Solid form of macrocyclic compound, preparation therefor and use thereof

Abstract

To provide a crystalline form of a free base of a compound which is an ALK and ROS1 kinase inhibitor having deuterium atoms, or a pharmaceutically acceptable salt thereof.SOLUTION: The present invention provides a crystalline form I of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using CuKα radiation includes at least the characteristic peaks located at the following °2θ: 16.175±0.2, 17.299±0.2 and 21.218±0.2.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure is in the field of pharmaceutical technology, and in particular relates to a crystalline form of the free base of the macrocyclic compound (10R)-7-amino-12-fluoro-2-(methyl-d3)-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (Compound of Formula (A) or Compound A) or a pharmaceutically acceptable salt thereof, and methods for preparing the same, and the use of the compound in the manufacture of a medicament for the treatment of diseases mediated by anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), or mutants thereof, such as non-small cell lung cancer. [Background technology]

[0002] Compound A has the chemical formula C 21 H 16 D3FN6O2, molecular weight 409.17 g / mol, chemical structure:

[0003] [ka] (A) is.

[0004] Compound A is an ALK- and ROS1-kinase inhibitor having a deuterium atom, and can be used to treat diseases mediated by ALK and ROS1 kinases and their mutants, cell proliferation diseases, inflammation, infection, immune diseases, organ transplants, viral diseases, cardiovascular diseases, or metabolic diseases, such as non-small cell lung cancer, lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer, osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer, colorectal cancer, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, or cystic fibrosis. International Patent Publication No. WO2017 / 148325A1 was the first to disclose this compound, but did not disclose a crystalline form of Compound A. The applicant for WO2017 / 148325A1 is Shenzhen TargetRx Inc. The corresponding Chinese application for WO2017 / 148325A1, CN201780013374.9, was published on October 18, 2019, under registration number CN108699081B. U.S. Application No. US16 / 081,611 was published on January 28, 2020, under registration number US10543199B2. Intention to grant a patent has been announced for European Application No. EP17759176.5. Japanese Application No. JP2018-545928 is still under prosecution. The contents of each of the above applications are incorporated herein by reference in their entirety.

[0005] ALK is a receptor protein tyrosine kinase belonging to the insulin receptor superfamily. It was discovered in 1994 by Morris and Shiota et al. as the product of chromosomal rearrangements in anaplastic large cell lymphoma (ALCL). The most common fusion is the fusion of the NPM (nucleophosmin) gene on chromosome 5 with the ALK gene on chromosome 2. NPM-ALK fusion proteins were detected in approximately 75% of patients with ALK-positive ALCL. Subsequent studies have found that different forms of ALK fusions exist in various cancers, including inflammatory myofibroblastoma and diffuse large B-cell lymphoma. In 2007, Soda et al. found that the incidence of EML4-ALK fusion proteins in non-small cell lung cancer (NSCLC) was 5%.

[0006] ROS1 is a proto-oncogene receptor tyrosine kinase belonging to the insulin receptor subfamily and involved in cell proliferation and differentiation processes. In humans, ROS1 is expressed in epithelial cells of various different tissues. ROS1 expression and / or activation has been found in glioblastoma and tumors of the central nervous system. Genetic alterations involving ROS1 result in aberrant fusion proteins of ROS1 kinase, including the FIG-ROS1 deletion translocation in glioblastoma and non-small cell lung cancer (NSCLC), the SLC34A2-ROS1 translocation in NSCLC, and the CD74-ROS1 translocation in NSCLC and cholangiocarcinoma. Additional fusions, including TPM3-ROS1, SDC4-ROS1, EZR-ROS1, and LRIG3-ROS1, have been reported in tumor samples from lung cancer patients. Summary of the Invention

[0007] In one aspect, the present disclosure provides various crystalline forms of Compound A free base.

[0008] In one embodiment, the present disclosure provides Crystalline Form I of Compound A (Compound A Crystalline Form I).

[0009] In one embodiment, the present disclosure provides Crystalline Form II of Compound A (Compound A Crystalline Form II).

[0010] In one embodiment, the present disclosure provides Crystalline Form III of Compound A (Compound A Crystalline Form III).

[0011] In one embodiment, the present disclosure provides crystalline Form IV of Compound A (Compound A Crystalline Form IV).

[0012] In one embodiment, the present disclosure provides Crystalline Form V of Compound A (Compound A Crystalline Form V).

[0013] In one embodiment, the present disclosure provides Crystalline Form VI of Compound A (Compound A Crystalline Form VI).

[0014] In one embodiment, the present disclosure provides Crystalline Form VII of Compound A (Compound A Crystalline Form VII).

[0015] In another aspect, the present disclosure provides various crystalline forms of salts of Compound A.

[0016] In one embodiment, the present disclosure provides crystalline Form I of Compound A maleate (Compound A maleate crystalline Form I).

[0017] In one embodiment, the present disclosure provides Crystalline Form I of Compound A acetate (Compound A acetate Crystalline Form I).

[0018] In one embodiment, the present disclosure provides Crystalline Form I of Compound A p-toluenesulfonate (Compound A p-toluenesulfonate Crystalline Form I).

[0019] In one embodiment, the present disclosure provides Compound A oxalate Crystalline Form I (Compound A oxalate Crystalline Form I).

[0020] In one embodiment, the present disclosure provides crystalline Form I of Compound A sulfate (Compound A sulfate crystalline Form I).

[0021] In one embodiment, the present disclosure provides Crystalline Form I of Compound A hydrobromide (Compound A hydrobromide Crystalline Form I).

[0022] In one embodiment, the present disclosure provides Crystalline Form I of Compound A hydrochloride (Compound A Hydrochloride Crystalline Form I).

[0023] In one embodiment, the present disclosure provides Crystalline Form I of Compound A mesylate (Compound A mesylate Crystalline Form I).

[0024] In another aspect, the present disclosure provides a pharmaceutical composition comprising any of the crystalline forms of the present disclosure and a pharmaceutically acceptable excipient.

[0025] In another aspect, the present disclosure provides a pharmaceutical composition comprising: (i) a crystalline form of the free base of Compound A or a crystalline form of a pharmaceutically acceptable salt thereof; (ii) a diluent; (iii) a disintegrant; (iv) a binder; and (v) a lubricant.

[0026] In another aspect, the present disclosure provides the use of any of the crystalline forms of the present disclosure in the manufacture of a medicament for the treatment and / or prevention of diseases mediated by ALK and ROS1 kinases and their mutants.

[0027] In another aspect, the present disclosure provides any of the crystalline forms of the present disclosure for use in treating and / or preventing diseases mediated by ALK and ROS1 kinases and their mutants.

[0028] In another aspect, the present disclosure provides a method of treating and / or preventing a disease mediated by ALK and ROS1 kinases and their mutants in a subject, comprising administering to the subject any of the crystalline forms of the present disclosure.

[0029] In one embodiment, the disease comprises a cell proliferative disease, inflammation, infection, immune disease, organ transplant, viral disease, cardiovascular disease or metabolic disease, such as non-small cell lung cancer, lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer, osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer, colorectal cancer, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, or cystic fibrosis. [Brief explanation of the drawings]

[0030] [Figure 1] XRPD pattern of Compound A Crystalline Form I. [Figure 2] DSC curve of Compound A Crystalline Form I. [Figure 3] TGA curve of Compound A Crystalline Form I. [Figure 4] DVS curve of Compound A Crystalline Form I. [Figure 5] XRPD comparison of Compound A Crystalline Form I before and after DVS testing. [Figure 6] 1H NMR spectrum of Compound A Crystalline Form I. [Figure 7] 13C NMR spectrum of Compound A Crystalline Form I. [Figure 8] DEPT spectrum of Compound A Crystalline Form I. [Figure 9] D NMR spectrum of Compound A Crystalline Form I. [Figure 10] 19F NMR spectrum of Compound A Crystalline Form I. [Figure 11] HSQC-NMR spectrum of Compound A Crystalline Form I. [Figure 12] HMBC-NMR spectrum of Compound A Crystalline Form I. [Figure 13] COSY-NMR spectrum of Compound A Crystalline Form I. [Figure 14] IR spectrum of Compound A Crystalline Form I. [Figure 15] UV spectrum of Compound A Crystalline Form I. [Figure 16]HR-MS spectrum of Compound A Crystalline Form I. [Figure 17] XRPD pattern of Compound A Crystalline Form II. [Figure 18] XRPD pattern of Compound A Crystalline Form III. [Figure 19] XRPD pattern of Compound A Crystalline Form IV. [Figure 20] XRPD pattern of Compound A Crystalline Form V. [Figure 21] XRPD pattern of Compound A Crystalline Form VI. [Figure 22] XRPD pattern of Compound A Crystalline Form VII. [Figure 23] XRPD pattern of the solid obtained by slurrying the free base of Compound A at room temperature. [Figure 24] XRPD pattern of Compound A Crystalline Form V heated to 190°C. [Figure 25] XRPD pattern of Compound A maleate crystalline Form I. [Figure 26] DVS curve of Compound A maleate crystalline form I. [Figure 27] XRPD comparison of Compound A maleate crystalline Form I before and after DVS testing. [Figure 28] XRPD pattern of Compound A acetate crystalline Form I. [Figure 29] DVS curve of Compound A acetate crystalline form I. [Figure 30] XRPD comparison of Compound A acetate crystalline Form I before and after DVS testing. [Figure 31] XRPD pattern of Compound A p-toluenesulfonate crystalline Form I. [Figure 32] DVS curve of Compound A p-toluenesulfonate crystalline form I. [Figure 33] XRPD comparison of Compound A p-toluenesulfonate crystalline Form I before and after DVS testing. [Figure 34] XRPD pattern of Compound A oxalate crystalline Form I. [Figure 35] XRPD pattern of Compound A sulfate crystalline Form I. [Figure 36] XRPD pattern of Compound A hydrobromide crystalline Form I. [Figure 37] XRPD pattern of Compound A hydrochloride crystalline Form I. [Figure 38] DVS curve of Compound A hydrochloride crystalline Form I. [Figure 39] XRPD comparison of Compound A hydrochloride crystalline Form I before and after DVS testing. [Figure 40] XRPD pattern of Compound A mesylate crystalline Form I. [Figure 41] XRPD pattern of accelerated stability study of Compound A crystalline Form I. [Figure 42] XRPD pattern of accelerated stability study of Compound A maleate crystalline Form I. [Figure 43] XRPD pattern of accelerated stability study of Compound A acetate crystalline Form I. [Figure 44] XRPD pattern of Compound A p-toluenesulfonate crystalline Form I from an accelerated stability study. [Figure 45] XRPD patterns of Compound A crystalline Form I in different dissolution media. [Figure 46] XRPD patterns of Compound A maleate crystalline Form I in different dissolution media. [Figure 47] XRPD patterns of Compound A acetate crystalline Form I in different dissolution media. [Figure 48] Single crystal structure of Compound A Crystalline Form I. [Figure 49] XRPD comparison of calculated and measured values ​​for a single crystal sample of Compound A. DETAILED DESCRIPTION OF THE INVENTION

[0031] The present disclosure can be more easily understood by referring to the following detailed description of the embodiments of the present disclosure and the examples contained herein. It should be understood that the terms used herein are intended only to describe specific embodiments and are not intended to be limiting. It should be further understood that unless otherwise defined by context, the terms used herein shall be given their ordinary meaning as known in the relevant technical field.

[0032] As used herein, the singular forms "a," "an," and "the" include plural references unless expressly stated otherwise. For example, the term "a" compound includes one or more compounds.

[0033] The term "about" means having a value that falls within an acceptable standard error of the mean when considered by one of ordinary skill in the art. For example, "about" means ±10% of the stated amount or ±5% of the stated amount.

[0034] As used herein, the term "substantially" means taking into account the typical variability of a particular method and the standard error of measurement. For example, with respect to the position of X-ray powder diffraction peaks, the term "substantially" means taking into account the typical variability of peak position and intensity. Those skilled in the art will recognize that peak positions (2θ) will exhibit some variability, typically up to ±0.2°. In addition, those skilled in the art will recognize that relative peak intensities will exhibit variability between devices and variability due to crystallinity, preferred orientation, the sample surface being tested, and other factors known to those skilled in the art. Similarly, 1 H, 13 C and 19 F NMR spectra (ppm) show variability, typically up to ±0.2 ppm.

[0035] As used herein, the terms "crystalline" and "crystalline form" refer to a solid composed of molecules in a regular repeating arrangement. Crystalline forms may differ with respect to thermodynamic stability, physical parameters, X-ray structure, and preparation process.

[0036] The term "amorphous" refers to a solid consisting of molecules with a disordered arrangement.

[0037] As used herein, the term "solvate" refers to a crystalline form having a stoichiometric or non-stoichiometric amount of a solvent (e.g., water, methanol, ethyl acetate, etc., or mixtures thereof) in the crystal lattice through non-covalent intermolecular bonds. The term "hydrate" refers to a solvate in which the solvent is water.

[0038] As used herein, the term "anhydrous" refers to a crystalline form containing less than about 1% (w / w) adsorbed water as determined by standard methods such as Karl Fischer analysis.

[0039] Compound A and its crystals The compound (10R)-7-amino-12-fluoro-2-(methyl-d3)-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile, referred to herein as Compound A or Compound A free base, has the formula:

[0040] [ka] (A) It has.

[0041] The present disclosure relates to various crystalline forms of Compound A, including "Compound A Crystalline Form I," "Compound A Crystalline Form II," "Compound A Crystalline Form III," "Compound A Crystalline Form IV," "Compound A Crystalline Form V," "Compound A Crystalline Form VI," and "Compound A Crystalline Form VII." In some embodiments, these crystalline forms of Compound A may be solvated, hydrated, or unsolvated.

[0042] Compound A Crystalline Form I In one embodiment, the present disclosure provides Compound A Crystalline Form I, which is anhydrous.

[0043] In another embodiment, CuK α An X-ray powder diffraction pattern of Crystalline Form I obtained using a 2000 NMR spectroscopy (NMR spectroscopy) system contains at least the following characteristic peaks located at °2θ: 16.175±0.2, 17.299±0.2, and 21.218±0.2. In another embodiment, the X-ray powder diffraction pattern further contains the following characteristic peaks located at °2θ: 9.637±0.2, 12.555±0.2, 14.343±0.2, and 19.366±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks located at the following degrees 2θ: 7.435±0.2, 10.11±0.2, 11.808±0.2, 14.922±0.2, 18.359±0.2, 19.859±0.2, 23.401±0.2, 23.939±0.2, 25.117±0.2, 25.727±0.2, 26.831±0.2, and 28.862±0.2.

[0044] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0045] [Table 1] It has.

[0046] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 3.1. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0047] In another embodiment, Form I has a melting endotherm peak at 232±2° C. in differential scanning calorimetry analysis.

[0048] In another embodiment, Crystalline Form I has substantially no weight loss before 150° C. in thermogravimetric analysis.

[0049] In another embodiment, Crystalline Form I has the following single crystal parameters:

[0050] [Table 2] It has.

[0051] In another embodiment, crystalline form I has the following cm -1 14. In another embodiment, Form I has an infrared absorption spectrum having absorption peaks at: 829±2, 878±2, 1069±2, 1252±2, 1344±2, 1368±2, 1395±2, 1420±2, 1433±2, 1491±2, 1499±2, 1616±2, 1645±2, 2228±2, 2934±2, 2980±2, 3111±2, 3184±2, 3308±2, 3383±2, and 3474±2. In another embodiment, Form I has an infrared absorption spectrum substantially as shown in FIG.

[0052] In another embodiment, Crystalline Form I has absorption peaks in the UV spectrum at the following nm: 206±2 and 317±2. In another embodiment, Crystalline Form I has a UV spectrum substantially as shown in FIG.

[0053] In one embodiment, the present disclosure provides Compound A Crystalline Form II, which is a solvate of butanone.

[0054] In another embodiment, CuK α An X-ray powder diffraction pattern of Crystalline Form II obtained using a 2000 NMR spectroscopy (NMR spectroscopy) system comprises at least the following characteristic peaks at °2θ: 7.591±0.2, 12.081±0.2, and 23.364±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks at °2θ: 14.577±0.2, 15.595±0.2, 16.948±0.2, 17.615±0.2, and 20.448±0.2.

[0055] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0056] [Table 3] It has.

[0057] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 3.2. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0058] In another embodiment, Form I has a melting endotherm peak at 230±2° C. in differential scanning calorimetry analysis.

[0059] In another embodiment, Crystalline Form I has a weight loss of about 6.69% before 160° C. in thermogravimetric analysis.

[0060] In one embodiment, the present disclosure provides Compound A Crystalline Form III, which is a solvate of butanone.

[0061] In another embodiment, CuK α The X-ray powder diffraction pattern of Crystalline Form III obtained using a 2000 NMR spectroscopy (NMR spectroscopy) system comprises at least the following characteristic peaks located at °2θ: 23.149±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks located at °2θ: 11.429±0.2, 13.027±0.2, 14.542±0.2, 17.949±0.2, and 26.994±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks located at °2θ: 10.543±0.2, 15.353±0.2, 18.362±0.2, 21.161±0.2, 22.506±0.2, and 26.006±0.2.

[0062] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0063] [Table 4] It has.

[0064] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 3.3. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0065] In another embodiment, Form III has a melting endotherm peak at 226±2° C. in differential scanning calorimetry analysis.

[0066] In another embodiment, Form III has a weight loss of about 5.31% before 165°C in thermogravimetric analysis.

[0067] In one embodiment, the present disclosure provides Compound A Crystalline Form IV, which is anhydrous.

[0068] In another embodiment, CuK α The X-ray powder diffraction pattern of Crystalline Form IV obtained using a 2000 NMR spectroscopy (NMR spectroscopy) system comprises at least the following characteristic peaks located at °2θ: 10.113±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks located at °2θ: 11.583±0.2, 11.768±0.2, 12.098±0.2, 17.143±0.2, and 19.267±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks located at °2θ: 9.718±0.2, 12.439±0.2, 13.339±0.2, 17.649±0.2, 20.703±0.2, 21.809±0.2, 22.427±0.2, 25.081±0.2, 27.576±0.2, and 28.959±0.2.

[0069] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0070] [Table 5] It has.

[0071] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 3.4. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0072] In another embodiment, Form IV has a melting endotherm peak at 232±2° C. in differential scanning calorimetry analysis.

[0073] In another embodiment, Form IV has a weight loss of about 0.28% before 200° C. in thermogravimetric analysis.

[0074] In one embodiment, the present disclosure provides Compound A Crystalline Form V, which is anhydrous.

[0075] In another embodiment, CuK α An X-ray powder diffraction pattern of Crystalline Form V obtained using a 2000 NMR spectroscopy (NMR spectroscopy) system comprises at least the following characteristic peaks at °2θ: 6.939±0.2, 16.276±0.2, and 17.494±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks at °2θ: 4.912±0.2, 9.774±0.2, 12.709±0.2, 14.246±0.2, 14.482±0.2, 17.242±0.2, 18.519±0.2, 19.425±0.2, 21.001±0.2, 21.317±0.2, 22.734±0.2, 25.218±0.2, and 29.688±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks located at the following degrees 2θ: 10.326±0.2, 10.859±0.2, 15.289±0.2, 16.708±0.2, 19.941±0.2, 23.09±0.2, 23.424±0.2, 24.25±0.2, 25.808±0.2, 26.241±0.2, 26.987±0.2, 28.841±0.2, 29.332±0.2, 31.071±0.2, and 31.856±0.2.

[0076] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0077] [Table 6] It has.

[0078] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 3.5. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0079] In another embodiment, Form V has a melting endotherm peak at 232±2° C. in differential scanning calorimetry analysis.

[0080] In another embodiment, Crystalline Form V has a weight loss of about 0.22% before 200° C. in thermogravimetric analysis.

[0081] In one embodiment, the present disclosure provides Compound A Crystalline Form VI, which is anhydrous.

[0082] In another embodiment, CuK α The X-ray powder diffraction pattern of Crystalline Form VI obtained using a 2000 NMR spectroscopy (NMR spectroscopy) system comprises at least the following characteristic peaks at °2θ: 10.247±0.2, 12.198±0.2, and 17.258±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks at °2θ: 12.514±0.2, 17.596±0.2, 19.406±0.2, 21.888±0.2, and 27.599±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks at °2θ: 18.659±0.2, 22.479±0.2, 23.799±0.2, 24.41±0.2, 25.158±0.2, and 28.504±0.2.

[0083] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0084] [Table 7] It has.

[0085] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 3.6. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0086] In another embodiment, Form VI has a melting endotherm peak at 233±2° C. in differential scanning calorimetry analysis.

[0087] In another embodiment, Form VI has substantially no weight loss before 200° C. in thermogravimetric analysis.

[0088] In one embodiment, the present disclosure provides Compound A Crystalline Form VII, which is a solvate.

[0089] In another embodiment, CuK α The X-ray powder diffraction pattern of Crystalline Form VII obtained using a 2000 NMR spectroscopy (NMR spectroscopy) system contains at least the following characteristic peaks located at °2θ: 7.138±0.2 and 9.876±0.2. In another embodiment, the X-ray powder diffraction pattern further contains the following characteristic peaks located at °2θ: 12.572±0.2, 12.945±0.2, 14.675±0.2, and 17.16±0.2.

[0090] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0091] [Table 8] It has.

[0092] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 3.7. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0093] In another embodiment, Form VII has a melting endotherm peak at 232±2° C. in differential scanning calorimetry analysis.

[0094] In another embodiment, Form VII has a weight loss of about 0.35% before 200° C. in thermogravimetric analysis.

[0095] Salts of compound A and their crystals The present disclosure relates to various salts of Compound A, such as maleate, acetate, p-toluenesulfonate, hydrobromide, sulfate, oxalate, hydrochloride, and mesylate salts.

[0096] The present disclosure also relates to crystalline forms of various salts of Compound A, such as "Compound A Maleate Crystalline Form I," "Compound A Acetate Crystalline Form I," "Compound A p-Toluenesulfonate Crystalline Form I," "Compound A Hydrobromide Crystalline Form I," "Compound A Sulfate Crystalline Form I," "Compound A Oxalate Crystalline Form I," "Compound A Hydrochloride Crystalline Form I," and "Compound A Mesylate Crystalline Form I."

[0097] Compound A maleate crystalline form I In one embodiment, the present disclosure provides Compound A maleate (1:1) crystalline Form I, which is anhydrous.

[0098] In another embodiment, CuK αAn X-ray powder diffraction pattern of the crystalline form obtained using radiation comprises at least the following characteristic peaks at °2θ: 9.737±0.2, 12.241±0.2, and 23.08±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks at °2θ: 11.982±0.2, 13.601±0.2, 16.495±0.2, 17.186±0.2, 19.625±0.2, and 24.527±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks located at the following degrees 2θ: 7.577±0.2, 15.286±0.2, 17.358±0.2, 17.553±0.2, 19.971±0.2, 22.087±0.2, 23.879±0.2, 25.239±0.2, 25.844±0.2, 26.189±0.2, 29.644±0.2, and 31.501±0.2.

[0099] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0100] [Table 9] It has.

[0101] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 7.1. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0102] In another embodiment, the crystalline form has a melting endotherm peak at 209±2° C. in differential scanning calorimetry analysis.

[0103] In another embodiment, the crystalline body has a weight loss of about 0.44% before 175°C in thermogravimetric analysis.

[0104] Compound A acetate (1:1) crystalline form I In one embodiment, the present disclosure provides Compound A acetate (1:1) crystalline Form I, which is anhydrous.

[0105] In another embodiment, CuK α An X-ray powder diffraction pattern of the crystalline form obtained using a 2000 NMR spectroscopy (NMR spectroscopy) system comprises at least the following characteristic peaks at °2θ: 12.866±0.2 and 23.129±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks at °2θ: 10.521±0.2, 11.409±0.2, 13.005±0.2, 14.521±0.2, 17.91±0.2, and 21.14±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks at °2θ: 15.349±0.2, 16.707±0.2, 17.236±0.2, 18.343±0.2, 19.961±0.2, 22.536±0.2, 25.985±0.2, and 26.993±0.2.

[0106] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0107] [Table 10] It has.

[0108] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 7.2. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0109] In another embodiment, the crystalline form has a melting endotherm peak at 232±2° C. in differential scanning calorimetry analysis.

[0110] In another embodiment, the crystalline body has a weight loss of about 0.67% before 140°C in thermogravimetric analysis.

[0111] Compound A p-toluenesulfonate (1:1) Crystalline Form I In one embodiment, the present disclosure provides Compound A p-toluenesulfonate (1:1) Crystalline Form I, which is an anhydrous form.

[0112] In another embodiment, CuK α An X-ray powder diffraction pattern of the crystalline form obtained using a 2000 NMR spectroscopy (NMR spectroscopy) system comprises at least the following characteristic peaks located at °2θ: 10.583±0.2 and 21.674±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks located at °2θ: 12.968±0.2 and 14.503±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks located at °2θ: 5.544±0.2, 14.012±0.2, 16.886±0.2, 18.417±0.2, 19.607±0.2, 21.298±0.2, 23.266±0.2, and 26.437±0.2.

[0113] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0114] [Table 11] It has.

[0115] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 7.3. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0116] In another embodiment, the crystalline form has a melting endotherm peak at 269±2° C. in differential scanning calorimetry analysis.

[0117] In another embodiment, the crystalline body has a weight loss of about 0.6% before 220°C in thermogravimetric analysis.

[0118] Compound A oxalate (1:1) Crystalline Form I In one embodiment, the present disclosure provides Compound A oxalate (1:1) Crystalline Form I, which is a solvate.

[0119] In another embodiment, CuK αAn X-ray powder diffraction pattern of the crystalline form obtained using radiation comprises at least the following characteristic peaks located at °2θ: 4.32±0.2 and 6.642±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks located at °2θ: 5.54±0.2, 10.366±0.2, 10.98±0.2, and 13.242±0.2.

[0120] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0121] [Table 12] It has.

[0122] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​of Table 7.4. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0123] In another embodiment, the crystalline form has a melting endotherm peak at 209±2° C. in differential scanning calorimetry analysis.

[0124] In another embodiment, the crystalline body has a weight loss of about 0.86% before 130° C. in thermogravimetric analysis.

[0125] Compound A sulfate crystalline form I In one embodiment, the present disclosure provides Compound A sulfate salt crystalline Form I, which is a monohydrate.

[0126] In another embodiment, CuK αAn X-ray powder diffraction pattern of the crystalline form obtained using radiation comprises at least the following characteristic peaks located at °2θ: 15.763±0.2 and 23.266±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks located at the following °2θ: 11.604±0.2, 13.318±0.2, 14.74±0.2, 15.961±0.2, 18.385±0.2, 19.228±0.2, 21.413±0.2, 22.361±0.2, 23.936±0.2, and 24.958±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks located at the following degrees 2θ: 11.78±0.2, 12.667±0.2, 19.447±0.2, 22.083±0.2, 22.576±0.2, 23.618±0.2, 27.303±0.2, 27.522±0.2, 28.765±0.2, 29.725±0.2, 30.906±0.2, and 32.032±0.2.

[0127] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0128] [Table 13] It has.

[0129] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 7.5. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 35.

[0130] In another embodiment, the crystalline form has a melting endotherm peak at 251±2° C. in differential scanning calorimetry analysis.

[0131] In another embodiment, the crystalline body has a weight loss of about 2.95% before 90° C. in thermogravimetric analysis.

[0132] Compound A Hydrobromide Crystalline Form I In one embodiment, the present disclosure provides Compound A hydrobromide Crystalline Form I, which is a monohydrate.

[0133] In another embodiment, CuK α An X-ray powder diffraction pattern of the crystalline form obtained using radiation comprises at least the following characteristic peaks at °2θ: 13.206±0.2, 23.995±0.2, and 24.941±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks at °2θ: 9.222±0.2, 11.905±0.2, 19.937±0.2, 26.773±0.2, and 27.5±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks located at the following degrees 2θ: 12.652±0.2, 14.702±0.2, 16.396±0.2, 16.924±0.2, 18.636±0.2, 19.148±0.2, 20.294±0.2, 21.102±0.2, 21.532±0.2, 25.492±0.2, and 33.154±0.2.

[0134] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0135] [Table 14] It has.

[0136] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​in Table 7.6. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0137] In another embodiment, the crystalline form has a melting endotherm peak at 241±2° C. in differential scanning calorimetry analysis.

[0138] In another embodiment, the crystalline body has a weight loss of about 8.18% before 150°C in thermogravimetric analysis.

[0139] Compound A Hydrochloride Crystalline Form I In one embodiment, the present disclosure provides Compound A hydrochloride crystalline Form I, which is a solvate.

[0140] In another embodiment, CuK α An X-ray powder diffraction pattern of the crystalline form obtained using radiation comprises at least the following characteristic peaks at °2θ: 12.079±0.2, 13.319±0.2, and 24.093±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks at °2θ: 9.38±0.2, 12.749±0.2, 24.92±0.2, and 27.559±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks located at the following degrees 2θ: 6.699±0.2, 7.944±0.2, 8.28±0.2, 14.111±0.2, 14.758±0.2, 17.103±0.2, 18.618±0.2, 19.996±0.2, 20.449±0.2, 21.83±0.2, 25.118±0.2, 26.613±0.2, and 27.006±0.2.

[0141] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0142] [Table 15] It has.

[0143] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​of Table 7.7. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 37.

[0144] In another embodiment, the crystalline form has a melting endotherm peak at 221±2° C. in differential scanning calorimetry analysis.

[0145] In another embodiment, the crystalline body has a weight loss of about 1.67% before 125°C and a weight loss of about 3.84% between 125°C and 230°C in thermogravimetric analysis.

[0146] Compound A mesylate (1:1) crystalline form I In one embodiment, the present disclosure provides Compound A mesylate (1:1) crystalline Form I.

[0147] In another embodiment, CuK α An X-ray powder diffraction pattern of the crystalline form obtained using radiation comprises at least the following characteristic peaks located at °2θ: 8.338±0.2: In another embodiment, the X-ray powder diffraction pattern further comprises the following characteristic peaks located at °2θ: 11.706±0.2, 13.932±0.2, 14.738±0.2, 18.341±0.2, 21.148±0.2, 21.588±0.2, 22.597±0.2, and 25.732±0.2. In another embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks located at the following degrees 2θ: 9.363±0.2, 10.092±0.2, 12.513±0.2, 15.053±0.2, 15.742±0.2, 19.093±0.2, 23.17±0.2, 23.716±0.2, 24.469±0.2, 24.65±0.2, 24.824±0.2, 30.238±0.2, and 32.189±0.2.

[0148] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0149] [Table 16] It has.

[0150] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values ​​of Table 7.8. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 40.

[0151] Substantially pure crystalline form of compound A The present disclosure provides a method for synthesizing crystalline Compound A of high purity and high chiral purity that is safe and suitable for large-scale production and can be used in compositions containing crystalline Compound A. On the one hand, the crystalline Compound A is produced by a commercial-scale process. The term "commercial-scale process" refers to a process that operates on a single batch of at least about 100 g. On the other hand, the method of the present application produces crystalline Compound A with limited impurities in improved yield (>90%).

[0152] The term "purity," as used herein, refers to the percentage of crystalline Compound A content based on HPLC. Purity is based on the "organic" purity of the compound. Purity is not related to water, solvents, metals, inorganic salts, etc. The purity of the crystalline Compound A is compared to the purity of a reference standard by comparing the areas under the peaks.

[0153] In one embodiment, the crystalline form of Compound A has a purity of about 96% or greater. In another embodiment, the crystalline form of Compound A has a purity of about 98% or greater. In yet another embodiment, the crystalline form of Compound A has a purity of about 98.5% or greater. In yet another embodiment, the crystalline form of Compound A has a purity of about 99% or greater. In yet another embodiment, the crystalline form of Compound A has a purity of about 99.5% or greater. In yet another embodiment, the crystalline form of Compound A has a purity of 96.0%, 96.1%, 96.2%, 96.3%, 96.4%, 96.5%, 96.6%, 96.7%, 96.8%, 96.9%, 97.0%, 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, having a purity of 97.9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.

[0154] The crystalline form of Compound A prepared in this disclosure contains a chiral carbon atom in the R configuration. The chiral center of the crystalline form of Compound A is introduced from the starting material and is not involved in subsequent steps. Racemization is not observed.

[0155] The term "chiral purity," as used herein, refers to the chiral purity of a crystalline form of Compound A as determined by chiral HPLC. Chiral purity is based on the "organic" purity of the compound. Chiral purity is not related to water, solvents, metals, inorganic salts, etc. The chiral purity of a crystalline form of Compound A is compared to the chiral purity of a reference standard by comparing the areas under the peaks.

[0156] In one embodiment, the crystalline form of Compound A has a chiral purity of about 96% or greater. In another embodiment, the crystalline form of Compound A has a chiral purity of about 98% or greater. In yet another embodiment, the crystalline form of Compound A has a chiral purity of about 99% or greater. In yet another embodiment, the crystalline form of Compound A has a chiral purity of about 99.4% or greater. In another embodiment, the crystalline form of Compound A has a chiral purity of 96.0%, 96.1%, 96.2%, 96.3%, 96.4%, 96.5%, 96.6%, 96.7%, 96.8%, 96.9%, 97.0%, 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 97.10%, 97.11%, 97.12%, 97.13%, 97.14%, 97.15%, 97.16%, 97.17%, 97.18%, 97.19 ... having a chiral purity of 9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.

[0157] In one embodiment, the present disclosure relates to a crystalline form of Compound A containing less than about 0.8% total impurities. In another embodiment, the total impurities are less than about 0.5%. In yet another embodiment, the total impurities are less than about 0.3%. In yet another embodiment, the total impurities are less than about 0.2%.

[0158] In one embodiment, the present disclosure relates to a crystalline form of Compound A containing about 1% or less water, about 0.8% or less water, about 0.7% or less water, about 0.6% or less water, about 0.5% or less water, about 0.4% or less water, about 0.3% or less water, about 0.2% or less water, about 0.1% or less water, about 0.09% or less water, about 0.08% or less water, about 0.07% or less water, about 0.06% or less water, or about 0.05% or less water. In another embodiment, the present disclosure relates to a crystalline form of Compound A containing about 0.11% or less water. In yet another embodiment, the present disclosure relates to a crystalline form of Compound A containing about 0.1% or less water. In yet another embodiment, the present disclosure relates to a crystalline form of Compound A containing about 0.09% or less water.

[0159] Pharmaceutical Composition In another aspect, the present disclosure provides a pharmaceutical composition comprising: (i) a crystalline form of a pharmaceutically active ingredient: Compound A free base or a pharmaceutically acceptable salt thereof; (ii) a diluent; (iii) a disintegrant; (iv) a binder; and (v) a lubricant.

[0160] In certain embodiments of the above aspects, the pharmaceutically active ingredient is a crystalline form of the free base of Compound A, alternatively the crystalline form is selected from Compound A Crystalline Form I, Compound A Crystalline Form II, Compound A Crystalline Form III, Compound A Crystalline Form IV, Compound A Crystalline Form V, Compound A Crystalline Form VI and Compound A Crystalline Form VII, alternatively the crystalline form is Compound A Crystalline Form I. In another particular embodiment, the pharmaceutically active ingredient is selected from Compound A maleate Crystalline Form I, Compound A acetate Crystalline Form I, Compound A p-toluenesulfonate Crystalline Form I, Compound A hydrobromide Crystalline Form I, Compound A sulfate Crystalline Form I, Compound A oxalate Crystalline Form I, Compound A hydrochloride Crystalline Form I and Compound A mesylate Crystalline Form I, alternatively the crystalline form is selected from Compound A maleate Crystalline Form I and Compound A acetate Crystalline Form I.

[0161] In another aspect, the disclosure provides the aforementioned pharmaceutical composition, wherein the crystalline form comprises 1-30% by weight, alternatively 2-20% by weight, alternatively 3-15% by weight, and further alternatively about 4%, 5%, 6%, 7%, 8%, 9% or 10% by weight of the total weight of the pharmaceutical composition, based on the weight of the free base of the compound; and alternatively, the amount of crystalline form in a unit dose is 1-100 mg, alternatively 2-50 mg, alternatively 3-40 mg, or alternatively about 5, 10, 15, 20, 25, 30, 35 or 40 mg.

[0162] In another aspect, the disclosure provides the aforementioned pharmaceutical composition, wherein the diluent comprises 65-95% by weight, alternatively 70-90% by weight, alternatively about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90% by weight of the total weight of the pharmaceutical composition; and alternatively, the amount of diluent in a unit dose is 50-380 mg, alternatively 60-360 mg, alternatively 70-350 mg, e.g., about 70 mg or 350 mg.

[0163] In another aspect, the disclosure provides the aforementioned pharmaceutical composition, wherein the diluent is selected from the group consisting of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and mannitol, e.g., microcrystalline cellulose 102, mannitol 100SD, and mannitol 50C, and mixtures thereof; alternatively, when both microcrystalline cellulose 102 and mannitol 50C are present, the weight ratio of microcrystalline cellulose 102 to mannitol 50C is 5:1 to 1:5, alternatively 3:1 to 1:2, or alternatively about 2:1.

[0164] In another aspect, the present disclosure provides the aforementioned pharmaceutical composition, wherein the disintegrant comprises 1-5% by weight, alternatively 2-4% by weight, alternatively about 2%, 2.5%, 3%, 3.5% or 4% by weight of the total weight of the pharmaceutical composition; and alternatively, the amount of disintegrant in a unit dose is 1-20 mg, alternatively 2-16 mg, alternatively about 2, 2.5, 3, 6, 9 or 12 mg.

[0165] In another aspect, the present disclosure provides the aforementioned pharmaceutical composition, wherein the disintegrant is croscarmellose sodium or crospovidone XL-10, alternatively croscarmellose sodium.

[0166] In another aspect, the disclosure provides the aforementioned pharmaceutical composition, wherein the binder comprises 1-5% by weight, alternatively 2-4% by weight, alternatively about 2%, 2.5%, 3%, 3.5% or 4% by weight of the total weight of the pharmaceutical composition; and alternatively, the amount of binder in a unit dose is 1-20 mg, alternatively 2-16 mg, alternatively about 2, 2.5, 3, 6, 9 or 12 mg.

[0167] In another aspect, the present disclosure provides the above pharmaceutical composition, wherein the binder is hydroxypropyl cellulose EXF or povidone K30, alternatively hydroxypropyl cellulose EXF.

[0168] In another aspect, the disclosure provides the aforementioned pharmaceutical composition, wherein the lubricant comprises 0.1 to 5% by weight, alternatively 0.5 to 2% by weight, alternatively about 1% by weight of the total weight of the pharmaceutical composition; and alternatively, the amount of lubricant in a unit dose is 0.1 to 20 mg, alternatively 0.5 to 8 mg, alternatively about 0.5, 1, 2, 3, 4, 5, 6, 7, or 8 mg.

[0169] In another aspect, the present disclosure provides the above pharmaceutical composition, wherein the lubricant is magnesium stearate or sodium stearyl fumarate PRUV, alternatively magnesium stearate.

[0170] In another aspect, the present disclosure provides a method for producing a composition comprising the following components: (i) 1 to 30 wt % of Compound A Crystalline Form I, (ii) 65-95 wt. % microcrystalline cellulose 102 and mannitol 50C (2:1 by weight); (iii) 2 to 4% by weight of croscarmellose sodium; (iv) 2 to 4% by weight of hydroxypropyl cellulose EXF, and (v) 0.1 to 5% by weight of magnesium stearate The pharmaceutical composition as described above is provided, which comprises:

[0171] In another aspect, the present disclosure provides a method for treating a rheumatoid arthritis, comprising administering to a subject a rheumatoid arthritis, ... (i) approximately 5 mg of Compound A Crystalline Form I; (ii) about 45 mg microcrystalline cellulose 102 and about 25 mg mannitol 50C; (iii) about 2.5 mg of croscarmellose sodium; (iv) about 2.5 mg of hydroxypropyl cellulose EXF, and (v) approximately 1 mg of magnesium stearate The pharmaceutical composition as described above is provided, comprising:

[0172] In another aspect, the present disclosure provides a method for treating a rheumatoid arthritis, comprising administering to a subject a rheumatoid arthritis, ... (i) approximately 25 mg of Compound A Crystalline Form VI; (ii) about 230 mg lactose monohydrate and about 120 mg microcrystalline cellulose; (iii) about 12 mg of croscarmellose sodium; (iv) about 12 mg of hydroxypropyl cellulose EXF, and (v) approximately 4 mg of magnesium stearate The pharmaceutical composition as described above is provided, comprising:

[0173] In another aspect, the present disclosure provides the above pharmaceutical composition which is a tablet, alternatively a coated tablet, alternatively wherein the coating is Opadry II 85F620077.

[0174] Pharmacology and efficacy In another aspect, the present disclosure provides a method of treating abnormal cell growth in a subject, comprising administering to the subject an effective amount of Compound A free base, or a pharmaceutically acceptable salt thereof, and various crystalline forms thereof.

[0175] In one embodiment, the abnormal cell growth is cancer. In another embodiment, the abnormal cell growth is cancer mediated by anaplastic lymphoma kinase (ALK). In another embodiment, the abnormal cell growth is a genetically altered ALK kinase. In another embodiment, the mutation is L1196M. In another embodiment, the mutation is G1202R. In another embodiment, the mutation is L1196M / G1202R.

[0176] In another embodiment, the abnormal cell growth is cancer mediated by ROS1 kinase. In another embodiment, the ROS1 kinase is a genetically altered ROS1 kinase. In another embodiment, the mutation is G2032R.

[0177] In another embodiment, the abnormal cell growth is a cancer selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) cancer, primary central nervous system lymphoma, spinal cord axial cancer, brain stem glioma, pituitary adenoma, or a combination thereof.

[0178] In another embodiment, the abnormal cell growth is NSCLC. In another embodiment, the NSCLC is mediated by ALK and / or ROS1. In another embodiment, the NSCLC is NSCLC mediated by genetically altered ALK and / or genetically altered ROS1. [Example]

[0179] Abbreviation SGF: Simulated gastric fluid FaSSIF: Fasted-state simulated intestinal fluid FeSSIF: Simulated intestinal fluid in the fed state HBr: Hydrobromic acid HCl: Hydrochloric acid H2SO4: sulfuric acid PTSA: p-toluenesulfonic acid CH3SO3H: Methanesulfonic acid PhSO3H: benzenesulfonic acid Oxalic acid: ethanedioic acid Maleic acid: Thoxylic acid MeOH: Methanol EtOH: ethanol IPA: Isopropyl alcohol IBA: Isobutanol MEK: Methyl ethyl ketone THF: tetrahydrofuran ACN: acetonitrile MTBE: Methyl tert-butyl ether EtOAc: ethyl acetate Acetone:Dimethyl ketone IPrOAc: Isopropyl acetate H2O: Water hr: time min:minutes μL: microliter

[0180] General Method 1. X-ray Powder Diffraction (XRPD) The solid samples obtained from the experiments were analyzed using a D8 advance powder X-ray diffractometer (Bruker) equipped with a LynxEye detector. The samples were examined using a D8 advance powder X-ray diffractometer (Bruker) with a 2θ scan angle ranging from 3° to 40°, a scan step length of 0.02°, and a scan rate of 0.3 seconds per step. The phototube voltage and phototube current were 40 kV and 40 mA, respectively.

[0181] General Method 2. Polarized Light Microscopy (PLM) The equipment model used for PLM analysis was ECLIPSE LV100POL polarized light microscope (Nikon, Japan).

[0182] General method 3. Nuclear magnetic resonance hydrogen spectroscopy ( 1 H NMR) The chemical structure of the solid sample 1 The results were confirmed by H NMR using a Bruker Advance 300 equipped with a B-ACS120 autosampling system. 1 H NMR analysis was performed.

[0183] General Method 4. Differential Scanning Calorimetry (DSC) The instrument model for differential scanning calorimetry analysis was Discovery DSC 250 (TA, USA). Approximately 2 mg of sample was weighed and placed in a DSC sample pot, which was punctured. The sample was equilibrated at 25°C and then heated to 300°C at a ramp rate of 10°C / min.

[0184] General method 5. Thermogravimetric analysis (TGA) The thermogravimetric analyzer model was Discovery TGA 55 (TA, USA). The sample was placed in an equilibrated open aluminum sample pot, and the mass was automatically weighed in the TGA heating oven. The sample was then heated to 300 °C at a ramp rate of 10 °C / min.

[0185] General Method 6. Dynamic Vapor Sorption and Desorption Analysis (DVS) Samples were tested for hygroscopicity using a DVS Intrinsic (SMS, UK). 30-50 mg of sample was placed in a sample pan and the change in sample mass with humidity at 25°C was recorded. The instrument parameters were:

[0186] [Table 17] It was.

[0187] After the hygroscopicity test was completed, the crystalline form of the sample was examined by XRPD. [Example 1]

[0188] Preparation of Compound A The following route was used for the synthesis:

[0189] [ka]

[0190] Step 1: Synthesis of compound G. Compound J (7.0 g, 42.2 mmol) and anhydrous dichloromethane (120 mL) were added to a 250 mL three-neck flask equipped with magnetic stirring, and the mixture was stirred until the solution became clear. Compound H (8.77 g, 46.4 mmol) was then added sequentially, followed by triethylamine (4.69 g, 46.4 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes, yielding a pale yellow, clear solution for further use.

[0191] Anhydrous aluminum chloride (6.17 g, 46.4 mmol) was added to another 500 mL three-neck flask equipped with magnetic stirring, and the system was evacuated and purged with nitrogen gas. Anhydrous dichloromethane (60 mL) was added under a nitrogen atmosphere, and the mixture was cooled to 0 °C in an ice-water bath. Triethylamine (6.39 g, 63.3 mmol) was added slowly dropwise. After the addition was complete, the mixture was stirred at this temperature for 10 minutes. The above solution of the raw material in dichloromethane was added slowly dropwise over 30 minutes. The mixture was allowed to react at this temperature with stirring for an additional 2 hours. The reaction was complete by TLC (PE:EA = 1:1) and HPLC monitoring. Water (200 mL) was added to quench the reaction. The organic phase was separated, and the aqueous layer was extracted with dichloromethane (100 mL × 2). The organic phases were combined and washed successively with water (100 mL) and then saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 12.66 g of a yellow oil in 94.0% yield and >90% purity (HPLC) (ee >98%). The intermediate is unstable at room temperature and should therefore be taken to the next step immediately or stored in a refrigerator at -20°C. LC-MS (APCI): m / z = 320.1 (M+1). + . 1H NMR(300 MHz, CDCl3) δ (ppm): 7.92-7.89(m, 1H), 7.27-7.17(m, 2H), 7.03-6.97(m, 1H), 6.84(s, 1H), 4.92(q, J=6.3 Hz, 1H), 4.83(s, 2H), 2.89(s, 3H), 1.50(d, J=6.3 Hz, 3H).

[0192] Step 2: Synthesis of Compound F. Compound G (12.6 g, 39.5 mmol) and anhydrous dichloromethane (120 mL) were added to a 250 mL three-neck flask equipped with magnetic stirring, and the mixture was stirred until the solution became clear. The mixture was cooled in an ice-water bath. Triethylamine (7.98 g, 79.5 mmol) was added, followed by the slow dropwise addition of methylsulfonyl chloride (5.85 g, 51.4 mmol). After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. TLC (DCM:MeOH = 20:1) indicated the reaction was complete. The reaction was quenched by adding ice-water (100 mL). The organic phase was separated, and the aqueous layer was extracted with dichloromethane (50 mL × 2). The combined organic phases were washed successively with water (50 mL) and then saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and then dissolved in anhydrous acetonitrile (50 mL) for further use.

[0193] Step 3: Synthesis of compound Da. Compound Ea (11.2 g, 59.3 mmol) and acetonitrile (200 mL) were added to a separate 250 mL three-neck flask equipped with magnetic stirring, and cesium carbonate (25.7 g, 79.0 mmol) was added with stirring. The mixture was heated to 50 °C under a nitrogen atmosphere, and the mixture was stirred at this temperature for 30 minutes. The above solution of compound F in acetonitrile was slowly added dropwise at 50 °C over 10 minutes. After the dropwise addition was completed, the mixture was reacted at this temperature with stirring for 2 hours. The reaction was complete by TLC (DCM:MeOH = 20:1) and HPLC monitoring. After cooling to room temperature, the reaction was quenched by adding water (200 mL). The reaction solution was diluted with ethyl acetate (300 mL), stirred for 5 minutes, and then filtered through Celite to remove insoluble solids. The filter cake was washed with ethyl acetate (50 mL). The organic layer was separated from the filtrate, and the aqueous phase was extracted with ethyl acetate (60 mL × 2). The organic phases were combined, washed with saturated aqueous sodium carbonate (100 mL x 3), then saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 17.5 g of a brown solid in 90.1% yield and >85% purity (HPLC) (ee >95%). LC-MS (APCI): m / z = 390.1 (M+1). + .

[0194] Step 4: Synthesis of Compound C. Compound Da (17.5 g, 35.8 mmol) and dichloromethane (200 mL) were added to a 250 mL single-neck flask equipped with magnetic stirring, and the mixture was stirred until the solution became clear. Triethylamine (14.5 g, 143.2 mmol) and then DMAP (850 mg, 7.2 mmol) were added successively. BocO (23.4 g, 107.4 mmol) was added slowly dropwise, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was complete by TLC (DCM:MeOH = 20:1) and HPLC monitoring. The reaction solution was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (EA / PE = 0-35%) to give 15.4 g of a white solid in 62.4% yield and >95% purity (HPLC) (ee > 95%). LC-MS (APCI): m / z = 590.1 (M+1-100). + . 1 H NMR(300 MHz, CDCl3) (δ / ppm): 8.06(d, J=1.8 Hz, 1H), 7.53-7.48(m, 1H), 7.24-7.20(m, 2H), 7.04-6.98(m, 1H), 6.81(s, 1H), 5.66-5.59(m, 1H), 4.89-4.69(m, 2H), 2.97(s, 3H), 1.58(d, J=6.0 Hz, 3H), 1.47(s, 18H).

[0195] Step 5: Synthesis of Compound B. Compound C (15.4 g, 22.3 mmol) and 2-methyl-2-butanol (300 mL) were added to a 500 mL single-neck flask equipped with magnetic stirring, and the mixture was stirred until the solution became clear. Potassium acetate (6.56 g, 66.9 mmol) was added. The system was evacuated and purged with nitrogen gas three times. Palladium acetate (0.75 g, 3.35 mmol) and n-butylbis(1-adamantyl)phosphine (1.60 g, 4.46 mmol) were quickly added. The system was evacuated and purged with nitrogen gas three times. The reaction solution was heated to 110 °C under a nitrogen atmosphere and allowed to react overnight at this temperature with stirring. The reaction was complete by TLC (PE:EA = 1:1) and HPLC monitoring. The reaction solution was cooled to room temperature, diluted with dichloromethane (300 mL), and filtered through Celite to remove insoluble solids. The filter cake was washed with dichloromethane (50 mL). The filtrates were combined and concentrated to dryness under reduced pressure. Acetonitrile (150 mL) was added to the residue, and the mixture was heated to reflux for 1 hour. The oil bath was removed, and the mixture was slowly cooled to room temperature. A large amount of white solid precipitated, and the precipitated solid was filtered. The filter cake was washed with acetonitrile (10 mL) and dried to give 8.2 g of a white solid in 60.4% yield and >99.5% purity (HPLC) (ee >99.9%). LC-MS (APCI): m / z = 510.1 (M + 1 - 100) + . 1 H NMR(300 MHz, CDCl3) (δ / ppm): 8.22(d, J=1.8 Hz, 1H), 7.29-7.25(m, 1H), 7.22-7.16(m, 2H), 7.03-6.96(m, 1H), 5.76-5.70(m, 1H), 4.42(q, J=14.1 Hz, 2H), 3.15(s, 3H), 1.76(d, J=6.0 Hz, 3H), 1.44(s, 18H).

[0196] Step 6: Synthesis of Compound A. Compound B (8.2 g, 13.5 mmol) and dichloromethane (100 mL) were added to a 250 mL single-neck flask equipped with magnetic stirring, and the mixture was stirred until the solution became clear. The mixture was cooled in an ice-water bath, and trifluoroacetic acid (20 mL) was slowly added dropwise. After the addition was complete, the ice bath was removed, and the mixture was allowed to react at room temperature with stirring for 2 hours. The reaction was complete by TLC (DCM:MeOH = 20:1) and HPLC monitoring. The reaction solution was evaporated under reduced pressure to remove the organic solvent. Dichloromethane (100 mL) and a saturated aqueous solution of sodium bicarbonate (60 mL) were added under cooling, and the mixture was stirred for 10 minutes. The organic phase was separated, and the aqueous layer was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed successively with water (30 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 5.1 g of an amorphous white solid in 92.6% yield and >99.5% purity (HPLC) (ee >99.9%). LC-MS (APCI): m / z = 410.2 (M+1). + . 1 H NMR(300 MHz, CDCl3) (δ)ppm 7.79(d, J=1.8 Hz, 1H), 7.31-7.27(m, 1H), 7.23-7.19 (m, 1H),7.06-6.97(m, 1H), 6.87(d, J=1.8 Hz, 1H), 5.75-5.70(m, 1H), 5.09(br s, 2H), 4.40(q, J = 14.1 Hz, 2H), 3.12(s, 3H), 1.78(d, J = 6.6 Hz, 3H). [Example 2]

[0197] Preparation of various crystalline forms of Compound A In screening various crystalline forms of the free base of Compound A, Compound A was used as the starting material to screen various crystalline forms of the free base of Compound A by evaporation at room temperature, stirring in suspension, and precipitation in an antisolvent. Four anhydrous crystalline forms (Crystalline Form I, Crystalline Form IV, Crystalline Form V, Crystalline Form VI) and three solvates (Crystalline Form II, Crystalline Form III, and Crystalline Form VII) were found. Example 2.1

[0198] Processing of Starting Materials and Preparation of Compound A Crystalline Form I Isobutanol was added as a solvent to a certain amount of starting material Compound A. The suspension was slurried at room temperature for 1 day and then filtered by suction. The solid was dried under vacuum at 50°C overnight to obtain 1 g of Compound A Crystalline Form I, which was an anhydrous crystalline form. Example 2.2

[0199] Screening of 13*13 (1:1) binary solvents in 96-well plates Approximately 30 mg of Compound A crystalline Form I was added to a vial (8 mL, 13 vials in total), and 3 mL of the corresponding solvent (methanol, ethanol, isopropanol, isobutanol, butanone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, water, dichloromethane, ethyl acetate, and isopropyl acetate, respectively) was added portionwise. The mixture was stirred at room temperature for a certain time and then filtered. The filtrate was set aside for use. The filtrate was used for screening binary solvents in a 96-well plate. The above corresponding filtrates were distributed in pairs into a 96-well plate with a volume of 100 μL for each filtrate. The 96-well plate was sealed with sealing film and evaporated to dryness at room temperature in a fume hood. The information of the 13 solvents in the 96-well plate is shown in Table 2.2.

[0200] Table 2.2: 13x13 solvent information in a 96-well plate [Table 18]

[0201] Note: AM stands for amorphous, CR stands for crystalline, and GL stands for glassy.

[0202] * indicates that the result for the sample in this well as shown in the table is an XRPD result, but the result for the sample in the other well is a PLM result.

[0203] The solids precipitated in the 96-well plate were examined by PLM and XRPD. The results indicated that a new crystalline form, designated Compound A Form II, was obtained. Form II was obtained in butanone / isopropanol, butanone / tetrahydrofuran, butanone / acetonitrile, butanone / acetone, butanone / dichloromethane, butanone / ethyl acetate, and butanone / isopropyl acetate. Amorphous or poorly crystallized solids were obtained in other solvents. Example 2.3

[0204] A study of evaporative crystallization in 13 single solvents. The remaining 13 single filtrates for plating into the 96-well plate in Example 2.2 were placed in a fume hood and evaporated to dryness at room temperature for 3 days. The samples were dried overnight under vacuum at 50°C to yield two new crystalline forms. Evaporation of the single solvent butanone yielded a new crystalline form designated Compound A Form III. Evaporation of the single solvent methanol yielded another new crystalline form designated Compound A Form IV. Evaporation of other solvents yielded amorphous or poorly crystallized solids. Example 2.4

[0205] Investigation of slurry formation in suspensions at room temperature Different solvents were added to a certain amount of Compound A Crystalline Form I. The suspension was slurried at room temperature for 1 day and then filtered by suction. The sample was dried under vacuum at 50°C overnight and characterized by XRPD. The test conditions and results are shown in Table 2.4.

[0206] Table 2.4 Test conditions and results for slurrying in suspension at room temperature [Table 19]

[0207] The results showed that in addition to Form I obtained in isopropyl acetate, ethanol, and MTBE / MeOH (9:1), three new forms named Form V, Form VI, and Form VII were obtained. Among the three new forms, Form V was obtained in a suspension of water and methanol, Form VI was obtained in a suspension of methanol, and Form VII was obtained in a suspension of water and acetonitrile. Example 2.5

[0208] Investigation of slurry formation in suspension at 50°C A suspension of 30 mg of Compound A Form I in 500 μL of antisolvent was prepared. The suspension was slurried at 50° C. for 1 day and then filtered by suction. The sample was dried under vacuum at 50° C. overnight and characterized by XRPD. The test conditions and results are shown in Table 2.5.

[0209] Table 2.5 Test conditions and results for slurrying in suspension at 50°C [Table 20]

[0210] The results showed that crystalline Form I was obtained in all solvent systems. Example 2.6

[0211] Investigation of precipitation in antisolvents 30 mg of Compound A Crystalline Form I was added to 200 μL of a good solvent, and the mixture was stirred at room temperature. Antisolvents were added separately for antisolvent precipitation tests. The resulting solids were subjected to XRPD characterization. The test conditions and results are shown in Table 2.6.

[0212] Table 2.6 Test conditions and results for precipitation in antisolvents [Table 21]

[0213] The results showed that only ethyl acetate / MTBE gave crystalline Form I, while other solvent systems failed to give solid precipitates. [Example 3] Characterization of various crystalline forms of the free base of Compound A Example 3.1

[0214] Characterization of Compound A Crystalline Form I Compound A Crystalline Form I was prepared by the method of Example 2.1 and characterized by XRPD, PLM, DSC, TGA, DVS, NMR, IR, UV and MS. The specific results are as follows:

[0215] XRPD analysis Figure 1 shows the XRPD data of Compound A Crystalline Form I obtained by General Method 1. A list of the XRPD peaks and their relative intensities at diffraction angles 2θ (°2θ) ± 0.2°2θ is provided in Table 3.1. The XRPD results indicated that Crystalline Form I had good crystallinity.

[0216] Table 3.1: XRPD Peak List (2θ°) of Compound A Crystalline Form I [Table 22]

[0217] PLM analysis Compound A Crystalline Form I was subjected to PLM analysis by General Method 2. The PLM results showed that Crystalline Form I was a granular crystal.

[0218] DSC and TGA thermal analysis 2 and 3 show the DSC and TGA curves of Compound A Crystalline Form I obtained by General Methods 4 and 5, respectively. The DSC results showed a narrow melting endotherm with an onset temperature of about 231.78°C and a peak temperature of about 232.48°C. The TGA results showed a weight loss of up to 0.01339% at 150°C. The DSC and TGA analyses indicated that the sample was an anhydrous crystalline form.

[0219] DVS analysis 4 shows the DVS curve of Compound A Crystalline Form I obtained by General Method 6. The DVS results showed a weight gain of 0.17% when humidity increased from 0% RH to 80% RH.

[0220] As shown in Figure 5, the crystal structure of the sample did not change before and after the DVS test.

[0221] NMR analysis Instruments and equipment: Bruker AVANCE III 400 MHz nuclear magnetic resonance spectrometer

[0222] Solvent: DMSO-d6 73.66 mg of Compound A Crystalline Form I was accurately weighed and completely dissolved by adding 0.6 mL of DMSO-d6. 1 H-NMR, 13 C-NMR, DEPT, 19 The solution was transferred to an NMR tube for F-NMR, HSQC, HMBC and COSY studies.

[0223] 36.81 mg of Compound A Crystalline Form I was accurately weighed and completely dissolved by adding 0.6 mL of DMSO-d6. An additional 50 μL of DMSO-d6 was then added. The solution was thoroughly mixed and transferred to an NMR tube for D-NMR testing.

[0224] The NMR atomic distribution structure of compound A is shown below:

[0225] [ka] .

[0226] The definitive HMBC and COSY related structures of compound A are shown below:

[0227] [ka]

[0228] 1 H-NMR Figure 6 shows the crystal structure of Compound A Crystalline Form I. 1 Table 3.2 shows the H NMR spectrum of Compound A Crystalline Form I. 1 The results of the H NMR spectrum are shown.

[0229] Table 3.2 Nuclear magnetic resonance hydrogen spectrum test results for Compound A Crystalline Form I [Table 23]

[0230] The results show that the hydrogen spectrum, in combination with HSQC, has 16 hydrogen signals, including 6 methyl hydrogens, 2 methylene hydrogens, 6 methenyl hydrogens, and 2 active hydrogens. H The hydrogen signal with a chemical shift of 6.23 (br s, 2H) has no HSQC correlation and is assigned to NH-12 based on HMBC correlation with C-8; H The aromatic hydrogen signal with a chemical shift of 7.61 (overlap, 1H) was assigned to H-20 based on HMBC correlations with C-14, C-15, C-16, C-18, and C-19; δ H 7.58 (overlap, 1H) has HMBC correlations with C-1, C-2, C-5, C-8, and C-9 and is assigned to H-10; δ H 7.45(dd,J=8.8,6.0Hz,1H) is δ H 7.16 (td, J = 8.8, 2.8 Hz, 1H) and COSY correlations, which, in combination with the HMBC correlation, are assigned to H-17 and H-18, respectively; δ H The chemical shift of 6.80 (d, J = 1.6 Hz, 1H) was assigned to H-5 based on HMBC correlations with C-1, C-2, C-8, C-9, and C-10; H 5.61(m,1H) is δ H The hydrogen signal at 1.68 (J = 6.0 Hz, 3H) has a COSY correlation, which, in combination with the HMBC correlation, is assigned to H-14 and H-32, respectively;H 4.41 (d, J = 14.4 Hz, 1H) and δ H The methylene hydrogen signal with a chemical shift of 4.19 (d, J = 14.4 Hz, 1H) has HMBC correlations with C-2, C-3, C-13, and C-23 and is assigned to H-4a and H-4b, respectively; H The methyl hydrogen signal with a chemical shift of 2.99 (s, 3H) is assigned to H-23 based on HMBC correlation with C-4 and C-13.

[0231] 13 C-NMR and DEPT 7 and 8 show the crystal structure of Compound A Crystalline Form I, respectively. 13 The C NMR spectrum and DEPT spectrum of Compound A Crystalline Form I are shown in Table 3.3. 13 The test results of C NMR spectrum are shown.

[0232] Table 3.3 Nuclear magnetic resonance carbon spectrum test results for Compound A Crystalline Form I [Table 24]

[0233] The results are: 13 The C-NMR spectrum showed a total of 21 carbon signals, which, in combination with DEPT, contained two methyl carbons, one methylene carbon, six methenyl carbons, one carbon bonded to a deuterium atom, and 11 carbons not bonded to hydrogen. According to the HSQC data, all of the above carbon signals bonded to hydrogen were assigned, and the remaining carbons not bonded to hydrogen were assigned based on chemical shifts and HMBC data. In the HMBC spectrum, δ C 168.24 is related to H-4, H-17, H-20 and H-23 and is assigned to C-13; δ C 164.57, 162.12 are related to H-14, H-17, H-18 and H-20 and are assigned to C-19 in combination with the coupling constants; δ C151.40 is related to H-5 and H-10 and assigned to C-9; C 144.24 is related to H-4 and is assigned to C-3 in combination with the chemical shift; δ C 143.88, 143.81 are related to H-14, H-17, H-18, H-20 and H-32 and are assigned to C-15 in combination with the coupling constants; δ C 138.63 is related to H-5, H-10, NH-12, and H-14 and assigned to C-8; δ C 133.16, 133.13 are related to H-14, H-17, H-18, and H-20 and are assigned to C-16; δ C 127.66 is related to H-4, H-5, and H-10 and assigned to C-2; δ C 113.18 is related to H-5 and H-10 and is assigned to C-1 in combination with the chemical shifts; δ C 111.78 and δ C 111.55 are assigned to C-24 / C-28 and C-28 / C-24, respectively, based on their chemical shifts; δ C 38.64, 38.43, 38.21 are assigned to C-27 based on chemical shifts and coupling constants.

[0234] D-NMR spectrum 9 shows the D-NMR spectrum of Compound A Crystalline Form I. In the D-NMR spectrum, the chemical shift at δ 3.97 is the signal of a deuterium atom.

[0235] 19 F-NMR spectrum FIG. 10 shows the crystal structure of Compound A Crystalline Form I. 19 The F-NMR spectrum is shown. 19 In the F-NMR spectrum, the chemical shift at δ 110.08 is the signal of fluorine attached to the benzene ring.

[0236] HSQC and HMBC spectra 11 and 12 show the NMR HSQC and HMBC spectra of Compound A Crystalline Form I. Table 3.4 shows the results of the NMR HSQC and HMBC spectra of Compound A Crystalline Form I.

[0237] Table 3.4 NMR HSQC and HMBC spectral results for Compound A Crystalline Form I [Table 25]

[0238] The results showed that in the HMBC spectrum, H-20 was associated with C-13, C-14, C-15, C-16, C-18, and C-19; H-17 was associated with C-13, C-14, C-15, C-16, C-18, C-19, and C-20; H-18 was associated with C-15, C-16, C-19, and C-20; H-14 was associated with C-8, C-15, C-16, C-19, C-20, and C-32; H-32 was associated with C-14 and C-15; H-10 was associated with C-1, C-2, C-5, C-8, and C-9; and H-5 was associated with C-1, C-2, C-8, C-9, and C-10. H-4 is associated with C-2, C-3, C-13, and C-23, and H-23 is associated with C-4 and C-13, consistent with the presence of fragment B in the structure; H-17 and H-20 are associated with C-13, indicating that C-16 of fragment A is linked to C-13 of fragment B; and H-5 and H-10 are associated with C-2, indicating that C-1 of fragment A is linked to C-2 of fragment B.

[0239] COSY Figure 13 shows the NMR COSY spectrum of Compound A Crystalline Form I. Table 3.5 shows the NMR COSY spectrum of Compound A Crystalline Form I.

[0240] Table 3.5 NMR COSY spectrum test results for Compound A Crystalline Form I [Table 26]

[0241] The results showed that H-17 was related to H-18 and H-14 was related to H-32 in the COSY spectrum, further demonstrating the presence of fragment A in the structure.

[0242] IR analysis Equipment and instruments: Shimadzu SHIMADZU IR Tracer 100 Fourier transform infrared spectrometer

[0243] The infrared absorption spectrum of Compound A Crystalline Form I was measured by the KBr pellet method from 4000 to 400 cm -1 The IR spectrum of Compound A Crystalline Form I was collected within a wavenumber range of 100 Hz to 100 Hz. Figure 14 shows the IR spectrum of Compound A Crystalline Form I. Table 3.6 shows the results of the IR spectrum of Compound A Crystalline Form I.

[0244] Table 3.6 IR spectrum test results for Compound A Crystalline Form I [Table 27]

[0245] The results show that the chemical structure of Compound A Crystalline Form I contains NH, C≡N, CH, CH, CH, C═O, a benzene ring, and an aryl ether structure. The specific analytical results are as follows: 3474, 3383, 3308 cm -1 represents the NH stretching vibration absorption peaks, which are consistent with the structure containing -NH; 3184, 3111 cm -1 = C-H stretching vibration absorption peaks, 1499 and 1491 cm -1 represents the C=C double bond stretching vibration absorption peaks, and 878 and 829 cm -1 represents the =CH out-of-plane bending vibration absorption peaks, which are consistent with the presence of a benzene ring structure; 2980, 2934 cm -1represents saturated C-H bond stretching vibration absorption peaks, and 1433, 1420, 1395, 1368, and 1344 cm -1 represents saturated C-H bond bending vibration absorption peaks, which are consistent with the presence of CH, CH, and CH structures; -1 represents the C≡N stretching vibration absorption peaks, which are consistent with a structure containing a C≡N moiety; 1645, 1616 cm -1 represents the C=O stretching vibration peak, which is consistent with a structure containing a carbonyl moiety; 1252 cm -1 represents the COC asymmetric stretching vibration absorption peak, and 1069 cm -1 represents the C-O-C symmetric stretching vibration absorption peak, which is consistent with a structure containing an aryl ether moiety.

[0246] UV analysis Instruments and equipment: UV-2600 UV-Vis spectrophotometer (Shimadzu Corporation, Japan).

[0247] UV analysis was performed using a methanol solution of the sample (15.23 μg / mL). Figure 15 shows the UV absorption spectrum of Compound A Crystalline Form I. Table 3.7 shows the test results of UV absorption of Compound A Crystalline Form I.

[0248] Table 3.7 UV absorption test results for Compound A Crystalline Form I [Table 28]

[0249] The result is λ max The absorption peaks at 317 and 206 nm are the absorption peaks of the n-π* transition of the conjugated system of the compound and the π-π* transition of the substituted benzene ring.

[0250] HR-MS Instrumentation: Ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry using a Waters Acquity I Class UPLC / Xevo G2-XS QT of HRMS system.

[0251] A solution of Compound A Crystalline Form I in methanol at a concentration of 15.23 μg / mL was used for chromatographic analysis.

[0252] Figure 16 shows the high-resolution mass spectrum of Compound A Crystalline Form I. The results are in agreement with the theoretical value (410.1820, C 21 H 17 D3FN6O2) deviates by less than 5 ppm from m / z 410.1822 [M+H] in the high-resolution mass spectrum + The sample shows an ion peak with a mass-to-charge ratio of C 21 H 16 This suggests that it is D3FN6O2. Example 3.2

[0253] Characterization of Compound A Crystalline Form II Compound A Crystalline Form II was prepared by the method of Example 2.2 after evaporation of the butanone / ethyl acetate solvent mixture and characterized by XRPD, PLM, DSC and TGA. The specific results are as follows:

[0254] XRPD analysis Figure 17 shows the XRPD data of Compound A Crystalline Form II obtained by General Method 1. A list of XRPD peaks and their relative intensities at diffraction angles 2θ (°2θ) ± 0.2°2θ is provided in Table 3.2. The XRPD results indicated that Crystalline Form II had good crystallinity.

[0255] Table 3.2: XRPD Peak List (2θ°) of Compound A Crystalline Form II [Table 29]

[0256] PLM analysis Compound A Crystalline Form II was subjected to PLM analysis by General Method 2. The PLM results showed that Crystalline Form II was an irregularly shaped crystal.

[0257] DSC and TGA thermal analysis DSC and TGA analyses of Compound A Crystalline Form II were performed by General Methods 4 and 5. DSC results showed a melting endotherm with an onset temperature of about 227.91°C and a peak temperature of about 230.09°C. TGA results showed a weight loss of about 6.69% at 160°C. DSC and TGA analyses indicated that the sample was a solvate of butanone. Example 3.3

[0258] Characterization of Compound A Crystalline Form III According to the method of Example 2.3, Compound A Crystalline Form III was obtained by evaporation of butanone in a single solvent, and characterized by XRPD, PLM, DSC and TGA. The specific results are as follows:

[0259] XRPD analysis Figure 18 shows the XRPD data of Compound A Crystalline Form III obtained by General Method 1. A list of the XRPD peaks at diffraction angles 2θ (°2θ) ± 0.2°2θ and their relative intensities is provided in Table 3.3. The XRPD results indicated that Crystalline Form III had good crystallinity.

[0260] Table 3.3: XRPD Peak List (2θ°) of Compound A Crystalline Form III [Table 30]

[0261] PLM analysis Compound A Crystalline Form III was subjected to PLM analysis by General Method 2. The PLM results showed that Crystalline Form III was an irregularly shaped crystal.

[0262] DSC and TGA thermal analysis DSC and TGA analyses of Compound A Crystalline Form III were performed by General Methods 4 and 5. DSC results showed a melting endotherm with an onset temperature of about 220.19°C and a peak temperature of about 226.13°C. TGA results showed a weight loss of about 5.31% at 165°C. DSC and TGA analyses indicated that the sample was a solvate of butanone. Example 3.4

[0263] Characterization of Compound A Crystalline Form IV Compound A Crystalline Form IV was obtained by evaporation in a single solvent of methanol according to the method of Example 2.3, and characterized by XRPD, PLM, DSC and TGA. The specific results are as follows:

[0264] XRPD analysis Figure 19 shows the XRPD data of Compound A crystalline Form IV obtained by General Method 1. A list of the XRPD peaks and their relative intensities at diffraction angles 2θ (°2θ) ± 0.2°2θ is provided in Table 3.4. The XRPD results showed that the crystallinity of crystalline Form IV was normal.

[0265] Table 3.4: XRPD Peak List (2θ°) of Compound A Crystalline Form IV [Table 31]

[0266] PLM analysis Compound A Crystalline Form IV was subjected to PLM analysis by General Method 2. The PLM results showed that Crystalline Form IV was an irregularly shaped crystal.

[0267] DSC and TGA thermal analysis DSC and TGA analyses of Compound A Crystalline Form IV were performed using General Methods 4 and 5. The DSC results showed an endothermic peak with an onset temperature of about 229.83°C and a peak temperature of about 231.62°C. The TGA results showed a weight loss of about 0.28% before 200°C. The DSC and TGA analyses indicated that the sample was an anhydrous crystalline form. Example 3.5

[0268] Characterization of Compound A Crystalline Form V Compound A Crystalline Form V was obtained after slurrying in a suspension in a mixed solvent (water:methanol=9:1) at room temperature according to the method of Example 2.4 and characterized by XRPD, PLM, DSC and TGA. The specific results are as follows:

[0269] XRPD analysis Figure 20 shows the XRPD data of Compound A Crystalline Form V obtained by General Method 1. A list of the XRPD peaks and their relative intensities at diffraction angles 2θ (°2θ) ± 0.2°2θ is provided in Table 3.5. The XRPD results indicated that Crystalline Form V had good crystallinity.

[0270] Table 3.5: XRPD Peak List (2θ°) of Compound A Crystalline Form V [Table 32] TIFF2025124707000038.tif184155

[0271] PLM analysis Compound A Crystalline Form V was subjected to PLM analysis by General Method 2. The PLM results showed that Crystalline Form V was an irregularly shaped crystal.

[0272] DSC and TGA thermal analysis DSC and TGA analyses of Compound A Crystalline Form V were performed using General Methods 4 and 5. DSC results showed a melting endotherm with an onset temperature of approximately 230.9°C and a peak temperature of approximately 232.13°C. TGA results showed a weight loss of approximately 0.22% (residual solvent) before 200°C. DSC and TGA analyses indicated that the sample was anhydrous crystalline. Example 3.6

[0273] Characterization of Compound A Crystalline Form VI Compound A Crystalline Form VI was obtained after slurrying in suspension in methanol solvent at room temperature according to the method of Example 2.4 and characterized by XRPD, PLM, DSC and TGA. Specific results are as follows:

[0274] XRPD analysis Figure 21 shows the XRPD data of Compound A crystalline Form VI obtained by General Method 1. A list of the XRPD peaks and their relative intensities at diffraction angles 2θ (°2θ) ± 0.2°2θ is provided in Table 3.6. The XRPD results indicated that Form VI had good crystallinity.

[0275] Table 3.6: XRPD Peak List (2θ°) of Compound A Crystalline Form VI [Table 33]

[0276] PLM analysis Compound A Form VI was subjected to PLM analysis by General Method 2. The PLM results showed that Form VI was an irregularly shaped crystal.

[0277] DSC and TGA thermal analysis DSC and TGA analyses of Compound A Crystalline Form VI were performed by General Methods 4 and 5. DSC results showed a melting endotherm with an onset temperature of about 231.56°C and a peak temperature of about 232.83°C. TGA results showed virtually no weight loss before 200°C. DSC and TGA analyses indicated that the sample was anhydrous crystalline. Example 3.7

[0278] Characterization of Compound A Crystalline Form VII Compound A Crystalline Form VII was obtained after slurrying in a suspension in a mixed solvent (water:acetonitrile=1:9) at room temperature according to the method of Example 2.4, and characterized by XRPD, PLM, DSC, and TGA. The specific results are as follows:

[0279] XRPD analysis Figure 22 shows the XRPD data for Compound A crystalline Form VII obtained by General Method 1. A list of the XRPD peaks and their relative intensities at diffraction angles 2θ (°2θ) ± 0.2°2θ is provided in Table 3.7. The XRPD results indicated that Form VII had normal crystallinity.

[0280] Table 3.7: XRPD Peak List (2θ°) of Compound A Crystalline Form VII [Table 34]

[0281] PLM analysis Compound A Form VII was subjected to PLM analysis by General Method 2. The PLM results showed that Form VII was a needle-like crystal.

[0282] DSC and TGA thermal analysis DSC and TGA analyses of Compound A Crystalline Form VII were performed by General Methods 4 and 5. DSC results showed a melting endotherm with an onset temperature of about 230.70°C and a peak temperature of about 232.38°C. TGA results showed a weight loss of about 0.35% before 200°C. DSC and TGA analyses indicated that the sample was a solvate. [Example 4]

[0283] Trans-crystallization study of compound A 4.1 Competitive slurry test at room temperature 10 mg of Compound A Form I, Form IV, Form V, and Form VI were added to 500 μL of each of three different solvent systems (isobutanol, isopropanol, and methyl tert-butyl ether). The mixtures were slurried at room temperature for 1 day. The solids were dried under vacuum at 50° C. overnight and characterized by XRPD. The results are shown in Table 4.1 and Figure 23.

[0284] Table 4.1 Results of competitive slurry tests at room temperature [Table 35]

[0285] The results showed that Forms IV, V, and VI of Compound A were all trans-crystallized to Form I in the three solvent systems of isobutanol, isopropanol, and methyl tert-butyl ether, further proving that Form I of Compound A is a stable crystalline form.

[0286] 4.2 Heating investigation Aliquots of crystalline Forms V and VI of Compound A were weighed and heated to 190° C., then characterized by XRPD. The results are shown in Figure 24. The results indicated that crystalline Form V of Compound A was transformed into crystalline Form I by heating to 190° C., further demonstrating that crystalline Form I of Compound A is a thermodynamically stable crystalline form. [Example 5]

[0287] Stability study of crystalline form I of compound A Stability-influencing factor testing was performed on samples of Crystalline Form I of Compound A. The corresponding set conditions and test results are listed in Table 5.

[0288] Table 5. Test data on factors influencing the stability of Crystalline Form I of Compound A [Table 36] [Example 6]

[0289] Preparation of crystalline salt of Compound A Initial attempts to prepare crystalline salts of Compound A using Compound A Form I as the starting material consisted of two phases. The first phase consisted of a stability study of the starting material and salt production screening in 96-well plates, and the second phase consisted of a scale-up preparation of crystalline salts that could be formed in milligram quantities. These initial attempts identified eight crystalline salts of Compound A: Compound A maleate Form I, Compound A acetate Form I, Compound A p-toluenesulfonate Form I, Compound A hydrobromide Form I, Compound A sulfate Form I, Compound A oxalate Form I, Compound A hydrochloride Form I, and Compound A mesylate Form I. Example 6.1

[0290] Solubility study of starting material (crystalline form I of compound A) Approximately 2 mg of starting material was added to a 2 mL vial and different solvents were added slowly (50 μL per hour) until the sample dissolved or the solubility was less than 1 mg / mL. The solubility results are listed in Table 6.1.

[0291] The results showed that the solubility of the starting material was relatively high in acetone, dichloromethane, tetrahydrofuran, methanol, acetonitrile, butanone, and ethyl acetate, all of which were higher than 100 mg / mL; the solubility decreased in isopropyl acetate and ethanol, both of which were about 20 mg / mL; and the solubility was relatively low in isopropanol, MTBE, isobutanol, and water, which were about 1-2 mg / mL.

[0292] Table 6.1: Solubility of the free base of the starting material (Crystalline Form I of Compound A) in different solvents [Table 37] Example 6.2

[0293] Salt screening in 96-well plates Eight 0.1M acid solutions were prepared by dissolving aliquots of hydrobromic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, and maleic acid in methanol and diluting to 10 mL. Approximately 750 mg of starting material was weighed and added to 25 mL of methanol to prepare a 30 mg / mL free base solution. 100 μL of the 30 mg / mL free base solution was added per well of a 96-well plate, and 75 μL of the corresponding acid solution was added to each well (37.5 μL of sulfuric acid was added). The 96-well plate was evaporated at room temperature, and 100 μL of methanol, ethanol, isopropanol, isobutanol, butanone, tetrahydrofuran, acetonitrile, MTBE, ethyl acetate, acetone, isopropyl acetate, and water were added to each column of wells after complete evaporation of the solvent. The 96-well plate was sealed with sealing film and punctured. The 96-well plate was placed in a fume hood at room temperature. The solvent was slowly evaporated to dryness and the resulting solid samples were then characterized by PLM. The conditions for screening salts in 96-well plates and in the solid state are listed in Table 6.2.

[0294] Table 6.2 Sample conditions for screening salts in a 96-well plate [Table 38]

[0295] Note: oil stands for oil, CR stands for crystalline, and GL stands for glassy.

[0296] The results of the 96-well plate test showed that a white solid was obtained in hydrobromic acid, hydrochloric acid, p-toluenesulfonic acid, and maleic acid. Example 6.3

[0297] Small-scale preparation of maleate crystalline form I of compound A Approximately 30.1 mg of the starting material (Crystalline Form I of Compound A) was weighed and dissolved in 400 μL of ethyl acetate to form a solution, and then 10.3 mg of maleic acid was added. The mixture was stirred at room temperature for 30 minutes to precipitate a solid. The mixture was stirred for an additional 30 minutes and then filtered. The solid obtained by filtration was dried under vacuum at 50° C. for 24 hours. Example 6.4

[0298] Small-scale preparation of acetate crystalline form I of compound A Approximately 29.5 mg of the starting material (Crystalline Form I of Compound A) was weighed and dissolved in 400 μL of ethyl acetate to form a solution, and then 5.15 μL of acetic acid was added. The mixture was stirred at room temperature for 10 minutes to precipitate a solid. The mixture was stirred for an additional 30 minutes and then filtered. The solid obtained by filtration was dried under vacuum at 50° C. for 24 hours. Example 6.5

[0299] Small-scale preparation of p-toluenesulfonate crystalline form I of compound A Approximately 29.9 mg of the starting material (Crystalline Form I of Compound A) was weighed and dissolved in 400 μL of ethyl acetate to form a solution, and then 16.8 mg of p-toluenesulfonic acid was added. The mixture was stirred at room temperature for 2.5 hours to precipitate a solid. The mixture was stirred for an additional 30 minutes and then filtered. The solid obtained by filtration was dried under vacuum at 50° C. for 24 hours. Example 6.6

[0300] Small-scale preparation of crystalline oxalate I of compound A Approximately 30.0 mg of the starting material (Crystalline Form I of Compound A) was weighed and dissolved in 400 μL of ethyl acetate to form a solution, and then 11.1 mg of oxalic acid was added. The mixture was stirred at room temperature for 30 minutes to precipitate a solid. The solid obtained by filtration was dried overnight under vacuum at 50° C. 30 mg of the dried solid was added to a mixed solvent of 160 μL of isopropanol and 40 μL of water, and the mixture was slurried at room temperature for 1 day. The mixture was then filtered under suction. The solid obtained by suction filtration was dried overnight under vacuum at 50° C. Example 6.7

[0301] Small-scale preparation of crystalline sulfate of compound A, Form I Approximately 40.0 mg of the starting material (Crystalline Form I of Compound A) was weighed and dissolved in 400 μL of ethyl acetate to form a solution, and then 4.71 μL of sulfuric acid was added. The mixture was stirred at room temperature, and a solid immediately precipitated. The solid obtained by filtration was dried overnight under vacuum at 50° C. 40 mg of the dried solid was added to a mixed solvent of 160 μL of isopropanol and 40 μL of water, and the mixture was slurried at room temperature for 1 day. The mixture was then filtered under suction. The solid obtained by suction filtration was dried overnight under vacuum at 50° C. Example 6.8

[0302] Small-scale preparation of crystalline form I of the hydrobromide salt of compound A Approximately 61.1 mg of the starting material (Crystalline Form I of Compound A) was weighed and dissolved in 800 μL of ethyl acetate to form a solution, and then 23.62 μL of hydrobromic acid was added. The solid was immediately precipitated at room temperature. The mixture was stirred for an additional 30 minutes and then filtered. The solid obtained by filtration was dried under vacuum at 50° C. overnight. Example 6.9

[0303] Small-scale preparation of crystalline form I of the hydrochloride salt of compound A Method 1: Approximately 29.8 mg of starting material (Crystalline Form I of Compound A) was weighed and dissolved in 300 μL of ethyl acetate to form a solution, and then 6.72 μL of hydrochloric acid was added. The solid was immediately precipitated at room temperature. The mixture was stirred for an additional 30 minutes and then filtered. The solid obtained by filtration was dried under vacuum at 50° C. overnight.

[0304] Method 2: Approximately 29.3 mg of the starting material (Crystalline Form I of Compound A) was weighed and dissolved in 180 μL of butanone to form a solution, and then 6.72 μL of hydrochloric acid was added. The solid was immediately precipitated at room temperature. The mixture was stirred for an additional 30 minutes and then filtered. The solid obtained by filtration was dried under vacuum at 50° C. overnight.

[0305] Method 3: Approximately 29.4 mg of the starting material (Crystalline Form I of Compound A) was weighed and dissolved in 330 μL of acetone to form a solution, and then 6.72 μL of hydrochloric acid was added. The solid was immediately precipitated at room temperature. The mixture was stirred for an additional 30 minutes and then filtered. The solid obtained by filtration was dried under vacuum at 50° C. overnight.

[0306] Method 4: Approximately 29.9 mg of the starting material (Crystalline Form I of Compound A) was weighed and dissolved in 1.4 mL of isopropyl acetate to form a solution, and then 6.72 μL of hydrochloric acid was added. A solid immediately precipitated at room temperature. The mixture was stirred for an additional 30 minutes and then filtered. The solid obtained by filtration was dried under vacuum at 50° C. overnight.

[0307] Method 5: Approximately 29.6 mg of starting material (Crystalline Form I of Compound A) was weighed and dissolved in 170 μL of acetonitrile to form a solution, and then 6.72 μL of hydrochloric acid was added. The solid was immediately precipitated at room temperature. The mixture was stirred for an additional 30 minutes and then filtered. The solid obtained by filtration was dried under vacuum at 50° C. overnight. Example 6.10

[0308] Small-scale preparation of crystalline mesylate I of compound A Approximately 30.2 mg of the starting material (Crystalline Form I of Compound A) was weighed and dissolved in 400 μL of ethyl acetate to form a solution, and then 5.84 μL of methanesulfonic acid was added. A solid immediately precipitated at room temperature. The mixture was stirred for an additional 30 minutes and then filtered. The solid obtained by filtration was dried under vacuum at 50° C. overnight. [Example 7] Characterization of the crystalline salt of compound A Example 7.1

[0309] Characterization of Compound A Maleate Crystalline Form I Crystalline maleate salt of Compound A, Form I, was prepared by the method in Example 6.3 and analyzed by XRPD, PLM, 1 Characterization was performed by H NMR, DSC, TGA, and DVS. Specific results are as follows:

[0310] XRPD analysis 25 shows the XRPD data of the maleate crystalline form I of Compound A obtained by General Method 1. Diffraction angle 2θ o ( o 2θ)±0.2 o A list of XRPD peaks and their relative intensities at 2θ is shown in Table 7.1. The XRPD results indicated that maleate salt Form I had good crystallinity.

[0311] Table 7.1: XRPD Peak List (2θ°) for Maleate Crystalline Form I of Compound A [Table 39]

[0312] PLM analysis The maleate salt Form I of Compound A was subjected to PLM analysis by General Method 2. The PLM results showed that the maleate salt Form I was an aggregated, irregular crystal with a small particle size.

[0313] 1 HNMR analysis Maleate Crystalline Form I of Compound A 1 H NMR analysis was carried out by general method 3. 1 HNMR results showed that the sample had chemical shifts such that the maleate salt was formed at a 1:1 molar ratio of maleic acid to free base. 1 H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.55 (m, 2H), 7.48 (dd, J = 8.6, 5.7 Hz, 1H), 7.20 (td, J = 8.5, 2.7 Hz, 1H), 6.88 (d, J = 1.7 Hz, 1H), 6.57 (s, 2H), 6.24 (s, 2H), 5.77 - 5.56 (m, 1H), 4.45 (d, J = 14.4 Hz, 1H), 4.21 (d, J = 14.4 Hz, 1H), 3.00 (s, 3H), 1.69 (d, J = 6.2 Hz, 3H).

[0314] DSC and TGA thermal analysis DSC and TGA analyses of Compound A maleate crystalline Form I were performed by general methods 4 and 5. DSC results showed a narrow melting endotherm with an onset temperature of approximately 205.24°C and a peak temperature of 208.87°C. TGA results showed a weight loss of approximately 0.44% (a small amount of residual solvent) before 175°C. DSC and TGA analyses indicated that the sample was anhydrous crystalline.

[0315] DVS analysis 26 shows the DVS curve of Compound A maleate crystalline Form I obtained by General Method 6. The DVS results showed a weight gain of about 2.3% when the humidity increased from 10% RH to 80% RH.

[0316] As shown in FIG. 27, the crystal structure of the sample did not change before and after the DVS test. Example 7.2

[0317] Characterization of Acetate Crystalline Form I of Compound A Crystalline acetate salt Form I of Compound A was prepared by the method of Example 6.4 and analyzed by XRPD, PLM, 1 Characterization was performed by H NMR, DSC, TGA, and DVS. Specific results are as follows:

[0318] XRPD analysis Figure 28 shows the XRPD data of acetate crystalline Form I of Compound A obtained by General Method 1. Diffraction angle 2θ o ( o 2θ)±0.2 o A list of XRPD peaks and their relative intensities at 2θ is shown in Table 7.2. The XRPD results indicated that acetate Form I had good crystallinity.

[0319] Table 7.2: XRPD Peak List (2θ°) for Acetate Form I of Compound A [Table 40]

[0320] PLM analysis Acetate Form I of Compound A was subjected to PLM analysis by General Method 2. The PLM results showed that acetate Form I was an irregular crystal with a small particle size.

[0321] 1 HNMR analysis Acetate Crystalline Form I of Compound A 1 H NMR analysis was carried out by general method 3. 1HNMR results showed that the sample had chemical shifts such that the acetate salt was formed at a 1:1 molar ratio of acetic acid to free base. 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 7.65 - 7.55 (m, 2H), 7.47 (dd, J = 8.5, 5.7 Hz, 1H), 7.18 (td, J = 8.5, 2.7 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.20 (s, 1H), 5.72 - 5.54 (m, 1H), 4.44 (d, J = 14.4 Hz, 1H), 4.20 (d, J = 14.4 Hz, 1H), 3.00 (s, 3H), 1.91 (s, 3H), 1.68 (d, J = 6.2 Hz, 3H).

[0322] DSC and TGA thermal analysis DSC and TGA analyses of Compound A acetate salt crystalline Form I were performed by general methods 4 and 5. The DSC results showed a melting endotherm with an onset temperature of about 227.27°C and a peak temperature of 231.99°C.

[0323] TGA results showed a rapid weight loss of about 0.67% (small amount of residual solvent) before 140°C.

[0324] DSC and TGA analysis showed the sample to be anhydrous crystalline.

[0325] DVS analysis 29 shows the DVS curve of Compound A acetate salt crystalline Form I obtained by General Method 6. The DVS results showed a weight gain of 0.01% when humidity increased from 10% RH to 80% RH.

[0326] As shown in FIG. 30, the crystal structure of the sample did not change before and after the DVS test. Example 7.3

[0327] Characterization of p-toluenesulfonate crystalline form I of compound A Crystalline Form I of the p-toluenesulfonate salt of Compound A was prepared by the method of Example 6.5 and analyzed by XRPD, PLM, 1 Characterization was performed by H NMR, DSC, TGA, and DVS. Specific results are as follows:

[0328] XRPD analysis 31 shows the XRPD data of p-toluenesulfonate crystalline Form I of Compound A obtained by General Method 1. Diffraction angle 2θ o ( o 2θ)±0.2 o A list of XRPD peaks and their relative intensities at 2θ is shown in Table 7.3. The XRPD results indicated that p-toluenesulfonate salt Form I had good crystallinity.

[0329] Table 7.3: XRPD peak list (2θ°) for p-toluenesulfonate crystalline form I of Compound A [Table 41]

[0330] PLM analysis p-Toluenesulfonate Crystalline Form I of Compound A was subjected to PLM analysis by General Method 2. The PLM results showed that p-toluenesulfonate Crystalline Form I was an irregular crystal with a small particle size.

[0331] 1 HNMR analysis p-Toluenesulfonate Crystalline Form I of Compound A 1 H NMR analysis was carried out by general method 3. 1 HNMR results showed that the sample had chemical shifts such that the p-toluenesulfonic acid salt was formed at a 1:1 molar ratio of p-toluenesulfonic acid to free base. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.66 - 7.42 (m, 5H), 7.26 (td, J = 8.5, 2.6 Hz, 1H), 7.20 - 7.05 (m, 2H), 5.86 - 5.72 (m, 1H), 4.48 (d, J = 14.6 Hz, 1H), 4.27 (d, J = 14.5 Hz, 1H), 3.00 (s, 3H), 2.29 (s, 3H), 1.73 (d, J = 6.2 Hz, 3H).

[0332] DSC and TGA thermal analysis DSC and TGA analyses of p-toluenesulfonate salt crystalline Form I of Compound A were performed by General Methods 4 and 5. The DSC results showed a melting endotherm with an onset temperature of about 263.64°C and a peak temperature of about 269.08°C. The TGA results showed that the sample exhibited a moderate weight loss of about 0.60% (a small amount of residual solvent) before 220°C. The DSC and TGA analyses indicated that the sample was an anhydrous crystalline form.

[0333] DVS analysis 32 shows the DVS curve of p-toluenesulfonate crystalline Form I of Compound A obtained by General Method 6. When the humidity increased from 10% RH to 80% RH, the DVS results showed a weight increase of 5.1%.

[0334] The crystal structure of the sample did not change before and after the DVS test, and it was speculated that a hydrate may have formed, as shown in FIG. Example 7.4

[0335] Characterization of Compound A Oxalate Crystalline Form I Crystalline Form I of the oxalate salt of Compound A was prepared by the method in Example 6.6 and analyzed by XRPD, PLM, 1 Characterization was performed by H NMR, DSC, and TGA. Specific results are as follows:

[0336] XRPD analysis Figure 34 shows the XRPD data of Compound A oxalate crystalline Form I obtained by General Method 1. Diffraction angle 2θ o ( o 2θ)±0.2 o A list of XRPD peaks and their relative intensities at 2θ is shown in Table 7.4. The XRPD results indicated that the oxalate salt Form I had good crystallinity.

[0337] Table 7.4: XRPD Peak List (2θ°) for Compound A Oxalate Crystalline Form I [Table 42]

[0338] PLM analysis Compound A oxalate crystalline Form I was subjected to PLM analysis by General Method 2. The PLM results showed that oxalate crystalline Form I was an irregularly shaped crystal.

[0339] 1 HNMR analysis Oxalate Crystalline Form I of Compound A 1 H NMR analysis was carried out by general method 3. 1 HNMR results showed that the sample had a significant chemical shift of a peak near 5.80 ppm and that the oxalate salt was formed at a 1:1 molar ratio of oxalic acid to free base. 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 1.7 Hz, 2H), 7.48 (dd, J = 8.5, 5.7 Hz, 1H), 7.20 (dd, J = 8.5, 2.6 Hz, 1H), 6.84 (s, 1H), 6.52 - 6.16 (m, 2H), 5.63 (d, J = 4.7 Hz, 1H), 4.45 (d, J = 14.4 Hz, 2H), 4.22 (s, 1H), 3.00 (s, 3H), 1.69 (d, J = 6.2 Hz, 3H).

[0340] DSC and TGA thermal analysis DSC and TGA analyses of Compound A oxalate crystalline Form I were performed by general methods 4 and 5. DSC results showed a melting endotherm with an onset temperature of about 182.04°C and a peak temperature of about 209.28°C. TGA results showed a weight loss of about 0.86% (a small amount of residual solvent) before 130°C. DSC and TGA analyses indicated that the sample was a solvate. Example 7.5

[0341] Characterization of Compound A Sulfate Crystalline Form I The sulfate salt crystalline Form I of Compound A was prepared by the method in Example 6.7 and analyzed by XRPD, PLM, 1 Characterization was performed by H NMR, DSC, and TGA. Specific results are as follows:

[0342] XRPD analysis Figure 35 shows the XRPD data of sulfate crystalline Form I of Compound A obtained by General Method 1. Diffraction angle 2θ o ( o 2θ)±0.2 o A list of XRPD peaks and their relative intensities at 2θ is shown in Table 7.5. The XRPD results indicated that the sulfate salt Form I had good crystallinity.

[0343] Table 7.5: XRPD Peak List (2θ°) for Compound A Sulfate Crystalline Form I [Table 43] TIFF2025124707000050.tif145155

[0344] PLM analysis The sulfate salt crystalline Form I of Compound A was subjected to PLM analysis by General Method 2. The PLM results showed that the sulfate salt crystalline Form I was an irregularly shaped crystal.

[0345] 1 HNMR analysis Sulfate Crystalline Form I of Compound A 1 H NMR analysis was carried out by general method 3. 1 HNMR results showed that the sample had a significant chemical shift of the peak near 5.80 ppm, indicating that sulfate salts were formed. 1 H NMR (400 MHz, DMSO-d6) δ 7.61 - 7.48 (m, 3H), 7.23 (dd, J = 8.1, 5.9 Hz, 1H), 7.04 (s, 1H), 5.73 (s, 1H), 4.47 (d, J = 14.4 Hz, 1H), 4.25 (d, J = 14.4 Hz, 1H), 3.00 (s, 3H), 1.72 (d, J = 6.1 Hz, 3H).

[0346] DSC and TGA thermal analysis DSC and TGA analyses of Compound A sulfate salt crystalline Form I were performed by general methods 4 and 5. The DSC results showed a melting endotherm with an onset temperature of about 244.89° C. and a peak temperature of about 250.97° C. The TGA results showed a weight loss of about 2.95% before 90° C., indicating a hydrate. Example 7.6

[0347] Characterization of Compound A Hydrobromide Crystalline Form I Crystalline Form I of the hydrobromide salt of Compound A was prepared by the method in Example 6.8 and was characterized by XRPD, PLM, 1 Characterization was performed by H NMR, DSC, and TGA. Specific results are as follows:

[0348] XRPD analysis Figure 36 shows the XRPD data of the hydrobromide salt crystalline form I of Compound A obtained by General Method 1. Diffraction angle 2θ o ( o 2θ)±0.2 o A list of XRPD peaks and their relative intensities at 2θ is shown in Table 7.6. The XRPD results indicated that the hydrobromide salt Form I had good crystallinity.

[0349] Table 7.6: XRPD Peak List (2θ°) for Hydrobromide Crystalline Form I of Compound A [Table 44] TIFF2025124707000052.tif167155

[0350] PLM analysis The hydrobromide salt crystalline Form I of Compound A was subjected to PLM analysis by General Method 2. The PLM results showed that the hydrobromide salt crystalline Form I was a rod-shaped crystal.

[0351] 1 HNMR analysis Hydrobromide Crystalline Form I of Compound A 1 H NMR analysis was carried out by general method 3. 1 HNMR results showed that the sample had a significant chemical shift of the peak near 5.80 ppm, indicating that the hydrobromide salt was formed. 1 H NMR (400 MHz, DMSO-d6) δ 8.02(br s, 1H), 8.24 - 7.80 (m, 2H), 7.60 (d, J = 1.6 Hz, 1H), 7.58 - 7.49 (m, 2H), 7.26 (td, J = 8.6, 2.6 Hz, 1H), 7.13 (s, 1H), 5.78 (q, J = 6.0 Hz, 1H), 4.48 (d, J = 14.6 Hz, 1H), 4.27 (d, J = 14.6 Hz, 1H), 3.00 (s, 3H), 1.73 (d, J = 6.2 Hz, 3H).

[0352] DSC and TGA thermal analysis DSC and TGA analyses of Compound A hydrobromide salt crystalline Form I were performed by general methods 4 and 5. The DSC results showed a melting endotherm with an onset temperature of about 232.49°C and a peak temperature of about 240.87°C. The TGA results showed that the sample had a rapid weight loss of about 8.18% (solvent residue) before 150°C. The DSC and TGA analyses indicated that the sample may be a solvate. Example 7.7

[0353] Characterization of Compound A Hydrochloride Crystalline Form I All five preparation methods according to Example 6.9 gave Compound A hydrochloride crystalline Form I, and the sample obtained by Method 1 was analyzed by XRPD, PLM, 1 Characterization was performed by H NMR, DSC, TGA, and DVS. Specific results are as follows:

[0354] XRPD analysis Figure 37 shows the XRPD data of the hydrochloride crystalline form I of Compound A obtained by General Method 1. Diffraction angle 2θ o ( o 2θ)±0.2 o A list of XRPD peaks and their relative intensities at 2θ is shown in Table 7.7. The XRPD results indicated that the hydrochloride salt crystalline Form I had good crystallinity.

[0355] Table 7.7: XRPD Peak List (2θ°) of Compound A Hydrochloride Crystalline Form I [Table 45] TIFF2025124707000054.tif139155

[0356] PLM analysis The hydrochloride salt crystalline Form I of Compound A was subjected to PLM analysis by General Method 2. The PLM results showed that the hydrochloride salt crystalline Form I was a large rod-like crystal.

[0357] 1 HNMR analysis Compound A hydrochloride crystalline form I 1 H NMR analysis was carried out by general method 3. 1 HNMR results showed that the hydrogen in the sample near 6.80 ppm had a chemical shift of about 0.12 ppm, indicating that the hydrochloride salt was formed with hydrochloric acid and the free base. 1 H NMR (400 MHz, DMSO) δ 8.24 - 7.85 (m, 3H), 7.62 (s, 1H), 7.54 (ddd, J = 14.3, 9.3, 4.2 Hz, 1H), 7.25 (td, J = 8.5, 2.6 Hz, 1H), 7.11 (s, 1H), 5.76 (t, J = 5.6 Hz, 1H), 4.47 (d, J = 14.6 Hz, 1H), 4.27 (d, J = 14.5 Hz, 1H), 3.00 (s, 3H), 1.73 (d, J = 6.2 Hz, 3H).

[0358] DSC and TGA thermal analysis DSC and TGA analyses of the collected Compound A hydrochloride crystalline Form I were performed using General Methods 4 and 5. DSC results showed a melting endotherm with an onset temperature of approximately 207.44°C and a peak temperature of approximately 221.36°C. TGA results showed a weight loss of approximately 1.67% before 125°C and a weight loss of approximately 3.84% from 125°C to 230°C due to a small amount of residual solvent. DSC and TGA analyses indicated that the sample may be a solvate.

[0359] DVS analysis 38 shows the DVS curve of Compound A hydrochloride crystalline Form I obtained by General Method 6. When the humidity increased from 10% RH to 80% RH, the DVS results showed a weight increase of 3.5%.

[0360] The crystal structure of the sample changed before and after the DVS test, and it was speculated that hydrates may have formed, as shown in FIG. Example 7.8

[0361] Characterization of Compound A Mesylate Crystalline Form I Crystalline mesylate salt of Compound A, Form I, was prepared by the method in Example 6.10 and analyzed by XRPD, PLM, and 1 Characterization was performed by HNMR, with the specific results being:

[0362] XRPD analysis Figure 40 shows the XRPD data of Compound A mesylate crystalline Form I obtained by General Method 1. Diffraction angle 2θ o ( o 2θ)±0.2 o A list of XRPD peaks and their relative intensities at 2θ is provided in Table 7.8. The XRPD results indicated that mesylate Form I had poor crystallinity.

[0363] Table 7.8: XRPD Peak List (2θ°) for Compound A Mesylate Crystalline Form I [Table 46]

[0364] PLM analysis Compound A mesylate crystalline Form I was subjected to PLM analysis by General Method 2. The PLM results showed that mesylate crystalline Form I was an irregularly shaped crystal.

[0365] 1 HNMR analysis Compound A mesylate crystalline form I 1 H NMR analysis was carried out by general method 3. 1 1 H NMR results showed that the sample hydrogen near 5.80 ppm had a significant chemical shift, indicating that the mesylate salt was formed at a 1:1 molar ratio of methylsulfonic acid to free base. 1H NMR (400 MHz, DMSO-d6) δ 8.17(br s, 1H), 7.61(d, J=4.0 Hz, 1H), 7.54 (ddd, J = 10.0, 8.6, 4.2 Hz, 2H), 7.26 (td, J = 8.5, 2.6 Hz, 1H), 7.14(s, 1H), 5.89 - 5.65 (m, 1H), 4.48 (d, J = 14.6 Hz, 1H), 4.28 (d, J = 14.6 Hz, 1H), 3.00(s, 3H), 2.33(s, 3H), 1.73 (d, J = 6.2 Hz, 3H). [Example 8]

[0366] Accelerated stability studies of Compound A free base and crystalline salts Aliquots of Compound A Crystalline Form I, Compound A Maleate Crystalline Form I, Compound A Acetate Crystalline Form I, and Compound A p-toluenesulfonate Crystalline Form I were placed in a stability chamber at 40°C / 75% RH and 60°C for 7 days, respectively. The crystals were examined by HPLC and XRPD at different time points.

[0367] The results showed that the crystalline form and purity of Compound A Form I, Compound A maleate Form I, Compound A acetate Form I, and Compound A p-toluenesulfonate Form I remained unchanged after 7 days of storage at 40°C / 75% RH and 60°C, demonstrating good stability, as shown in Figures 41-44. Specific results are listed in Table 8.

[0368] Table 8. Results of accelerated stability studies of Compound A free base and crystalline salts [Table 47] [Example 9]

[0369] Solubility studies of the free base and crystalline salt of Compound A in different vehicles The solubility and stability of Compound A Crystalline Form I, Compound A Maleate Crystalline Form I, and Compound A Acetate Crystalline Form I in water, SGF (simulated gastric fluid), FaSSIF (simulated intestinal fluid in the fasted state), and FeSSIF (simulated intestinal fluid in the fed state) were investigated. Specific results are listed in Table 9.

[0370] Table 9. Solubility of Compound A free base and crystalline salt in different vehicles [Table 48]

[0371] The results showed that Compound A Form I had good solubility (>5 mg / mL) in the SGF biological vehicle and low solubility (3 mg / mL) in water, FaSSIF, and FeSSIF biological vehicles. The crystalline form of Compound A Form I did not change in water. The crystallinity of Compound A Form I decreased to nearly amorphous in the FaSSIF and FeSSIF biological vehicles as shown in Figure 45, indicating that Compound A Form I did not precipitate as a solid over time in the FaSSIF and FeSSIF biological vehicles but always remained dissolved.

[0372] Compound A maleate crystalline Form I had good solubility (>5 mg / mL) in the biological vehicles of water and SGF, but low solubility (<3 mg / mL) in the biological vehicles of FaSSIF and FeSSIF. The crystalline form of Compound A maleate crystalline Form I did not change in water. The crystallinity of Compound A maleate crystalline Form I decreased to nearly amorphous in FaSSIF and FeSSIF after 24 hours, as shown in Figure 46, indicating that Compound A maleate crystalline Form I did not precipitate as a solid over time in the biological vehicles of FaSSIF and FeSSIF, but always remained dissolved.

[0373] Compound A acetate crystalline Form I had good solubility (>5 mg / mL) in the biological vehicle SGF and low solubility (<3 mg / mL) in the biological vehicles water, FaSSIF, and FeSSIF. The crystallinity of Compound A acetate crystalline Form I decreased to nearly amorphous in FaSSIF and FeSSIF as shown in Figure 47, indicating that Compound A acetate crystalline Form I did not precipitate as a solid over time in the biological vehicles FaSSIF and FeSSIF but always remained dissolved.

[0374] The solubility of the maleate and acetate salts of Compound A in water increased significantly compared to the free base, from less than 0.2 mg / mL to more than 0.8 mg / mL (more than 6 mg / mL for the maleate), and in the biologically relevant medium FaSSIF, maleate solubility increased significantly compared to the free base. [Example 10]

[0375] Single crystal X-ray structure and absolute stereochemistry of compound A An attempt was made to form single crystals of Compound A at room temperature using a gentle evaporation method. Experiments were performed in 1.5 mL vials (commonly used liquid-phase analytical vials) by dissolving approximately 100 mg of Compound A Form I in acetone, ethyl acetate, isopropyl acetate, and ethanol. To the clear solution, n-heptane was added as an antisolvent until the solution became slightly cloudy. One or two drops of solvent were added and the temperature was raised until the solution became clear again. The cap was loosened, and the vial was left to slowly evaporate at room temperature. After one day, single crystals were obtained in the ethyl acetate and n-heptane solvent mixture.

[0376] Collection and analysis of single crystal structure data were performed at the Institute of Crystallography, Peking University. Single crystal diffraction data for the samples were obtained using an Agilent SuperNova XRD diffraction system at 180 K using a Cu target Kα spectral line (λ = 1.54178 Å). Data modification and absorption correction were performed using the CrysAlisPro program, and the structure was determined by a dual linear space algorithm using the SHELXT program. Non-hydrogen atoms could be located in different Fourier graphs, and hydrogen atoms were geometrically filled to their parent atoms. Final structure refinement was performed using the SHELXL program. 2 The calculation was based on the full-matrix least squares method.

[0377] The refined single crystal structure of Compound A is shown in Figure 48. The parameters of the crystal structure obtained by resolution are listed in Table 10. The single crystal is a bulk crystal, C 21 H 16 It has the structural formula D3FN6O2 and belongs to the monoclinic P21 space group.

[0378] The single crystal sample was tested for XRPD and compared with the calculated values ​​as shown in Figure 49. All characteristic peaks in the XRPD could be compared with the simulated values ​​and were consistent with the XRPD of Compound A Form I, indicating that it was a single crystal of Compound A Form I.

[0379] Table 10. Crystal structure parameters of compound A [Table 49] [Example 11]

[0380] Representative tablet formulation of Crystalline Form I of Compound A Oral film-coated tablets were prepared using a direct powder tableting process at doses of 5 mg and 25 mg. The tablet compositions are shown in Table 11-1.

[0381] Table 11-1. Composition of tablet product in unit dose [Table 50]

[0382] Notes: * Purified water 1 was used as a wetting agent in the granulation process and removed in the drying process. Purified water 1 was not counted in the calculation of materials. The general dosage of purified water was 35% by weight. However, the actual dosage can be adjusted according to the actual condition of wet granulation.

[0383] ** The ingredients of Opadry II 85F620077 are titanium dioxide, polyvinyl alcohol, talc powder, polyethylene glycol, and iron oxide yellow.

[0384] *** Purified water 2 was used as a solvent during the preparation of the coating solution and was removed during the coating process. Purified water 2 was not counted in the material calculations.

[0385] The 5 mg and 25 mg tablets of this product were formulated in equal proportions by using the same batch of total mixed materials and then pressing them into different tablet specifications.Taking a representative batch of 20,000 tablets of 5 mg specification and 30,000 tablets of 25 mg specification produced in total, the batch composition information is shown in Table 11-2 below.

[0386] Table 11-2. Composition information for GMP batches of 5 mg / 25 mg specifications [Table 51]

[0387] Notes: *Purified water 1 was used as a wetting agent in the granulation process and removed in the drying process. Purified water 1 was not counted in the calculation of materials. The general dosage of purified water was 35% by weight. However, the actual dosage can be adjusted according to the actual condition of wet granulation.

[0388] ** The ingredients of Opadry II 85F620077 are titanium dioxide, polyvinyl alcohol, talc powder, polyethylene glycol, and iron oxide yellow.

[0389] *** Purified water 2 was used as a solvent during the preparation of the coating solution and was removed during the coating process. Purified water 2 was not counted in the material calculations.

[0390] Tablets were prepared as follows: 1.Weighing API Compound A Crystalline Form I and the additives were weighed according to the blending amounts.

[0391] 2. Sifting Compound A Crystalline Form I was passed through a 120 mesh sieve (the LDPE bag containing the API was washed with approximately ¼ of the total amount of mannitol 50C, and the washings were passed through the same 120 mesh sieve). The remaining amount of mannitol 50C was passed through a 60 mesh sieve, and magnesium stearate was passed through a 60 mesh sieve.

[0392] 3.Wet granulation Blending: Microcrystalline cellulose 102, Compound A Crystalline Form I, mannitol 50C, croscarmellose sodium, and hydroxypropyl cellulose EXF were added to a wet granulation pot and premixed at a stirring paddle speed of 250 rpm, a shear rate of 400 rpm, and a blending time of 10 minutes.

[0393] Liquid spraying: After mixing was completed, the stirring paddle speed was set to 200 rpm, the shear rate was set to 1000 rpm, and the peristaltic pump rotation speed was set to 241.7 rpm. The blended amount of purified water was sprayed into the material pot of the wet granulator for approximately 3 minutes.

[0394] Granulation: After liquid spraying was completed, granulation was carried out for 2 minutes at a stirring paddle speed of 200 rpm and a shear rate of 1000 rpm.

[0395] Wet finishing: The granulated material was finished in a finishing machine at a speed of 1500 rpm and mesh size of 6x6 mm.

[0396] Drying: Fluidized bed, inlet air temperature 50-70°C, inlet air volume 35-120 m 3 / h, filter bag shaking period 0.5 s, and shaking bag interval 3-5 s. The wet granules were preheated and then dried to a material moisture of <2% w / w.

[0397] Dry finishing: The dried material was finished in a finishing machine at a speed of 1500 rpm and a mesh size of 1.0 mm.

[0398] 4. Mixing the whole The dried and finished materials were added to a hopper mixer. Magnesium stearate was added and mixed thoroughly at a mixing speed of 20 rpm and a mixing duration of 5 minutes. Samples were taken and tested for overall blend uniformity.

[0399] 5. Tableting The punch for the 5 mg tablets was a 6 mm dimpled circular punch, and the punch for the 25 mg tablets was a 10.0 mm dimpled circular punch. After the equipment was commissioned, formal production was carried out. Tablet weight, hardness, and friability were monitored online to ensure that the tablets met the following criteria:

[0400] Table 11-3 Tableting criteria for the preparation process of tablets of crystalline Form I of Compound A [Table 52]

[0401] 6. Coating A 12% Opadry coating solution was freshly prepared in purified water.

[0402] Preheating: The inlet air temperature was set to 50 to 60°C, and the coating pan was preheated at a rotation speed of 2 rpm.

[0403] Liquid spray: Spray coating was performed when the coating pan was preheated to an exhaust air temperature of 42°C.

[0404] Equipment parameters: inlet air temperature set at 50-70°C, pot speed set at 5-12 rpm, inlet air volume set at 300±100 m 3 / h. The pump flow rate was set to 8 ml / min to 80 ml / min, the spray pressure was set to 1.5 ± 1 bar, and the spray angle control pressure was set to 1 ± 0.5 bar for 5 mg tablets and 2.5 ± 1 bar for 25 mg tablets. Coating parameters and coating weight gain were monitored. Spraying was stopped when the coating weight gain reached the target range of 3.0 ± 0.5%.

[0405] Drying: Heating was stopped. The rotation speed of the coating pan was adjusted to 5 rpm, and the inlet air volume was adjusted to 200-500 m 3 / h. The product was discharged after drying for 5 minutes.

[0406] 7. Packaging The packaging materials for the 5 mg tablets and 25 mg tablets were 45 mL and 75 mL high density polyethylene bottles for oral solid dosage forms, respectively. 30 tablets were placed in each bottle.

[0407] 8. Labeling Bottle labels were applied to the product bottles with one label per bottle.

Claims

1. CuK α 1. A compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a 200 MHz X-ray source contains characteristic peaks at least at the following °2θ: 16.175±0.2, 17.299±0.2, and 21.218±0.

2. 【Chemical Formula 1】 (A) Crystalline Form I of the compound of formula (I).

2. CuK α 2. Crystalline Form I of the compound of formula (A) according to claim 1, characterized in that its X-ray powder diffraction pattern obtained using a ray source further comprises characteristic peaks located at the following °2θ: 9.637±0.2, 12.555±0.2, 14.343±0.2 and 19.366±0.

2.

3. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 1】 3. Crystalline Form I of the compound of formula (A) according to claim 2, characterized in that it has the formula:

4. CuK α 4. Crystalline Form I of compound of formula (A) according to claim 2 or 3, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following °2θ: 7.435±0.2, 10.11±0.2, 11.808±0.2, 14.922±0.2, 18.359±0.2, 19.859±0.2, 23.401±0.2, 23.939±0.2, 25.117±0.2, 25.727±0.2, 26.831±0.2 and 28.862±0.

2.

5. 2. Crystalline Form I of the compound of formula (A) according to claim 1, characterized in that it has an X-ray powder diffraction pattern substantially as shown in FIG.

6. Crystalline Form I of the compound of formula (A) according to any one of claims 1 to 5, further characterized by having an endothermic peak at 232±2°C in differential scanning calorimetry analysis.

7. Crystalline Form I of the compound of formula (A) according to any one of claims 1 to 6, further characterized by having substantially no weight loss before 150°C in thermogravimetric analysis.

8. The following parameters: 【Table 2】 Crystalline Form I of the compound of formula (A), characterized in that it has:

9. The following cm －１ Crystalline Form I of the compound of formula (A) according to any one of claims 1 to 8, characterized in that it has absorption peaks in its infrared absorption spectrum at: 829±2, 878±2, 1069±2, 1252±2, 1344±2, 1368±2, 1395±2, 1420±2, 1433±2, 1491±2, 1499±2, 1616±2, 1645±2, 2228±2, 2934±2, 2980±2, 3111±2, 3184±2, 3308±2, 3383±2 and 3474±2.

10. 10. Crystalline Form I of the compound of formula (A) according to claim 9, further characterized by having an infrared absorption spectrum substantially as shown in Figure 14.

11. Crystalline Form I of the compound of formula (A) according to any one of claims 1 to 10, further characterized by having absorption peaks in the UV spectrum at the following nm: 206±2 and 317±2.

12. 12. Crystalline Form I of the compound of formula (A) according to claim 11, further characterized by having a UV spectrum substantially as shown in Figure 15.

13. CuK α Crystalline Form II of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy contains characteristic peaks at least at the following °2θ: 7.591±0.2, 12.081±0.2, and 23.364±0.

2.

14. CuK α 14. Crystalline Form II of the compound of formula (A) according to claim 13, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks located at the following °2θ: 14.577±0.2, 15.595±0.2, 16.948±0.2, 17.615±0.2 and 20.448±0.

2.

15. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 3】 15. Crystalline Form II of the compound of formula (A) according to claim 14, characterized in that it has the formula:

16. 14. Crystalline Form II of the compound of formula (A) according to claim 13, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 17.

17. Crystalline Form II of the compound of formula (A) according to any one of claims 13 to 16, further characterized by having an endothermic peak at 230±2°C in differential scanning calorimetry analysis.

18. Crystalline Form II of the compound of formula (A) according to any one of claims 13 to 17, further characterized by having a weight loss of about 6.69% before 160°C in thermogravimetric analysis.

19. CuK α Crystalline Form III of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a ray contains at least the following characteristic peaks located at °2θ: 23.149±0.

2.

20. CuK α 20. Crystalline Form III of the compound of formula (A) according to claim 19, characterized in that its X-ray powder diffraction pattern obtained using a 200 MHz X-ray source further comprises characteristic peaks located at the following °2θ: 11.429±0.2, 13.027±0.2, 14.542±0.2, 17.949±0.2 and 26.994±0.

2.

21. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 4】 21. Crystalline Form III of the compound of formula (A) according to claim 20, characterized in that it has the formula:

22. CuK α 22. Crystalline Form III of the compound of formula (A) according to claim 20 or 21, characterized in that its X-ray powder diffraction pattern obtained using a 2000 MHz X-ray source further comprises characteristic peaks located at the following °2θ: 10.543±0.2, 15.353±0.2, 18.362±0.2, 21.161±0.2, 22.506±0.2 and 26.006±0.

2.

23. 20. Crystalline Form III of the compound of formula (A) according to claim 19, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 18.

24. Crystalline Form III of the compound of formula (A) according to any one of claims 19 to 23, further characterized by having an endothermic peak at 226±2°C in differential scanning calorimetry analysis.

25. Crystalline Form III of the compound of formula (A) according to any one of claims 19 to 24, further characterized by having a weight loss of about 5.31% before 165°C in thermogravimetric analysis.

26. CuK α Crystalline Form IV of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a ray contains at least the following characteristic peaks located at °2θ: 10.113±0.

2.

27. CuK α 27. Crystalline Form IV of the compound of formula (A) according to claim 26, characterized in that its X-ray powder diffraction pattern obtained using a ray source further comprises characteristic peaks located at the following °2θ: 11.583±0.2, 11.768±0.2, 12.098±0.2, 17.143±0.2 and 19.267±0.

2.

28. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 5】 28. Crystalline Form IV of the compound of formula (A) according to claim 27, characterized in that it has the formula:

29. CuK α 29. Crystalline Form IV of the compound of formula (A) according to claim 27 or 28, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks located at the following °2θ: 9.718±0.2, 12.439±0.2, 13.339±0.2, 17.649±0.2, 20.703±0.2, 21.809±0.2, 22.427±0.2, 25.081±0.2, 27.576±0.2 and 28.959±0.

2.

30. 27. Crystalline Form IV of the compound of formula (A) according to claim 26, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 19.

31. Crystalline Form IV of the compound of formula (A) according to any one of claims 26 to 30, further characterized by having an endothermic peak at 232±2°C in differential scanning calorimetry analysis.

32. Crystalline Form IV of the compound of formula (A) according to any one of claims 26 to 31, further characterized by having a weight loss of about 0.28% before 200°C in thermogravimetric analysis.

33. CuK α Crystalline Form V of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a ray contains characteristic peaks at least at the following °2θ: 6.939±0.2, 16.276±0.2, and 17.494±0.

2.

34. CuK α 34. Crystalline Form V of the compound of formula (A) according to claim 33, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following °2θ: 4.912±0.2, 9.774±0.2, 12.709±0.2, 14.246±0.2, 14.482±0.2, 17.242±0.2, 18.519±0.2, 19.425±0.2, 21.001±0.2, 21.317±0.2, 22.734±0.2, 25.218±0.2 and 29.688±0.

2.

35. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 6】 35. Crystalline Form V of the compound of formula (A) according to claim 34, characterized in that it has the formula:

36. CuK α 36. Crystalline Form V of compound of formula (A) according to claim 34 or 35, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following °2θ: 10.326±0.2, 10.859±0.2, 15.289±0.2, 16.708±0.2, 19.941±0.2, 23.09±0.2, 23.424±0.2, 24.25±0.2, 25.808±0.2, 26.241±0.2, 26.987±0.2, 28.841±0.2, 29.332±0.2, 31.071±0.2 and 31.856±0.

2.

37. 34. Crystalline Form V of the compound of formula (A) according to claim 33, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 20.

38. Crystalline Form V of the compound of formula (A) according to any one of claims 33 to 37, further characterized by having an endothermic peak at 232±2°C in differential scanning calorimetry analysis.

39. Crystalline Form V of the compound of formula (A) according to any one of claims 33 to 38, further characterized by having a weight loss of about 0.22% before 200°C in thermogravimetric analysis.

40. CuK α Crystalline Form VI of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a ray containing characteristic peaks located at at least the following °2θ: 10.247±0.2, 12.198±0.2, and 17.258±0.

2.

41. CuK α 41. Crystalline Form VI of the compound of formula (A) according to claim 40, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks located at the following °2θ: 12.514±0.2, 17.596±0.2, 19.406±0.2, 21.888±0.2, and 27.599±0.

2.

42. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 7】 42. Crystalline Form VI of the compound of formula (A) according to claim 41, characterized in that it has the formula:

43. CuK α 43. Crystalline Form VI of the compound of formula (A) according to claim 41 or 42, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks located at the following °2θ: 18.659±0.2, 22.479±0.2, 23.799±0.2, 24.41±0.2, 25.158±0.2 and 28.504±0.

2.

44. 41. Crystalline Form VI of the compound of formula (A) according to claim 40, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 21.

45. Crystalline Form VI of the compound of formula (A) according to any one of claims 40 to 44, further characterized by having an endothermic peak at 233±2°C in differential scanning calorimetry analysis.

46. Crystalline Form VI of the compound of formula (A) according to any one of claims 40 to 45, further characterized by having substantially no weight loss before 200°C in thermogravimetric analysis.

47. CuK α Crystalline Form VII of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a 2000 MHz X-ray source contains at least the following characteristic peaks located at °2θ: 7.138±0.2 and 9.876±0.

2.

48. CuK α 48. Crystalline Form VII of the compound of formula (A) according to claim 47, characterized in that its X-ray powder diffraction pattern obtained using a 2000 MHz X-ray source further comprises characteristic peaks located at the following °2θ: 12.572±0.2, 12.945±0.2, 14.675±0.2, and 17.16±0.

2.

49. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 8】 49. Crystalline Form VII of the compound of formula (A) according to claim 48, characterized in that it has the formula:

50. 48. Crystalline Form VII of the compound of formula (A) according to claim 47, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 22.

51. Crystalline Form VII of the compound of formula (A) according to any one of claims 47 to 50, further characterized by having an endothermic peak at 232±2°C in differential scanning calorimetry analysis.

52. Crystalline Form VII of the compound of formula (A) of any one of claims 47-51, further characterized by having a weight loss of about 0.35% before 200°C in thermogravimetric analysis.

53. CuK α 1. A crystalline form I of the maleate salt (1:1) of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a 2000 MHz X-ray source contains characteristic peaks at least at the following °2θ positions: 9.737±0.2, 12.241±0.2, and 23.08±0.

2.

54. CuK α 54. The maleate (1:1) crystalline Form I of the compound of formula (A) according to claim 53, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following °2θ: 11.982±0.2, 13.601±0.2, 16.495±0.2, 17.186±0.2, 19.625±0.2 and 24.527±0.

2.

55. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 9】 55. The maleate (1:1) crystalline Form I of the compound of formula (A) according to claim 54, characterized in that it has the following structure:

56. CuK α 56. The maleate (1:1) Crystalline Form I of the compound of formula (A) according to claim 54 or 55, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following °2θ: 7.577±0.2, 15.286±0.2, 17.358±0.2, 17.553±0.2, 19.971±0.2, 22.087±0.2, 23.879±0.2, 25.239±0.2, 25.844±0.2, 26.189±0.2, 29.644±0.2 and 31.501±0.

2.

57. 54. The maleate (1:1) crystalline Form I of the compound of formula (A) according to claim 53, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 25.

58. 58. The maleate (1:1) crystalline Form I of the compound of formula (A) according to any one of claims 53 to 57, further characterized by having an endothermic peak at 209±2°C in differential scanning calorimetry analysis.

59. 59. The maleate (1:1) crystalline Form I of the compound of formula (A) according to any one of claims 53 to 58, further characterized by having a weight loss of about 0.44% before 175°C in thermogravimetric analysis.

60. CuK α Crystalline Form I of the acetate salt (1:1) of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy contains at least the following characteristic peaks located at °2θ: 12.866±0.2 and 23.129±0.

2.

61. CuK α 61. The acetate (1:1) crystalline Form I of the compound of formula (A) according to claim 60, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following °2θ: 10.521±0.2, 11.409±0.2, 13.005±0.2, 14.521±0.2, 17.91±0.2, and 21.14±0.

2.

62. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 10】 62. The acetate (1:1) crystalline Form I of the compound of formula (A) according to claim 61, characterized in that it has the formula:

63. CuK α 63. Crystalline Form I of the acetate salt (1:1) of compound of formula (A) according to claim 61 or 62, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following °2θ: 15.349±0.2, 16.707±0.2, 17.236±0.2, 18.343±0.2, 19.961±0.2, 22.536±0.2, 25.985±0.2 and 26.993±0.

2.

64. 61. The acetate (1:1) crystalline Form I of the compound of formula (A) according to claim 60, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 28.

65. 65. Crystalline Form I of the acetate salt (1:1) of compound of formula (A) according to any one of claims 60 to 64, further characterized by having an endothermic peak at 232±2°C in differential scanning calorimetry analysis.

66. 66. The acetate (1:1) Crystalline Form I of the compound of formula (A) according to any one of claims 60 to 65, further characterized by having a weight loss of about 0.67% before 140°C in thermogravimetric analysis.

67. CuK α Crystalline Form I of the p-toluenesulfonate salt (1:1) of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy contains at least the following characteristic peaks located at °2θ: 10.583±0.2 and 21.674±0.

2.

68. CuK α 68. The p-toluenesulfonate (1:1) Crystalline Form I of the compound of formula (A) according to claim 67, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following °2θ: 12.968±0.2 and 14.503±0.

2.

69. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 11】 69. The p-toluenesulfonate (1:1) crystalline Form I of the compound of formula (A) according to claim 68, characterized in that it has the following structure:

70. CuK α 70. Crystalline Form I of the p-toluenesulfonate salt (1:1) of compound of formula (A) according to claim 68 or 69, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following degrees 2θ: 5.544±0.2, 14.012±0.2, 16.886±0.2, 18.417±0.2, 19.607±0.2, 21.298±0.2, 23.266±0.2 and 26.437±0.

2.

71. 68. The p-toluenesulfonate (1:1) crystalline Form I of the compound of formula (A) according to claim 67, characterized in that it has an X-ray powder diffraction pattern substantially as shown in FIG.

31.

72. 72. Crystalline Form I of the p-toluenesulfonate salt (1:1) of compound of formula (A) according to any one of claims 67 to 71, further characterized by having an endothermic peak at 269±2°C in differential scanning calorimetry analysis.

73. 73. The p-toluenesulfonate (1:1) Crystalline Form I of the compound of formula (A) according to any one of claims 67 to 72, further characterized by having a weight loss of about 0.6% before 220°C in thermogravimetric analysis.

74. CuK α 1. The oxalate (1:1) crystalline Form I of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a 2000 MHz X-ray source contains at least the following characteristic peaks located at °2θ: 4.32±0.2 and 6.642±0.

2.

75. CuK α 75. The oxalate (1:1) crystalline Form I of the compound of formula (A) according to claim 74, characterized in that its X-ray powder diffraction pattern obtained using a ray source further comprises characteristic peaks located at the following °2θ: 5.54±0.2, 10.366±0.2, 10.98±0.2 and 13.242±0.

2.

76. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 12】 76. The oxalate (1:1) crystalline Form I of the compound of formula (A) according to claim 75, characterized in that it has the following structure:

77. 75. Crystalline Form I of the oxalate salt (1:1) of the compound of formula (A) according to claim 74, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 34.

78. 78. The oxalate (1:1) Crystalline Form I of the compound of formula (A) according to any one of claims 74 to 77, further characterized by having an endothermic peak at 209±2°C in differential scanning calorimetry analysis.

79. 79. The oxalate (1:1) Crystalline Form I of the compound of formula (A) according to any one of claims 74 to 78, further characterized by having a weight loss of about 0.86% before 130°C in thermogravimetric analysis.

80. CuK α Crystalline Form I of the sulfate salt of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a 2000 MHz X-ray source contains at least the following characteristic peaks located at °2θ: 15.763±0.2 and 23.266±0.

2.

81. CuK α 81. The sulfate salt crystalline Form I of the compound of formula (A) according to claim 80, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks located at the following °2θ: 11.604±0.2, 13.318±0.2, 14.74±0.2, 15.961±0.2, 18.385±0.2, 19.228±0.2, 21.413±0.2, 22.361±0.2, 23.936±0.2, and 24.958±0.

2.

82. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 13】 82. The sulfate crystalline Form I of the compound of formula (A) according to claim 81, characterized in that it has:

83. CuK α 83. Crystalline Form I of the sulfate salt of compound of formula (A) according to claim 81 or 82, characterized in that its X-ray powder diffraction pattern, obtained using a 2000 NMR spectroscopy (DMAC) line, further comprises characteristic peaks located at the following °2θ: 11.78±0.2, 12.667±0.2, 19.447±0.2, 22.083±0.2, 22.576±0.2, 23.618±0.2, 27.303±0.2, 27.522±0.2, 28.765±0.2, 29.725±0.2, 30.906±0.2 and 32.032±0.

2.

84. 81. Crystalline Form I of the sulfate salt of the compound of formula (A) according to claim 80, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 35.

85. 85. Crystalline Form I of the sulfate salt of the compound of formula (A) according to any one of claims 80 to 84, further characterized by having an endothermic peak at 251±2°C in differential scanning calorimetry analysis.

86. 86. The sulfate salt crystalline Form I of the compound of formula (A) according to any one of claims 80 to 85, further characterized by having a weight loss of about 2.95% before 90°C in thermogravimetric analysis.

87. CuK α Crystalline Form I of the hydrobromide salt of compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a 2000 MHz X-ray source contains characteristic peaks at least at the following °2θ: 13.206±0.2, 23.995±0.2, and 24.941±0.

2.

88. CuK α 88. Crystalline Form I of the hydrobromide salt of compound of formula (A) according to claim 87, characterized in that its X-ray powder diffraction pattern obtained using a ray source further comprises characteristic peaks located at the following °2θ: 9.222±0.2, 11.905±0.2, 19.937±0.2, 26.773±0.2, and 27.5±0.

2.

89. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 14】 89. Crystalline Form I of the hydrobromide salt of the compound of formula (A) according to claim 88, characterized in that it has the following structure:

90. CuK α 90. Crystalline Form I of the hydrobromide salt of compound of formula (A) according to claim 88 or 89, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following °2θ: 12.652±0.2, 14.702±0.2, 16.396±0.2, 16.924±0.2, 18.636±0.2, 19.148±0.2, 20.294±0.2, 21.102±0.2, 21.532±0.2, 25.492±0.2 and 33.154±0.

2.

91. 88. Crystalline Form I of the hydrobromide salt of the compound of formula (A) according to claim 87, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 36.

92. 92. Crystalline Form I of the hydrobromide salt of compound of formula (A) according to any one of claims 87 to 91, further characterized by having an endothermic peak at 241±2°C in differential scanning calorimetry analysis.

93. 93. Crystalline Form I of the hydrobromide salt of compound of formula (A) according to any one of claims 87 to 92, further characterized by having a weight loss of about 8.18% before 150°C in thermogravimetric analysis.

94. CuK α Crystalline Form I of the hydrochloride salt of compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a ray containing characteristic peaks at least at the following °2θ: 12.079±0.2, 13.319±0.2, and 24.093±0.

2.

95. CuK α 95. The hydrochloride salt crystalline Form I of compound of formula (A) according to claim 94, characterized in that its X-ray powder diffraction pattern obtained using a ray source further comprises characteristic peaks located at the following °2θ: 9.38±0.2, 12.749±0.2, 24.92±0.2 and 27.559±0.

2.

96. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: 【Table 15】 96. Crystalline hydrochloride salt form I of the compound of formula (A) according to claim 95, characterized in that it has the following structure:

97. CuK α 97. Crystalline Form I of the hydrochloride salt of compound of formula (A) according to claim 95 or 96, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following °2θ: 6.699±0.2, 7.944±0.2, 8.28±0.2, 14.111±0.2, 14.758±0.2, 17.103±0.2, 18.618±0.2, 19.996±0.2, 20.449±0.2, 21.83±0.2, 25.118±0.2, 26.613±0.2 and 27.006±0.

2.

98. 95. Crystalline Form I of the hydrochloride salt of the compound of formula (A) according to claim 94, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 37.

99. 99. Crystalline Form I of the hydrochloride salt of compound of formula (A) according to any one of claims 94 to 98, further characterized by having an endothermic peak at 221±2°C in differential scanning calorimetry analysis.

100. 100. The hydrochloride salt Crystalline Form I of compound of formula (A) according to any one of claims 94 to 99, further characterized by having a weight loss of about 1.67% before 125°C and a weight loss of about 3.84% between 125 and 230°C in thermogravimetric analysis.

101. CuK α 1. The mesylate (1:1) crystalline form I of the compound of formula (A), characterized in that its X-ray powder diffraction pattern obtained using a ray contains at least the following characteristic peak located at °2θ: 8.338±0.

2.

102. CuK α 102. The mesylate (1:1) crystalline Form I of the compound of formula (A) according to claim 101, characterized in that its X-ray powder diffraction pattern obtained using a 2000 NMR spectroscopy further comprises characteristic peaks at the following °2θ: 11.706±0.2, 13.932±0.2, 14.738±0.2, 18.341±0.2, 21.148±0.2, 21.588±0.2, 22.597±0.2 and 25.732±0.

2.

103. CuK α Its X-ray powder diffraction pattern obtained using a 2000 MHz NMR spectroscopy shows the following characteristic peaks: Table 16 103. The mesylate (1:1) crystalline form I of the compound of formula (A) according to claim 102, characterized in that it has the following structure:

104. CuK α 104. Crystalline Form I of the mesylate (1:1) salt of the compound of formula (A) according to claim 102 or 103, characterized in that its X-ray powder diffraction pattern obtained using a 200 MHz X-ray source further comprises characteristic peaks at the following °2θ: 9.363±0.2, 10.092±0.2, 12.513±0.2, 15.053±0.2, 15.742±0.2, 19.093±0.2, 23.17±0.2, 23.716±0.2, 24.469±0.2, 24.65±0.2, 24.824±0.2, 30.238±0.2 and 32.189±0.

2.

105. 102. The mesylate (1:1) crystalline form I of the compound of formula (A) according to claim 101, characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 40.

106. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 105 and a pharmaceutically acceptable excipient.

107. Ingredients: (i) the crystalline form according to any one of claims 1 to 105; (ii) a diluent; (iii) a disintegrant, (iv) a binder, and (v) lubricant 10. A pharmaceutical composition comprising:

108. 108. The pharmaceutical composition of claim 107, wherein the crystalline form comprises 1-30%, alternatively 2-20%, alternatively 3-15%, and further alternatively about 4%, 5%, 6%, 7%, 8%, 9% or 10% by weight of the total weight of the pharmaceutical composition, based on the weight of the free base of the compound, and alternatively the amount of crystalline form in a unit dose is 1-100 mg, alternatively 2-50 mg, alternatively 3-40 mg, or alternatively about 5, 10, 15, 20, 25, 30, 35 or 40 mg.

109. 109. The pharmaceutical composition of any one of claims 107-108, wherein the diluent constitutes 65-95% by weight, alternatively 70-90% by weight, alternatively about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90% by weight of the total weight of the pharmaceutical composition, and alternatively the amount of diluent in a unit dose is 50-380 mg, alternatively 60-360 mg, alternatively 70-350 mg, for example about 70 mg or 350 mg.

110. 110. The pharmaceutical composition of any one of claims 107 to 109, wherein the diluent is selected from the group consisting of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and mannitol, e.g., microcrystalline cellulose 102, mannitol 100SD, and mannitol 50C, and mixtures thereof; alternatively, when both microcrystalline cellulose 102 and mannitol 50C are present, the weight ratio of microcrystalline cellulose 102 to mannitol 50C is from 5:1 to 1:5, alternatively from 3:1 to 1:2, alternatively about 2:

1.

111. 111. The pharmaceutical composition of any one of claims 107-110, wherein the disintegrant comprises 1-5% by weight, alternatively 2-4% by weight, alternatively about 2%, 2.5%, 3%, 3.5% or 4% by weight of the total weight of the pharmaceutical composition, and alternatively the amount of disintegrant in a unit dose is 1-20 mg, alternatively 2-16 mg, alternatively about 2, 2.5, 3, 6, 9 or 12 mg.

112. 112. The pharmaceutical composition of any one of claims 107 to 111, wherein the disintegrant is croscarmellose sodium or crospovidone XL-10, alternatively croscarmellose sodium.

113. 113. The pharmaceutical composition of any one of claims 107-112, wherein the binder constitutes 1-5% by weight, alternatively 2-4% by weight, alternatively about 2%, 2.5%, 3%, 3.5% or 4% by weight of the total weight of the pharmaceutical composition, and alternatively the amount of binder in a unit dose is 1-20 mg, alternatively 2-16 mg, alternatively about 2, 2.5, 3, 6, 9 or 12 mg.

114. 114. The pharmaceutical composition of any one of claims 107 to 113, wherein the binder is hydroxypropyl cellulose EXF or povidone K30, alternatively hydroxypropyl cellulose EXF.

115. 115. The pharmaceutical composition of any one of claims 107-114, wherein the lubricant comprises 0.1 to 5% by weight, alternatively 0.5 to 2% by weight, alternatively about 1% by weight of the total weight of the pharmaceutical composition, and alternatively the amount of lubricant in a unit dose is 0.1 to 20 mg, alternatively 0.5 to 8 mg, alternatively about 0.5, 1, 2, 3, 4, 5, 6, 7 or 8 mg.

116. 116. A pharmaceutical composition according to any one of claims 107 to 115, wherein the lubricant is magnesium stearate or sodium stearyl fumarate PRUV, alternatively magnesium stearate.

117. Ingredients: (i) 1 to 30 wt % of Compound A Crystalline Form I; (ii) 65-95% by weight of microcrystalline cellulose 102 and mannitol 50C (2:1 by weight); (iii) 2-4 wt. % croscarmellose sodium; (iv) 2-4 wt. % of hydroxypropyl cellulose EXF, and (v) 0.1 to 5% by weight of magnesium stearate 117. The pharmaceutical composition of any one of claims 107 to 116, comprising:

118. Unit doses of the following ingredients: (i) approximately 5 mg of Compound A Crystalline Form I; (ii) about 45 mg microcrystalline cellulose 102 and about 25 mg mannitol 50C; (iii) about 2.5 mg of croscarmellose sodium; (iv) about 2.5 mg of hydroxypropyl cellulose EXF, and (v) about 1 mg of magnesium stearate 118. The pharmaceutical composition of claim 117, comprising:

119. Unit doses of the following ingredients: (i) approximately 25 mg of Compound A Crystalline Form VI; (ii) about 230 mg lactose monohydrate and about 120 mg microcrystalline cellulose; (iii) about 12 mg of croscarmellose sodium; (iv) about 12 mg of hydroxypropyl cellulose EXF, and (v) about 4 mg of magnesium stearate 118. The pharmaceutical composition of claim 117, comprising:

120. 120. The pharmaceutical composition of any one of claims 107 to 119, which is a tablet, alternatively a coated tablet, alternatively the coating agent is Opadry II 85F620077.

121. Use of the crystalline form of any one of claims 1 to 105 in the manufacture of a medicament for the treatment and / or prevention of diseases mediated by ALK and ROS1 kinases and their mutants.

122. 106. Use of a crystalline form according to any one of claims 1 to 105 in the manufacture of a medicament for the treatment and / or prevention of the following diseases: cell proliferative disorders, inflammation, infection, immune disorders, organ transplantation, viral disorders, cardiovascular disorders or metabolic disorders, such as non-small cell lung cancer, lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer, osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer, colorectal cancer, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, or cystic fibrosis.

123. A crystalline form according to any one of claims 1 to 105 for use in the treatment and / or prevention of diseases mediated by ALK and ROS1 kinases and mutants thereof.

124. 106. A crystalline form of a compound of formula (A) according to any one of claims 1 to 105 for use in the treatment and / or prevention of a cell proliferative disorder, inflammation, infection, immune disorder, organ transplant, viral disease, cardiovascular disease or metabolic disorder, such as non-small cell lung cancer, lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer, osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer, colorectal cancer, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, or cystic fibrosis.

125. A method of treating and / or preventing diseases mediated by ALK and ROS1 kinases and their mutants in a subject, comprising administering to the subject a crystalline form according to any one of claims 1 to 105.

126. 106. A method for treating and / or preventing the following diseases in a subject, comprising administering to the subject a crystalline form of the compound of formula (A) of any one of claims 1 to 105: a cell proliferative disease, inflammation, infection, immune disease, organ transplant, viral disease, cardiovascular disease or metabolic disease, such as non-small cell lung cancer, lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer, osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer, colorectal cancer, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, or cystic fibrosis.

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