[0014] In one aspect, the present invention relates to a crystalline form of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine (compound (I)), which is a complex of the free base with a pharmaceutically acceptable acid, or the free base.

[0015]

[0016] In some embodiments, the complex of the free base with a pharmaceutically acceptable acid, or the free base, is a solvate or a non-solvate. In some embodiments, the complex of the free base with a pharmaceutically acceptable acid is a salt or a co-crystal or a co-crystal of a salt. In some embodiments, there is disclosed a crystalline form of compound (I) designated as A-type fumarate, B-type fumarate, C-type fumarate, E-type fumarate, A-type free base, B-type free base, C-type free base, D-type free base, E-type free base, F-type free base, G-type free base, A-type hydrochloride, B-type hydrochloride, A-type mesylate, B-type mesylate, A-type phosphate, A-type L-tartrate, and A-type adipate.

[0017] In another aspect, the present invention relates to an amorphous form of compound (I), which is a pharmaceutically acceptable salt or the free base. In some embodiments, there is disclosed an amorphous form of compound (I) designated as amorphous fumarate and amorphous free base.

[0018] In another aspect, the present invention relates to a method for preparing the crystalline form of compound (I).

[0019] In addition, there is disclosed a method for preparing the amorphous form of compound (I).

[0020] In another aspect, the present invention relates to a pharmaceutical composition comprising a crystalline form or an amorphous form of compound (I), and a pharmaceutically acceptable carrier or excipient.

[0021] In another aspect, the present invention relates to a pharmaceutical dosage form comprising a therapeutically effective amount of a crystalline form, an amorphous form, or a pharmaceutical composition as described herein.

[0022] In another aspect, the present invention relates to a method of treating or ameliorating a hyperproliferative disease in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form or an amorphous form of compound (I).

[0023] In another aspect, the present invention relates to a crystalline form or an amorphous form of compound (I) for use in treating or ameliorating a hyperproliferative disease.

[0024] In another aspect, the present invention relates to the use of a crystalline form or an amorphous form of compound (I) in the manufacture of a medicament for treating or ameliorating a hyperproliferative disease.

[0025] The present invention also relates to the following items:

[0026] 1. A crystalline form of a compound (I) represented by the following structural formula:

[0027]

[0028] wherein the crystalline form is a complex of the free base with a pharmaceutically acceptable acid, or the free base.

[0029] 2. The crystalline form according to item 1, wherein the complex or the free base is a solvate or a non-solvate.

[0030] 3. The crystalline form according to item 1 or 2, wherein the complex is a salt, a co-crystal, or a co-crystal of a salt.

[0031] 4. The crystalline form according to any one of items 1 to 3, wherein the complex has an acid / base molar ratio of 0.5:1 to 3:1, preferably 0.5:1 to 2.5:1, more preferably 1:1 to 1.5:1.

[0032] 5. The crystalline form according to any one of items 1 to 4, wherein the pharmaceutically acceptable acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid.

[0033] 6. The crystalline form according to any one of items 1 to 5, wherein the pharmaceutically acceptable acid is fumaric acid.

[0034] 7. The crystalline form according to item 6, wherein the crystalline form is fumarate A, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.9 and 11.5.

[0035] 8. The crystalline form according to item 7, wherein the crystalline form is A-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.8, 6.9, 11.5, 12.1 and 17.7.

[0036] 9. The crystalline form according to item 8, wherein the crystalline form is A-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.8, 6.9, 11.5, 12.1, 17.7, 20.8 and 24.0.

[0037] 6. The crystalline form according to item 9, wherein the crystalline form is A-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.8, 6.9, 11.5, 12.1, 17.7, 18.9, 20.8, 23.1, 23.7, 24.0 and 28.8.

[0038] 10. The crystalline form according to item 10, wherein the crystalline form is A-type fumarate, characterized by an X-ray powder diffraction pattern that is substantially the same as

[0039] 11. The crystalline form according to item 10, wherein the crystalline form is A-type fumarate, characterized by an X-ray powder diffraction pattern that is substantially the same as Figure 1 11. The crystalline form according to item 10, wherein the crystalline form is A-type fumarate, characterized by an X-ray powder diffraction pattern that is substantially the same as

[0040] 12. The crystalline form according to any one of items 7 to 11, characterized by a differential scanning calorimeter peak phase transition temperature of about 167.6 °C.

[0041] 13. The crystalline form according to item 6, wherein the crystalline form is B-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.6 and 11.4.

[0042] 14. The crystalline form according to item 13, wherein the crystalline form is B-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.6, 10.7, 11.4, 12.9, 25.1 and 28.2.

[0043] 2θ (±0.2°) of the peak of the X-ray powder diffraction pattern.

[0044] 15. The crystalline form according to item 14, wherein the crystalline form is B-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.6, 10.7, 11.4, 12.9, 15.8, 17.9,

[0045] 19.7, 25.1 and 28.2 of the X-ray powder diffraction pattern of the peak at 2θ (±0.2°).

[0046] 16. The crystalline form according to item 15, wherein the crystalline form is the B-type fumarate, characterized by an X-ray powder diffraction pattern Figure 6 substantially the same as

[0047] 17. The crystalline form according to any one of items 13 to 16, characterized by a differential scanning calorimetry peak phase transition temperature between about 91.3 °C and about 166.3 °C.

[0048] 18. The crystalline form according to item 6, wherein the crystalline form is the C-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.8 and 11.8.

[0049] 19. The crystalline form according to item 18, wherein the crystalline form is the C-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±

[0050] 0.2°) of 6.8, 11.2, 11.8, 13.6 and 18.4.

[0051] 20. The crystalline form according to item 19, wherein the crystalline form is the C-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.8, 11.2, 11.8, 13.6, 15.1, 16.0,

[0052] 17.2, 18.4 and 24.5.

[0053] 21. The crystalline form according to item 20, wherein the crystalline form is the C-type fumarate, characterized by an X-ray powder diffraction pattern Figure 10 substantially the same as

[0054] 22. The crystalline form according to item 6, wherein the crystalline form is the E-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.7, 11.6 and 28.5 of the X

[0055] ray.

[0056] 23. The crystalline form according to item 22, wherein the crystalline form is the E-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.7, 10.9, 11.6, 16.9, 25.2 and 28.5.

[0057] 24. The crystalline form according to item 23, wherein the crystalline form is the E-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.7, 10.9, 11.6, 12.9, 15.3, 16.9,

[0058] X-ray powder diffraction patterns of peaks at 2θ (±0.2°) of 19.9, 25.2, and 28.5.

[0059] 25. The crystalline form according to item 24, wherein the crystalline form is the E-type fumarate, characterized by at least including the X-ray powder diffraction pattern of peaks at 2θ (±0.2°) of 5.5, 6.7, 10.9, 11.6, 12.9, 15.3, 16.9, 18.1, 19.9, 25.2, 27.5, and 28.5.

[0060] 26. The crystalline form according to item 25, wherein the crystalline form is the E-type fumarate, characterized by being Figure 11 substantially the same X-ray powder diffraction pattern.

[0061] 27. The crystalline form according to any one of items 22 to 26, characterized by a differential scanning calorimeter peak phase transition temperature of about 134.5 °C to about 166.0 °C.

[0062] 28. The crystalline form according to item 1 or 2, wherein the crystalline form is the B-type free base, characterized by at least including the X-ray powder diffraction pattern of peaks at 2θ (±0.2°) of 8.0 and 11.5.

[0063] 29. The crystalline form according to item 28, wherein the crystalline form is the B-type free base, characterized by at least including the X-ray powder diffraction pattern of peaks at 2θ (±

[0064] 0.2°) of 8.0, 11.5, 16.0, 17.2, 18.8, and 24.3.

[0065] 30. The crystalline form according to item 29, wherein the crystalline form is the B-type free base, characterized by at least including the X-ray powder diffraction pattern of peaks at 2θ (±0.2°) of 8.0, 11.5, 16.0, 17.2, 18.2, 18.8, 20.3,

[0066] 21.9, and 24.3.

[0067] 31. The crystalline form according to item 30, wherein the crystalline form is the B-type free base, characterized by at least including the X-ray powder diffraction pattern of peaks at 2θ (±0.2°) of 8.0, 11.5, 13.1, 16.0, 17.2, 18.2, 18.8, 20.3, 21.2, 21.9, 24.3, and 27.7.

[0068] 32. The crystalline form according to item 31, wherein the crystalline form is the free base of Form B, characterized in that it has an X-ray powder diffraction pattern Figure 14 substantially the same as that of

[0069] 33. The crystalline form according to any one of items 28 to 32, characterized in that it has a differential scanning calorimetry peak phase transition temperature of about 169.4 °C.

[0070] 34. The crystalline form according to item 1 or 2, wherein the crystalline form is the free base of Form C, characterized in that it has an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.6 and 18.8.

[0071] 35. The crystalline form according to item 34, wherein the crystalline form is the free base of Form C, characterized in that it has an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.6, 12.7, 18.8, 20.7 and 24.4

[0072] thereof.

[0073] 36. The crystalline form according to item 35, wherein the crystalline form is the free base of Form C, characterized in that it has an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.6, 12.7, 14.1, 18.1, 18.8, 20.7, 23.4,

[0074] 24.4 and 26.7 thereof.

[0075] 37. The crystalline form according to item 36, wherein the crystalline form is the free base of Form C, characterized in that it has an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.6, 9.4, 12.7, 14.1, 14.9, 18.1, 18.8, 20.7, 22.9, 23.4, 24.4 and 26.7.

[0076] 38. The crystalline form according to item 37, wherein the crystalline form is the free base of Form C, characterized in that it has an X-ray powder diffraction pattern Figure 19 substantially the same as that of

[0077] 39. The crystalline form according to any one of items 34 to 38, characterized in that it has differential scanning calorimetry peak phase transition temperatures of about 86.2 °C and about 114.4 °C.

[0078] 40. The crystalline form according to item 1 or 2, wherein the crystalline form is the free base of Form D, characterized in that it has an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.7, 5.8 and 18.8.

[0079] 41. The crystalline form according to item 40, wherein the crystalline form is the D-type free base, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.7, 5.8, 11.8, 12.6, 18.8, 20.6 and 24.3.

[0080] 42. The crystalline form according to item 41, wherein the crystalline form is the D-type free base, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.7, 5.8, 11.8, 12.6, 18.8, 20.6, 22.8,

[0081] 23.3 and 24.3.

[0082] 43. The crystalline form according to item 42, wherein the crystalline form is the D-type free base, characterized by Figure 23 an X-ray powder diffraction pattern substantially the same as

[0083] 44. The crystalline form according to item 1 or 2, wherein the crystalline form is the E-type free base, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 7.2, 18.2 and 22.3.

[0084] 45. The crystalline form according to item 44, wherein the crystalline form is the E-type free base, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±

[0085] 0.2°) of 7.2, 18.2, 19.2, 22.3, 23.0 and 24.0.

[0086] 46. The crystalline form according to item 45, wherein the crystalline form is the E-type free base, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 7.2, 14.9, 16.7, 18.2, 19.2, 22.3, 23.0,

[0087] 24.0 and 26.8.

[0088] 47. The crystalline form according to item 46, wherein the crystalline form is the E-type free base, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 7.2, 12.6, 14.9, 16.7, 18.2, 19.2, 19.7, 20.5, 22.3, 23.0, 24.0 and 26.8.

[0089] 48. The crystalline form according to item 47, wherein the crystalline form is the E-type free base, characterized by Figure 24 an X-ray powder diffraction pattern substantially the same as

[0090] 49. The crystalline form according to item 1 or 2, wherein the crystalline form is the free base of Form F, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.2, 11.6 and 12.6.

[0091] 50. The crystalline form according to item 49, wherein the crystalline form is the free base of Form F, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±

[0092] 0.2°) of 6.2, 11.6, 12.6, 14.8, 16.5 and 24.4.

[0093] 51. The crystalline form according to item 50, wherein the crystalline form is the free base of Form F, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.2, 11.6, 12.6, 14.8, 16.5, 17.6, 19.3,

[0094] 24.4 and 26.0.

[0095] 52. The crystalline form according to item 51, wherein the crystalline form is the free base of Form F, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.2, 9.3, 11.6, 12.6, 14.8, 16.5, 17.6,

[0096] 18.7, 19.3, 24.4 and 26.0.

[0097] 53. The crystalline form according to item 52, wherein the crystalline form is the free base of Form F, characterized by being Figure 25 substantially the same X-ray powder diffraction pattern.

[0098] 54. The crystalline form according to any one of items 49 to 53, characterized by a differential scanning calorimetry peak phase transition temperature of about 55.4 °C to about 109.5 °C.

[0099] 55. The crystalline form according to item 1 or 2, wherein the crystalline form is the free base of Form G, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.7, 5.9 and 12.7.

[0100] 56. The crystalline form according to item 55, wherein the crystalline form is the free base of Form G, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±

[0101] 0.2°) of 5.7, 5.9, 11.9, 12.7, 14.5 and 26.2.

[0102] 57. The crystalline form according to item 56, wherein the crystalline form is the G-type free base, characterized by comprising at least X-ray powder diffraction patterns of peaks at 2θ (±0.2°) of 5.7, 5.9, 11.9, 12.7, 14.5, 17.6, 19.7,

[0103] and 22.9 and 26.2.

[0104] 58. The crystalline form according to item 57, wherein the crystalline form is the G-type free base, characterized by comprising at least X-ray powder diffraction patterns of peaks at 2θ (±0.2°) of 5.7, 5.9, 11.9, 12.7, 14.5, 17.2, 17.6,

[0105] 19.7, 20.6, 22.9, 24.8 and 26.2.

[0106] 59. The crystalline form according to item 58, wherein the crystalline form is the G-type free base, characterized by being Figure 28 substantially the same X-ray powder diffraction pattern.

[0107] 60. The crystalline form according to any one of items 55 to 59, characterized by differential scanning calorimeter peak phase transition temperatures of about

[0108] 32.9 °C, about 59.2 °C and about 110.2 °C.

[0109] 61. The crystalline form according to item 1 or 2, wherein the crystalline form is an acetone solvate, which is the A-type free base, characterized by comprising at least X-ray powder diffraction of peaks at 2θ (±0.2°) of 7.0, 9.0 and 23.3

[0110] of the.

[0111] 62. The crystalline form according to item 61, wherein the crystalline form is an acetone solvate, which is the A-type free base, characterized by comprising at least X-ray powder diffraction of peaks at 2θ (±0.2°) of 7.0, 9.0, 11.6, 13.6, 15.4, 18.1, 19.6 and 23.3.

[0112] 63. The crystalline form according to item 62, wherein the crystalline form is an acetone solvate, which is the A-type free base, characterized by being Figure 31 substantially the same X-ray powder diffraction pattern.

[0113] 64. The crystalline form according to any one of items 61 to 63, characterized by a differential scanning calorimeter peak phase transition temperature of about 71.3 °C.

[0114] 65. The crystalline form according to any one of Items 1 to 5, wherein the salt is a type A hydrochloride, characterized by an X-ray powder diffraction pattern that includes at least a peak at 2θ (±0.2°) of 18.1.

[0115] 66. The crystalline form according to Item 65, wherein the salt is a type A hydrochloride, characterized by Figure 35 an X-ray powder diffraction pattern substantially the same as that shown.

[0116] 67. The crystalline form according to any one of Items 65 to 66, characterized by a differential scanning calorimeter peak phase transition temperature of about 110.0 °C.

[0117] 68. The crystalline form according to any one of Items 1 to 5, wherein the salt is a type B hydrochloride, characterized by an X-ray powder diffraction pattern that includes at least peaks at 2θ (±0.2°) of 6.9, 12.4, and 25.0.

[0118] 69. The crystalline form according to Item 68, wherein the salt is a type B hydrochloride, characterized by an X-ray powder diffraction pattern that includes at least peaks at 2θ (±0.2°) of 6.9, 11.9, 12.4, 17.0, 25.0, and 29.1

[0119] at.

[0120] 70. The crystalline form according to Item 69, wherein the salt is a type B hydrochloride, characterized by an X-ray powder diffraction pattern that includes at least peaks at 2θ (±0.2°) of 6.9, 9.6, 11.9, 12.4, 17.0, 21.2, 22.7, 25.0, and

[0121] 29.1.

[0122] 71. The crystalline form according to Item 70, wherein the salt is a type B hydrochloride, characterized by an X-ray powder diffraction pattern that includes at least peaks at 2θ (±0.2°) of 6.9, 9.6, 11.9, 12.4, 17.0, 19.9, 21.2, 22.7, 25.0, 25.9, 27.2, and 29.1.

[0123] 72. The crystalline form according to Item 71, wherein the salt is a type B hydrochloride, characterized by Figure 38 an X-ray powder diffraction pattern substantially the same as that shown.

[0124] 73. The crystalline form according to any one of Items 68 to 72, characterized by about

[0125] Differential scanning calorimetry peak phase transition temperature of 241.7 °C.

[0126] 74. The crystalline form according to any one of items 1 to 5, wherein the salt is A-type mesylate, characterized by X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.5, 19.6 and 21.0.

[0127] 75. The crystalline form according to item 74, wherein the salt is A-type mesylate, characterized by X-ray powder diffraction comprising at least peaks at 2θ (±

[0128] 0.2°) of 5.3, 6.5, 7.8, 13.1, 15.7, 19.6 and 21.0.

[0129] 76. The crystalline form according to item 75, wherein the salt is A-type mesylate, characterized by being Figure 41 substantially the same X-ray powder diffraction pattern as shown.

[0130] 77. The crystalline form according to any one of items 74 to 76, characterized by a differential scanning calorimetry peak phase transition temperature of about 65.1 °C.

[0131] 78. The crystalline form according to any one of items 1 to 5, wherein the salt is B-type mesylate, characterized by X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.0, 16.3 and 18.3.

[0132] 79. The crystalline form according to item 78, wherein the salt is B-type mesylate, characterized by X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.0, 7.2, 12.4, 16.3, 18.3, 21.5 and 26.5.

[0133] 80. The crystalline form according to item 79, wherein the salt is B-type mesylate, characterized by being Figure 44 substantially the same X-ray powder diffraction pattern as shown.

[0134] 81. The crystalline form according to any one of items 78 to 80, characterized by a differential scanning calorimetry peak phase transition temperature of about 63.4 °C.

[0135] 82. The crystalline form according to any one of items 1 to 5, wherein the salt is A-type phosphate, characterized by X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.4, 14.0 and 22.9.

[0136] 83. The crystalline form according to item 82, wherein the salt is a type A phosphate, characterized by X-ray powder diffraction with peaks at 2θ (±0.2°) of at least 6.4, 14.0, 14.9, 20.5, 22.9, and 24.5

[0137] and the X-ray powder diffraction of the peak at

[0138] 84. The crystalline form according to item 83, wherein the salt is a type A phosphate, characterized by X-ray powder diffraction with peaks at 2θ (±0.2°) of at least 6.4, 14.0, 14.9, 16.3, 18.7, 20.5, 21.4, 22.9, and

[0139] 24.5

[0140] 85. The crystalline form according to item 84, wherein the salt is a type A phosphate, characterized by being substantially the same as the Figure 47 shown X-ray powder diffraction pattern.

[0141] 86. The crystalline form according to any one of items 82 to 85, characterized by a differential scanning calorimetry peak phase transition temperature of about 79.1 °C to about 194.8 °C.

[0142] 87. The crystalline form according to any one of items 1 to 5, wherein the salt is a type A L-tartrate, characterized by X-ray powder diffraction with peaks at 2θ (±0.2°) of at least 6.5, 12.7, and 18.8.

[0143] 88. The crystalline form according to item 87, wherein the salt is a type A L-tartrate, characterized by X-ray powder diffraction with peaks at 2θ (±0.2°) of at least 6.5, 9.4, 12.7, 18.8, 20.7, 22.7, 24.4, and

[0144] 26.5

[0145] 89. The crystalline form according to item 88, wherein the salt is a type A L-tartrate, characterized by being substantially the same as the Figure 50 shown X-ray powder diffraction pattern.

[0146] 90. The crystalline form according to any one of items 87 to 89, characterized by a differential scanning calorimetry peak phase transition temperature of about 77.6 °C to about 164.7 °C.

[0147] 91. The crystalline form according to any one of items 1 to 5, wherein the salt is a type A adipate, characterized by X-ray powder diffraction with peaks at 2θ (±0.2°) of at least 7.4, 10.8, and 25.7.

[0148] 92. The crystalline form according to item 91, wherein the salt is an A-type adipate salt, characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 7.4, 10.8, 16.0, 17.7, 19.7 and 25.7.

[0149] 93. The crystalline form according to item 92, wherein the salt is an A-type adipate salt, characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 7.4, 10.8, 12.6, 16.0, 17.7, 19.7, 20.9, 23.6 and 25.7.

[0150] 94. The crystalline form according to item 93, wherein the salt is an A-type adipate salt, characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 7.4, 8.5, 10.8, 12.6, 14.9, 15.5, 16.0, 16.9, 17.7, 19.0, 19.7, 20.9, 23.6, 25.7 and 32.3.

[0151] 95. The crystalline form according to item 94, wherein the salt is an A-type adipate salt, characterized by being Figure 53 substantially the same X-ray powder diffraction pattern as shown.

[0152] 96. The crystalline form according to any one of items 91 to 95, characterized by a differential scanning calorimeter peak phase transition temperature of about

[0153] 106.7 °C.

[0154] 97. An amorphous form of a compound (I) represented by the following structural formula:

[0155]

[0156] wherein the amorphous form is a medicinal salt or a free base.

[0157] 98. The amorphous form according to item 97, wherein the amorphous form is an amorphous fumarate salt, characterized by being Figure 56 substantially the same X-ray powder diffraction pattern.

[0158] 99. The amorphous form according to item 98, characterized by being Figure 58 substantially the same modulated differential scanning calorimeter thermogram curve.

[0159] 100. The amorphous form according to item 97, wherein the amorphous form is an amorphous free

[0160] free base, characterized in that it has an Figure 59 X-ray powder diffraction pattern that is substantially the same.

[0161] 101. The amorphous form according to item 100, characterized in that it has a Figure 61 modulated differential scanning calorimetry thermogram curve that is substantially the same

[0162] as that.

[0163] 102. A method for preparing a crystalline form according to any one of items 1 to 96,

[0164] which comprises:

[0165] in the case where the crystalline form is a complex of a free base and a medicinal acid,

[0166] a) adding compound (I) and an acid to a solvent, and

[0167] b) slurrying at a temperature and for a time sufficient to initiate precipitation of the complex;

[0168] in the case where the crystalline form is a free base,

[0169] a) adding compound (I) to a solvent; and

[0170] b) slurrying at a temperature and for a time sufficient to initiate precipitation of the free base.

[0171] 103. The method according to item 102, wherein the acid is selected from the group consisting of: salts

[0172] acids, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid.

[0173] 104. The method according to item 102 or 103, wherein in step a), in the case where the crystalline form

[0174] is a complex of a free base and a medicinal acid, compound (I) and the acid are added to the solvent in an acid / base molar ratio in the range of 0.5:1 to 3:1, preferably 0.5:1 to 2.5:1, more preferably 1:1 to 1.5:1.

[0175] 105. The method according to any one of items 102 to 104, wherein the solvent is selected from the group consisting of

[0176] the following: H2O, EtOH, EtOAc, n-heptane, ethyl formate, acetone, cyclohexane, isopropanol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, and combinations thereof.

[0177] 106. The method according to any one of items 102 to 105 further comprises subjecting the solvent

[0178] to inoculation with the crystalline form according to any one of items 1 to 96.

[0179] 107. The method according to any one of items 102 to 106, wherein the temperature is about 5 °C to 50 °C.

[0180] 108. The method according to any one of items 102 to 107, wherein the time is about 2

[0181] hours to 7.5 hours.

[0182] 109. A method for preparing the A-form fumarate crystalline form of the compound (I) according to any one of items 7 to 12, comprising:

[0183] a) dissolving the free base of compound (I) in an ester or an alcohol to form a free base solution;

[0184] b) dissolving fumaric acid in EtOH to form an acid solution;

[0185] c) adding the acid solution dropwise to the free base solution while stirring;

[0186] d) adding an alkane dropwise; and then optionally inoculating the mixture with the A-form fumarate crystalline form of compound (I);

[0187] e) stirring at 0 °C to 10 °C for 12 hours to 24 hours; and

[0188] f) separating the solid by filtration and then drying the solid under vacuum at 40 °C to 60 °C.

[0189] 110. The method according to item 109, wherein the ester is selected from the group consisting of ethyl acetate, ethyl formate,

[0190] methyl acetate, and isopropyl acetate.

[0191] 111. The method according to item 110, wherein the ester is ethyl acetate.

[0192] 112. The method according to item 109, wherein the alcohol is selected from the group consisting of methanol, ethanol,

[0193] n-propanol, and isopropyl alcohol.

[0194] 113. The method according to item 112, wherein the alcohol is ethanol.

[0195] 114. The method according to item 109, wherein the alkane is selected from the group consisting of hexane, heptane,

[0196] 114. The method according to item 109, wherein the alkane is selected from the group consisting of n - hexane, n - heptane,

[0197] n - octane, and mixtures thereof.

[0198] 115. The method according to item 114, wherein the alkane is n - heptane.

[0199] 116. A method for preparing the B - form

[0200] fumarate crystalline form of the compound (I) according to any one of items 13 to 17, comprising:

[0201] a) suspending the A - form fumarate crystalline form of the compound (I) in H2O;

[0202] b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 11 days; and

[0203] c) separating the solid by centrifugation and storing the solid open at ambient conditions for about 4 days.

[0204] 117. A method for preparing the C - form

[0205] fumarate crystalline form of the compound (I) according to any one of items 18 to 21, comprising:

[0206] a) suspending the A - form fumarate crystalline form of the compound (I) in H2O;

[0207] b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 9 days; and

[0208] c) separating the wet solid.

[0209] 118. A method for preparing the E - form

[0210] fumarate crystalline form of the compound (I) according to any one of items 22 to 27, comprising:

[0211] a) dissolving the fumarate - type crystalline form of the compound (I) in ethyl formate;

[0212] b) evaporating the ethyl formate at about room temperature;

[0213] c) separating the solid.

[0214] 119. A method for preparing the A - form

[0215] free - base crystalline form of the compound (I) according to any one of items 61 to 64, comprising:

[0216] a) Suspend the amorphous free base of compound (I) in an acetone /

[0217] n - heptane solvent having a volume ratio of about 1:4;

[0218] b) Magnetically stir at about room temperature at a speed of about 1000 rpm for about 3 days; and

[0219] c) Separate the solid by centrifugation and dry the solid under ambient conditions for about 1 day.

[0220] 120. A method for preparing the B - type

[0221] free - base crystalline form of the compound (I) according to any one of items 28 to 33, comprising:

[0222] a) Suspend the amorphous free base of compound (I) in a methyl isobutyl ketone / cyclohexane solvent having a volume ratio of about 1:4;

[0223] b) Magnetically stir at about 5 °C at a speed of about 1000 rpm for about 7 days; and

[0224] c) Separate the solid by centrifugation.

[0225] 121. A method for preparing the C - type

[0226] free - base crystalline form of the compound (I) according to any one of items 34 to 39, comprising:

[0227] a) Suspend the amorphous free base of compound (I) in a tetrahydrofuran / H₂O solvent having a volume ratio of about 1:4;

[0228] b) Magnetically stir at about 5 °C at a speed of about 1000 rpm for about 7 days; and

[0229] c) Separate the solid by centrifugation.

[0230] 122. A method for preparing the D - type

[0231] free - base crystalline form of the compound (I) according to any one of items 40 to 43, comprising:

[0232] a) Suspend the amorphous free base of compound (I) in a tetrahydrofuran / H₂O solvent having a volume ratio of about 1:4;

[0233] b) Magnetically stir at about 5 °C at a speed of about 1000 rpm for about 3 days; and

[0234] c) Separate the solid by centrifugation and dry the solid under ambient conditions for about 2 hours.

[0235] 123. A method for preparing the E-type

[0236] free base crystalline form of the compound (I) according to any one of Items 44 to 48, which comprises:

[0237] a) Suspending the amorphous free base of compound (I) in a tetrahydrofuran / H2O solvent having a volume ratio of about 1:4;

[0238] b) Magnetically stirring at about 5 °C at a speed of about 1000 rpm for about 4 days;

[0239] c) Separating the solid by centrifugation and drying the solid under ambient conditions for about 2 hours;

[0240] and

[0241] d) Purging the solid with N2 at about 30 °C for about 20 min.

[0242] 124. A method for preparing the F-type

[0243] free base crystalline form of the compound (I) according to any one of Items 49 to 54, which comprises:

[0244] a) Suspending the amorphous free base of compound (I) in an acetonitrile / n-heptane solvent;

[0245] b) Magnetically stirring at about room temperature at a speed of about 1000 rpm for about 2 days;

[0246] c) Separating the solid.

[0247] 125. A method for preparing the G-type

[0248] free base crystalline form of the compound (I) according to any one of Items 55 to 60, which comprises:

[0249] a) Dissolving the amorphous free base of compound (I) in EtOH;

[0250] b) Adding H2O and obtaining a suspension;

[0251] c) Separating the solid from the suspension.

[0252] 126. A method for preparing the A-type

[0253] hydrochloride of the compound (I) according to any one of Items 65 to 67, which comprises:

[0254] a) Adding the amorphous free base of compound (I) and concentrated hydrochloric acid in an acid / base molar ratio of about 2:1 to an EtOAc / n-heptane solvent having a volume ratio of about 1:2;

[0255] b) Magnetically stir at a speed of about 1000 rpm at about room temperature for about 3 days; and

[0256] c) Centrifuge to separate the solid and dry the solid under ambient conditions for about 1 day.

[0257] 127. A method for preparing the B-type

[0258] hydrochloride of the compound (I) according to any one of items 68 to 73, which comprises:

[0259] a) Dissolve the amorphous free base of the compound (I) in EtOAc to form a free base solution;

[0260] b) Dilute the EtOAc solution of hydrochloric acid in EtOH to form an acid solution;

[0261] c) Optionally add seeds of the B-type hydrochloride of the compound (I) to the free base solution, wherein the seeds are not completely dissolved;

[0262] d) Dropwise add the acid solution while stirring at a speed of about 1000 rpm;

[0263] e) Further stir at room temperature for about 8 hours, then stir at about 5 °C for about 13 hours;

[0264] f) Separate the solid by filtration, and then dry the solid under vacuum at about room temperature overnight;

[0265] wherein the molar ratio of acid / base is about 2:1.

[0266] 128. A method for preparing the A-type

[0267] methanesulfonate of the compound (I) according to any one of items 74 to 77, which comprises:

[0268] a) Suspend the amorphous free base of the compound (I) and methanesulfonic acid in an acetone / n-heptane solvent with a volume ratio of about 1:4 at an acid / base molar ratio of about 2:1;

[0269] b) Magnetically stir at a speed of about 1000 rpm at about room temperature for about 3 days; and

[0270] c) Centrifuge to separate the solid and dry the solid under ambient conditions for about 1 day.

[0271] 129. A method for preparing the B-type

[0272] methanesulfonate of the compound (I) according to any one of items 78 to 81, which comprises:

[0273] a) Suspend the amorphous free base of compound (I) and methanesulfonic acid in an isopropanol / cyclohexane solvent with a volume ratio of about 1:4 at an acid / base feeding molar ratio of about 2:1;

[0274] b) Magnetically stir at about 1000 rpm for about 3 days at about room temperature; and

[0275] c) Separate the solid by centrifugation and dry the solid under ambient conditions for about 1 day.

[0276] 130. A method for preparing type A

[0277] phosphate of the compound (I) according to any one of items 82 to 86, comprising:

[0278] a) Suspend the amorphous free base of compound (I) and concentrated H3PO4 in an acetone / n-heptane solvent with a volume ratio of about 1:4 at an acid / base molar ratio of about 1:1;

[0279] b) Magnetically stir at about 1000 rpm for about 3 days at room temperature; and

[0280] c) Separate the solid by centrifugation and dry the solid under ambient conditions for about 1 day.

[0281] 131. A method for preparing type A L-tartrate of the compound (I) according to any one of items 87 to 90, comprising:

[0282] a) Suspend the amorphous free base of compound (I) and L-tartaric acid in an EtOAc / n-heptane solvent with a volume ratio of about 1:2 at an acid / base molar ratio of about 1:1;

[0283] b) Magnetically stir at about 1000 rpm for about 3 days at about room temperature; and

[0284] c) Separate the solid by centrifugation and dry the solid under ambient conditions for about 1 day.

[0285] 132. A method for preparing type A

[0286] adipate of the compound (I) according to any one of items 91 to 96, comprising:

[0287] a) Suspend the amorphous free base of compound (I) and adipic acid in an EtOAc / n-heptane solvent with a volume ratio of about 1:2 at an acid / base molar ratio of about 1:1;

[0288] b) Magnetically stir at about 1000 rpm for about 3 days at about room temperature; and

[0289] c) Centrifuge the solid and dry the solid under ambient conditions for about 1 day.

[0290] 133. A method for preparing the amorphous form of the compound (I) according to any one of items 97 to 101, comprising:

[0291] a) Dissolve the compound (I) in a solvent; and

[0292] b) Remove the solvent.

[0293] 134. The method according to item 133, wherein the solvent is selected from the group consisting of:

[0294] H2O, EtOH, EtOAc, n-heptane, ethyl formate, acetone, cyclohexane, isopropanol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, and combinations thereof.

[0295] 135. A method for preparing the amorphous fumarate of the compound (I) according to item 98 or 99, comprising:

[0296] a) Dissolve the fumarate of type A of the compound (I) in MeOH; and

[0297] b) Remove the MeOH by rotary evaporation at about 60 °C.

[0298] 136. A method for preparing the amorphous free base of the compound (I) according to item 100 or 101, comprising:

[0299] a) Dissolve the free base of type B of the compound (I) in DCM; and

[0300] b) Remove the DCM by rotary evaporation at about 40 °C.

[0301] 138. A dosage form comprising a therapeutically effective amount of the crystalline form according to any one of items 1 to 96, the amorphous form according to any one of items 97 to 101, or the pharmaceutical composition according to item 137.

[0302] 137. A pharmaceutical composition comprising the crystalline form according to any one of items 1 to 96 or the amorphous form according to any one of items 97 to 101, and a pharmaceutical carrier or excipient.

[0303] 139. A method for treating or ameliorating a hyperproliferative disease in a subject, comprising administering to a subject in need thereof

[0304] 138. A dosage form comprising a therapeutically effective amount of the crystalline form according to any one of items 1 to 96, the amorphous form according to any one of items 97 to 101, or the pharmaceutical composition according to item 137.

[0305] 139. A method for treating or ameliorating a hyperproliferative disease in a subject, comprising administering to a subject in need thereof

[0306] administering a therapeutically effective amount of the crystalline form according to any one of items 1 to 96 or the amorphous form according to any one of items 97 to 101 to a subject in need thereof.

[0307] 140. The method according to item 139, wherein the hyperproliferative disease is cancer.

[0308] 141. The method according to item 140, wherein the cancer is ErbB2 positive.

[0309] 142. The method according to item 140 or 141, wherein the cancer is selected from the group consisting of: breast cancer, gastric cancer, cholangiocarcinoma, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer.

[0310] 143. The method according to any one of items 139 to 142, wherein one or more additional compounds having anti-cancer

[0311] properties are administered in combination.

[0312] 144. The crystalline form according to any one of items 1 to 96 or the amorphous form according to any one of items 97 to 101

[0313] for use in treating or ameliorating a hyperproliferative disease.

[0314] 145. The crystalline form or amorphous form according to item 144, wherein the hyperproliferative disease is cancer.

[0315] 146. The crystalline form or amorphous form according to item 145, wherein the cancer is ErbB2 positive.

[0316] 147. The crystalline form or amorphous form according to item 145 or 146, wherein the cancer is selected from breast cancer, gastric cancer, cholangiocarcinoma, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer.

[0317] 148. The crystalline form or amorphous form according to any one of items 144 to 147, wherein one or more additional compounds having anti-cancer properties are administered in combination.

[0318] 149. Use of the crystalline form according to any one of items 1 to 96 or the amorphous form according to any one of items 97 to 101 in the manufacture of a medicament for treating or ameliorating a hyperproliferative disease.

[0319] 150. The use according to item 149, wherein the hyperproliferative disease is cancer.

[0320] 151. Use according to item 150, wherein the cancer is ErbB2 positive.

[0321] 152. Use according to item 150 or 151, wherein the cancer is selected from the group consisting of: breast cancer, gastric cancer, cholangiocarcinoma, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer.

[0322] 153. Use according to any one of items 149 to 152, wherein one or more anti-tumor agents are administered in combination. Description of the Drawings

[0323] The invention content and the following detailed description can be further understood when read in conjunction with the drawings. For the purpose of illustrating the invention, exemplary embodiments of the invention are shown in the drawings; however, the invention is not limited to the specific disclosure of the drawings. In the drawings:

[0324] Figure 1 Representative XRPD pattern of fumarate salt of type A.

[0325] Figure 2 Representative TGA curve of fumarate salt of type A.

[0326] Figure 3 Representative DSC curve of fumarate salt of type A.

[0327] Figure 4 Representative 1 1H NMR spectrum of fumarate salt of type A.

[0328] Figure 5 Representative PLM image of fumarate salt of type A.

[0329] Figure 6 Representative XRPD pattern of fumarate salt of type B.

[0330] Figure 7 Representative TGA curve of fumarate salt of type B.

[0331] Figure 8 Representative DSC curve of fumarate salt of type B.

[0332] Figure 9 Representative 1 1H NMR spectrum of fumarate salt of type B.

[0333] Figure 10 Representative XRPD pattern of fumarate salt of type C.

[0334] Figure 11 Representative XRPD pattern of fumarate salt of type E.

[0335] Figure 12 Representative TGA curve of the E-type fumarate.

[0336] Figure 13 Representative DSC curve of the E-type fumarate.

[0337] Figure 14 Representative XRPD pattern of the B-type free base.

[0338] Figure 15 Representative TGA curve of the B-type free base.

[0339] Figure 16 Representative DSC curve of the B-type free base.

[0340] Figure 17 Representative 1 1H NMR spectrum of the B-type free base.

[0341] Figure 18 Representative PLM image of the B-type free base.

[0342] Figure 19 Representative XRPD pattern of the C-type free base.

[0343] Figure 20 Representative TGA curve of the C-type free base.

[0344] Figure 21 Representative DSC curve of the C-type free base.

[0345] Figure 22 Representative 1 1H NMR spectrum of the C-type free base.

[0346] Figure 23 Representative XRPD pattern of the D-type free base.

[0347] Figure 24 Representative XRPD pattern of the E-type free base.

[0348] Figure 25 Representative XRPD pattern of the F-type free base.

[0349] Figure 26 Representative TGA curve of the F-type free base.

[0350] Figure 27 Representative DSC curve of the F-type free base.

[0351] Figure 28 Representative XRPD pattern of the G-type free base.

[0352] Figure 29It is the representative TGA curve of the free base of type G.

[0353] Figure 30 It is the representative DSC curve of the free base of type G.

[0354] Figure 31 It is the representative XRPD pattern of the free base of type A.

[0355] Figure 32 It is the representative TGA curve of the free base of type A.

[0356] Figure 33 It is the representative DSC curve of the free base of type A.

[0357] Figure 34 It is the representative 1 1H NMR spectrum of the free base of type A.

[0358] Figure 35 It is the representative XRPD pattern of the hydrochloride salt of type A.

[0359] Figure 36 It is the representative TGA curve of the hydrochloride salt of type A.

[0360] Figure 37 It is the representative DSC curve of the hydrochloride salt of type A.

[0361] Figure 38 It is the representative XRPD pattern of the hydrochloride salt of type B.

[0362] Figure 39 It is the representative TGA curve of the hydrochloride salt of type B.

[0363] Figure 40 It is the representative DSC curve of the hydrochloride salt of type B.

[0364] Figure 41 It is the representative XRPD pattern of the mesylate salt of type A.

[0365] Figure 42 It is the representative TGA curve of the mesylate salt of type A.

[0366] Figure 43 It is the representative DSC curve of the mesylate salt of type A.

[0367] Figure 44 It is the representative XRPD pattern of the mesylate salt of type B.

[0368] Figure 45 It is the representative TGA curve of the mesylate salt of type B.

[0369] Figure 46 It is the representative DSC curve of the mesylate salt of type B.

[0370] Figure 47 Representative XRPD pattern of type A phosphate.

[0371] Figure 48 Representative TGA curve of type A phosphate.

[0372] Figure 49 Representative DSC curve of type A phosphate.

[0373] Figure 50 Representative XRPD pattern of type A L-tartrate.

[0374] Figure 51 Representative TGA curve of type A L-tartrate.

[0375] Figure 52 Representative DSC curve of type A L-tartrate.

[0376] Figure 53 Representative XRPD pattern of type A adipate.

[0377] Figure 54 Representative TGA curve of type A adipate.

[0378] Figure 55 Representative DSC curve of type A adipate.

[0379] Figure 56 Representative XRPD pattern of amorphous fumarate.

[0380] Figure 57 Representative TGA curve of amorphous fumarate.

[0381] Figure 58 Representative mDSC curve of amorphous fumarate.

[0382] Figure 59 Representative XRPD pattern of amorphous free base.

[0383] Figure 60 Representative TGA curve of amorphous free base.

[0384] Figure 61 Representative mDSC curve of amorphous free base. Detailed implementation manners

[0385] Reference will now be made in detail to certain embodiments, examples of which are illustrated in the accompanying detailed description. While the enumerated embodiments will be described, it should be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be used in the practice of the invention. The invention is in no way limited to the described methods and materials. If one or more of the incorporated documents and similar materials are different or inconsistent with this application, including but not limited to defined terms, term usage, described techniques, or the like, this application shall prevail.

[0386] It should be understood that, for the sake of clarity, certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, the various features of the invention described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0387] Definition

[0388] The terms used herein have their ordinary meanings, and the meaning of such terms is independent each time they appear. However, unless otherwise specified, the following definitions apply throughout the specification and claims.

[0389] As used herein, the terms "comprise", "comprising", "include", and "including" are intended to specify the presence of the stated features, wholes, components, or steps, but they do not preclude the presence or addition of one or more other features, wholes, components, steps, or groups thereof.

[0390] As used herein, the term "about" means approximately, roughly, generally, or around. When the term "about" is used in combination with a numerical range, it modifies the range by extending the boundaries above and below that numerical value. Generally, the term "about" is used herein to modify a numerical value that varies by 20%, typically 10%, more typically 5%, even more typically 1%, and even more typically 0.1% above and below a given value. Sometimes, such ranges may be within the experimental error (for the type of standard method used to measure and / or determine the given value or range). When the term "about" is used with reference to a temperature from a differential scanning calorimetry (DSC) thermogram (e.g., the onset of an endothermic transition, melting, etc.), each temperature value should be understood to mean the given value ±5°C, more typically ±2°C, unless otherwise specified.

[0391] As used herein, the term "substantially the same" with reference to X-ray powder diffraction means that variations in the reflection positions and relative intensities of the reflections are to be considered. For example, the typical precision of 2-Theta (2θ) values is within the range of ±0.2° of a given value in 2θ, and more typically within the range of ±0.1° of a given value in 2θ. Thus, for example, on most X-ray diffractometers under standard conditions, a reflection that typically appears at 2θ 6.9° may appear between 2θ 6.7° and 7.1°, and more typically between 2θ 6.8° and 7.0°. In addition, those skilled in the art will recognize that relative reflection intensities will exhibit variability between instruments as well as variability due to crystallinity, preferred orientation, sample preparation, and other factors known to those skilled in the art, and should only be considered a qualitative measure.

[0392] As used herein, when one or more temperatures from a differential scanning calorimetry (DSC) thermogram (e.g., the onset of an endothermic transition, melting, etc.) are used to identify a polymorphic form, each temperature value should be understood to mean a given value ±5 °C, and more typically ±2 °C, unless otherwise stated.

[0393] Crystalline and Amorphous Forms

[0394] In one aspect, the present disclosure provides crystalline forms of compound (I), particularly those designated as follows: fumarate form A, fumarate form B, fumarate form C, fumarate form E, free base form A, free base form B, free base form C, free base form D, free base form E, free base form F, free base form G, hydrochloride form A, hydrochloride form B, mesylate form A, mesylate form B, phosphate form A, L-tartrate form A, and adipate form A. Additionally, the present disclosure provides amorphous forms of compound (I), particularly those designated as amorphous fumarate and amorphous free base. Also provided are methods for preparing the crystalline or amorphous forms, and pharmaceutical compositions comprising the crystalline or amorphous forms.

[0395] The crystalline forms of compound (I) can be complexes of the free base with a pharmaceutically acceptable acid, or the free base. Such complexes contemplated include, but are not limited to, salts or co-crystals or co-crystals of salts. The amorphous forms of compound (I) can be pharmaceutically acceptable salts or the free base.

[0396] As used herein, the term "crystalline form" means a crystal structure in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all having the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. The recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0397] As used herein, the term "polymorphic form" or "polymorph" in the context of this specification refers to crystalline and amorphous forms, as well as solvate and hydrate forms. Crystalline forms have different molecular arrangements and / or conformations in the crystal lattice. Amorphous forms consist of disordered arrangements of molecules and do not have a distinguishable crystal lattice. Solvates are crystalline forms that contain a stoichiometric or non-stoichiometric amount of solvent. When an active pharmaceutical ingredient exists in polymorphic forms, it is said to exhibit polymorphism.

[0398] As used herein, the term "complex" refers to a crystalline material composed of two or more different molecules associated by ionic / non-ionic and electrovalent / non-covalent bonds in the same crystal lattice, where one molecule is the active pharmaceutical ingredient (API). In the context of this specification, the API may refer to compound (I).

[0399] As used herein, the term "eutectic" refers to a crystalline material composed of two or more different molecules associated by non-ionic and non-covalent bonds in the same crystal lattice, where one molecule is the API.

[0400] As used herein, the term "salt" refers to any one of many compounds obtained by replacing some or all of the acidic hydrogens of an acid to form an ionic or electrovalent compound.

[0401] As used herein, the term "salt eutectic" refers to a crystalline form in which the API that forms the salt and the co-former (or vice versa) are associated by non-ionic and non-covalent bonds in the same crystal lattice.

[0402] As used herein, the term "pharmaceutically acceptable" means that a substance or composition is chemically and / or toxicologically compatible with the other components of the formulation and / or the subject to be treated.

[0403] As used herein, the term "pharmaceutically acceptable acid" may be such an acid containing a pharmaceutically acceptable anion. Preferably, exemplary examples of pharmaceutically acceptable acids described herein include, but are not limited to, hydrochloric acid, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid. More examples of suitable acids can be found, for example, in P.H. Stahl and C.G. Wermuth, eds. Handbook of Pharmaceutical Salts: Properties, Selectionand Use , Weinheim / Zürich: Wiley-VCH / VHCA, 2002。

[0404] Unless otherwise specified, the term "pharmaceutically acceptable salt" as used herein includes salts that retain the biological effectiveness of the free base of the designated compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable salt forms contemplated include, but are not limited to, mono-salts, di-salts, tri-salts, tetra-salts, etc. The pharmaceutically acceptable salts are non-toxic at the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical properties of the compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug.

[0405] Pharmaceutically acceptable salts can include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, mesylate, esylate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinate salts. Preferably, exemplary examples of the pharmaceutically acceptable salts described herein include hydrochloride, mesylate, phosphate, tartrate, fumarate, and adipate salts. The salts described herein can have an acid / base molar ratio of from about 0.5:1 to about 3:1, typically from about 0.5:1 to about 2.5:1, more typically from about 1:1 to about 1.5:1. For example, the salts described herein can have an acid / base molar ratio of about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, and about 2.5:1.

[0406] Pharmaceutically acceptable salts can be obtained from suitable acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, mesylic acid, esylic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid. Preferably, exemplary examples of suitable acids can include hydrochloric acid, mesylic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid.

[0407] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent (such as an aqueous solution or a water-alcohol solution containing the appropriate acid), and then separated by evaporation of the solution. Thus, when the particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art (e.g., treating the free base with an inorganic acid or with an organic acid).

[0408] It should be understood that the crystalline or amorphous compounds described herein can exist in non-solvated or solvated forms, and the present invention is intended to cover all such forms.

[0409] As used herein, the terms "solvate" and "solvated" refer to solvate addition forms containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state to form solvates. For example, if the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate; if the solvent is acetone, the solvate formed is an acetone solvate. A hydrate is formed by the combination of one or more water molecules with one molecule of a substance, in which water retains its molecular state H2O. Examples of solvents that form solvates include but are not limited to water, isopropyl alcohol, ethanol, methanol, acetone, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0410] As used herein, the terms "non-solvate" and "non-solvated" mean the absence of an organic solvent coordinated or accommodated by a solid structure, which includes both crystal structures and amorphous structures. The non-solvated form may still contain residual organic solvents that are not part of the solid structure but may be adsorbed on the surface of the solid structure or in the disordered regions of the solid structure. Typically, the non-solvated form does not contain more than 2.0% by weight, typically not more than 1.0% by weight, and more typically not more than 0.5% by weight of organic solvents based on the weight of the crystalline form. The organic solvent content can be determined by thermogravimetric analysis (TGA), for example, by determining the weight loss in the range from 25 °C to the melting point of the solid form at a heating rate of 10 K / min and / or by gas chromatography.

[0411] Thus, in one aspect, the present invention provides a crystalline form of a compound (I) represented by the following structural formula:

[0412]

[0413] wherein the crystalline form is a complex of a free base and a pharmaceutically acceptable acid, or a free base.

[0414] In certain embodiments, the complex or free base is a solvate or a non-solvate.

[0415] In certain embodiments, the complex is a salt or a co-crystal or a co-crystal of a salt.

[0416] In certain embodiments, the complex has an acid / base molar ratio of about 3:1, preferably about 0.5:1 to about 2.5:1, more preferably about 1:1 to about 1.5:1.

[0417] In certain embodiments, the pharmaceutical acid is selected from the group consisting of: hydrochloric acid, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid.

[0418] In certain embodiments, the pharmaceutical acid is fumaric acid.

[0419] Form A Fumarate

[0420] In certain embodiments, provided herein is a crystalline form of compound (I) which is the A-type fumarate salt, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.9 and 11.5; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.8, 6.9, 11.5, 12.1, and 17.7; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.8, 6.9, 11.5, 12.1, 17.7, 20.8, and 24.0; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.8, 6.9, 11.5, 12.1, 17.7, 18.9, 20.8, 23.1, 23.7, 24.0, and 28.8; even more typically, characterized by an X-ray powder diffraction pattern Figure 1 substantially the same as. In certain embodiments, provided herein is a crystalline form of compound (I) which is the A-type fumarate salt, characterized by a differential scanning calorimetry peak phase transition temperature of about 167.6 °C.

[0421] Form B Fumarate

[0422] In certain embodiments, provided herein is a crystalline form of compound (I) which is the B-type fumarate salt, characterized by an X-ray powder diffraction pattern comprising at least peaks at 6.6 and 11.4; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.6, 10.7, 11.4, 12.9, 25.1, and 28.2; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.6, 10.7, 11.4, 12.9, 15.8, 17.9, 19.7, 25.1, and 28.2; even more typically, characterized by an X-ray powder diffraction pattern Figure 6 substantially the same as. In certain embodiments, provided herein is a crystalline form of compound (I) which is the B-type fumarate salt, characterized by differential scanning calorimetry peak phase transition temperatures of about 91.3 °C and about 166.3 °C.

[0423] Form C Fumarate

[0424] In certain embodiments, provided herein is a crystalline form of compound (I), which is the C-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.8 and 11.8; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.8, 11.2, 11.8, 13.6 and 18.4; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.8, 11.2, 11.8, 13.6, 15.1, 16.0, 17.2, 18.4 and 24.5; even more typically, characterized by an X-ray powder diffraction pattern Figure 10 substantially the same as that of

[0425] Form E Fumarate

[0426] In certain embodiments, provided herein is a crystalline form of compound (I), which is the E-type fumarate, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.7, 11.6 and 28.5; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.7, 10.9, 11.6, 16.9, 25.2 and 28.5; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.7, 10.9, 11.6, 12.9, 15.3, 16.9, 19.9, 25.2 and 28.5; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 5.5, 6.7, 10.9, 11.6, 12.9, 15.3, 16.9, 18.1, 19.9, 25.2, 27.5 and 28.5; even more typically, characterized by an X-ray powder diffraction pattern Figure 11 substantially the same as that of. In certain embodiments, provided herein is a crystalline form of compound (I), which is the E-type fumarate, characterized by differential scanning calorimetry peak phase transition temperatures of about 134.5 °C and about 166.0 °C.

[0427] Form B Free Base

[0428] In certain embodiments, provided herein is a crystalline form of compound (I), which is the free base of Form B, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 8.0 and 11.5; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 8.0, 11.5, 16.0, 17.2, 18.8, and 24.3; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 8.0, 11.5, 16.0, 17.2, 18.2, 18.8, 20.3, 21.9, and 24.3; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 8.0, 11.5, 13.1, 16.0, 17.2, 18.2, 18.8, 20.3, 21.2, 21.9, 24.3, and 27.7; even more typically, characterized by an X-ray powder diffraction pattern Figure 14 substantially the same as. In certain embodiments, provided herein is a crystalline form of compound (I), which is the free base of Form B, characterized by a differential scanning calorimetry peak phase transition temperature of about 169.4 °C.

[0429] Form C Free Base

[0430] In certain embodiments, provided herein is a crystalline form of compound (I), which is the free base of Form C, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.6 and 18.8; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.6, 12.7, 18.8, 20.7, and 24.4; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.6, 12.7, 14.1, 18.1, 18.8, 20.7, 23.4, 24.4, and 26.7; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.6, 9.4, 12.7, 14.1, 14.9, 18.1, 18.8, 20.7, 22.9, 23.4, 24.4, and 26.7; even more typically, characterized by an X-ray powder diffraction pattern Figure 19 substantially the same as. In certain embodiments, provided herein is a crystalline form of compound (I), which is the free base of Form C, characterized by differential scanning calorimetry peak phase transition temperatures of about 86.2 °C and about 114.4 °C.

[0431] Form D Free Base

[0432] In certain embodiments, provided herein is a crystalline form of compound (I), which is the D free base and is characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 5.7, 5.8, and 18.8; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 5.7, 5.8, 11.8, 12.6, 18.8, 20.6, and 24.3; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 5.7, 5.8, 11.8, 12.6, 18.8, 20.6, 22.8, 23.3, and 24.3; even more typically, characterized by an X-ray powder diffraction pattern substantially the same as Figure 23 and

[0433] Form E Free Base

[0434] In certain embodiments, provided herein is a crystalline form of compound (I), which is the E free base and is characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 7.2, 18.2, and 22.3; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 7.2, 18.2, 19.2, 22.3, 23.0, and 24.0; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 7.2, 14.9, 16.7, 18.2, 19.2, 22.3, 23.0, 24.0, and 26.8; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 7.2, 12.6, 14.9, 16.7, 18.2, 19.2, 19.7, 20.5, 22.3, 23.0, 24.0, and 26.8; even more typically, characterized by an X-ray powder diffraction pattern substantially the same as Figure 24 and

[0435] Form F Free Base

[0436] In certain embodiments, provided herein are crystalline forms of compound (I), which are the free base of Form F, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.2, 11.6, and 12.6; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.2, 11.6, 12.6, 14.8, 16.5, and 24.4; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.2, 11.6, 12.6, 14.8, 16.5, 17.6, 19.3, 24.4, and 26.0; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.2, 9.3, 11.6, 12.6, 14.8, 16.5, 17.6, 18.7, 19.3, 24.4, and 26.0; even more typically, characterized by an X-ray powder diffraction pattern substantially the same as Figure 25 In certain embodiments, provided herein are crystalline forms of compound (I), which are the free base of Form F, characterized by differential scanning calorimetry peak phase transition temperatures of about 55.4 °C and about 109.5 °C.

[0437] Form G Free Base

[0438] In certain embodiments, provided herein are crystalline forms of compound (I), which are the free base of Form G, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 5.7, 5.9, and 12.7; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 5.7, 5.9, 11.9, 12.7, 14.5, and 26.2; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 5.7, 5.9, 11.9, 12.7, 14.5, 17.6, 19.7, 22.9, and 26.2; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 5.7, 5.9, 11.9, 12.7, 14.5, 17.2, 17.6, 19.7, 20.6, 22.9, 24.8, and 26.2; even more typically, characterized by an X-ray powder diffraction pattern substantially the same as Figure 28 In certain embodiments, provided herein are crystalline forms of compound (I), which are the free base of Form G, characterized by differential scanning calorimetry peak phase transition temperatures of about 32.9 °C, about 59.2 °C, and about 110.2 °C.

[0439] Form A Free Base

[0440] In certain embodiments, provided herein is a crystalline form of Compound (I), which is the free base of Form A, characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) 7.0, 9.0, and 23.3; typically, characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) 7.0, 9.0, 11.6, 13.6, 15.4, 18.1, 19.6, and 23.3; more typically, characterized by an X-ray powder diffraction pattern Figure 31 substantially the same as that of

[0441] Form A Hydrochloride

[0442] In certain embodiments, provided herein is a crystalline form of Compound (I), which is the hydrochloride of Form A, characterized by an X-ray powder diffraction comprising at least a peak at 2θ (±0.2°) 18.1; typically, characterized by an X-ray powder diffraction pattern Figure 35 substantially the same as that shown. In certain embodiments, provided herein is a crystalline form of Compound (I), which is the hydrochloride of Form A, characterized by a differential scanning calorimetry peak phase transition temperature of about 110.0 °C.

[0443] Form B Hydrochloride

[0444] In certain embodiments, provided herein is a crystalline form of Compound (I), which is the hydrochloride of Form B, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.9, 12.4, and 25.0; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.9, 11.9, 12.4, 17.0, 25.0, and 29.1; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.9, 9.6, 11.9, 12.4, 17.0, 21.2, 22.7, 25.0, and 29.1; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) 6.9, 9.6, 11.9, 12.4, 17.0, 19.9, 21.2, 22.7, 25.0, 25.9, 27.2, and 29.1; even more typically, characterized by an X-ray powder diffraction pattern Figure 38 substantially the same as that of

[0445] Form A Mesylate

[0446] In certain embodiments, provided herein is a crystalline form of compound (I), which is the A-type methanesulfonate and is characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.5, 19.6, and 21.0; typically, characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 5.3, 6.5, 7.8, 13.1, 15.7, 19.6, and 21.0; more typically, characterized by an X-ray powder diffraction pattern substantially the same as that Figure 41 shown. In certain embodiments, provided herein is a crystalline form of compound (I), which is the A-type methanesulfonate and is characterized by a differential scanning calorimetry peak phase transition temperature of about 65.1 °C.

[0447] Form B Mesylate

[0448] In certain embodiments, provided herein is a crystalline form of compound (I), which is the B-type methanesulfonate and is characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.0, 16.3, and 18.3; typically, characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.0, 7.2, 12.4, 16.3, 18.3, 21.5, and 26.5; more typically, characterized by an X-ray powder diffraction pattern substantially the same as that Figure 44 shown. In certain embodiments, provided herein is a crystalline form of compound (I), which is the B-type methanesulfonate and is characterized by a differential scanning calorimetry peak phase transition temperature of about 63.4 °C.

[0449] Form A Phosphate

[0450] In certain embodiments, provided herein is a crystalline form of compound (I), which is the A-type phosphate and is characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.4, 14.0, and 22.9; typically, characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.4, 14.0, 14.9, 20.5, 22.9, and 24.5; more typically, characterized by an X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.4, 14.0, 14.9, 16.3, 18.7, 20.5, 21.4, 22.9, and 24.5; even more typically, characterized by an X-ray powder diffraction pattern substantially the same as that Figure 47 shown. In certain embodiments, provided herein is a crystalline form of compound (I), which is the A-type phosphate and is characterized by differential scanning calorimetry peak phase transition temperatures of 79.1 °C and about 194.8 °C.

[0451] Form A L-Tartrate

[0452] In certain embodiments, provided herein is a crystalline form of Compound (I), which is the A-type L-tartrate salt, characterized by X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.5, 12.7, and 18.8; typically, characterized by X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 6.5, 9.4, 12.7, 18.8, 20.7, 22.7, 24.4, and 26.5; more typically, characterized by an X-ray powder diffraction pattern substantially the same as that Figure 50 shown. In certain embodiments, provided herein is a crystalline form of Compound (I), which is the A-type L-tartrate salt, characterized by differential scanning calorimetry peak phase transition temperatures of 77.6 °C and about 164.7 °C.

[0453] Form A Adipate

[0454] In certain embodiments, provided herein is a crystalline form of Compound (I), which is the A-type adipate salt, characterized by X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 7.4, 10.8, and 25.7; typically, characterized by X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 7.4, 10.8, 16.0, 17.7, 19.7, and 25.7; more typically, characterized by X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 7.4, 10.8, 12.6, 16.0, 17.7, 19.7, 20.9, 23.6, and 25.7; more typically, characterized by X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 7.4, 8.5, 10.8, 12.6, 14.9, 15.5, 16.0, 16.9, 17.7, 19.0, 19.7, 20.9, 23.6, 25.7, and 32.3; even more typically, characterized by an X-ray powder diffraction pattern substantially the same as that Figure 53 shown. In certain embodiments, provided herein is a crystalline form of Compound (I), which is the A-type adipate salt, characterized by a differential scanning calorimetry peak phase transition temperature of about 106.7 °C.

[0455] On the other hand, provided herein is an amorphous form of Compound (I) represented by the following structural formula:

[0456]

[0457] wherein the amorphous form is a pharmaceutical salt or a free base.

[0458] Amorphous Fumarate

[0459] In certain embodiments, provided herein is an amorphous form of compound (I), which is an amorphous fumarate, characterized by an X-ray powder diffraction pattern substantially the same as that of Figure 56 In certain embodiments, provided herein is an amorphous form of compound (I), which is an amorphous fumarate, characterized by an X-ray powder diffraction pattern substantially the same as that of Figure 58 a differential scanning calorimetry thermogram curve substantially the same as that of.

[0460] Amorphous Free Base

[0461] In certain embodiments, provided herein is an amorphous form of compound (I), which is an amorphous free base, characterized by an X-ray powder diffraction pattern substantially the same as that of Figure 59 In certain embodiments, provided herein is an amorphous form of compound (I), which is an amorphous free base, characterized by an X-ray powder diffraction pattern substantially the same as that of Figure 61 a differential scanning calorimetry thermogram curve substantially the same as that of.

[0462] In certain embodiments, the crystalline or amorphous form of compound (I) described herein can be provided in a substantially pure form. Specifically, the crystalline forms of compound (I), particularly those designated as: fumarate form A, fumarate form B, fumarate form C, fumarate form E, free base form A, free base form B, free base form C, free base form D, free base form E, free base form F, free base form G, hydrochloride form A, hydrochloride form B, mesylate form A, mesylate form B, phosphate form A, L-tartrate form A, and adipate form A, and the amorphous forms of compound (I), particularly those designated as amorphous fumarate and amorphous free base, can exist in a substantially pure form.

[0463] As used herein, the term "substantially pure" means that the polymorphic form or amorphous material comprises less than about 15% by weight of impurities (including other polymorphic forms). In certain embodiments, the substantially pure polymorphic form or amorphous material comprises less than about 10% by weight of impurities (including other polymorphic forms). In certain embodiments, the substantially pure polymorphic form or amorphous material comprises less than about 5% by weight of impurities (including other polymorphic forms). In certain embodiments, the substantially pure polymorphic form or amorphous material comprises less than about 1% by weight of impurities (including other polymorphic forms). In certain embodiments, the substantially pure polymorphic form or amorphous material does not comprise impurities (including other polymorphic forms).

[0464] The present invention also includes crystalline and amorphous forms of isotopically labeled (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine (Compound (I)), which are identical, but in fact, one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, and oxygen, such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O and 18 O. Polymorphs containing the above isotopes and / or other isotopes of other atoms described herein are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those incorporating radioactive isotopes (such as 3 H and 14 C), can be used for drug and / or substrate tissue distribution assays. Tritiation (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly widely used because they are easy to prepare and detect. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus can be used in some specific situations. Isotopically labeled salts of the present invention can generally be prepared by performing the procedures disclosed in WO 2020 / 057511A1, which involves replacing non-isotopically labeled reagents with readily available isotopically labeled reagents during the preparation, or using isotopically labeled sulfuric acid in the preparation of salts if necessary.

[0465] Synthesis of the Compound

[0466] The compounds described herein can be synthesized by the following synthetic routes, which include (especially in view of the description contained herein) methods similar to those well known in the chemical art. Starting materials can generally be obtained from commercial sources such as Sigma-Aldrich (St. Louis, MO), Alfa Aesar (Ward Hill, MA), or TCI (Portland, OR), or can be readily prepared using methods well known to those skilled in the art (e.g., prepared by the methods generally described below: Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Volumes 1 - 23, New York: Wiley, 1967 - 2006 (also available via the Wiley website); or Beilsteins Handbuch der organischen Chemie , 4th ed., Springer - Verlag, Berlin, including supplements (also available via the Beilstein online database).

[0467] Generally, compound (I) can be prepared by coupling 4 - chloro - 5 - ((3,3 - difluoro - 1 - methylpiperidin - 4 - yl)oxy)-6 - methoxyquinazoline with 4 - ([1,2,4]triazolo[1,5 - c]pyrimidin - 7 - yloxy)-3 - methylaniline. The coupling can be carried out, for example, in a solvent (such as propan - 2 - ol) at 100 °C under the catalysis of p - toluenesulfonic acid TsOH·H2O, and then the two isomers of the racemic product are separated by chiral supercritical fluid chromatography (SFC). For illustrative purposes, a more detailed description of each reaction step can be found in the example section of WO 2020 / 057511 A1, which is incorporated herein by reference in its entirety. Those skilled in the art will recognize that other synthetic routes can be used to synthesize the compound.

[0468] The final crystallization or isolation will determine the polymorphic form, which is further detailed in the example section of this document.

[0469] Preparation of the Crystalline Forms

[0470] In one aspect, the present document provides a method for preparing a crystalline form of compound (I), the method comprising:

[0471] In the case where the crystalline form is a complex of the free base and a pharmaceutical acid,

[0472] a) adding compound (I) and the acid to a solvent, and

[0473] b) slurrying at a temperature and for a time sufficient to initiate precipitation of the complex;

[0474] In the case where the crystalline form is the free base,

[0475] a) adding compound (I) to a solvent; and

[0476] b) slurrying at a temperature and for a time sufficient to initiate precipitation of the free base.

[0477] In certain embodiments, the acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid.

[0478] In certain embodiments, in step a), in the case where the crystalline form is a complex of the free base and a medicinal acid, compound (I) and the acid are added to the solvent at an acid / base molar ratio in the range of about 0.5:1 to 3:1, preferably about 0.5:1 to about 2.5:1, more preferably about 1:1 to about 1.5:1. For example, the salts described herein may have an acid / base molar ratio of about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, and about 2.5:1.

[0479] In certain embodiments, the solvent is selected from the group consisting of: H2O, EtOH, EtOAc, n-heptane, ethyl formate, acetone, cyclohexane, isopropanol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, and methyl tert-butyl ether and combinations thereof.

[0480] In certain embodiments, the method described herein further comprises seeding the solvent with the crystalline form described herein.

[0481] In certain embodiments, in step b), the temperature is about 5°C to 50°C.

[0482] In certain embodiments, in step b), the time is about 2 hours to 7.5 hours.

[0483] In certain embodiments, there is provided a method for preparing the crystalline form of the A-type fumarate of compound (I) described herein, the method comprising:

[0484] a) dissolving the free base of compound (I) in an ester or an alcohol to form a free base solution;

[0485] b) dissolving fumaric acid in EtOH to form an acid solution;

[0486] c) adding the acid solution dropwise to the free base solution while stirring;

[0487] d) adding an alkane dropwise; then optionally seeding the mixture with the crystalline form of the A-type fumarate of compound (I);

[0488] e) stirring at 0°C to 10°C for 12 hours to 24 hours; and

[0489] f) separating the solid by filtration, and then drying the solid in vacuo at 40°C to 60°C.

[0490] In certain embodiments, the ester is selected from the group consisting of ethyl acetate, ethyl formate, methyl acetate, and isopropyl acetate.

[0491] In certain embodiments, the ester is ethyl acetate.

[0492] In certain embodiments, the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol.

[0493] In certain embodiments, the alcohol is ethanol.

[0494] In certain embodiments, the alkane is selected from the group consisting of n-hexane, n-heptane, n-octane, and mixtures thereof.

[0495] In certain embodiments, the alkane is n-heptane.

[0496] In certain embodiments, provided herein is a method for preparing the crystalline form B fumarate of compound (I) described herein, the method comprising:

[0497] a) suspending the crystalline form A fumarate of compound (I) in H2O;

[0498] b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 11 days; and

[0499] c) separating the solid by centrifugation and storing the solid open to the environment for about 4 days.

[0500] In certain embodiments, provided herein is a method for preparing the crystalline form C fumarate of compound (I) described herein, the method comprising:

[0501] a) suspending the crystalline form A fumarate of compound (I) in H2O;

[0502] b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 9 days; and

[0503] c) separating the wet solid.

[0504] In certain embodiments, provided herein is a method for preparing the crystalline form E fumarate of compound (I) described herein, the method comprising:

[0505] a) dissolving the fumarate-type crystalline form of compound (I) in ethyl formate;

[0506] b) evaporating the ethyl formate at about room temperature;

[0507] c) separating the solid.

[0508] In certain embodiments, provided herein is a method for preparing the free base crystalline Form A of compound (I) described herein, the method comprising:

[0509] a) suspending the amorphous free base of compound (I) in an acetone / n - heptane solvent having a volume ratio of about 1:4;

[0510] b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and

[0511] c) separating the solid by centrifugation and drying the solid under ambient conditions for about 1 day.

[0512] In certain embodiments, provided herein is a method for preparing the free base crystalline Form B of compound (I) described herein, the method comprising:

[0513] a) suspending the amorphous free base of compound (I) in a methyl isobutyl ketone / cyclohexane solvent having a volume ratio of about 1:4;

[0514] b) magnetically stirring at about 5 °C at a speed of about 1000 rpm for about 7 days; and

[0515] c) separating the solid by centrifugation.

[0516] In certain embodiments, provided herein is a method for preparing the free base crystalline Form C of compound (I) described herein, the method comprising:

[0517] a) suspending the amorphous free base of compound (I) in a tetrahydrofuran / H₂O solvent having a volume ratio of about 1:4;

[0518] b) magnetically stirring at about 5 °C at a speed of about 1000 rpm for about 7 days; and

[0519] c) separating the solid by centrifugation.

[0520] In certain embodiments, provided herein is a method for preparing the free base crystalline Form D of compound (I) described herein, the method comprising:

[0521] a) suspending the amorphous free base of compound (I) in a tetrahydrofuran / H₂O solvent having a volume ratio of about 1:4;

[0522] b) magnetically stirring at about 5 °C at a speed of about 1000 rpm for about 3 days; and

[0523] c) separating the solid by centrifugation and drying the solid under ambient conditions for about 2 hours.

[0524] In certain embodiments, provided herein is a method for preparing the E-form free base crystalline form of compound (I) described herein, the method comprising:

[0525] a) suspending the amorphous free base of compound (I) in a tetrahydrofuran / H2O solvent having a volume ratio of about 1:4;

[0526] b) magnetically stirring at about 5 °C at a speed of about 1000 rpm for about 4 days;

[0527] c) separating the solid by centrifugation and drying the solid under ambient conditions for about 2 hours; and

[0528] d) purging the solid with N2 at about 30 °C for about 20 min.

[0529] In certain embodiments, provided herein is a method for preparing the F-form free base crystalline form of compound (I) described herein, the method comprising:

[0530] a) suspending the amorphous free base of compound (I) in an acetonitrile / n-heptane solvent;

[0531] b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 2 days;

[0532] c) separating the solid.

[0533] In certain embodiments, provided herein is a method for preparing the G-form free base crystalline form of compound (I) described herein, the method comprising:

[0534] a) dissolving the amorphous free base of compound (I) in EtOH;

[0535] b) adding H2O and obtaining a suspension;

[0536] c) separating the solid from the suspension.

[0537] In certain embodiments, provided herein is a method for preparing the A-form hydrochloride of compound (I) described herein, the method comprising:

[0538] a) adding the amorphous free base of compound (I) and concentrated hydrochloric acid in an acid / base molar ratio of about 2:1 to an EtOAc / n-heptane solvent having a volume ratio of about 1:2;

[0539] b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and

[0540] c) separating the solid by centrifugation and drying the solid under ambient conditions for about 1 day.

[0541] In certain embodiments, provided herein is a method for preparing the B-type hydrochloride salt of compound (I) described herein, the method comprising:

[0542] a) Dissolving the amorphous free base of compound (I) in EtOAc to form a free base solution;

[0543] b) Diluting a solution of hydrochloric acid in EtOAc with EtOH to form an acid solution;

[0544] c) Optionally adding seeds of the B-type hydrochloride salt of compound (I) to the free base solution, wherein the seeds do not completely dissolve;

[0545] d) Dropwise adding the acid solution while stirring at a speed of about 1000 rpm;

[0546] e) Further stirring at room temperature for about 8 hours, then stirring at about 5 °C for about 13 hours;

[0547] f) Separating the solid by filtration, and then drying the solid under vacuum at about room temperature overnight;

[0548] wherein the molar ratio of acid / base is about 2:1.

[0549] In certain embodiments, provided herein is a method for preparing the A-type mesylate salt of compound (I) described herein, the method comprising:

[0550] a) Suspending the amorphous free base of compound (I) and methanesulfonic acid in an acetone / n-heptane solvent having a volume ratio of about 1:4 at an acid / base molar ratio of about 2:1;

[0551] b) Magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and

[0552] c) Separating the solid by centrifugation and drying the solid under ambient conditions for about 1 day.

[0553] In certain embodiments, provided herein is a method for preparing the B-type mesylate salt of compound (I) described herein, the method comprising:

[0554] a) Suspending the amorphous free base of compound (I) and methanesulfonic acid in an isopropanol / cyclohexane solvent having a volume ratio of about 1:4 at an acid / base feeding molar ratio of about 2:1;

[0555] b) Magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and

[0556] c) Separating the solid by centrifugation and drying the solid under ambient conditions for about 1 day.

[0557] In certain embodiments, provided herein is a method for preparing the A-type phosphate salt of compound (I) described herein, the method comprising:

[0558] a) suspending the amorphous free base of compound (I) and concentrated H3PO4 in an acetone / n-heptane solvent having a volume ratio of about 1:4 at an acid / base molar ratio of about 1:1;

[0559] b) magnetically stirring at about 1000 rpm at room temperature for about 3 days; and

[0560] c) separating the solid by centrifugation and drying the solid under ambient conditions for about 1 day.

[0561] In certain embodiments, provided herein is a method for preparing the A-type L-tartrate salt of compound (I) described herein, the method comprising:

[0562] a) suspending the amorphous free base of compound (I) and L-tartaric acid in an EtOAc / n-heptane solvent having a volume ratio of about 1:2 at an acid / base molar ratio of about 1:1;

[0563] b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and

[0564] c) separating the solid by centrifugation and drying the solid under ambient conditions for about 1 day.

[0565] In certain embodiments, provided herein is a method for preparing the A-type adipate salt of compound (I) described herein, the method comprising:

[0566] a) suspending the amorphous free base of compound (I) and adipic acid in an EtOAc / n-heptane solvent having a volume ratio of about 1:2 at an acid / base molar ratio of about 1:1;

[0567] b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and

[0568] c) separating the solid by centrifugation and drying the solid under ambient conditions for about 1 day.

[0569] Furthermore, in another aspect, provided herein is a method for preparing the amorphous form of compound (I) described herein, the method comprising:

[0570] a) dissolving compound (I) in a solvent; and

[0571] b) removing the solvent.

[0572] In certain embodiments, the solvent is selected from the group consisting of H2O, MeOH, EtOH, EtOAc, DCM, n-heptane, ethyl formate, acetone, cyclohexane, isopropanol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, and combinations thereof.

[0573] In certain embodiments, provided herein is a method for preparing an amorphous fumarate salt of compound (I) described herein, the method comprising:

[0574] a) dissolving the fumarate form A of compound (I) in MeOH; and

[0575] b) MeOH was removed by rotary evaporation at about 60 °C.

[0576] In certain embodiments, provided herein is a method for preparing an amorphous free base of Compound (I) described herein, the method comprising:

[0577] a) dissolving the free base Form B of compound (I) in DCM; and

[0578] b) DCM was removed by rotary evaporation at about 40 °C.

[0579] As used herein, the term "seeding" or "seeding" refers to the addition of a crystalline material to a solution or mixture to initiate crystallization or recrystallization.

[0580] Use

[0581] The crystalline form and amorphous form of Compound (I) described herein may exhibit high inhibitory activity against type I receptor tyrosine kinases, particularly HER2.

[0582] As used herein, the term "inhibitory activity against type I receptor tyrosine kinase" means that, as a direct or indirect response to the presence of a crystalline form or an amorphous form of Compound (I), the activity of a type I receptor tyrosine kinase is reduced relative to the activity of a type I receptor tyrosine kinase in the absence of a crystalline form or an amorphous form of Compound (I). Such reduction in activity may be due to a direct interaction of a crystalline form or an amorphous form of Compound (I) with a type I receptor tyrosine kinase, or due to an interaction of a crystalline form or an amorphous form of Compound (I) with one or more other factors that in turn affect the activity of a type I receptor tyrosine kinase. For example, a crystalline form or an amorphous form of Compound (I) described herein may reduce the activity of a type I receptor tyrosine kinase by directly binding to a type I receptor tyrosine kinase, by causing (directly or indirectly) another factor to reduce the activity of a type I receptor tyrosine kinase, or by (directly or indirectly) reducing the amount of a type I receptor tyrosine kinase present in a cell or organism.

[0583] Due to their inhibitory activity against receptor tyrosine kinases of type I, the crystalline and amorphous forms of compound (I) can be used in therapy, for example, for treating diseases or medical conditions (including cancer) that are at least partially mediated by one or more receptor tyrosine kinases of type I.

[0584] As used herein, the term “cancer” refers to or describes a physiological condition in a mammal that is typically characterized by abnormal or uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific instances of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer (“NSCLC”)), lung adenocarcinoma and squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, brain cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, anal cancer, penile cancer, skin cancer (including melanoma), and head and neck cancer. Typically, such cancers include breast cancer, gastric cancer, cholangiocarcinoma, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer. As used herein, the term “cancer” is intended to cover both non-metastatic cancer and metastatic cancer. In this context, treating cancer involves treating both the primary tumor and tumor metastases.

[0585] As used herein, the term “mammal” means a warm-blooded animal that has or is at risk of developing a disease described herein, and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates (including humans).

[0586] As used herein, the term "therapy" is intended to have its ordinary meaning, which addresses a disease to completely or partially relieve one, some, or all of its symptoms, or correct or compensate for an underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, detectable or undetectable symptom relief, reduced disease severity, disease state stabilization (i.e., non-worsening), delay or slowing of disease progression, improvement or alleviation of disease state, and remission (whether partial or complete). "Therapy" may also mean extended survival as compared to the expected survival of an individual not receiving the therapy. Individuals in need of therapy include those who already have a disorder or disease, as well as those who are predisposed to having a disorder or disease or are to be prophylactically treated against a disorder or disease. Unless specifically indicated to the contrary, the term "therapy" also encompasses prophylaxis. The terms "therapeutic" and "therapeutically" shall be construed in a corresponding manner.

[0587] As used herein, the term "prophylaxis" is intended to have its ordinary meaning and includes primary prevention of the development of a disease, as well as secondary prevention in which the disease has already developed and the patient is temporarily or permanently protected from disease exacerbation or progression or the development of new symptoms associated with the disease.

[0588] The term "treatment" is used synonymously with "therapy". Similarly, the term "treatment" can be regarded as "administering a therapy", where "therapy" is as defined herein.

[0589] In some embodiments, the compounds of the present invention have anti-cell proliferation properties, which are believed to result from their type I receptor tyrosine kinase inhibitory activity. Accordingly, it is expected that the compounds of the present invention can be used to treat diseases or disorders mediated, either alone or in part, by type I receptor tyrosine kinases, i.e., the compounds can be used to produce an anti-proliferative effect mediated, either alone or in part, by inhibition of type I receptor tyrosine kinases. In some embodiments, such diseases or disorders treated by providing an anti-proliferative effect are type I receptor tyrosine kinase-sensitive cancers, including, but not limited to, breast cancer, lung cancer, colon cancer, rectal cancer, gastric cancer, prostate cancer, bladder cancer, pancreatic cancer, and ovarian cancer, or other cell proliferative diseases (such as psoriasis).

[0590] Accordingly, in one aspect, the present disclosure provides a crystalline or amorphous form of the compound (I) described herein for use in therapy. In some embodiments, the present disclosure provides a crystalline and amorphous form of the compound (I) described herein for use as a medicament. In some embodiments, the present invention provides a crystalline and amorphous form of the compound (I) described herein for use in treating a disease or disorder mediated alone or in part by a type I receptor tyrosine kinase. In some embodiments, the present invention provides a crystalline and amorphous form of the compound (I) described herein for use in treating or ameliorating a proliferative disorder (typically cancer, more typically an ErbB2-positive cancer).

[0591] In another aspect, the present disclosure provides a crystalline or amorphous form of the compound (I) described herein for use in the manufacture of a medicament for treating a type I receptor tyrosine kinase-related disease or disorder (preferably an ErbB2-related disease or disorder). In some embodiments, the present disclosure provides a crystalline or amorphous form of the compound (I) described herein for use in the manufacture of a medicament for treating or ameliorating a proliferative disorder (typically cancer, more typically an ErbB2-positive cancer).

[0592] Pharmaceutical Compositions / Formulations

[0593] The crystalline and amorphous forms of the compound (I) described herein may be administered by any convenient route suitable for the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), ocular, vaginal, intraperitoneal, intrapulmonary, and intranasal.

[0594] The crystalline and amorphous forms of the compound (I) described herein may be administered in any convenient dosage form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical formulations, for example, diluents, carriers, pH regulators, sweeteners, fillers, and other active agents. For example, if parenteral administration is required, the composition will be sterile and in the form of a solution or suspension suitable for injection or infusion.

[0595] Typical formulations are prepared by mixing the crystalline and amorphous forms of the compound (I) described herein with a pharmaceutical carrier or excipient.

[0596] As used herein, the term "pharmaceutically acceptable carrier or excipient" means a carrier or excipient that can be used in the preparation of a pharmaceutical composition, which is generally safe and non-toxic, neither biologically undesirable nor otherwise undesirable, and includes carriers or excipients acceptable for veterinary use as well as for human pharmaceutical use. "Pharmaceutically acceptable carrier or excipient" as used in this specification and the claims includes one and more than one such carrier or excipient. The particular excipient, carrier or diluent used will depend on the manner and purpose for which the compounds of the invention are to be applied. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems . Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy . Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients . Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, coloring agents, sweetening agents, flavoring agents, taste masking agents, diluents and other known additives to provide an aesthetically pleasing presentation of the medicament (i.e., the crystalline or amorphous form of compound (I) described herein or its pharmaceutical composition) or to facilitate the manufacture of the pharmaceutical product (i.e., the medicament).

[0597] Accordingly, in one aspect, there is provided herein a pharmaceutical composition comprising the crystalline or amorphous form of compound (I) described herein as the active ingredient. In certain embodiments, there is provided herein a pharmaceutical composition comprising the crystalline or amorphous form of compound (I) described herein and a pharmaceutically acceptable carrier or excipient.

[0598] The pharmaceutical compositions described herein can be formulated into dosage forms containing a therapeutically effective amount of the crystalline form, amorphous form or pharmaceutical composition described herein.

[0599] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents the identified disease or disorder, or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. The precise effective amount for a subject will depend upon the subject's weight, size, and general health; the nature and extent of the condition; the rate of administration; the particular therapeutic agent or combination of therapeutic agents selected for administration; and the judgment of the prescribing physician. A therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the treating physician.

[0600] In some embodiments, the pharmaceutical composition can be formulated such that a dose between 0.001 and 500 mg / kg body weight / day (e.g., 0.01 mg / kg body weight / day to 400 mg / kg body weight / day, 0.01 mg / kg body weight / day to 300 mg / kg body weight / day, 0.1 mg / kg body weight / day to 200 mg / kg body weight / day, 0.1 mg / kg body weight / day to 150 mg / kg body weight / day, 0.1 mg / kg body weight / day to 100 mg / kg body weight / day, 0.5 mg / kg body weight / day to 100 mg / kg body weight / day, 0.5 mg / kg body weight / day to 80 mg / kg body weight / day, 0.5 mg / kg body weight / day to 60 mg / kg body weight / day, 0.5 mg / kg body weight / day to 50 mg / kg body weight / day, 1 mg / kg body weight / day to 50 mg / kg body weight / day, 1 mg / kg body weight / day to 40 mg / kg body weight / day) of the crystalline or amorphous form of Compound (I) described herein can be administered. In some cases, a dosage level below the lower limit of the above range may be sufficient, while in other cases, larger doses can be employed without causing any harmful side effects, provided that such larger doses are first divided into several smaller doses for administration throughout the day. For further information regarding routes of administration and dosing regimens, see Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, Volume 5, Chapter 25.3, which is specifically incorporated herein by reference.

[0601] Therapeutic Methods

[0602] In another aspect, provided herein is a method of treating or ameliorating a proliferative disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline or amorphous form described herein, which is attributable to the type I receptor tyrosine kinase inhibitory activity and brain penetration ability of the compounds of the present invention.

[0603] As used herein, the term "subject in need" refers to a subject suffering from a type I receptor tyrosine kinase-related disease or disorder (e.g., cancer), or a subject having an increased risk of developing a type I receptor tyrosine kinase-related disease relative to the general population. In the case of cancer, the subject in need may have a pre-cancerous condition. The term "subject" includes warm-blooded animals. In some embodiments, the warm-blooded animal is a mammal. In some embodiments, the warm-blooded animal is a human.

[0604] In certain embodiments, the hyperproliferative disease is cancer.

[0605] In certain embodiments, the cancer is ErbB2 positive.

[0606] In certain embodiments, the cancer is selected from the group consisting of breast cancer, gastric cancer, cholangiocarcinoma, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer.

[0607] In certain embodiments, one or more additional compounds having anti-cancer properties are administered in combination.

[0608] Combination Therapies

[0609] The crystalline forms, amorphous forms, and pharmaceutical compositions described herein can be used alone or in combination with additional therapeutic agents for treatment. Useful additional therapeutic agents include, but are not limited to, anti-tumor agents, such as additional compounds having anti-cancer properties. The additional therapeutic agents of the pharmaceutical combination formulations or dosing regimens preferably have activities complementary to the compounds described herein such that they do not have an adverse effect on each other. Such molecules are suitably present in combination in an amount effective for the intended purpose.

[0610] As used herein, the term "combination" refers to administration simultaneously, separately, or sequentially. In some embodiments, "combination" refers to simultaneous administration. In some embodiments, "combination" refers to separate administration. In some embodiments, "combination" refers to sequential administration. When administered sequentially or separately, the delay in administering the second component should not result in the loss of the beneficial effects of the combination.

[0611] Illustrative examples of useful anti-tumor agents can be selected from the following categories:

[0612] (i) Anti-proliferative / anti-tumor agents and combinations thereof, such as TKIs; DNA alkylating agents; anti-metabolites; anti-tumor antibiotics; anti-mitotic agents; and topoisomerase inhibitors; inhibitors of DNA repair mechanisms such as CHK kinases; DNA-dependent protein kinase inhibitors; inhibitors of poly(ADP-ribose) polymerase (PARP inhibitors); and Hsp90 inhibitors, such as tanespimycin and retaspimycin, inhibitors of ATR kinase; and inhibitors of WEE1 kinase;

[0613] (ii) Cell growth inhibitors, such as anti-estrogens; estrogen receptor down-regulating modulators; anti-androgens; LHRH antagonists or LHRH agonists; progestins; aromatase inhibitors; inhibitors of 5α-reductase; and p38 inhibitors;

[0614] (iii) Agents that inhibit cancer cell invasion;

[0615] (iv) Inhibitors of growth factor function, such as growth factor antibodies, growth factor receptor antibodies, antibody-drug conjugates, farnesyl transferase inhibitors, tyrosine kinase inhibitors, and serine-threonine kinase inhibitors; inhibitors of the platelet-derived growth factor family; inhibitors of the hepatocyte growth factor family; and MEK inhibitors and compounds such as those disclosed in U.S. Patent Publication 2004 / 0116710;

[0616] (v) Anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor, such as but not limited to the anti-vascular endothelial growth factor antibody bevacizumab, VEGF receptor tyrosine kinase inhibitors; compounds such as those disclosed in International Patent Applications WO 97 / 22596, WO 97 / 30035, WO 97 / 32856, and WO 98 / 13354; and compounds that act by other mechanisms, or inhibitors of angiopoietin and its receptors (Tie-1 and Tie-2), inhibitors of PLGF, inhibitors of delta-like ligand (DLL-4);

[0617] (vi) Vascular damaging agents;

[0618] (vii) Antisense therapy;

[0619] (viii) Gene therapy methods, including for example GVAX TM and methods of replacing abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) methods, and methods of increasing a patient's tolerance to chemotherapy or radiotherapy (such as multidrug resistance gene therapy);

[0620] (ix) Interferons;

[0621] (x) Immunotherapy methods, including but not limited to ex vivo and in vivo methods for increasing the immunogenicity of a patient's tumor cells; methods for reducing T cell anergy or regulatory T cell function; methods for enhancing T cell responses to tumors; methods using transfected immune cells; methods using cytokine-transfected tumor cell lines, methods using antibodies against tumor-associated antigens, and antibodies that deplete target cell types; methods using anti-idiotypic antibodies; methods for enhancing natural killer cell function; and methods utilizing antibody-toxin conjugates; immunotoxins; agonists of Toll-like receptor 7 or Toll-like receptor 9;

[0622] (xi) Efficacy enhancers, such as leucovorin.

[0623] For illustrative purposes, more detailed examples of such combination therapies can be found in WO 2020 / 057511A1, which is incorporated herein by reference in its entirety.

[0624] In certain embodiments, the additional anti-tumor agents (additional compounds having anti-cancer properties) are selected from the group consisting of TKIs (such as lapatinib, neratinib, and afatinib), anti-HER2 agents (e.g., monoclonal antibodies such as trastuzumab, ADCs such as T-DM1, T-DXd), and combinations thereof. In some embodiments, the additional anti-tumor agents include capecitabine, anti-HER2 antibodies, T-DXd, and T-DM1. In some embodiments, there is one additional anti-tumor agent. In some embodiments, there are two additional anti-tumor agents. In some embodiments, there are three or more additional anti-tumor agents.

[0625] Salt Screening and Evaluation

[0626] Using the amorphous free base or the B-form free base of compound (I) as the starting material, salt screening experiments were carried out using different acids or co-formers in different solvent systems. HCl, methanesulfonic acid, and p-toluenesulfonic acid were tested at 2 feeding ratios. Seven crystalline salts were obtained: hydrochloride A-form, hydrochloride B-form, methanesulfonate A-form, methanesulfonate B-form, phosphate A-form, L-tartrate A-form, fumarate A-form, and adipate A-form. In addition, one crystalline free base, namely free base A-form, was also observed in the screening.

[0627] Polymorph Research

[0628] Use amorphous free base, Form B free base, and Form G free base as starting materials for the polymorph screening of the free base of Compound (I). Establish polymorph screening experiments using methods including but not limited to slow evaporation, slow cooling, slurrying, solid-vapor diffusion, liquid-vapor diffusion, and anti-solvent addition. A total of six crystalline forms of the free base were observed during the screening and identification process, which were designated as Form B, Form C, Form D, Form E, Form F, and Form G free base, respectively. Most forms were characterized by XRPD, TGA, DSC, and 1 1H NMR. The identification results showed that Form B and Form E free bases are anhydrates, Form C, Form D, Form F, and Form G free bases are hydrates, and Form A free base is an acetone solvate.

[0629] Perform a slurry competition experiment to study the interconversion relationship between Form B free base and Form C free base. The results showed that Form B free base was obtained after slurrying in solvent systems with water activities (Aw) of approximately 0.4, 0.6, and 0.8 at 24 °C ± 3 °C. Form C free base was obtained after slurrying in H2O with a water activity of approximately 1, indicating that the critical water activity between Form B and Form C free bases is in the range of 0.8 to 1. Further study the interconversion relationship between Form B anhydrous free base and Form C / F / G hydrates at different water activities at RT. The saturated solution of Form B free base was obtained by slurrying Form B free base in the corresponding solvent system overnight at RT. A mixture of Form B + C + F + G free bases was added to the corresponding saturated solution of Form B free base to form a suspension. After stirring the suspension at 750 rpm for four days at RT, the suspension was sampled for XRPD. Form B free base was observed in the EtOH and EtOH / H2O (aw = 0.2, 0.4, 0.6, 0.8) systems, while Form G free base was obtained in the pure H2O system.

[0630] Examples

[0631] For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit the invention but are only intended to suggest methods of practicing the invention. Those skilled in the art will recognize that the chemical reactions can be readily adjusted to prepare the crystalline or amorphous forms described herein, and alternative methods for preparing the crystalline or amorphous forms are considered to be within the scope of the invention. For example, by modifications that are obvious to those skilled in the art, such as by using other suitable reagents known in the art in addition to the reagents described or by making conventional modifications to the reaction conditions, the preparation of the crystalline or amorphous forms described herein can be successfully carried out. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for preparing the crystalline or amorphous forms described herein. Those skilled in the art will also recognize that the crystalline and amorphous forms can be readily adjusted to prepare other crystalline and amorphous forms, and alternative methods for preparing the crystalline and amorphous forms are within the scope of the invention.

[0632] In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar or TCI and used without further purification unless otherwise stated.

[0633] The crystalline or amorphous forms of compound (I) were characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Chemical stoichiometry was determined using 1 H solution nuclear magnetic resonance ( 1 H NMR) or high performance liquid chromatography (HPLC) coupled with ion chromatography (IC).

[0634] Abbreviations

[0635] Most of the abbreviations used in the present invention are listed in Table 1.

[0636] Table 1 Abbreviations

[0637]

[0638]

[0639]

[0640] Analysis Conditions

[0641] X-ray Powder Diffraction (XRPD)

[0642] XRPD analysis was performed using a PANalytical Empyrean or X'Pert3 X-ray powder diffractometer. Table 2 lists the typical XRPD parameters used for salt screening and evaluation as well as polymorph studies.

[0643] Table 2 Typical XRPD parameters

[0644]

[0645] Thermogravimetric Analysis and Differential Scanning Calorimetry (TGA and DSC)

[0646] In salt screening and evaluation as well as polymorph studies, TGA was performed using a TA Q500, TA Q5000 or Discovery 5500 TGA from TA Instruments. DSC or mDSC was performed using a TA Q200 / Q2000 or Discovery 2500 DSC from TA Instruments. The typical parameters are listed in Tables 3 and 4.

[0647] Table 3 Parameters for TGA and DSC tests in salt screening and evaluation as well as polymorph studies

[0648]

[0649] Table 4 Parameters for mDSC tests in salt screening and evaluation as well as polymorph studies

[0650]

[0651] Dynamic Vapor Sorption (DVS)

[0652] DVS was measured via SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25 °C was calibrated according to the deliquescence points of LiCl, Mg(NO3)2 and KCl. The typical parameters for DVS tests are listed in Table 5.

[0653] Table 5 Parameters for DVS tests

[0654]

[0655] 1 H-Nuclear Magnetic Resonance Spectroscopy( 1 H-NMR)

[0656] 1H solution NMR was acquired on a Bruker 400M NMR spectrometer using DMSO-d6 as the solvent 1

[0657] Polarizing Microscope (PLM)

[0658] ​The PLM images were taken at RT using a Carl Zeiss Axio Scope.A1 microscope.

[0659] High Performance Liquid Chromatography (HPLC)

[0660] An Agilent 1260 HPLC instrument was used and the detailed chromatographic conditions for purity and solubility analysis are listed in Table 6.

[0661] Table 6 Chromatographic conditions and parameters

[0662]

[0663] *: The data described in this report correspond to a UV wavelength of 214 nm.

[0664] Ion Chromatograph (IC)

[0665] A Thermo Fisher ICS-1100 was used and the detailed parameters are listed in Table 7.

[0666] Table 7 Ion chromatograph conditions and parameters

[0667]

[0668]

[0669] Example 1

[0670] Form A Fumarate of Compound (I)

[0671] The A-form fumarate of compound (I) was prepared according to the following method:

[0672] a) 500 mg of the free base of compound (I) was dissolved in about 10 mL of EtOAc to form a free base solution;

[0673] b) 158.6 mg of fumaric acid (feed molar ratio 1.5:1, acid / free base) was dissolved in about 5 mL of EtOH to form an acid solution;

[0674] c) The acid solution was added dropwise to the free base solution with stirring;

[0675] d) About 13 mL of n-heptane was added dropwise; then the mixture was optionally seeded with the crystalline form of the A-form fumarate of compound (I);

[0676] e) Stirred at about 5 °C for about 16 hours; and

[0677] f) The solid was separated by filtration and then the solid was dried in vacuo at about 50 °C.

[0678] The A-form fumarate of compound (I) is an anhydrous and slightly hygroscopic rod-shaped crystal (shown via PLM in Figure 5 ), with an acid / base stoichiometric ratio of approximately 1.5:1, which is characterized by XRPD, TGA, DSC, and 1 H NMR. The XRPD pattern and data are shown in Figure 1 and Table 8, respectively. Figure 2 and Figure 3 The TGA / DSC results in Figure 4 show that up to 150 °C, the weight loss is 1.9%, and there is a sharp endothermic peak at 167.6 °C. Figure 4 The 1 H NMR results in Figure 4 show an acid / base molar ratio of 1.5:1.

[0679] Table 8 XRPD data of the A-form fumarate of compound (I)

[0680]

[0681]

[0682]

[0683] Example 2

[0684] Form B Fumarate of Compound (I)

[0685] Suspend approximately 15 mg of the A-form fumarate of compound (I) in 0.5 mL of H2O in an HPLC vial. Stir the suspension magnetically at about 1000 rpm at RT for 11 days. Separate the solid by centrifugation and leave it open to the air under ambient conditions for 4 days to obtain the B-form fumarate of compound (I). The XRPD results are shown in Figure 6 and Table 9. The TGA and DSC results are shown in Figure 7 and Figure 8 The TGA curve shows that up to 150 °C, the weight loss is 4.9%. The DSC curve shows a broad endothermic peak at 91.3 °C, which may be due to the removal of water or solvent, and a sharp endothermic peak at 166.3 °C. Figure 9 The 1 H NMR results in Figure 9 show a fumaric acid / free base molar ratio of 1:1. After heating the B-form fumarate of compound (I) to 140 °C and cooling it to room temperature, the A-form fumarate of compound (I) is obtained. Therefore, the B-form fumarate of compound (I) is a hydrate, which is converted to the anhydrous form by losing the crystallization water upon heating.

[0686] Table 9 XRPD data of the B-form fumarate of compound (I)

[0687]

[0688] Example 3

[0689] Form C Fumarate of Compound (I)

[0690] Suspend approximately 15 mg of the A-form fumarate of compound (I) in 0.5 mL of H2O in an HPLC vial. Stir the suspension magnetically at about 1000 rpm at RT for 9 days. Separate the wet solid to obtain the C-form fumarate of compound (I) (analyze the wet sample). During storage under ambient conditions, a polymorphic transformation between the C-form and B-form fumarates of compound (I) was observed, and thus no further characterization was performed. The C-form fumarate of compound (I) has an acid / base stoichiometric ratio of 1:1. The XRPD pattern and data are shown in Figure 10 and Table 10, respectively.

[0691] Table 10 XRPD data for the C-form fumarate of compound (I)

[0692]

[0693] Example 4

[0694] Form E Fumarate of Compound (I)

[0695] Dissolve approximately 30 mg of the A-form fumarate of compound (I) in 1 mL of ethyl formate in a glass vial. Keep the solution at room temperature for evaporation to obtain the E-form fumarate of compound (I). The XRPD pattern and data are shown in Figure 11 and Table 11, respectively. Figure 12 and Figure 13 The TGA and DSC results in show a weight loss of 9.4% up to 150 °C and endothermic peaks at 134.5 °C and 166.0 °C. The molar ratio of formic acid:free base is 1.5:1.

[0696] Table 11 XRPD data for the E-form fumarate of compound (I)

[0697]

[0698] Example 5

[0699] Form B Free Base of Compound (I)

[0700] Suspend the amorphous free base of about 15 mg of compound (I) in 0.5 mL of MIBK / cyclohexane (1:4, v / v) in an HPLC vial. Stir the suspension magnetically at about 1000 rpm at 5 °C for 7 days. Separate the solid by centrifugation to obtain the B-form free base of compound (I). The XRPD patterns and data are shown in Figure 14 and Table 12, respectively. Figure 15 and Figure 16 The TGA and DSC results in show that up to 150 °C, the weight loss is 3.5%, and there is a sharp endothermic peak at 169.4 °C (peak). Figure 17 in 1 The 1H NMR results show that the molar ratio of residual solvent cyclohexane / free base is 0.1:1 (corresponding to a 0.2% TGA weight loss). Figure 18 The PLM in shows that the B-form free base of compound (I) is anhydrous and is slightly hygroscopic irregular particles with aggregation.

[0701] Table 12 XRPD data of the B-form free base of compound (I)

[0702]

[0703]

[0704] Example 6

[0705] Form C Free Base of Compound (I)

[0706] Suspend the amorphous free base of about 15 mg of compound (I) in 0.5 mL of THF / H2O (1:4, v / v) in an HPLC vial. Stir the suspension magnetically at about 1000 rpm at 5 °C for 7 days. Separate the solid by centrifugation to obtain the C-form free base of compound (I). The XRPD results are shown in Figure 19 and Table 13. The TGA and DSC results are shown in Figure 20 and Figure 21 respectively. It is observed on the TGA / DSC curve that up to 150 °C, the weight loss is 1.5%, and there are two endothermic peaks at 86.2 °C and 114.4 °C (peak). Figure 22 in 1 The 1H NMR results show that no solvent THF is detected. Combining with the characterization results of the D-form free base of compound (I) (see Example 7), it is speculated that the C-form free base of compound (I) is a hydrate.

[0707] Table 13 XRPD data of the C-form free base of compound (I)

[0708]

[0709]

[0710] Example 7

[0711] Form D Free Base of Compound (I)

[0712] Suspend the amorphous free base of about 60 mg of compound (I) in 2 mL of THF / H2O (1:4, v / v) in an HPLC vial. Stir the suspension magnetically at about 1000 rpm at 5 °C for 3 days. Separate the solid and dry it under ambient conditions for about 2 hours to obtain the D-form free base of compound (I). The XRPD results are shown in Figure 23 and Table 14. The D-form free base of compound (I) is a hydrate and can be obtained by placing the C-form free base of compound (I) under ambient conditions.

[0713] Table 14 XRPD data of the D-form free base of compound (I)

[0714]

[0715]

[0716] Example 8

[0717] Form E Free Base of Compound (I)

[0718] Suspend the amorphous free base of about 60 mg of compound (I) in 2 mL of THF / H2O (1:4, v / v) in an HPLC vial. Stir the suspension magnetically at about 1000 rpm at 5 °C for 4 days. Separate the solid by centrifugation and dry it under ambient conditions for about 2 hours. After purging the solid with N2 at 30 °C for 20 min, the E-form free base of compound (I) is obtained. The XRPD pattern and XRPD data are shown in Figure 24 and Table 15. It is speculated that the E-form free base is an anhydrate, which is converted to the C-form free base of compound (I) after being exposed to ambient conditions for 30 min.

[0719] Table 15 XRPD data of the E-form free base of compound (I)

[0720]

[0721]

[0722] Example 9

[0723] Form F Free Base of Compound (I)

[0724] Suspend the amorphous free base of approximately 15 mg of compound (I) in 0.5 mL of ACN / heptane (1:9, v / v) in an HPLC vial. Stir the suspension magnetically at approximately 1000 rpm at RT for 2 days. Separate the solid by centrifugation. The F-form free base is a hydrate. The XRPD patterns and data are as shown in Figure 25 and Table 16. Figure 26 The TGA curve in Figure 27 shows a weight loss of 5.7% up to 70 °C.

[0725] Table 16 XRPD data of the F-form free base of compound (I)

[0726]

[0727] Example 10

[0728] Form G Free Base of Compound (I)

[0729] Dissolve the amorphous free base of approximately 15 mg of compound (I) in 0.5 mL of EtOH in a glass vial. Then add the anti-solvent of H2O to the EtOH solution and obtain a suspension. Separate the solid by centrifugation. The G-form free base is a hydrate. The XRPD patterns and data are as shown in Figure 28 and Table 17. Figure 29 The TGA curve in Figure 30 shows a weight loss of 7.3% up to 70 °C.

[0730] Table 17 XRPD data of the G-form free base of compound (I)

[0731]

[0732] Example 11

[0733] Form A Free Base of Compound (I)

[0734] Suspend the amorphous free base of approximately 15 mg of compound (I) in 0.5 mL of acetone / heptane (1:4, v:v) in an HPLC vial. Stir the suspension magnetically at approximately 1000 rpm at RT for 3 days. Separate the solid by centrifugation and dry it for 1 day under ambient conditions. The A-form free base of compound (I) is an acetone solvate, which is obtained by slurrying the amorphous free base in acetone / heptane (1:4) at RT for 3 days. The XRPD patterns and data are shown in Figure 31 and Table 18, respectively. Figure 32 and Figure 33The TGA and DSC curves in show that up to 140 °C, the weight loss is 9.9% and there is an endotherm at 71.3 °C (peak temperature). Figure 34 as shown in 1 The 1H NMR results show that the molar ratio of acetone: free base is 0.7:1 (6.9 wt%).

[0735] Table 18 XRPD data of the free base of compound (I) of type A

[0736]

[0737] Example 12

[0738] Form A Hydrochloride of Compound (I)

[0739] About 15 mg of the amorphous free base of compound (I) and 4.6 μL of concentrated hydrochloric acid (feed molar ratio 2:1, acid / free base) were suspended in 0.5 mL of EtOAc / heptane (1:2, v:v) in an HPLC vial. The suspension was magnetically stirred at RT at about 1000 rpm for 3 days. The solid was separated by centrifugation and dried for 1 day under ambient conditions to afford the hydrochloride salt of compound (I) of type A. The XRPD patterns and data are shown in Figure 35 and Table 19, respectively. Figure 36 and Figure 37 The TGA and DSC curves in show that up to 150 °C, the weight loss is 8.8% and there is an endotherm at 110.0 °C (peak temperature). The molar ratio of hydrochloric acid: free base is 2.5:1.

[0740] Table 19 XRPD data of the hydrochloride salt of compound (I) of type A

[0741]

[0742] Example 13

[0743] Form B Hydrochloride of Compound (I)

[0744] About 500 mg of the amorphous free base of compound (I) was dissolved in about 10 mL of EtOAc. A solution of 935 μL of hydrochloric acid in EtOAc (feed molar ratio 2:1, acid / free base) was diluted to 15 mL in EtOH. Optionally, the hydrochloride salt of type B of compound (I) was added as a seed to the free base solution and it did not completely dissolve. Then the acid solution was added dropwise while stirring at about 1000 rpm. After the mixture became turbid, it was stirred at RT for 8 h and then further stirred at 5 °C for 13 h. The precipitated solid was separated by filtration and dried under vacuum at RT overnight to afford the hydrochloride salt of compound (I) of type B. The XRPD patterns and data are shown in Figure 38shown in Table 20. Figure 39 and Figure 40 The TGA and DSC curves in show a 2.3% weight loss up to 150 °C and an endotherm at 241.7 °C (peak temperature). The molar ratio of hydrochloric acid: free base is 2.2:1.

[0745] XRPD data of the B-form hydrochloride salt of compound (I) in Table 20

[0746]

[0747] Example 14

[0748] Form A Mesylate of Compound (I)

[0749] About 15 mg of the amorphous free base of compound (I) and 5.5 mg of methanesulfonic acid (feed molar ratio 2:1, acid / free base) were suspended in 0.5 mL of acetone / n - heptane (1:4, v / v) in an HPLC vial. The suspension was magnetically stirred at RT at about 1000 rpm for 3 days. The solid was separated by centrifugation and dried for 1 day under ambient conditions to afford the A-form methanesulfonate salt of compound (I). The XRPD patterns and data are shown in Figure 41 and Table 21. Figure 42 and Figure 43 The TGA and DSC curves in show a 10.2% weight loss up to 150 °C and an endotherm at 65.1 °C (peak temperature). The molar ratio of acid: free base is 2.0:1.

[0750] XRPD data of the A-form methanesulfonate salt of compound (I) in Table 21

[0751]

[0752]

[0753] Example 15

[0754] Form B Mesylate of Compound (I)

[0755] About 15 mg of the amorphous free base of compound (I) and 5.4 mg of methanesulfonic acid (feed molar ratio 2:1, acid / free base) were suspended in 0.5 mL of IPA / cyclohexane (1:4, v / v) in an HPLC vial. The suspension was magnetically stirred at RT at about 1000 rpm for 3 days. The solid was separated by centrifugation and dried for 1 day under ambient conditions to afford the B-form methanesulfonate salt of compound (I). The XRPD patterns and data are shown in Figure 44 and Table 22. Figure 45 and Figure 46The TGA and DSC curves in show a weight loss of 7.6% up to 150° C. and an endotherm at 63.4° C. (peak temperature). The molar ratio of acid:free base is 1.7:1.

[0756] Table 22 XRPD data of Type B mesylate of Compound (I)

[0757]

[0758] Example 16

[0759] Form A Phosphate of Compound (I)

[0760] About 15 mg of amorphous free base of compound (I) and 1.9 μL concentrated H3PO4 (addition molar ratio of 1:1, acid / free base) were suspended in 0.5 mL acetone / n-heptane (1:4, v:v) in an HPLC vial. The suspension was magnetically stirred at about 1000 rpm for 3 days at RT. The solid was separated by centrifugation and dried at ambient conditions for 1 day to obtain the A-type phosphate salt of compound (I). The XRPD pattern and data are respectively at Figure 47 and as shown in Table 23. Figure 48 and Figure 49 The TGA and DSC curves in show a weight loss of 9.5% up to 150° C., and endotherms at 79.1° C. and 194.8° C. (peak temperatures). The molar ratio of acid:free base is 1.1:1.

[0761] Table 23 XRPD data of type A phosphate of compound (I)

[0762]

[0763] Example 17

[0764] Form A L-Tartrate of Compound (I)

[0765] About 15 mg of amorphous free base of compound (I) and 4.3 mg of L-tartaric acid (feed molar ratio of 1:1, acid / free base) were suspended in 0.5 mL of EtOAc / n-heptane (1:2, v:v) in an HPLC vial. The suspension was magnetically stirred at RT at a speed of about 1000 rpm for 3 days. The solid was separated by centrifugation and dried at ambient conditions for 1 day to obtain the A-type L-tartrate of compound (I). The XRPD patterns and data are respectively at Figure 50 and as shown in Table 24. Figure 51 and Figure 52 The TGA and DSC curves in show that the weight loss is 3.7% up to 150° C., and there are endothermic peaks at 77.6° C. and 164.7° C. The molar ratio of L-tartaric acid:free base is 0.5:1.

[0766] XRPD data of the A-form L-tartrate salt of compound (I) in Table 24

[0767]

[0768]

[0769] Example 18

[0770] Form A Adipate of Compound (I)

[0771] Suspend about 15 mg of the amorphous free base of compound (I) and 4.3 mg of adipic acid (feed molar ratio 1:1, acid / free base) in 0.5 mL of EtOAc / n-heptane (1:2, v:v) in an HPLC vial. Stir the suspension magnetically at about 1000 rpm at RT for 3 days. Separate the solid by centrifugation and dry it under ambient conditions for 1 day to obtain the A-form adipate salt of compound (I). The XRPD pattern and data are shown in Figure 53 and Table 25, respectively. Figure 54 and Figure 55 The TGA and DSC curves in show that up to 150 °C, the weight loss is 3.0% and there is an endotherm at 106.7 °C (peak temperature). The molar ratio of adipic acid:free base is 1.3:1.

[0772] XRPD data of the A-form adipate salt of compound (I) in Table 25

[0773]

[0774] Example 19

[0775] Amorphous Fumarate of Compound (I)

[0776] Dissolve about 3 g of the A-form fumarate salt of compound (I) in about 50 mL of MeOH in a glass vial. Transfer the solution to a rotary evaporator and remove the solvent by rotary evaporation at 60 °C to obtain the amorphous fumarate salt of compound (I). The XRPD pattern is as shown in Figure 56 shown. Figure 57 The TGA curve in shows that up to 150 °C, the weight loss is 3.6%. Figure 58 The mDSC curve in shows that the intermediate temperatures for thermogravimetric analysis (TG) are 79.9 °C and 107.5 °C. The molar ratio of fumaric acid:free base is 1.5:1.

[0777] Example 20

[0778] Amorphous Free Base of Compound (I)

[0779] Dissolve approximately 2 g of the free base of Form B of compound (I) in approximately 40 mL of DCM in a glass vial. Transfer the solution to a rotary evaporator and remove the solvent by rotary evaporation at 40 °C to obtain the amorphous free base of compound (I). The XRPD pattern is as shown in Figure 59 . Figure 60 The TGA curve in Figure 61 shows that up to 150 °C, the weight loss is 1.9%.

[0780] Example 21: Comparison of the solubility of the amorphous free base, fumarate Form B, and fumarate Form E in FaSSIF

[0781] Measure the kinetic solubility of the amorphous free base and fumarate Forms B / E in FaSSIF to evaluate solubility. All solubility samples (initial solid content of 5 mg / mL to 10 mg / mL) were kept rotating on a rotator and sampled at 37 °C at 1 hour, 4 hours, and 24 hours, respectively. After centrifugation, the supernatant was collected for HPLC analysis.

[0782] The results are summarized in Table 26. Compared with the amorphous free base seen in the prior art, fumarate Form B and fumarate Form E show higher solubility in FaSSIF.

[0783] Table 26 Summary of the results of the kinetic solubility evaluation in FaSSIF

[0784]

[0785] Example 22 Comparison of the solubility of the amorphous free base and fumarate Forms A / B / E in H2O

[0786] At 37 °C, determine the equilibrium solubility of the amorphous free base and fumarate Forms A / B / E in H2O. Suspend approximately 5 mg to 10 mg of the solid in H2O to obtain a mixture. Stir the suspension for 24 hours, then centrifuge and filter to obtain the supernatant for HPLC analysis.

[0787] The results are summarized in Table 27. Compared with the amorphous free base seen in the prior art, fumarate Form A, fumarate Form B, and fumarate Form E show much better solubility in H2O.

[0788] Table 27 Summary of the results of the equilibrium solubility evaluation in H2O

[0789]

[0790] Comparison of Solubilities of Amorphous Free Base, B Form Free Base, and A / B / E Form Fumarate in pH 4.5 Buffer

[0791] At 37 °C, the equilibrium solubilities of amorphous free base, B form free base, and A / B / E form fumarate were evaluated in pH 4.5 buffer. Approximately 5 mg to 10 mg of solid was suspended in pH 4.5 buffer to obtain a mixture. The suspension was stirred for 24 hours, then centrifuged and filtered to obtain the supernatant for HPLC analysis.

[0792] The results are summarized in Table 28. Compared with the amorphous free base seen in the prior art, the B form free base, A form fumarate, B form fumarate, and E form fumarate showed better solubilities in pH 4.5 buffer.

[0793] Table 28 Summary of Results of Equilibrium Solubility Evaluation in pH 4.5 Buffer

[0794]

[0795] Example 24 Comparison of Solubilities of Amorphous Free Base and B / E Form Fumarate in pH 6.8 Buffer

[0796] At 37 °C, the equilibrium solubilities of amorphous free base and B / E form fumarate were evaluated in pH 6.8 buffer. Approximately 5 mg to 10 mg of solid was suspended in pH 6.8 buffer to obtain a mixture. The suspension was stirred for 24 hours, then centrifuged and filtered to obtain the supernatant for HPLC analysis.

[0797] The results are summarized in Table 29. Compared with the amorphous free base seen in the prior art, the B form fumarate and E form fumarate showed improved solubilities in pH 6.8 buffer.

[0798] Table 29 Summary of Results of Equilibrium Solubility Evaluation in pH 6.8 Buffer

[0799]

[0800]

[0801] Example 25: Flowability and Compressibility

[0802] The bulk density was determined by adding an appropriate amount (m) of the material to a 5 mL graduated cylinder and recording its apparent volume (v0). The bulk density was obtained by dividing the amount of the material by the apparent volume of the unsedimented material (ρ0 = m / v0). For the tapped density, the graduated cylinder was then tapped 200 times. The tapped density was then calculated by dividing the amount of the material by its final tapped volume (ρ1 = m / v1). Carr's Index = (ρ1 - ρ0) / ρ1.

[0803] A repose angle is formed on a fixed base with a flange to retain a layer of powder on the base. A symmetrical powder cone is carefully constructed. The repose angle is determined by measuring the height (h) and the base circle radius (r) of the powder cone and calculating the repose angle α according to the following equation α = tan -1 (h / r).

[0804] The results of the flowability and compressibility of the amorphous free base, Form F free base, Form B fumarate, and Form E fumarate are summarized in Table 30. Generally, powders with a smaller Carr's index will exhibit better compressibility and flowability. And powders with a smaller repose angle will exhibit better flowability.

[0805] The results show that compared with the amorphous free base, the Form F free base, Form B fumarate, and Form E fumarate exhibit relatively better flowability and compressibility.

[0806] Table 30 Summary of powder characteristic data

[0807]

[0808] Example 26: Contact angle

[0809] The wettability of the solid forms is evaluated by the contact angle with water. The results summarized in Table 31 show that all samples of the selected solid forms can be wetted by water. Compared with the amorphous free base samples, the Form A fumarate and Form B fumarate exhibit relatively smaller contact angles, indicating that the Form A fumarate and Form B fumarate may be more easily wetted by water.

[0810] Table 31 Summary of contact angle results

[0811]

[0812]

[0813] Example 27: Crystal habit

[0814] The crystal habits of the particles (amorphous free base and Form A fumarate) are observed using PLM. The results show that the amorphous free base samples are composed of irregularly shaped particles without distinct boundaries. The Form A fumarate is rod-shaped particles with regular shapes. Compared with the amorphous free base, the Form A fumarate exhibits better crystal habit, which is more suitable for further development.

[0815] Example 28: Hygroscopicity

[0816] DVS isotherm plots were collected at 25 °C to study the change in stability of the selected solid forms with humidity. The results are summarized in Table 32. Compared to the amorphous free base, the free base form B, fumarate form A, fumarate form B, and fumarate form E have lower hygroscopicity at 80% RH / 25 °C.

[0817] Table 32 Summary of DVS results

[0818]

[0819] Example 29: Mechanical stability

[0820] The mechanical stability of the solid forms was evaluated by monitoring the XRPD form changes after grinding (about 5 min) and tableting (about 234 Mpa). The XRPD results showed that no form changes of the free base form B, fumarate form A, and fumarate form E were observed after grinding or tableting (Table 33), which confirmed that the free base form B, fumarate form A, and fumarate form E exhibited good mechanical stability.

[0821] Table 33 Summary of mechanical stability results

[0822] Solid Forms XRPD Form Change after Grinding XRPD Form Change after Tabletting Form B Free Base No No Form A Fumarate No No Form E Fumarate No No

[0823] Example 30: Solid state stability

[0824] To evaluate the solid state stability of the selected forms (amorphous free base, free base form F, fumarate form A, and fumarate form B), the samples were stored at 40 °C / 75% RH / open air for 1 month. The stability samples were characterized by XRPD to check for any solid form changes, and by HPLC characterization to check for purity changes. All the results are summarized in Table 34.

[0825] The results showed that: (1) the free base form F, fumarate form A, and fumarate form B showed good physical stability, as evidenced by the absence of form changes under all conditions; (2) compared with the purity change of the amorphous free base after storage at 40 °C / 75% RH for 1 month, the free base form F, fumarate form A, and fumarate form B showed better chemical stability with lower purity changes.

[0826] Table 34 Results of solid state stability evaluation

[0827]

[0828] Characterization Results

[0829] The characterization results of the fumarate form, free base form, and crystalline salt form of compound (I) are summarized in Tables 35 to 37.

[0830] Table 35 Characterization Results of Fumarate Forms

[0831]

[0832] --: Due to the form transformation between type B and type C fumarates, type C fumarate was not characterized and identified.

[0833] *: Intermediate temperature of thermogravimetric analysis

[0834] Table 36 Characterization Results of Free Base Forms

[0835]

[0836] --: Due to limited amount of the material and the form transformation to type E free base after N2 purge, type D free base was not characterized by TGA / DSC. Type E free base transforms to type D after exposure to ambient conditions and was not characterized by TGA / DSC.

[0837] *: Tg, intermediate temperature.

[0838] Table 37 Characterization Results of Crystalline Salts

[0839]

[0840] The foregoing description is to be considered merely illustrative of the principles of the invention. Further, since numerous modifications and changes will be apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process as described above. Accordingly, all suitable modifications and equivalent arrangements are considered to fall within the scope of the invention as defined by the appended claims.

Claims

1. A crystalline form of a compound (I) represented by the following structural formula: wherein the crystalline form is a complex of the free base and a pharmaceutically acceptable acid, or the free base.

2. An amorphous form of a compound (I) represented by the following structural formula: wherein the amorphous form is a pharmaceutically acceptable salt or the free base.

3. A method for preparing the crystalline form according to claim 1, which comprises: in the case where the crystalline form is a complex of the free base and a pharmaceutically acceptable acid, a) adding the compound (I) and an acid to a solvent, and b) slurrying at a temperature and for a time sufficient to initiate precipitation of the complex; in the case where the crystalline form is the free base, a) adding the compound (I) to a solvent; and b) slurrying at a temperature and for a time sufficient to initiate precipitation of the free base.

4. A method for preparing the amorphous form of the compound (I) according to claim 2, which comprises: a) dissolving the compound (I) in a solvent; and b) removing the solvent.

5. A pharmaceutical composition comprising the crystalline form according to claim 1 or the amorphous form according to claim 2, and a pharmaceutically acceptable carrier or excipient.

6. A dosage form comprising a therapeutically effective amount of the crystalline form according to claim 1, the amorphous form according to claim 2, or the pharmaceutical composition according to claim 5.

7. A method for treating or ameliorating a hyperproliferative disease in a subject, which comprises administering to a subject in need thereof a therapeutically effective amount of the crystalline form according to claim 1 or the amorphous form according to claim 2.

8. The crystalline form according to claim 1 or the amorphous form according to claim 2, for use in the treatment or amelioration of a hyperproliferative disease.

9. Use of the crystalline form according to claim 1 or the amorphous form according to claim 2 in the manufacture of a medicament for the treatment or amelioration of a hyperproliferative disease.

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