Solid forms of macrocyclic compounds and their preparation and use

Abstract

The present invention relates to a crystalline form of a free base of a compound of formula (A) (compound A) or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, and the use of the compound in the preparation of a medicament for the treatment and / or prevention of diseases mediated by ALK kinase and mutants thereof, the invention also relates to the use of the pharmaceutical composition in treating diseases such as cell proliferative diseases, inflammation, infection, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases. # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with application date of May 18, 2021 and application number 202180034182.2. Field of the Invention

[0002] The present invention belongs to the field of medical technology, and in particular relates to a crystalline form of a free base or a pharmaceutically acceptable salt of a macrocyclic compound (10R)-7-amino-12-fluoro-2-(methyl-d3)-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(methylene bridge)pyrazolo[4,3-h][2,5,11]benzoxadiazatetradecane-3-carbonitrile (compound of formula (A) or compound A), a preparation method thereof, and use of the compound in the preparation of a drug for treating diseases mediated by anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) and mutants thereof, such as non-small cell lung cancer. Background Art

[0003] The chemical formula of compound A is C 21 H 16 D3FN6O2, with a molecular weight of 409.17 g / mol, has the following chemical structure:

[0004]

[0005] Compound A is a deuterium-containing ALK and ROS1 kinase inhibitor that can be used to treat diseases mediated by ALK and ROS1 kinases and their mutants, including cell proliferative disorders, inflammation, infection, immune diseases, organ transplantation, 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, gastric cancer, liver cancer, bladder cancer, thyroid cancer, or colorectal cancer, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, or cystic fibrosis. International Patent Publication No. WO 2017 / 148325 A1 initially disclosed this compound, but did not disclose a crystalline form of Compound A. The applicant for WO 2017 / 148325 A1 is Shenzhen Tajiri Biopharmaceutical Co., Ltd. Its corresponding Chinese application CN 201780013374.9 was published on October 18, 2019, under Grant Publication No. CN 108699081 B. Its US application US 16 / 081,611 was published on January 28, 2020, under Grant Publication No. US10543199 B2. Its European application EP 17759176.5 has received a Letter of Intent. Its Japanese application JP2018-545928 is still under review. The contents of each of the aforementioned applications are incorporated herein by reference in their entirety.

[0006] ALK is a receptor-type protein tyrosine kinase that belongs to the insulin receptor superfamily. It was discovered in 1994 by Morris, Shiota, and colleagues as a product of a chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). The most common fusion occurs between the NPM (Nucleophosmin) gene on chromosome 5 and the ALK gene on chromosome 2. NPM-ALK fusion protein is detected in nearly 75% of ALK-positive ALCL patients. Subsequent studies have found different ALK fusion forms in a variety of cancers, including inflammatory myofibroblastic tumor and diffuse large B-cell lymphoma. In 2007, Soda et al. found that the EML4-ALK fusion protein occurs in 5% of non-small-cell lung cancer (NSCLC) cases.

[0007] ROS1 is a proto-oncogene receptor tyrosine kinase belonging to the insulin receptor subfamily and is involved in cell proliferation and differentiation. ROS1 is expressed in epithelial cells of various human tissues. ROS1 expression and / or activation have been found in glioblastoma and tumors of the central nervous system. Genetic alterations of ROS1 that result in abnormal fusion proteins leading to ROS1 kinase include FIG-ROS1 deletion translocation in glioblastoma and non-small cell lung cancer (NSCLC), SLC34A2-ROS1 translocation in NSCLC, and CD74-ROS1 translocation in NSCLC and cholangiocarcinoma. Additional fusions have been found in tumor samples from lung cancer patients, including TPM3-ROS1, SDC4-ROS1, EZR-ROS1, and LRTG3-ROS1. SUMMARY OF THE INVENTION

[0008] In one aspect, the present invention provides various crystalline forms of the free base of Compound A.

[0009] In one embodiment, the present invention provides Form I of Compound A (Compound A Form I).

[0010] In one embodiment, the present invention provides Form II of Compound A (Compound A Form II).

[0011] In one embodiment, the present invention provides Form III of Compound A (Compound A Form III).

[0012] In one embodiment, the present invention provides Form IV of Compound A (Compound A Form IV).

[0013] In one embodiment, the present invention provides Form V of Compound A (Compound A Form V).

[0014] In one embodiment, the present invention provides Form VI of Compound A (Compound A Form VI).

[0015] In one embodiment, the present invention provides Form VII of Compound A (Compound A Form VII).

[0016] In another aspect, the present invention provides various crystalline forms of salts of Compound A.

[0017] In one embodiment, the present invention provides Compound A maleate salt Form I (Compound A maleate salt Form I).

[0018] In one embodiment, the present invention provides Compound A acetate salt Form I (Compound A acetate salt Form I).

[0019] In one embodiment, the present invention provides Compound A p-toluenesulfonate crystalline Form I (Compound A p-toluenesulfonate crystalline Form I).

[0020] In one embodiment, the present invention provides Compound A oxalate Form I (Compound A oxalate Form I).

[0021] In one embodiment, the present invention provides Compound A sulfate salt Form I (Compound A sulfate salt Form I).

[0022] In one embodiment, the present invention provides Compound A hydrobromide Form I (Compound A hydrobromide Form I).

[0023] In one embodiment, the present invention provides Compound A hydrochloride Form I (Compound A hydrochloride Form I).

[0024] In one embodiment, the present invention provides Compound A mesylate Form I (Compound A mesylate Form I).

[0025] In another aspect, the present invention provides a pharmaceutical composition comprising any crystalline form of the present invention, and a pharmaceutically acceptable excipient.

[0026] In another aspect, the present invention provides a pharmaceutical composition comprising (i) a pharmaceutically active ingredient: 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.

[0027] In another aspect, the present invention provides use of any crystalline form of the present invention in preparing a method for treating and / or preventing diseases mediated by ALK and ROS1 kinases and mutants thereof.

[0028] In another aspect, the present invention provides any crystalline form of the present invention for use in treating and / or preventing diseases mediated by ALK and ROS1 kinases and mutants thereof.

[0029] In another aspect, the present invention provides a method for treating and / or preventing a disease mediated by ALK and ROS1 kinases and mutants thereof in a subject, comprising administering any crystalline form of the present invention to the patient.

[0030] In one embodiment, the diseases include cell proliferative diseases, inflammation, infection, immune diseases, organ transplantation, 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, or colorectal cancer, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, or cystic fibrosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 XRPD pattern of Compound A Form I.

[0032] Figure 2 DSC graph of Compound A Form I.

[0033] Figure 3 TGA chart of Compound A Form I.

[0034] Figure 4 DVS pattern of Compound A Form I.

[0035] Figure 5 XRPD comparison of compound A Form I before and after DVS testing.

[0036] Figure 6 Compound A Form I 1 H NMR spectrum.

[0037] Figure 7 Compound A Form I 13 C NMR spectrum.

[0038] Figure 8 DEPT diagram of Compound A Form I.

[0039] Figure 9 D NMR spectrum of Compound A Form I.

[0040] Figure 10 Compound A Form I 19 F NMR spectrum.

[0041] Figure 11 HSQC-NMR spectrum of Compound A Form I.

[0042] Figure 12 HMBC-NMR spectrum of Compound A Form I.

[0043] Figure 13 COSY-NMR spectrum of Compound A Form I.

[0044] Figure 14IR spectrum of Compound A Form I.

[0045] Figure 15 UV image of Compound A Form I.

[0046] Figure 16 HR-MS spectrum of Compound A Form I.

[0047] Figure 17 XRPD pattern of Compound A Form II.

[0048] Figure 18 XRPD pattern of Compound A Form III.

[0049] Figure 19 XRPD pattern of Compound A Form IV.

[0050] Figure 20 XRPD pattern of Compound A Form V.

[0051] Figure 21 XRPD pattern of Compound A Form VI.

[0052] Figure 22 XRPD pattern of Compound A Form VII.

[0053] Figure 23 XRPD pattern of the solid obtained by slurrying the free base of Compound A at room temperature.

[0054] Figure 24 XRPD pattern of Compound A Form V heated to 190°C.

[0055] Figure 25 XRPD pattern of Compound A maleate salt Form I.

[0056] Figure 26 DVS image of Compound A maleate salt Form I.

[0057] Figure 27 XRPD comparison of Compound A maleate salt Form I before and after DVS test.

[0058] Figure 28 XRPD pattern of Compound A acetate salt Form I.

[0059] Figure 29 DVS pattern of Compound A acetate salt Form I.

[0060] Figure 30 XRPD comparison of Compound A acetate Form I before and after DVS testing.

[0061] Figure 31 XRPD pattern of Compound A p-toluenesulfonate Form I.

[0062] Figure 32 DVS pattern of Compound A p-toluenesulfonate Form I.

[0063] Figure 33 XRPD comparison of Compound A p-toluenesulfonate Form I before and after DVS test.

[0064] Figure 34 XRPD pattern of Compound A oxalate Form I.

[0065] Figure 35 XRPD pattern of Compound A sulfate salt Form I.

[0066] Figure 36 XRPD pattern of Compound A hydrobromide salt Form I.

[0067] Figure 37 XRPD pattern of Compound A hydrochloride Form I.

[0068] Figure 38 DVS image of Compound A hydrochloride Form I.

[0069] Figure 39 XRPD comparison of Compound A hydrochloride Form I before and after DVS test.

[0070] Figure 40 XRPD pattern of Compound A mesylate salt Form I.

[0071] Figure 41 XRPD pattern of Compound A Form I from the accelerated stability study.

[0072] Figure 42 XRPD pattern of accelerated stability study of Compound A maleate salt Form I.

[0073] Figure 43 XRPD pattern of accelerated stability study of Compound A acetate salt Form I.

[0074] Figure 44 XRPD pattern of the accelerated stability study of compound A p-toluenesulfonate Form I.

[0075] Figure 45 XRPD patterns of Compound A Form I in different dissolution media.

[0076] Figure 46 XRPD patterns of Compound A maleate salt Form I in different dissolution media.

[0077] Figure 47 XRPD patterns of compound A acetate salt form I in different dissolution media.

[0078] Figure 48Single crystal structure of Compound A Form I.

[0079] Figure 49 Comparison of the calculated and measured XRPD patterns of a single crystal sample of Compound A. Detailed Description of the Invention

[0080] The present invention may be more readily understood by reference to the following detailed description of embodiments of the invention and the examples included herein. It should be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. It should be further understood that, unless otherwise specifically defined herein, the terms used herein should be given their ordinary meanings known in the relevant art.

[0081] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. For example, "a" compound includes one or more compounds.

[0082] The term "about" refers to a value that falls within the accepted standard error of the mean when considered by one of ordinary skill in the art. For example, "about" means ±10% of the indicated amount, or ±5% of the indicated amount.

[0083] As used herein, the term "substantially" means taking into account the variability typical of a particular method and the standard error of the measured values. For example, with respect to the positions of X-ray powder diffraction peaks, the term "substantially" means taking into account the typical variability of peak positions and intensities. One skilled in the art will recognize that peak positions (2θ) will show some variability, typically up to ±0.2°. In addition, one skilled in the art will recognize that relative peak intensities will show variability between devices as well as variability due to crystallinity, preferred orientation, sample surface tested, and other factors known to one skilled in the art. Similarly, 1 H. 13 C and 19 The NMR spectrum of F (ppm) showed variability, typically up to ±0.2 ppm.

[0084] As used herein, the terms "crystalline" and "crystal form" refer to a solid having a regularly repeating arrangement of molecules. Crystalline forms can differ in thermodynamic stability, physical parameters, X-ray structure, and preparation process.

[0085] The term "amorphous" refers to a solid composed of a disordered arrangement of molecules.

[0086] As used herein, the term "solvate" refers to a crystalline form having a stoichiometric or non-stoichiometric amount of a solvent (such as water, methanol, ethyl acetate, or the like, or a mixture thereof) bound in the crystal lattice by non-covalent intermolecular bonding. The term "hydrate" refers to a solvate wherein the solvent is water.

[0087] As used herein, the term "anhydrous" refers to crystalline forms containing less than about 1% (w / w) adsorbed water as determined by standard methods such as Karl Fisher analysis.

[0088] Compound A and its crystal form

[0089] The compound, (10R)-7-amino-12-fluoro-2-(methyl-d3)-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(methine-bridged)pyrazolo[4,3-h][2,5,11]benzoxadiazatetradecane-3-carbonitrile, referred to herein as Compound A, or Compound A free base, has the following formula:

[0090]

[0091] The present invention relates to various crystalline forms of Compound A, such as "Compound A Form I," "Compound A Form II," "Compound A Form III," "Compound A Form IV," "Compound A Form V," "Compound A Form VI," and "Compound A Form VII." In some embodiments, the crystalline forms of these compounds may be in the form of solvates, hydrates, or non-solvates.

[0092] Compound A Crystal Form I

[0093] In one embodiment, the present invention provides Compound A Form I, which is an anhydrate.

[0094] In another embodiment, in the presence of CuK α The X-ray powder diffraction pattern of the crystalline Form I obtained by irradiation includes at least characteristic peaks located at the following °2θ: 16.175±0.2, 17.299±0.2, and 21.218±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located at the following °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 includes characteristic peaks located 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.

[0095] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0096]

[0097]

[0098] 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 Figure 1 shown.

[0099] In another embodiment, Form I has a melting endotherm at 232±2°C in differential scanning calorimetry.

[0100] In another embodiment, Form I exhibits substantially no weight loss before 150° C. in thermogravimetric analysis.

[0101] In another embodiment, Form I has the following single crystal parameters:

[0102]

[0103] In another embodiment, Form I has an infrared absorption spectrum at the following cm -1 In another embodiment, Form I has 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. Figure 14 Infrared absorption spectrum shown.

[0104] In another embodiment, Form I has absorption peaks in the UV spectrum at the following nm: 206±2 and 317±2. In another embodiment, Form I has substantially Figure 15 UV spectrum shown.

[0105] In one embodiment, the present invention provides Compound A Form II, which is a butanone complex.

[0106] In another embodiment, in the presence of CuK αThe X-ray powder diffraction pattern of Form II obtained by irradiation includes at least characteristic peaks located at the following °2θ: 7.591±0.2, 12.081±0.2, and 23.364±0.2. In another embodiment, the X-ray powder diffraction pattern further includes 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.

[0107] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0108] Angle °2θ±0.2°2θ Relative strength % 7.591 100 12.081 24.7 14.577 12.9 15.595 10.2 16.948 14.2 17.615 14.4 20.448 14.6 23.364 17.4 .

[0109] 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 Figure 17 shown.

[0110] In another embodiment, Form I has a melting endotherm at 230±2°C in differential scanning calorimetry.

[0111] In another embodiment, Form I has a weight loss of about 6.69% by 160°C in thermogravimetric analysis.

[0112] In one embodiment, the present invention provides Compound A Form III, which is a butanone complex.

[0113] In another embodiment, in the presence of CuK α The X-ray powder diffraction pattern of the crystalline Form III obtained by irradiation includes at least a characteristic peak located at the following °2θ: 23.149 ± 0.2. In another embodiment, the X-ray powder diffraction pattern further includes 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. In another embodiment, the X-ray powder diffraction pattern further includes 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.

[0114] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0115] Angle °2θ±0.2°2θ Relative strength % 11.429 22.2 13.027 21.7 14.542 21.3 17.949 19.1 23.149 100 26.994 20.4 .

[0116] 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 Figure 18 shown.

[0117] In another embodiment, Form III has a melting endotherm at 226 ± 2 °C in differential scanning calorimetry.

[0118] In another embodiment, Form III has a weight loss of about 5.31% by 165°C in thermogravimetric analysis.

[0119] In one embodiment, the present invention provides Compound A Form IV, which is an anhydrate.

[0120] In another embodiment, in the presence of CuK α The X-ray powder diffraction pattern of the crystalline Form IV obtained by irradiation comprises at least a characteristic peak located at the following °2θ: 10.113±0.2. In another embodiment, the X-ray powder diffraction pattern 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. In another embodiment, the X-ray powder diffraction pattern 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.

[0121] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0122] Angle °2θ±0.2°2θ Relative strength % 10.113 100 11.583 31 11.768 35.2 12.098 25.9 17.143 46.2 19.267 26.6 .

[0123] 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 Figure 19 shown.

[0124] In another embodiment, Form IV has a melting endotherm at 232 ± 2 °C in differential scanning calorimetry.

[0125] In another embodiment, Form IV has a weight loss of about 0.28% by 200°C in thermogravimetric analysis.

[0126] In one embodiment, the present invention provides Compound A Form V, which is an anhydrate.

[0127] In another embodiment, in the presence of CuK α The X-ray powder diffraction pattern of the crystalline form V obtained by irradiation includes at least characteristic peaks located at the following °2θ: 6.939±0.2, 16.276±0.2 and 17.494±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located 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. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located 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.

[0128] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0129] Angle °2θ±0.2°2θ Relative strength % 4.912 28.1 6.939 100 9.774 30.1 12.709 41.4 14.246 29.4 14.482 33.4 16.276 55.9 17.242 42.4 17.494 76.9 18.519 25.7 19.425 34.7 21.001 27.3 21.317 29.5 22.734 26.7 25.218 28.2 29.688 26.1 .

[0130] 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 Figure 20 shown.

[0131] In another embodiment, Form V has a melting endotherm at 232 ± 2 °C in differential scanning calorimetry.

[0132] In another embodiment, Form V has a weight loss of about 0.22% by 200°C in thermogravimetric analysis.

[0133] In one embodiment, the present invention provides Compound A Form VI, which is an anhydrate.

[0134] In another embodiment, in the presence of CuK αThe X-ray powder diffraction pattern of Form VI obtained by radiation includes at least characteristic peaks located at the following °2θ: 10.247±0.2, 12.198±0.2 and 17.258±0.2. In another embodiment, the X-ray powder diffraction pattern further includes 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. In another embodiment, the X-ray powder diffraction pattern further includes 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.

[0135] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0136] Angle °2θ±0.2°2θ Relative strength % 10.247 100 12.198 70.6 12.514 42.8 17.258 53.8 17.596 44.5 19.406 27.9 21.888 30.3 27.599 27.5 .

[0137] 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 Figure 21 shown.

[0138] In another embodiment, Form VI has a melting endotherm at 233 ± 2 °C in differential scanning calorimetry.

[0139] In another embodiment, Form VI shows almost no weight loss before 200° C. in thermogravimetric analysis.

[0140] In one embodiment, the present invention provides Compound A Form VII, which is a solvate.

[0141] In another embodiment, in the presence of CuK α The X-ray powder diffraction pattern of Form VII obtained by irradiation includes at least characteristic peaks located at the following °2θ: 7.138±0.2 and 9.876±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located at the following °2θ: 12.572±0.2, 12.945±0.2, 14.675±0.2, and 17.16±0.2.

[0142] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0143] Angle °2θ±0.2°2θ Relative strength % 7.138 100 9.876 51.2 12.572 31.6 12.945 38.5 14.675 30.3 17.16 26.2 .

[0144] 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 Figure 22 shown.

[0145] In another embodiment, Form VII has a melting endotherm at 232 ± 2 °C in differential scanning calorimetry.

[0146] In another embodiment, Form VII has a weight loss of about 0.35% by 200°C in thermogravimetric analysis.

[0147] Salt of compound A and its crystal form

[0148] The present invention relates to various salts of Compound A, such as maleate, acetate, p-toluenesulfonate, hydrobromide, sulfate, oxalate, hydrochloride, and methanesulfonate.

[0149] The present invention also relates to various crystalline forms of compound A salts, such as "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 methanesulfonate form I".

[0150] Compound A maleate salt form I

[0151] In one embodiment, the present invention provides Compound A maleate (1:1) crystalline Form I, which is an anhydrate.

[0152] In another embodiment, in the presence of CuK α The X-ray powder diffraction pattern of the crystalline form obtained by irradiation includes at least characteristic peaks located at the following °2θ: 9.737±0.2, 12.241±0.2 and 23.08±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located 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. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located 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.

[0153] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0154] Angle °2θ±0.2°2θ Relative strength % 9.737 80 11.982 41 12.241 100 13.601 28 16.495 32 17.186 25 19.625 38 23.08 98 24.527 36 .

[0155] 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 Figure 25 shown.

[0156] In another embodiment, the crystalline form has a melting endotherm peak at 209±2°C in differential scanning calorimetry analysis.

[0157] In another embodiment, the crystalline form has a weight loss of about 0.44% before 175°C in thermogravimetric analysis.

[0158] Compound A acetate (1:1) Form I

[0159] In one embodiment, the present invention provides Compound A acetate (1:1) Form I, which is an anhydrate.

[0160] In another embodiment, in the presence of CuK α The X-ray powder diffraction pattern of the crystalline form obtained by irradiation includes at least characteristic peaks located at the following °2θ: 12.866±0.2 and 23.129±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located 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. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located 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.

[0161] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0162] Angle °2θ±0.2°2θ Relative strength % 10.521 35.1 11.409 46.7 12.866 50.7 13.005 26.2 14.521 45.3 17.91 39.3 21.14 27.3 23.129 100 .

[0163] 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 Figure 28 shown.

[0164] In another embodiment, the crystalline form has a melting endotherm peak at 232±2°C in differential scanning calorimetry analysis.

[0165] In another embodiment, the crystalline form has a weight loss of about 0.67% before 140°C in thermogravimetric analysis.

[0166] Compound A p-toluenesulfonate (1:1) Form I

[0167] In one embodiment, the present invention provides Compound A p-toluenesulfonate (1:1) crystalline Form I, which is an anhydrate.

[0168] In another embodiment, in the presence of CuK α The X-ray powder diffraction pattern of the crystalline form obtained by irradiation includes at least characteristic peaks located at the following °2θ: 10.583±0.2 and 21.674±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located at the following °2θ: 12.968±0.2 and 14.503±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located at the following °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.

[0169] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0170] Angle °2θ±0.2°2θ Relative strength % 10.583 100 12.968 29.6 14.503 38.6 21.674 51.3 .

[0171] 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 Figure 31 shown.

[0172] In another embodiment, the crystalline form has a melting endotherm peak at 269±2°C in differential scanning calorimetry analysis.

[0173] In another embodiment, the crystalline form has a weight loss of about 0.6% before 220°C in thermogravimetric analysis.

[0174] Compound A oxalate (1:1) Form I

[0175] In one embodiment, the present invention provides Compound A oxalate (1:1) Form I, which is a solvate.

[0176] In another embodiment, in the presence of CuK α The X-ray powder diffraction pattern of the crystalline form obtained by irradiation includes at least characteristic peaks located at the following °2θ: 4.32±0.2 and 6.642±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located at the following °2θ: 5.54±0.2, 10.366±0.2, 10.98±0.2 and 13.242±0.2.

[0177] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0178]

[0179]

[0180] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values in Table 7.4. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 34 shown.

[0181] In another embodiment, the crystalline form has a melting endotherm peak at 209±2°C in differential scanning calorimetry analysis.

[0182] In another embodiment, the crystalline form has a weight loss of about 0.86% before 130°C in thermogravimetric analysis.

[0183] Compound A sulfate crystal form I

[0184] In one embodiment, the present invention provides Compound A sulfate salt Form I, which is a monohydrate.

[0185] In another embodiment, in the presence of CuK αThe X-ray powder diffraction pattern of the crystalline form obtained by radiation includes at least characteristic peaks located at the following °2θ: 15.763±0.2 and 23.266±0.2. In another embodiment, the X-ray powder diffraction pattern further includes 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 includes 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.

[0186] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0187] Angle °2θ±0.2°2θ Relative strength % 11.604 33.5 13.318 37.9 14.74 30.9 15.763 96.3 15.961 28.5 18.385 45.4 19.228 28.6 21.413 44.1 22.361 44.3 23.266 100 23.936 27.4 24.958 28.3 .

[0188] 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 shown.

[0189] In another embodiment, the crystalline form has a melting endotherm peak at 251±2°C in differential scanning calorimetry analysis.

[0190] In another embodiment, the crystalline form has a weight loss of about 2.95% before 90°C in thermogravimetric analysis.

[0191] Compound A hydrobromide salt form I

[0192] In one embodiment, the present invention provides Compound A hydrobromide salt Form I, which is a monohydrate.

[0193] In another embodiment, in the presence of CuK αThe X-ray powder diffraction pattern of the crystalline form obtained by irradiation includes at least characteristic peaks located at the following °2θ: 13.206±0.2, 23.995±0.2, and 24.941±0.2. In another embodiment, the X-ray powder diffraction pattern further includes 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. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located 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.

[0194] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0195] Angle °2θ±0.2°2θ Relative strength % 9.222 25.3 11.905 39.8 13.206 100 19.937 28 23.995 83.3 24.941 60.9 26.773 33.3 27.5 45.1 .

[0196] 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. Figure 36 shown.

[0197] In another embodiment, the crystalline form has a melting endotherm peak at 241±2°C in differential scanning calorimetry analysis.

[0198] In another embodiment, the crystalline form has a weight loss of about 8.18% before 150°C in thermogravimetric analysis.

[0199] Compound A hydrochloride form I

[0200] In one embodiment, the present invention provides Compound A hydrochloride Form I, which is a solvate.

[0201] In another embodiment, in the presence of CuK αThe X-ray powder diffraction pattern of the crystalline form obtained by irradiation includes at least characteristic peaks located at the following °2θ: 12.079±0.2, 13.319±0.2 and 24.093±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located at the following °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 includes characteristic peaks located 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.

[0202] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0203] Angle °2θ±0.2°2θ Relative strength % 9.38 35.3 12.079 52 12.749 26.8 13.319 100 24.093 59.9 24.92 47 27.559 25.7 .

[0204] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values in Table 7.7. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 37 shown.

[0205] In another embodiment, the crystalline form has a melting endotherm peak at 221±2°C in differential scanning calorimetry analysis.

[0206] In another embodiment, the crystalline form 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.

[0207] Compound A methanesulfonate (1:1) Form I

[0208] In one embodiment, the present invention provides Compound A mesylate (1:1) Form I.

[0209] In another embodiment, in the presence of CuK αThe X-ray powder diffraction pattern of the crystalline form obtained by irradiation includes at least a characteristic peak located at the following °2θ: 8.338±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located 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. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks located 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.

[0210] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks:

[0211] Angle °2θ±0.2°2θ Relative strength % 8.338 100 11.706 91.7 13.932 80.9 14.738 56.7 18.341 82.2 21.148 50.3 21.588 72 22.597 51 25.732 69.4 .

[0212] In another embodiment, the X-ray powder diffraction pattern comprises one or more peaks at the 2θ values in Table 7.8. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. Figure 40 shown.

[0213] Substantially pure crystalline form of Compound A

[0214] The present invention provides a method for synthesizing a high-purity and high-chiral-purity crystalline form of Compound A that is safe and suitable for large-scale production and can be used in compositions comprising the crystalline form of Compound A. In one aspect, the crystalline form of Compound A is produced in a commercial-scale process. The term "commercial-scale process" refers to a method that operates in a single batch of at least about 100 g. In one aspect, the method of the present application produces the crystalline form of Compound A with improved yield (>90%) and limited impurities.

[0215] As used herein, the term "purity" refers to the percentage of Compound A crystalline form present as determined by HPLC. Purity is based on the "organic" purity of the compound. Purity excludes water, solvents, metals, inorganic salts, etc. The purity of Compound A crystalline form is compared to the purity of a reference standard by comparing the area under the peak.

[0216] In one embodiment, the crystalline form of Compound A has a purity of not less than about 96%. In another embodiment, the crystalline form of Compound A has a purity of not less than about 98%. In another embodiment, the crystalline form of Compound A has a purity of not less than about 98.5%. In another embodiment, the crystalline form of Compound A has a purity of not less than about 99%. In another embodiment, the crystalline form of Compound A has a purity of not less than about 99.5%. In another embodiment, the purity of the crystalline form of Compound A is 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%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98 ... .8%, 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%.

[0217] The crystal form of Compound A prepared by the present invention contains a chiral carbon atom and is in the R-configuration. The chiral center of the crystal form of Compound A is introduced by the starting material and does not participate in subsequent steps, and no racemization phenomenon is observed.

[0218] As used herein, the term "chiral purity" refers to the chiral purity of the Compound A crystalline form as determined by chiral high-performance liquid chromatography. Chiral purity is based on the "organic" purity of the compound. Chiral purity excludes water, solvents, metals, inorganic salts, etc. The chiral purity of the Compound A crystalline form is compared with the chiral purity of a reference standard by comparing the area under the peak.

[0219] In one embodiment, the crystalline form of Compound A has a chiral purity of not less than about 96%. In another embodiment, the crystalline form of Compound A has a chiral purity of not less than about 98%. In another embodiment, the crystalline form of Compound A has a chiral purity of not less than about 99%. In another embodiment, the crystalline form of Compound A has a chiral purity of not less than about 99.4%. In another embodiment, the chiral purity of the crystalline form of Compound A is 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%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98 ... 7.8%, 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%.

[0220] In one embodiment, the present invention relates to a crystalline form of Compound A that contains less than about 0.8% total impurities. In another embodiment, the total impurities are less than about 0.5%. In another embodiment, the total impurities are less than about 0.3%. In another embodiment, the total impurities are less than about 0.2%.

[0221] In one embodiment, the present invention relates to Compound A crystalline form containing no more than about 1% water, no more than about 0.8% water, no more than about 0.7% water, no more than about 0.6% water, no more than about 0.5% water, no more than about 0.4% water, no more than about 0.3% water, no more than about 0.2% water, no more than about 0.1% water, no more than about 0.09% water, no more than about 0.08% water, no more than about 0.07% water, no more than about 0.06% water, no more than about 0.05% water. In another embodiment, the present invention relates to Form A containing no more than about 0.11% water. In another embodiment, the present invention relates to Form A containing no more than about 0.1% water. In another embodiment, the present invention relates to Form A containing no more than about 0.09% water.

[0222] Pharmaceutical composition

[0223] In another aspect, the present invention provides a pharmaceutical composition comprising (i) a pharmaceutically active ingredient: 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.

[0224] In a specific embodiment of the above aspects, the pharmaceutically active ingredient is a crystalline form of Compound A free base; preferably, 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; preferably, the crystalline form is Compound A crystalline form I. In another specific 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 methanesulfonate crystalline form I; preferably, the crystalline form is selected from Compound A maleate crystalline form I and Compound A acetate crystalline form I.

[0225] In another aspect, the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the crystalline form in the total weight of the pharmaceutical composition is 1-30%, preferably 2-20%, preferably 3-15%, more preferably about 4%, 5%, 6%, 7%, 8%, 9% or 10%, calculated based on the weight of the free base of the compound; preferably, the content of the crystalline form in a unit dose is 1-100 mg, preferably 2-50 mg, preferably 3-40 mg, preferably about 5, 10, 15, 20, 25, 30, 35 or 40 mg.

[0226] In another aspect, the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the diluent to the total weight of the pharmaceutical composition is 65-95%, preferably 70-90%, preferably about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%; preferably, the content of the diluent in the unit dose is 50-380 mg, preferably 60-360 mg, preferably 70-350 mg, for example about 70 mg or 350 mg.

[0227] In another aspect, the present invention provides the above-mentioned pharmaceutical composition, wherein the diluent is selected from microcrystalline cellulose, anhydrous calcium hydrogen phosphate and mannitol, such as microcrystalline cellulose 102, mannitol 100SD and mannitol 50C, and mixtures thereof; preferably, when microcrystalline cellulose 102 and mannitol 50C are present at the same time, the weight ratio of microcrystalline cellulose 102 to mannitol 50C is 5:1 to 1:5, preferably 3:1 to 1:2, preferably about 2:1.

[0228] In another aspect, the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the disintegrant to the total weight of the pharmaceutical composition is 1-5%, preferably 2-4%, preferably about 2%, 2.5%, 3%, 3.5% or 4%; preferably, the content of the disintegrant in a unit dose is 1-20 mg, preferably 2-16 mg, preferably about 2, 2.5, 3, 6, 9 or 12 mg.

[0229] In another aspect, the present invention provides the above pharmaceutical composition, wherein the disintegrant is cross-linked carboxymethyl cellulose sodium or cross-linked povidone XL-10, preferably cross-linked carboxymethyl cellulose sodium.

[0230] On the other hand, the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the binder to the total weight of the pharmaceutical composition is 1-5%, preferably 2-4%, preferably about 2%, 2.5%, 3%, 3.5% or 4%; preferably, the content of the binder in the unit dose is 1-20 mg, preferably 2-16 mg, preferably about 2, 2.5, 3, 6, 9 or 12 mg.

[0231] In another aspect, the present invention provides the above pharmaceutical composition, wherein the binder is hydroxypropylcellulose EXF or povidone K30, preferably hydroxypropylcellulose EXF.

[0232] In another aspect, the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the lubricant to the total weight of the pharmaceutical composition is 0.1-5%, preferably 0.5-2%, preferably about 1%; preferably, the content of the lubricant in the unit dose is 0.1-20 mg, preferably 0.5-8 mg, preferably about 0.5, 1, 2, 3, 4, 5, 6, 7 or 8 mg.

[0233] In another aspect, the present invention provides the above pharmaceutical composition, wherein the lubricant is magnesium stearate or sodium stearyl fumarate PRUV, preferably magnesium stearate.

[0234] In another aspect, the present invention provides the above-mentioned pharmaceutical composition, comprising the following ingredients:

[0235] (i) 1-30% by weight of Compound A, Form I,

[0236] (ii) 65-95% by weight of microcrystalline cellulose 102 and mannitol 50C (weight ratio of about 2:1),

[0237] (iii) 2-4% by weight of cross-linked sodium carboxymethyl cellulose,

[0238] (iv) 2-4% by weight of hydroxypropylcellulose EXF, and

[0239] (v) 0.1-5% by weight of magnesium stearate.

[0240] In another aspect, the present invention provides the above pharmaceutical composition, wherein the unit dose comprises the following components:

[0241] (i) about 5 mg of Compound A Form I,

[0242] (ii) about 45 mg of microcrystalline cellulose 102 and about 25 mg of mannitol 50C,

[0243] (iii) about 2.5 mg croscarmellose sodium,

[0244] (iv) about 2.5 mg of hydroxypropylcellulose EXF, and

[0245] (v) about 1 mg magnesium stearate.

[0246] In another aspect, the present invention provides the above pharmaceutical composition, wherein the unit dose comprises the following components:

[0247] (i) about 25 mg of Compound A, Form VI,

[0248] (ii) about 230 mg lactose monohydrate and about 120 mg microcrystalline cellulose,

[0249] (iii) about 12 mg croscarmellose sodium,

[0250] (iv) about 12 mg of hydroxypropylcellulose EXF, and

[0251] (v) about 4 mg magnesium stearate.

[0252] In another aspect, the present invention provides the above pharmaceutical composition, which is a tablet, preferably a coated tablet; preferably, the coating agent is Opadry II 85F620077.

[0253] Pharmacology and efficacy

[0254] In another aspect, the present invention provides a method for 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.

[0255] In one embodiment, the abnormal cell growth is cancer. In another embodiment, the abnormal cell growth is a 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.

[0256] In another embodiment, the abnormal cell growth is a cancer mediated by ROS1 kinase. In another embodiment, the ROS1 kinase is a genetically altered ROS1 kinase. In another embodiment, the mutation is G2032R.

[0257] 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 melanoma 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, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) cancer, primary CNS lymphoma, spinal axis cancer, brainstem glioma, pituitary adenoma, or a combination thereof.

[0258] 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

[0259] Abbreviations

[0260] SGF: artificial gastric juice

[0261] FaSSIF: artificial gastric fluid in the fasting state

[0262] FeSSIF: artificial gastric fluid in the fed state

[0263] HBr: hydrobromic acid

[0264] HCl: hydrochloric acid

[0265] H2SO4: sulfuric acid

[0266] PTSA: p-toluenesulfonic acid

[0267] CH3SO3H: Methanesulfonic acid

[0268] PhSO3H: benzenesulfonic acid

[0269] Oxalic acid:

[0270] Maleic acid

[0271] MeOH: methanol

[0272] EtOH: ethanol

[0273] IPA: Isopropyl alcohol

[0274] IBA: Isobutanol

[0275] MEK: Butanone

[0276] THF: Tetrahydrofuran

[0277] ACN: acetonitrile

[0278] MTBE: Methyl tert-butyl ether

[0279] EtOAc: ethyl acetate

[0280] Acetone: Acetone

[0281] IPrOAc: isopropyl acetate

[0282] H2O: water

[0283] hr: hours

[0284] min: minutes

[0285] μL: microliter

[0286] General Method 1. X-ray Powder Diffraction (XRPD)

[0287] The solid samples obtained in the experiment were analyzed using a D8 advance powder X-ray diffraction analyzer (Bruker). The instrument was equipped with a LynxEye detector. The D8 advance powder X-ray diffraction analyzer (Bruker) scanned the samples at a 2θ angle of 3° to 40°, with a scan step of 0.02° and a scan speed of 0.3 seconds per step. The light tube voltage and light tube current were 40 kV and 40 mA, respectively.

[0288] General Method 2. Polarized Light Microscopy (PLM)

[0289] The PLM analysis was performed using an ECLIPSE LV100POL polarizing microscope (Nikon, Japan).

[0290] General Method 3. H NMR Spectroscopy Analysis ( 1 H NMR)

[0291] through 1 H NMR confirmed the chemical structure of the solid sample. 1 H NMR analysis was performed using a Bruker Advance 300 equipped with a B-ACS120 autosampler.

[0292] General Method 4. Differential Scanning Calorimetry (DSC)

[0293] Differential scanning calorimetry was performed using a Discovery DSC 250 (TA, USA). Approximately 2 mg of sample was weighed and placed in a DSC sample pan, which was then punctured. The sample was then equilibrated at 25°C and heated to 300°C at a rate of 10°C / min.

[0294] General Method 5. Thermogravimetric Analysis (TGA)

[0295] The thermogravimetric analyzer model is Discovery TGA 55 (TA, USA). The sample is placed in a balanced open aluminum sample pan, the mass is automatically weighed in the TGA heating furnace, and the sample is heated to 300°C at a rate of 10°C / min.

[0296] General Method 6. Dynamic Water Sorption / Desorption Analysis (DVS)

[0297] The hygroscopicity of the samples was tested using a DVS Intrinsic (SMS, UK). 30-50 mg of sample was weighed and placed in a sample pan. The change in sample mass with humidity at 25°C was recorded. The instrument parameters are as follows:

[0298] Balance: 60 minutes

[0299] RH(%) measurement point:

[0300] Adsorption: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90

[0301] Desorption: 90, 80, 70, 60, 50, 40, 30, 20, 10, 0

[0302] After the hygroscopicity test was completed, the sample crystal form was tested using XRPD.

[0303] Example 1 Preparation of Compound A

[0304] The following synthesis route is adopted:

[0305]

[0306] Step 1: Synthesis of Compound G.

[0307] To a 250 mL three-necked flask equipped with a magnetic stirrer, compound J (7.0 g, 42.2 mmol) and anhydrous dichloromethane (120 mL) were added and stirred until dissolved. Compound H (8.77 g, 46.4 mmol) and triethylamine (4.69 g, 46.4 mmol) were added in sequence. The mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes to obtain a light yellow clear solution for later use.

[0308] To a separate 500mL three-necked flask equipped with a magnetic stirrer, add anhydrous aluminum chloride (6.17g, 46.4mmol), evacuate, and replace the atmosphere with nitrogen. Under a nitrogen atmosphere, add anhydrous dichloromethane (60mL), cool to 0°C in an ice-water bath, and slowly add triethylamine (6.39g, 63.3mmol) dropwise. After completion, incubate with stirring for 10 minutes. Slowly add a dichloromethane solution of the above ingredients dropwise over 30 minutes, and continue incubating with stirring for 2 hours. TLC (PE:EA = 1:1) and HPLC confirmed the reaction was complete. Water (200mL) was added to quench the reaction, and the organic phase was separated. The aqueous layer was extracted with dichloromethane (100mL x 2). The combined organic phases were washed with water (100mL) and then saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to yield 12.66g of a yellow oil with a yield of 94.0%, HPLC >90%, and ee >98%. This intermediate is unstable at room temperature and should be used directly in the next step or stored in a refrigerator at -20°C. LC-MS (APCI): m / z = 320.1 (M+1) + . 1 H NMR(300MHz, 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=6.3Hz,1H),4.83(s,2H),2.89(s,3H),1.50(d,J=6.3Hz,3H).

[0309] Step 2: Synthesis of Compound F

[0310] Compound G (12.6 g, 39.5 mmol) and anhydrous dichloromethane (120 mL) were added to a 250 mL three-necked flask equipped with a magnetic stirrer. Stirring was continued until the solution was 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 that the reaction was complete. Ice water (100 mL) was added to quench the reaction. The organic phase was separated and the aqueous layer was extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with water (50 mL) and then with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and dissolved in anhydrous acetonitrile (50 mL) for later use.

[0311] Step 3: Synthesis of compound Da.

[0312] To a separate 250 mL three-necked flask equipped with a magnetic stirrer, add compound Ea (11.2 g, 59.3 mmol) and acetonitrile (200 mL). Cesium carbonate (25.7 g, 79.0 mmol) was added with stirring. The mixture was heated to 50°C under a nitrogen atmosphere and stirred for 30 minutes. The acetonitrile solution of compound F was slowly added dropwise at 50°C over 10 minutes. After completion of the addition, the mixture was stirred and heated for 2 hours. TLC (DCM:MeOH = 20:1) and HPLC monitoring showed the reaction was complete. The mixture was cooled to room temperature and quenched with water (200 mL). The reaction solution was diluted with ethyl acetate (300 mL) and stirred for 5 minutes. Insoluble solids were filtered through celite and washed with ethyl acetate (50 mL). The filtrate was separated into an organic layer, and the aqueous phase was extracted with ethyl acetate (60 mL*2). The organic phases were combined, washed with saturated sodium carbonate (100 mL*3) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain 17.5 g of a brown solid, with a yield of 90.1%, HPLC>85%, and ee>95%. LC-MS (APCI): m / z=390.1 (M+1). + .

[0313] Step 4: Synthesis of Compound C.

[0314] To a 250 mL single-necked flask equipped with a magnetic stirrer, compound Da (17.5 g, 35.8 mmol) and dichloromethane (200 mL) were added. Stirring allowed to dissolve, triethylamine (14.5 g, 143.2 mmol) and DMAP (850 mg, 7.2 mmol) were added sequentially, and Boc2O (23.4 g, 107.4 mmol) was slowly added dropwise. The reaction was stirred at room temperature overnight under a nitrogen atmosphere. TLC (DCM:MeOH = 20:1) and HPLC monitoring indicated the reaction was complete. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (EA / PE = 0-35%) to afford 15.4 g of a white solid, with a yield of 62.4%, HPLC >95%, and ee >95%. LC-MS (APCI): m / z = 590.1 (M+1-100). + . 1H NMR (300MHz, CDCl3) (δ / ppm): 8.06 (d, J = 1.8Hz, 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 = 6.0Hz, 3H), 1.47 (s, 18H).

[0315] Step 5: Synthesis of compound B.

[0316] Compound C (15.4 g, 22.3 mmol) and 2-methyl-2-butanol (300 mL) were added to a 500 mL single-necked flask equipped with a magnetic stirrer, and the mixture was stirred to dissolve. Potassium acetate (6.56 g, 66.9 mmol) was added, and the mixture was evacuated and replaced with nitrogen three times. Palladium acetate (0.75 g, 3.35 mmol) and n-butyldi(1-adamantyl)phosphine (1.60 g, 4.46 mmol) were quickly added, and the mixture was evacuated and replaced with nitrogen three times. The reaction temperature was raised to 110°C under a liquid nitrogen atmosphere and the mixture was stirred and reacted overnight. The reaction was complete as monitored by TLC (PE:EA = 1:1) and HPLC. The reaction mixture was cooled to room temperature and diluted with dichloromethane (300 mL). Insoluble solids were filtered through celite and the filter cake was washed with dichloromethane (50 mL). The combined filtrates were concentrated to dryness under reduced pressure and acetonitrile (150 mL) was added. 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 was filtered. The filter cake was washed with acetonitrile (10 mL) and dried to obtain 8.2 g of the white solid, with a yield of 60.4%. HPLC results were >99.5%, and ee >99.9%. LC-MS (APCI): m / z = 510.1 (M+1-100). + . 1 H NMR(300MHz, CDCl3)(δ / ppm):8.22(d,J=1.8Hz,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=14.1Hz,2H),3.15(s,3H),1.76(d,J=6.0Hz,3H),1.44(s,18H).

[0317] Step 6: Synthesis of Compound A.

[0318] Compound B (8.2 g, 13.5 mmol) and dichloromethane (100 mL) were added to a 250 mL single-necked flask equipped with a magnetic stirrer. Stirring allowed to dissolve, the mixture was cooled in an ice-water bath, and trifluoroacetic acid (20 mL) was slowly added dropwise. After completion, the ice bath was removed and the mixture was stirred at room temperature for 2 hours. The reaction was monitored for completion by TLC (DCM:MeOH = 20:1) and HPLC. The organic solvent was evaporated under reduced pressure. Dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (60 mL) were added with cooling. The mixture was stirred for 10 minutes, and the organic phase was separated. The aqueous layer was extracted with dichloromethane (50 mL x 2). The combined organic phases were washed sequentially with water (30 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 5.1 g of an amorphous white solid in a 92.6% yield, HPLC >99.5%, and ee >99.9%. LC-MS (APCI): m / z = 410.2 (M+1). + .1 H NMR(300MHz, CDCl3)(δ)ppm 7.79(d, J=1.8Hz,1H),7.31-7.27(m,1H),7.23-7.19(m,1H),7.06-6.97(m,1H),6.87(d,J=1.8Hz,1H),5.75-5.70(m,1H),5.09(br s, 2H), 4.40 (q, J = 14.1Hz, 2H), 3.12 (s, 3H), 1.78 (d, J = 6.6Hz, 3H).

[0319] Example 2 Preparation of polymorphs of compound A

[0320] In the polymorph screening of the free base of Compound A, Compound A was used as the starting material and the room temperature volatilization method, suspension stirring and anti-solvent precipitation methods were used to screen the polymorphs of the free base of Compound A. Four anhydrous crystalline forms (Form I, Form IV, Form V, Form VI) and three solvates (Form II, Form III and Form VII) were found.

[0321] Example 2.1 Treatment of starting materials and preparation of compound A crystalline form I

[0322] A certain amount of the starting material compound A was weighed, and isobutanol solvent was added thereto. The mixture was suspended and slurried at room temperature for one day and then filtered. The solid was vacuum-dried at 50°C overnight to obtain 1 g of compound A form I, which was an anhydrous crystalline form.

[0323] Example 2.2 Screening of 13×13 (1:1) binary solvents in 96-well plates

[0324] Approximately 30 mg of Compound A Form I was weighed and added to 13 8 mL vials. 3 mL of the corresponding solvents were gradually added: methanol, ethanol, isopropanol, isobutanol, butanone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, water, dichloromethane, ethyl acetate, and isopropyl acetate. Stir at room temperature for a period of time, then filter and set aside the filtrate. The filtrate was used to screen binary solvents in a 96-well plate. The corresponding filtrates were distributed in pairs across the plate, with each filtrate volume reaching 100 μL. The 96-well plate was sealed with parafilm and evaporated to dryness in a fume hood at room temperature. Information on the 13 solvents used in the 96-well plate is shown in Table 2.2.

[0325] Table 2.2: Information on 13×13 solvents in a 96-well plate

[0326]

[0327] Note: AM is amorphous; CR is crystalline; GL is glassy

[0328] *The sample results in the wells shown in the table are XRPD results, and the samples in other wells are PLM results

[0329] PLM and XRPD analysis of the solid precipitated in a 96-well plate revealed a new crystalline form, designated Compound A Form II. 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 crystalline solids were obtained in other solvents.

[0330] Example 2.3 Evaporation and crystallization studies of 13 single solvents

[0331] The remaining 13 single filtrates from Example 2.2, used to plate the 96-well plates, were placed in a fume hood and naturally evaporated at room temperature for 3 days. The samples were then vacuum-dried at 50°C overnight to yield two new crystalline forms. Evaporation in a single solvent of butanone yielded one new crystalline form, designated Compound A Form III. Evaporation in a single solvent of methanol yielded another new crystalline form, designated Compound A Form IV. Evaporation in other solvents yielded amorphous or less crystalline solids.

[0332] Example 2.4 Study on room temperature suspension beating

[0333] A certain amount of Compound A Form I was added to various solvents, suspended and slurried at room temperature for one day, then filtered. The sample was vacuum-dried at 50°C overnight and characterized by XRPD. The experimental conditions and results are shown in Table 2.4.

[0334] Table 2.4 Experimental conditions and results of room temperature suspension beating

[0335] serial number Compound A Form I (mg) solvent Solvent volume (μL) Volume ratio (V:V) result 1 33.2 IPrOAc 500 / Form I 2 33.3 EtOH 500 / Form I 3 31.6 MTBE / MeOH 500 9：1 Form I 4 31.2 IPA / EtOAc 500 4：1 N / A 5 33.0 IBA / EtOAc 500 4：1 N / A 6 35.0 <![CDATA[H2O / MeOH]]> 500 9：1 Form V 7 32.3 MeOH 500 / Form VI 8 32.3 <![CDATA[H2O / ACN]]> 500 9：1 Form VII

[0336] The results showed that in addition to Form I obtained in isopropyl acetate, ethanol, and MTBE / MeOH (9:1), three new crystalline forms were obtained, designated Form V, Form VI, and Form VII. Form V was obtained from a suspension in water and methanol; Form VI was obtained from a suspension in methanol; and Form VII was obtained from a suspension in water and acetonitrile.

[0337] Example 2.5 Study on suspension beating at 50°C

[0338] 30 mg of Compound A Form I was placed in 500 μL of a poor solvent to prepare a suspension. The suspension was suspended and slurried at 50°C for one day before being filtered. The sample was vacuum-dried at 50°C overnight and characterized by XRPD. The experimental conditions and results are shown in Table 2.5.

[0339] Table 2.5 Experimental conditions and results of 50℃ suspension beating

[0340] serial number Compound A Form I (mg) solvent Solvent volume (μL) result 1 30.0 <![CDATA[H2O]]> 500 Form I 2 30.0 Heptane 500 Form I 3 30.0 IBA 500 Form I 4 30.0 IPA 500 Form I 5 30.0 MTBE 500 Form I

[0341] The results showed that Form I was obtained in all solvent systems.

[0342] Example 2.6 Antisolvent precipitation study

[0343] 30 mg of Compound A Form I was placed in 200 μL of a good solvent and stirred at room temperature. Antisolvent precipitation experiments were then performed with the addition of antisolvents. The resulting solids were characterized by XRPD. Experimental conditions and results are shown in Table 2.6.

[0344] Table 26 Experimental conditions and results of antisolvent precipitation

[0345] serial number Compound A Form I (mg) Good solvent / volume Antisolvent / volume result 1 34.1 Acetone (200 μL) MTBE (6.2 μL) N / A 2 30.8 THF (200 μL) MTBE (5 μL) N / A 3 33.2 ACN (200 μL) MTBE (4 μL) N / A 4 34.1 EtOAc (200 μL) MTBE (2 μL) Form I 5 33.7 Acetone (200 μL) IPA (4 μL) N / A 6 33.3 THF (200 μL) IPA (4 μL) N / A 7 31.1 ACN (200 μL) IPA (4 μL) N / A 8 34.9 EtOAc (200 μL) IPA (4 μL) N / A

[0346] The results showed that Form I was obtained only in ethyl acetate / MTBE, and no solid was precipitated in the others.

[0347] Example 3 Characterization of Polymorphs of Compound A Free Base

[0348] Example 3.1 Characterization of Compound A Form I

[0349] Compound A Form I was prepared according to the method in Example 2.1 and characterized by XRPD, PLM, DSC, TGA, DVS, NMR, IR, UV and MS. The specific results are as follows:

[0350] XRPD analysis

[0351] Figure 1 XRPD data of Compound A, Form I, collected according to General Method 1 is shown. A list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 3.1. The XRPD results indicate that Form I has good crystallinity.

[0352] Table 3.1: XRPD peak list of Compound A Form I (2θ°)

[0353]

[0354]

[0355] PLM Analytics

[0356] Compound A Form I was subjected to PLM analysis by General Method 2. The PLM results showed that Form I was a granular crystal.

[0357] DSC and TGA thermal analysis

[0358] Figure 2 and 3 The DSC and TGA traces of Compound A Form I collected using General Methods 4 and 5 are shown, respectively. DSC results show a narrow melting endotherm with a peak temperature of approximately 232.48°C and an onset temperature of approximately 231.78°C. TGA results indicate a 0.01339% weight loss at 150°C. Both DSC and TGA analyses indicate that the sample is an anhydrous crystalline form.

[0359] DVS analysis

[0360] Figure 4 The DVS pattern of Compound A Form I collected by General Method 6 is shown. The DVS results show that the humidity increased from 0% RH to 80% RH, resulting in a weight gain of 0.17%.

[0361] The crystal form of the sample did not change before and after the DVS test, such as Figure 5 .

[0362] NMR analysis

[0363] Instruments and equipment: Bruker AVANCE III 400MHz NMR instrument

[0364] Solvent: DMSO-d6

[0365] Accurately weigh 73.66 mg of Compound A Form I, add 0.6 mL DMSO-d6 and dissolve completely, then transfer to an NMR tube and perform 1 H-NMR, 13 C-NMR, DEPT, 19 F-NMR, HSQC, HMBC and COSY tests.

[0366] Accurately weigh 36.81 mg of Compound A Form I, add 0.6 mL of DMSO to completely dissolve it, then add 50 μL of DMSO-d6 to mix well, transfer to an NMR tube, and perform D-NMR analysis.

[0367] The NMR atomic distribution structure of compound A is as follows:

[0368]

[0369] Key HMBC and COSY related structures of compound A:

[0370]

[0371] 1 H-NMR

[0372] Figure 6The H NMR spectrum of Compound A crystalline form I is shown, and Table 3.2 shows the H NMR spectrum measurement results of Compound A crystalline form I.

[0373] Table 3.2 Results of H NMR spectroscopy of Compound A Form I

[0374] Chemical shift (ppm) Peak shape Number of protons Attribution 7.61 overlapping 1H H-20 7.58 overlapping 1H H-10 7.45 dd (J = 8.8, 6.0 Hz) 1H H-17 7.16 td(J=8.8,2.8Hz) 1H H-18 6.80 d(J=1.6Hz) 1H H-5 6.23 br s 2H NH-12 5.61 m 1H H-14 4.41 d(J=14.4Hz) 1H H-4a 4.19 d(J=14.4Hz) 1H H-4b 2.99 s 3H H-23 1.68 d(J=6.0Hz) 3H H-32

[0375] The results showed that the hydrogen spectrum gave a total of 16 hydrogen signals, including 6 methyl hydrogens, 2 methylene hydrogens, 6 methine hydrogens, and 2 active hydrogens. The chemical shift was H The hydrogen signal at 6.23 (br s, 2H) had no HSQC correlation and was assigned to NH-12 based on its HMBC correlation with C-8; the chemical shift was in δ H The aromatic hydrogen signal at 7.61 (overlapping, 1H) was assigned to H-20 based on HMBC correlation with C-14, C-15, C-16, C-18, and C-19; δ H 7.58 (overlapping, 1H) has HMBC correlation 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, 6.0 Hz, 1H) and δ H 7.16 (td, J = 8.8, 2.8 Hz, 1H) with COSY correlation and HMBC correlation, respectively assigned to H-17 and H-18; chemical shift in δ H 6.80 (d, J = 1.6 Hz, 1H) was assigned to H-5 based on the HMBC correlation of C-1, C-2, C-8, C-9 and C-10; δ H 5.61 (m, 1H) and δ H The hydrogen signal at 1.68 (J = 6.0 Hz, 3H) has COSY correlation and HMBC correlation, which are assigned to H-14 and H-32 respectively; the chemical shift is in δ H 4.41 (d, J = 14.4 Hz, 1H) and δ H The methylene hydrogen signal at 4.19 (d, J = 14.4 Hz, 1H) has HMBC correlation with C-2, C-3, C-13 and C-23 and is assigned to H-4a and H-4b, respectively; the chemical shift is in δ H The methyl hydrogen signal at 2.99 (s, 3H) was assigned to H-23 based on the HMBC correlation with C-4 and C-13.

[0376] 13 C-NMR and DEPT

[0377] Figure 7 and 8The C NMR spectrum and DEPT spectrum of Compound A Crystal Form I are shown respectively. Table 3.3 shows the C NMR spectrum measurement results of Compound A Crystal Form I.

[0378] Table 3.3 Results of C-NMR spectroscopy of Compound A Form I

[0379] Chemical shift (ppm) Type of carbon Attribution 168.24 C=O C-13 164.57, 162.12 (J = 245 Hz) C C-19 151.40 C C-9 144.24 C C-3 143.88, 143.81 (J=7Hz) C C-15 138.63 C C-8 137.15 CH C-10 133.16, 133.13 (J = 3 Hz) C C-16 129.04, 128.96 (J=8Hz) CH C-17 127.66 C C-2 119.00 CH C-5 115.63, 115.41 (J = 22 Hz) CH C-18 114.39, 114.17 (J = 22 Hz) CH C-20 113.18 C C-1 111.78 C C-24 / C-28 111.55 C C-28 / C-24 71.26 CH C-14 46.96 <![CDATA[CH2]]> C-4 38.64, 38.43, 38.21 (J = 22 Hz) <![CDATA[CD3]]> C-27 31.40 <![CDATA[CH3]]> C-23 22.44 <![CDATA[CH3]]> C-32

[0380] The results show that: 13 The C-NMR spectrum gives a total of 21 carbon signals. Combined with DEPT, it shows that there are 2 methyl carbons, 1 methylene carbon, 6 methine carbons, 1 carbon connected to a deuterium atom, and 11 non-hydrogen-connected carbons. Through HSQC data, all the above hydrogen-connected carbon signals were assigned, and the remaining non-hydrogen-connected carbons were assigned through chemical shift 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 combined with the coupling constants, they are attributed to C-19; δ C 151.40 is related to H-5 and H-10 and is assigned to C-9; δ C 144.24 is related to H-4 and, combined with the chemical shift, is assigned to C-3; δ C 143.88, 143.81 are related to H-14, H-17, H-18, H-20 and H-32, and the coupling constants are assigned to C-15; δ C 138.63 is related to H-5, H-10, NH-12 and H-14 and is 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 is 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 shift; δ C 111.78 and δ C 111.55 According to their chemical shifts, they are assigned to C-24 / C-28 and C-28 / C-24 respectively; δ C 38.64, 38.43, and 38.21 were assigned to C-27 based on the chemical shifts and coupling constants.

[0381] D-NMR spectrum

[0382] Figure 9The deuterium nuclear magnetic resonance spectrum of Compound A crystalline form I is shown. In the D-NMR spectrum, the chemical shift at δ 3.97 is the deuterium atomic signal.

[0383] 19 F-NMR spectrum

[0384] Figure 10 Shows the NMR fluorine spectrum of Compound A Crystal Form I. 19 In the F-NMR spectrum, the chemical shift at δ110.08 is the fluorine signal connected to the benzene ring.

[0385] HSQC and HMBC spectra

[0386] Figure 11 and 12 The NMR HSQC and HMBC spectra of Compound A Crystalline Form I are shown, and Table 3.4 shows the NMR HSQC and HMBC spectra measurement results of Compound A Crystalline Form I.

[0387] Table 3.4 HSQC and HMBC spectrum measurement results of Compound A Form I

[0388]

[0389] The results showed that in the HMBC spectrum, H-20 correlated with C-13, C-14, C-15, C-16, C-18 and C-19; H-17 correlated with C-13, C-14, C-15, C-16, C-18, C-19 and C-20; H-18 correlated with C-15, C-16, C-19 and C-20; H-14 correlated with C-8, C-15, C-16, C-19, C-20 and C-32; H-32 correlated with C-14, C-15; H-10 correlated with C-1, C-2 -2, C-5, C-8 and C-9, H-5 is correlated with C-1, C-2, C-8, C-9 and C-10, which is consistent with the existence of fragment A in the structure; H-4 is correlated with C-2, C-3, C-13 and C-23, and H-23 is correlated with C-4 and C-13, which is consistent with the existence of fragment B in the structure; H-17 and H-20 are correlated with C-13, indicating that C-16 of fragment A is connected to C-13 of fragment B, and H-5 and H-10 are correlated with C-2, indicating that C-1 of fragment A is connected to C-2 of fragment B.

[0390] COSY

[0391] Figure 13 The COSY NMR spectrum of Compound A crystalline form I is shown, and Table 3.5 shows the COSY NMR spectrum measurement results of Compound A crystalline form I.

[0392] Table 3.5 COSY spectrum measurement results of Compound A Form I

[0393] <![CDATA[ 1 H-NMR(ppm)]]> Attribution COSY 7.45 H-17 H-18 5.61 H-14 H-32

[0394] The results showed that in the COSY spectrum, H-17 was correlated with H-18, and H-14 was correlated with H-32, further proving the presence of fragment A in the structure.

[0395] IR analysis

[0396] Instruments and equipment: Shimadzu SHIMADZU IR Tracer 100 Fourier transform infrared spectrometer

[0397] Using KBr pellet method at 4000-400cm -1 The infrared absorption spectrum of compound A crystal form I was collected within a wavenumber range. Figure 14 The infrared spectrum of Compound A Crystal Form I is shown, and Table 3.6 shows the infrared spectrum measurement results of Compound A Crystal Form I.

[0398] Table 3.6 Infrared spectrum measurement results of Compound A Form I

[0399] <![CDATA[Absorption wave number (cm -1 )]]> Vibration type Attribution 3474，3383，3308 <![CDATA[ν N-H ]]> <![CDATA[NH2]]> 3184，3111 <![CDATA[ν ＝C-H ]]> Benzene ring 2980，2934 <![CDATA[ν C-H ]]> <![CDATA[CH3,CH2,CH]]> 2228 <![CDATA[ν C≡N ]]> C≡N 1645，1616 <![CDATA[v C＝O ]]> C=O 1499，1491 <![CDATA[ν C＝C ]]> Benzene ring 1433，1420，1395，1368，1344 <![CDATA[δ C-H ]]> <![CDATA[CH3,CH2,CH]]> 1252，1069 <![CDATA[ν C-O-C ]]> Aryl ether 878，829 <![CDATA[γ ＝C-H ]]> Benzene ring

[0400] The results show that the chemical structure of compound A crystal form I contains NH2, C≡N, CH3, CH2, CH, C=O, benzene ring, aryl ether and other structures. The specific analysis is as follows: 3474, 3383, 3308cm -1 The NH stretching vibration absorption peak is at 3184, 3111 cm -1 The stretching vibration absorption peaks of =CH are at 1499, 1491 cm -1 The stretching vibration absorption peaks of C=C double bond are at 878, 829 cm -1 The absorption peaks are the out-of-plane bending vibrations of =CH, which is consistent with the benzene ring structure in the structure; 2980, 2934 cm -1 The stretching vibration absorption peaks of saturated CH bonds are at 1433, 1420, 1395, 1368, and 1344 cm -1 The absorption peak at 2228cm is the bending vibration absorption peak of the saturated CH bond, which is consistent with the structure containing CH3, CH2 and CH. -1 The peaks at 1645 and 1616 cm are the stretching vibration absorption peaks of the C≡N bond, which is consistent with the C≡N structure in the structure. -1 The C=O stretching vibration peak is at 1252 cm, which is consistent with the presence of carbonyl structure in the structure; -1 The COC asymmetric stretching vibration absorption peak is 1069 cm -1 The absorption peak of COC symmetric stretching vibration is at , which is consistent with the presence of aromatic ether structure in the structure.

[0401] UV analysis

[0402] Instruments and equipment: UV-2600 ultraviolet-visible spectrophotometer (Shimadzu Corporation, Japan)

[0403] UV analysis was performed using a methanol sample solution (15.23 μg / mL). Figure 15 The UV absorption spectrum of Compound A Crystalline Form I is shown, and Table 3.7 shows the UV absorption test results of Compound A Crystalline Form I.

[0404] Table 3.7 UV measurement results of Compound A Form I

[0405] Serial number Peak / Valley Wavelength (nm) ABS <![CDATA[ε(*10 4 )]]> 1 peak 317 0.3153 0.85 2 peak 206 0.9317 2.50 3 valley 278 0.1373 -

[0406] The results show that: max The absorption peaks at 317 and 206 nm are the n-π* transition absorption peaks of the conjugated system of the compound and the π-π* transition absorption peaks of the substituted benzene ring.

[0407] HR-MS

[0408] Instruments and equipment: Waters Acquity I Class UPLC / Xevo G2-XS QT of HRMS ultra-high performance liquid chromatography high-resolution mass spectrometry system.

[0409] Chromatographic analysis was performed using a methanol solution of Compound A Form I with a concentration of 15.23 μg / mL.

[0410] Figure 16 The high-resolution mass spectrum of compound A crystal form I is shown. The results show that the mass-to-charge ratio in the high-resolution mass spectrum is m / z 410.1822 [M+H] + The ion peak of C 21 H 17 D3FN6O2), indicating that the sample molecular formula is C 21 H 16 D3FN6O2.

[0411] Example 3.2 Characterization of Compound A Form II

[0412] Compound A Form II was prepared by the method in Example 2.2 after evaporation of the butanone / ethyl acetate mixed solvent. The results were characterized by XRPD, PLM, DSC, and TGA. The specific results are as follows:

[0413] XRPD analysis

[0414] Figure 17XRPD data of Compound A Form II collected according to General Method 1 are shown. A list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 3.2. The XRPD results indicate that Form II has good crystallinity.

[0415] Table 3.2: XRPD peak list of Compound A Form II (2θ°)

[0416] peak Angle °2θ±0.2°2θ Relative Strength 1 7.591 100.0 2 10.198 4.9 3 12.081 24.7 4 13.025 7.3 5 13.846 4.8 6 14.577 12.9 7 15.595 10.2 8 16.510 7.7 9 16.948 14.2 10 17.615 14.4 11 20.017 8.8 12 20.448 14.6 13 21.076 3.6 14 22.703 3.8 15 23.364 17.4 16 24.369 8.4 17 24.933 4.2 18 25.990 4.8 19 26.700 3.9 20 27.957 4.0 21 28.976 3.1

[0417] PLM Analytics

[0418] Compound A Form II was subjected to PLM analysis by General Method 2. PLM results showed that Form II was an irregular crystal.

[0419] DSC and TGA thermal analysis

[0420] DSC and TGA analysis of Compound A Form II were performed using General Methods 4 and 5. DSC results showed a melting endotherm with a peak temperature of approximately 230.09°C and an onset temperature of approximately 227.91°C. TGA results revealed a weight loss of approximately 6.69% at 160°C. These DSC and TGA analyses indicated that the sample was a butanone solvate.

[0421] Example 3.3 Characterization of Compound A Form III

[0422] Compound A Form III was obtained by evaporation in a single solvent of butanone according to the method in Example 2.3 and characterized by XRPD, PLM, DSC and TGA. The specific results are as follows:

[0423] XRPD analysis

[0424] Figure 18 XRPD data of Compound A, Form III, collected according to General Method 1 is shown. Table 3.3 provides a list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities. The XRPD results indicate that Form III has good crystallinity.

[0425] Table 3.3: XRPD peak list of Compound A Form III (2θ°)

[0426]

[0427]

[0428] PLM Analytics

[0429] Compound A Form III was subjected to PLM analysis by General Method 2. The PLM results showed that Form III was an irregular crystal.

[0430] DSC and TGA thermal analysis

[0431] DSC and TGA analysis of Compound A Form III were performed using General Methods 4 and 5. DSC results showed a melting endotherm with a peak temperature of approximately 226.13°C and an onset temperature of approximately 220.19°C. TGA results showed a weight loss of approximately 5.31% at 165°C. DSC and TGA analysis indicated that the sample was a butanone solvate.

[0432] Example 3.4 Characterization of Compound A Form IV

[0433] Compound A Form IV was obtained by evaporation in a single solvent of methanol according to the method in Example 2.3 and characterized by XRPD, PLM, DSC and TGA. The specific results are as follows:

[0434] XRPD analysis

[0435] Figure 19 XRPD data for Compound A, Form IV, collected according to General Method 1 is shown. A list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 3.4. The XRPD results indicate that Form IV is of average crystallinity.

[0436] Table 3.4: XRPD peak list of Compound A Form IV (2θ°)

[0437]

[0438]

[0439] PLM Analytics

[0440] Compound A Form IV was subjected to PLM analysis by General Method 2. The PLM results showed that Form IV was an irregular crystal.

[0441] DSC and TGA thermal analysis

[0442] DSC and TGA analysis of Compound A Form IV were performed using General Methods 4 and 5. DSC results revealed an endothermic peak with a peak temperature of approximately 231.62°C and an onset temperature of approximately 229.83°C. TGA analysis revealed a weight loss of approximately 0.28% before 200°C. Both DSC and TGA analyses indicated that the sample was an anhydrous crystalline form.

[0443] Example 3.5 Characterization of Compound A Form V

[0444] According to the method in Example 2.4, Compound A Form V was obtained by suspension and slurrying in a mixed solvent (water:methanol=9:1) at room temperature and characterized by XRPD, PLM, DSC and TGA. The specific results are as follows:

[0445] XRPD analysis

[0446] Figure 20 XRPD data for Compound A, Form V, collected according to General Method 1 is shown. A list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 3.5. The XRPD results indicate that Form V has good crystallinity.

[0447] Table 3.5: XRPD peak list of Compound A Form V (2θ°)

[0448]

[0449]

[0450] PLM Analytics

[0451] PLM analysis of Compound A Form V was performed using General Method 2. PLM results showed that Form V was an irregular crystal.

[0452] DSC and TGA thermal analysis

[0453] DSC and TGA analysis of Compound A Form V were performed using General Methods 4 and 5. DSC results showed a melting endotherm with a peak temperature of approximately 232.13°C and an onset temperature of approximately 230.9°C. TGA results revealed a weight loss of approximately 0.22% before 200°C, attributable to residual solvent. DSC and TGA analyses confirmed that the sample was an anhydrous crystalline form.

[0454] Example 3.6 Characterization of Compound A Form VI

[0455] Compound A Form VI was obtained by suspension and slurrying in methanol solvent at room temperature according to the method in Example 2.4, and characterized by XRPD, PLM, DSC and TGA. The specific results are as follows:

[0456] XRPD analysis

[0457] Figure 21 XRPD data for Compound A Form VI collected according to General Method 1 are shown. A list of XRPD peaks at diffraction angles of 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 3.6. The XRPD results indicate that Form VI has good crystallinity.

[0458] Table 3.6: XRPD peak list of Compound A Form VI (2θ°)

[0459] peak Angle °2θ±0.2°2θ Relative Strength 1 10.247 100.0 2 12.198 70.6 3 12.514 42.8 4 14.302 5.1 5 17.258 53.8 6 17.596 44.5 7 18.659 10.4 8 19.406 27.9 9 20.432 4.1 10 21.020 4.4 11 21.888 30.3 12 22.479 11.9 13 23.014 5.9 14 23.799 14.7 15 24.410 23.3 16 25.158 21.0 17 26.259 7.3 18 27.599 27.5 19 28.504 15.3 20 29.902 7.4 21 30.434 4.9 22 34.102 2.6 23 34.453 4.1 24 37.089 2.5

[0460] PLM Analytics

[0461] Compound A Form VI was subjected to PLM analysis using General Method 2. The PLM results showed that Form VI was an irregular crystal.

[0462] DSC and TGA thermal analysis

[0463] DSC and TGA analysis of Compound A Form VI were performed using General Methods 4 and 5. DSC results revealed a melting endotherm with a peak temperature of approximately 232.83°C and an onset temperature of approximately 231.56°C. TGA analysis revealed minimal weight loss before 200°C. These DSC and TGA analyses confirmed the sample to be an anhydrous crystalline form.

[0464] Example 3.7 Characterization of Compound A Form VII

[0465] According to the method in Example 2.4, Compound A Form VII was obtained by suspension and slurrying in a mixed solvent (water:acetonitrile = 1:9) at room temperature. The crystals were characterized by XRPD, PLM, DSC and TGA. The specific results are as follows:

[0466] XRPD analysis

[0467] Figure 22 XRPD data for Compound A, Form VII, collected according to General Method 1 is shown. A list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 3.7. The XRPD results indicate that Form VII is of fair crystallinity.

[0468] Table 3.7: XRPD peak list of Compound A Form VII (2θ°)

[0469] peak Angle °2θ±0.2°2θ Relative Strength 1 7.138 100.0 2 9.876 51.2 3 12.572 31.6 4 12.945 38.5 5 14.675 30.3 6 17.160 26.2

[0470] PLM Analytics

[0471] Compound A Form VII was subjected to PLM analysis by General Method 2. PLM results showed that Form VII was a needle-shaped crystal.

[0472] DSC and TGA thermal analysis

[0473] DSC and TGA analysis of Compound A Form VII were performed using General Methods 4 and 5. DSC results showed a melting endotherm with a peak temperature of approximately 232.38°C and an onset temperature of approximately 230.70°C. TGA results showed a weight loss of approximately 0.35% before 200°C. DSC and TGA analyses indicated that the sample was a solvate.

[0474] Example 4 Study on the Crystalline Form Conversion of Compound A

[0475] 4.1 Competitive beating experiment at room temperature

[0476] 10 mg of Compound A Form I, Form IV, Form V, and Form VI were weighed and placed in 500 μL of three different solvents (isobutanol, isopropanol, and methyl tert-butyl ether) and slurried at room temperature for one day. The resulting solids were vacuum dried at 50°C overnight and characterized by XRPD. The results are shown in Tables 4.1 and Figure 23 shown.

[0477] Table 4.1 Room temperature competitive beating test results

[0478] serial number Sample (mg) solvent Solvent volume (μL) result Compound A Crystal Forms I, IV, V and VI 40 IBA 500 Form I Compound A Crystal Forms I, IV, V and VI 40 IPA 500 Form I Compound A Crystal Forms I, IV, V and VI 40 MTBE 500 Form I

[0479] The results showed that compound A forms IV, V and VI all transformed into form I in three solvent systems: isobutanol, isopropanol and methyl tert-butyl ether, further proving that compound A form I is a stable form.

[0480] 4.2 Heating study

[0481] A certain amount of Compound A crystal forms V and VI were weighed and heated to 190°C for XRPD characterization. The results were as follows: Figure 24 The results showed that Compound A Form V was transformed into Form I by heating to 190°C, further proving that Compound A Form I is a thermodynamically stable form.

[0482] Example 5 Stability Study of Compound A Form I

[0483] For samples of Compound A Form I, a test on factors affecting stability was conducted, and the corresponding storage conditions and test results are listed in Table 5.

[0484] Table 5 Experimental data on factors affecting the stability of Compound A Form I

[0485]

[0486] Example 6 Preparation of Crystalline Salt of Compound A

[0487] Initial attempts to prepare crystalline salts of Compound A, using Compound A Form I as the starting material, were divided into two phases. Phase 1 included solubility studies of the starting material and salt screening in a 96-well plate; Phase 2 involved milligram-scale preparation of potential crystalline salts. These initial attempts yielded eight crystalline salt forms 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 methanesulfonate Form I.

[0488] Example 6.1 Solubility Study of Starting Material (Compound A Form I)

[0489] Weigh approximately 2 mg of the starting material into a 2 mL vial and slowly add 50 μL of different solvents each time until the sample is dissolved or the solubility is less than 1 mg / mL. The solubility results are listed in Table 6.1.

[0490] The results showed that the starting material had relatively high solubility in acetone, dichloromethane, tetrahydrofuran, methanol, acetonitrile, butanone and ethyl acetate, all greater than 100 mg / mL; the solubility in isopropyl acetate and ethanol was reduced to about 20 mg / mL; the solubility in isopropanol, MTBE, isobutanol and water was relatively low, about 1-2 mg / mL.

[0491] Table 61: Solubility of the starting material (Compound A Form I) free base in different solvents

[0492] solvent Solubility (mg / mL) acetone ～246 dichloromethane ～240 Tetrahydrofuran ～215 Methanol ～190 Acetonitrile ～183 Butanone ～173 Ethyl acetate ～100 Isopropyl acetate ～22 ethanol ～21 Isopropyl alcohol ～2.5 Methyl tert-butyl ether ～2.5 Isobutanol ～1.7 water ～1

[0493] Example 6.2 Salt type screening in 96-well plates

[0494] A certain amount of hydrobromic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, and maleic acid were dissolved in methanol and diluted to 10 mL to prepare 8 acid solutions with a concentration of 0.1 M. Approximately 750 mg of the starting material was weighed and added to 25 mL of methanol to prepare a free base solution with a concentration of 30 mg / mL. The 30 mg / mL free base solution was added to a 96-well plate, with 100 μL added to each well. After that, 75 μL of the corresponding acid solution was added to each well (the volume of sulfuric acid added was 37.5 μL). The 96-well plate was placed at room temperature to evaporate. After the solvent evaporated completely, 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. The 96-well plate was sealed with sealing film and punctured, and placed in a fume hood at room temperature. After slowly evaporating the solvent, the resulting solid sample was subjected to PLM characterization. The conditions and solid state of the 96-well plate salt type screening are listed in Table 6.2.

[0495] 6.2 Sample Status for 96-Well Plate Salt Type Screening

[0496]

[0497] Note: oil is oily, CR is crystal, GL is glassy

[0498] From the results of the 96-well plate experiment, it can be seen that white solids were obtained in hydrobromic acid, hydrochloric acid, p-toluenesulfonic acid and maleic acid.

[0499] Example 6.3 Small-scale preparation of Compound A maleate salt Form I

[0500] Approximately 30.1 mg of the starting material (Compound A Form I) was weighed and dissolved in 400 μL of ethyl acetate to form a solution. 10.3 mg of maleic acid was then added. The solution was stirred at room temperature for 30 minutes to precipitate a solid. Stirring was continued for 30 minutes before filtration. The filtered solid was vacuum dried at 50°C for 24 hours.

[0501] Example 6.4 Small-scale preparation of Compound A acetate salt Form I

[0502] Approximately 29.5 mg of the starting material (Compound A Form I) was weighed and dissolved in 400 μL of ethyl acetate to form a solution. 5.15 μL of acetic acid was then added. The solution was stirred at room temperature for 10 minutes to precipitate a solid. Stirring was continued for 30 minutes before filtration. The filtered solid was vacuum dried at 50°C for 24 hours.

[0503] Example 6.5 Small-scale preparation of compound A p-toluenesulfonate salt form I

[0504] Approximately 29.9 mg of the starting material (Compound A Form I) was weighed and dissolved in 400 μL of ethyl acetate to form a solution. 16.8 mg of p-toluenesulfonic acid was then added. After stirring at room temperature for 2.5 hours, a solid precipitated. Stirring was continued for 30 minutes before filtration. The filtered solid was vacuum dried at 50°C for 24 hours.

[0505] Example 6.6 Small-scale preparation of Compound A oxalate Form I

[0506] Approximately 30.0 mg of the starting material (Compound A Form I) was weighed and dissolved in 400 μL of ethyl acetate to form a solution. 11.1 mg of oxalic acid was then added and stirred at room temperature for 30 minutes to precipitate a solid. The solid was filtered and dried under vacuum at 50°C overnight. 30 mg of the dried solid was slurried in a mixture of 160 μL of isopropanol and 40 μL of water at room temperature for one day, then filtered. The filtered solid was dried under vacuum at 50°C overnight.

[0507] Example 6.7 Small-scale preparation of compound A sulfate salt form I

[0508] Approximately 40.0 mg of the starting material (Compound A Form I) was weighed and dissolved in 400 μL of ethyl acetate to form a solution. 4.71 μL of sulfuric acid was then added and stirred at room temperature to immediately precipitate a solid. The filtered solid was then dried under vacuum at 50°C overnight. 40 mg of the dried solid was slurried in a mixture of 160 μL of isopropanol and 40 μL of water at room temperature for one day, then filtered. The filtered solid was then dried under vacuum at 50°C overnight.

[0509] Example 6.8 Small-scale preparation of Compound A hydrobromide salt Form I

[0510] Approximately 61.1 mg of the starting material (Compound A Form I) was weighed and dissolved in 800 μL of ethyl acetate to form a solution. 23.62 μL of hydrobromic acid was then added. A solid immediately precipitated at room temperature. Stirring was continued for 30 minutes before filtration. The filtered solid was vacuum dried at 50°C overnight.

[0511] Example 6.9 Small-scale preparation of Compound A hydrochloride Form I

[0512] Method 1: Weigh approximately 29.8 mg of the starting material (Compound A Form I) and dissolve it in 300 μL of ethyl acetate to form a solution. 6.72 μL of hydrochloric acid is then added. A solid precipitates immediately at room temperature. Stir for 30 minutes and filter. The filtered solid is vacuum-dried at 50°C overnight.

[0513] Method 2: Approximately 29.3 mg of the starting material (Compound A Form I) was dissolved in 180 μL of butanone to form a solution. 6.72 μL of hydrochloric acid was then added. A solid immediately precipitated at room temperature. Stirring was continued for 30 minutes before filtration. The filtered solid was vacuum dried at 50°C overnight.

[0514] Method 3: Approximately 29.4 mg of the starting material (Compound A Form I) was weighed and dissolved in 330 μL of acetone to form a solution. 6.72 μL of hydrochloric acid was then added. A solid precipitated immediately at room temperature. Stirring was continued for 30 minutes, followed by filtration. The filtered solid was vacuum-dried at 50°C overnight.

[0515] Method 4: Approximately 29.9 mg of the starting material (Compound A Form I) was dissolved in 1.4 mL of isopropyl acetate to form a solution. 6.72 μL of hydrochloric acid was then added. A solid precipitated immediately at room temperature. Stirring was continued for 30 minutes, followed by filtration. The filtered solid was vacuum dried at 50°C overnight.

[0516] Method 5: Approximately 29.6 mg of the starting material (Compound A Form I) was weighed and dissolved in 170 μL of acetonitrile to form a solution. 6.72 μL of hydrochloric acid was then added. A solid precipitated immediately at room temperature. Stirring was continued for 30 minutes, followed by filtration. The filtered solid was vacuum dried at 50°C overnight.

[0517] Example 6.10 Small-scale preparation of Compound A methanesulfonate Form I

[0518] Approximately 30.2 mg of the starting material (Compound A Form I) was weighed and dissolved in 400 μL of ethyl acetate to form a solution. 5.84 μL of methanesulfonic acid was then added. A solid immediately precipitated at room temperature. Stirring was continued for 30 minutes before filtration. The filtered solid was vacuum dried at 50°C overnight.

[0519] Example 7 Characterization of the Crystalline Salt of Compound A

[0520] Example 7.1 Characterization of Compound A Maleate Salt Form I

[0521] Compound A maleate salt form I was prepared according to the method in Example 6.3, and the results of XRPD, PLM, 1 HNMR, DSC, TGA and DVS characterization, the specific results are as follows:

[0522] XRPD analysis

[0523] Figure 25 XRPD data for Compound A maleate salt Form I collected according to General Method 1 are shown. A list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 7.1. The XRPD results indicate that the maleate salt Form I has good crystallinity.

[0524] Table 7.1: XRPD peak list (2θ°) of Compound A maleate salt Form I

[0525]

[0526]

[0527] PLM Analytics

[0528] PLM analysis of Compound A maleate Form I was performed using General Method 2. PLM results showed that maleate Form I was irregular crystals with smaller particles and agglomeration.

[0529] 1 H NMR analysis

[0530] Compound A maleate salt Form I was prepared by General Method 3 1 H NMR analysis.1 H NMR results showed that the sample had a chemical shift, and maleic acid and free base formed maleate in a 1:1 molar ratio. 1 H NMR (400MHz, DMSO-d6) δ7.64–7.55(m,2H),7.48(dd,J=8.6,5.7Hz,1H),7.20(td,J=8.5,2.7Hz,1H),6.88(d,J=1.7Hz,1H),6. 57(s,2H),6.24(s,2H),5.77–5.56(m,1H),4.45(d,J=14.4Hz,1H),4.21(d,J=14.4Hz,1H),3.00(s,3H),1.69(d,J=6.2Hz,3H).

[0531] DSC and TGA thermal analysis

[0532] DSC and TGA analysis of Compound A maleate Form I were performed using General Methods 4 and 5. DSC results revealed a narrow melting endotherm with a peak temperature of approximately 208.87°C and an onset temperature of approximately 205.24°C. TGA analysis revealed a weight loss of approximately 0.44% before 175°C, attributable to a small amount of residual solvent. DSC and TGA analysis indicated that the sample was an anhydrous crystalline form.

[0533] DVS analysis

[0534] Figure 26 The DVS pattern of Compound A maleate salt Form I collected by General Method 6 is shown. The DVS results show that the weight gain from 10% RH to 80% RH is approximately 2.3%.

[0535] The crystal form of the sample did not change before and after the DVS test, such as Figure 27 .

[0536] Example 7.2 Characterization of Compound A Acetate Form I

[0537] Compound A acetate form I was prepared according to the method in Example 6.4, and the results of XRPD, PLM, 1 HNMR, DSC, TGA and DVS characterization, the specific results are as follows:

[0538] XRPD analysis

[0539] Figure 28 XRPD data for Compound A acetate salt Form I collected according to General Method 1 are shown. A list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 7.2. The XRPD results indicate that the acetate salt Form I has good crystallinity.

[0540] Table 72: XRPD peak list (2θ°) of Compound A acetate salt Form I

[0541]

[0542]

[0543] PLM Analytics

[0544] Compound A acetate Form I was subjected to PLM analysis by General Method 2. The PLM results showed that acetate Form I was irregular crystals with smaller particles.

[0545] 1 H NMR analysis

[0546] Compound A acetate form I was prepared by general method 3 1 H NMR analysis. 1 H NMR results showed that the sample had a chemical shift, and acetic acid and free base formed acetate in a 1:1 molar ratio. 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),7.65–7.55(m,2H),7.47(dd,J=8.5,5.7Hz,1H),7.18(td,J=8.5,2.7Hz,1H),6.82(d,J=1.7Hz, 1H),6.20(s,1H),5.72–5.54(m,1H),4.44(d,J=14.4Hz,1H),4.20(d,J=14.4Hz,1H),3.00(s,3H),1.91(s,3H),1.68(d,J=6.2Hz,3H).

[0547] DSC and TGA thermal analysis

[0548] DSC and TGA analysis of Compound A acetate Form I were performed using General Methods 4 and 5. The DSC results showed that the peak temperature of the melting endothermic peak of the sample was approximately 231.99°C, and the onset temperature was approximately 227.27°C.

[0549] TGA results showed that the sample had a rapid weight loss of about 0.67% before 140°C, which was due to a small amount of residual solvent.

[0550] DSC and TGA analysis showed that the sample was anhydrous crystalline.

[0551] DVS analysis

[0552] Figure 29 The DVS pattern of Compound A acetate salt Form I collected by General Method 6 is shown. The DVS results show that the humidity increased from 10% RH to 80% RH, resulting in a weight gain of 0.01%.

[0553] The crystal form of the sample did not change before and after the DVS test, such as Figure 30 .

[0554] Example 7.3 Characterization of Compound A p-toluenesulfonate Form I

[0555] Compound A p-toluenesulfonate Form I was prepared according to the method in Example 6.5, and the results of XRPD, PLM, 1 H NMR, DSC, TGA and DVS characterization, the specific results are as follows:

[0556] XRPD analysis

[0557] Figure 31 XRPD data for Compound A p-toluenesulfonate Form I collected according to General Method 1 are shown. A list of XRPD peaks at diffraction angles of 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 7.3. The XRPD results indicate that p-toluenesulfonate Form I has good crystallinity.

[0558] Table 7.3: XRPD peak list (2θ°) of Compound A p-toluenesulfonate Form I

[0559] peak Angle °2θ±0.2°2θ Relative Strength 1 5.544 20.2 2 10.583 100.0 3 12.968 29.6 4 14.012 16.5 5 14.503 38.6 6 16.886 22.9 7 17.478 9.5 8 18.417 11.1 9 19.607 16.0 10 21.298 24.5 11 21.674 51.3 12 23.266 24.1 13 24.421 4.3 14 25.063 5.4 15 26.437 14.8 16 28.290 7.8

[0560] PLM Analytics

[0561] PLM analysis of Compound A p-toluenesulfonate Form I was performed by General Method 2. The PLM results showed that p-toluenesulfonate Form I was irregular crystals with smaller particles.

[0562] 1 H NMR analysis

[0563] Compound A p-toluenesulfonate Form I was prepared by General Method 3 1 H NMR analysis. 1 H NMR results showed that the sample had a chemical shift, and p-toluenesulfonic acid and free base formed p-toluenesulfonate in a 1:1 molar ratio. 1 H NMR(400MHz, DMSO-d6)δ8.12(s,1H),7.66–7.42(m,5H),7.26(td,J=8.5,2.6Hz,1H),7.20–7.05(m,2H),5.86– 5.72(m,1H),4.48(d,J=14.6Hz,1H),4.27(d,J=14.5Hz,1H),3.00(s,3H),2.29(s,3H),1.73(d,J=6.2Hz,3H).

[0564] DSC and TGA thermal analysis

[0565] DSC and TGA analysis of Compound A p-toluenesulfonate Form I were performed using General Methods 4 and 5. DSC results revealed a melting endotherm with a peak temperature of approximately 269.08°C and an onset temperature of approximately 263.64°C. TGA analysis revealed a slow weight loss of 0.60% before 220°C, indicating a small amount of residual solvent. DSC and TGA analysis indicated that the sample was an anhydrous crystalline form.

[0566] DVS analysis

[0567] Figure 32 The DVS pattern of Compound A p-toluenesulfonate Form I collected by General Method 6 is shown. The DVS results show that a weight gain of 5.1% occurs when the humidity increases from 10% RH to 80% RH.

[0568] The crystal form of the sample changed before and after the DVS test, and it was speculated that hydrates might be formed, such as Figure 33 .

[0569] Example 7.4 Characterization of Compound A Oxalate Form I

[0570] Compound A oxalate Form I was prepared according to the method in Example 6.6, and the oxalate was analyzed by XRPD, PLM, 1 HNMR, DSC and TGA characterization, the specific results are as follows:

[0571] XRPD analysis

[0572] Figure 34 XRPD data of Compound A oxalate Form I collected according to General Method 1 are shown. A list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 7.4. The XRPD results indicate that the oxalate Form I has good crystallinity.

[0573] Table 7.4: XRPD peak list of Compound A oxalate Form I (2θ°)

[0574] peak Angle °2θ±0.2°2θ Relative Strength 1 4.320 31.2 2 5.540 27.5 3 6.642 100.0 4 8.810 4.3 5 10.366 18.1 6 10.980 15.0 7 11.606 5.0 8 12.712 4.4 9 13.242 19.6 10 14.226 8.7 11 18.385 3.3 12 18.772 7.2 13 19.886 2.0 14 20.230 1.5 15 21.334 4.1 16 21.888 5.4 17 22.774 3.7 18 23.088 6.6 19 27.342 2.5 20 30.237 5.0

[0575] PLM Analytics

[0576] PLM analysis of Compound A oxalate Form I was performed using General Method 2. PLM results showed that oxalate Form I was an irregularly shaped crystal.

[0577] 1 H NMR analysis

[0578] Compound A oxalate Form I was prepared by General Method 3 1 H NMR analysis.1 H NMR results showed that the peak of the sample at around 5.80 ppm had an obvious chemical shift, and oxalic acid and free base formed oxalate in a molar ratio of 1:1. 1 HNMR (400MHz, DMSO-d6) δ7.58(d,J=1.7Hz,2H),7.48(dd,J=8.5,5.7Hz,1H),7.20(dd,J=8.5,2.6Hz,1H),6.84(s,1H ),6.52–6.16(m,2H),5.63(d,J=4.7Hz,1H),4.45(d,J=14.4Hz,2H),4.22(s,1H),3.00(s,3H),1.69(d,J=6.2Hz,3H).

[0579] DSC and TGA thermal analysis

[0580] DSC and TGA analysis of Compound A oxalate Form I were performed using General Methods 4 and 5. DSC results showed that the melting endotherm peak of the sample had a peak temperature of approximately 209.28°C and an onset temperature of approximately 182.04°C. TGA results showed that the sample experienced a weight loss of approximately 0.86% before 130°C, indicating a small amount of residual solvent. DSC and TGA analysis indicated that the sample was a solvate.

[0581] Example 7.5 Characterization of Compound A Sulfate Form I

[0582] Compound A sulfate crystal form I was prepared according to the method in Example 6.7, and the results of XRPD, PLM, 1 HNMR, DSC and TGA characterization, the specific results are as follows:

[0583] XRPD analysis

[0584] Figure 35 XRPD data for Compound A Sulfate Salt Form I collected according to General Method 1 are shown. A list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 7.5. The XRPD results indicate that Sulfate Salt Form I has good crystallinity.

[0585] Table 7.5: XRPD peak list of Compound A sulfate salt form I (2θ°)

[0586]

[0587]

[0588] PLM Analytics

[0589] PLM analysis of Compound A sulfate Form I was performed using General Method 2. PLM results showed that sulfate Form I was an irregularly shaped crystal.

[0590] 1 H NMR analysis

[0591] Compound A sulfate form I was prepared by general method 3 1 H NMR analysis. 1 H NMR results showed that the peak of the sample near 5.80 ppm had an obvious chemical shift, indicating the formation of sulfate. 1 H NMR(400MHz, DMSO-d6)δ7.61–7.48(m,3H),7.23(dd,J=8.1,5.9Hz,1H),7.04(s,1H),5.73( s,1H),4.47(d,J=14.4Hz,1H),4.25(d,J=14.4Hz,1H),3.00(s,3H),1.72(d,J=6.1Hz,3H).

[0592] DSC and TGA thermal analysis

[0593] DSC and TGA analysis of Compound A Sulfate Form I were performed using General Methods 4 and 5. DSC results showed a melting endotherm with a peak temperature of approximately 250.97°C and an onset temperature of approximately 244.89°C. TGA results indicated a weight loss of approximately 2.95% before 90°C, indicating the presence of a hydrated compound.

[0594] Example 7.6 Characterization of Compound A Hydrobromide Form I

[0595] Compound A hydrobromide salt form I was prepared according to the method in Example 6.8, and the results of XRPD, PLM, 1 HNMR, DSC and TGA characterization, the specific results are as follows:

[0596] XRPD analysis

[0597] Figure 36 XRPD data for Compound A hydrobromide salt Form I collected according to General Method 1 are shown. A list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 7.6. The XRPD results indicate that the hydrobromide salt Form I has good crystallinity.

[0598] Table 7.6: XRPD peak list of Compound A hydrobromide salt form I (2θ°)

[0599]

[0600]

[0601] PLM Analytics

[0602] Compound A hydrobromide salt Form I was subjected to PLM analysis by General Method 2. PLM results showed that the hydrobromide salt Form I was a rod-shaped crystal.

[0603] 1 H NMR analysis

[0604] Compound A hydrobromide Form I was prepared by General Method 3 1 H NMR analysis. 1 H NMR results showed that the peak of the sample near 5.80 ppm had an obvious chemical shift, and hydrobromide was generated. 1 H NMR(400MHz,DMSO-d6)δ8.02(br s,1H),8.24–7.80(m,2H),7.60(d,J=1.6Hz,1H),7.58–7.49(m,2H),7.26(td,J=8.6,2.6Hz,1H),7.13(s,1H ),5.78(q,J=6.0Hz,1H),4.48(d,J=14.6Hz,1H),4.27(d,J=14.6Hz,1H),3.00(s,3H),1.73(d,J=6.2Hz,3H).

[0605] DSC and TGA thermal analysis

[0606] DSC and TGA analysis of Compound A hydrobromide Form I were performed using General Methods 4 and 5. DSC results revealed a melting endotherm with a peak temperature of approximately 240.87°C and an onset temperature of approximately 232.49°C. TGA analysis revealed a rapid weight loss of approximately 8.18% before 150°C, attributable to residual solvent. These DSC and TGA analyses suggest that the sample may be a solvate.

[0607] Example 7.7 Characterization of Compound A Hydrochloride Form I

[0608] Compound A hydrochloride form I was obtained by all five preparation methods in Example 6.9, and the sample obtained by method 1 was subjected to XRPD, PLM, 1 H NMR, DSC, TGA and DVS characterization, the specific results are as follows:

[0609] XRPD analysis

[0610] Figure 37XRPD data for Compound A hydrochloride Form I collected according to General Method 1 are shown. Table 7.7 provides a list of XRPD peaks at diffraction angles of 2θ° (°2θ) ± 0.2°2θ and their relative intensities. The XRPD results indicate that the hydrochloride Form I has good crystallinity.

[0611] Table 7.7: XRPD peak list (2θ°) of Compound A hydrochloride Form I

[0612]

[0613]

[0614] PLM Analytics

[0615] A PLM image of Compound A hydrochloride Form I was performed using General Method 2. The PLM results showed that the hydrochloride Form I was a relatively large rod-shaped crystal.

[0616] 1 H NMR analysis

[0617] Compound A hydrochloride Form I was prepared by General Method 3 1 H NMR analysis. 1 The H NMR results showed that the hydrogen in the sample around 6.80 ppm had a chemical shift of about 0.12 ppm, indicating that hydrochloric acid reacted with the free base to form a hydrochloride. 1 H NMR (400MHz, DMSO) δ8.24–7.85(m,3H),7.62(s,1H),7.54(ddd,J=14.3,9.3,4.2Hz,1H),7.25(td,J=8.5,2.6Hz,1H),7 .11(s,1H),5.76(t,J=5.6Hz,1H),4.47(d,J=14.6Hz,1H),4.27(d,J=14.5Hz,1H),3.00(s,3H),1.73(d,J=6.2Hz,3H).

[0618] DSC and TGA thermal analysis

[0619] DSC and TGA analysis of the collected Compound A hydrochloride Form I were performed using General Methods 4 and 5. DSC results revealed a melting endotherm with a peak temperature of approximately 221.36°C and an onset temperature of approximately 207.44°C. TGA analysis revealed a weight loss of approximately 1.67% before 125°C, attributed to a small amount of residual solvent. Approximately 3.84% weight loss occurred between 125°C and 230°C. These DSC and TGA analyses suggest that the sample may be a solvate.

[0620] DVS analysis

[0621] Figure 38 The DVS pattern of Compound A hydrochloride Form I collected by General Method 6 is shown. The DVS results show that a 3.5% weight gain occurs when the humidity increases from 10% RH to 80% RH.

[0622] The crystal form of the sample changed before and after DVS test, and it is speculated that hydrate may be formed, such as Figure 39 .

[0623] Example 7.8 Characterization of Compound A Methanesulfonate Form I

[0624] Compound A mesylate salt Form I was prepared according to the method in Example 6.10, and XRPD, PLM and 1 H NMR characterization, the specific results are as follows:

[0625] XRPD analysis

[0626] Figure 40 XRPD data for Compound A mesylate salt Form I collected according to General Method 1 is shown. A list of XRPD peaks at diffraction angles 2θ° (°2θ) ± 0.2°2θ and their relative intensities are provided in Table 7.8. The XRPD results indicate that the mesylate salt Form I is poorly crystalline.

[0627] Table 7.8: XRPD peak list (2θ°) of Compound A mesylate salt Form I

[0628] peak Angle °2θ±0.2°2θ Relative Strength 1 8.338 100.0 2 9.363 40.1 3 10.092 31.8 4 11.706 91.7 5 12.513 28.7 6 13.932 80.9 7 14.738 56.7 8 15.053 35.0 9 15.742 47.1 10 16.711 24.8 11 18.341 82.2 12 19.093 37.6 13 21.148 50.3 14 21.588 72.0 15 22.597 51.0 16 23.170 33.1 17 23.716 27.4 18 24.469 35.7 19 24.650 49.7 20 24.824 35.7 21 25.732 69.4 22 30.238 33.1 23 32.189 29.3

[0629] PLM Analytics

[0630] Compound A mesylate salt Form I was subjected to PLM analysis by General Method 2. The PLM results showed that the mesylate salt Form I was an irregularly shaped crystal.

[0631] 1 H NMR analysis

[0632] Compound A mesylate salt Form I was prepared by General Method 3 1 H NMR analysis. 1 The H NMR results showed that the sample had an obvious chemical shift of hydrogen around 5.80 ppm, indicating that methanesulfonic acid and free base formed methanesulfonate in a 1:1 ratio. 1H NMR(400MHz,DMSO-d6)δ8.17(br s,1H),7.61(d,J=4.0Hz,1H),7.54(ddd,J=10.0,8.6,4.2Hz,2H),7.26(td,J=8.5,2.6Hz,1H),7.14(s,1H),5.8 9–5.65(m,1H),4.48(d,J=14.6Hz,1H),4.28(d,J=14.6Hz,1H),3.00(s,3H),2.33(s,3H),1.73(d,J=6.2Hz,3H).

[0633] Example 8 Accelerated Stability Study of Compound A Free Base and Crystalline Salt

[0634] A certain amount of samples of Compound A Form I, Compound A maleate Form I, Compound A acetate Form I and Compound A p-toluenesulfonate Form I were placed in a stability test chamber and maintained at 40°C / 75% RH and 60°C for 7 days, respectively, and the HPLC and XRPD of the crystals were tested at different time periods.

[0635] The results showed that after keeping Compound A Form I, Compound A maleate Form I, Compound A acetate Form I and Compound A p-toluenesulfonate Form I at 40°C / 75% RH and 60°C for 7 days, the crystal form and purity did not change, indicating good stability. Figures 41-44 The specific results are listed in Table 8.

[0636] Table 8 Accelerated stability study results of compound A free base and crystalline salt

[0637]

[0638] Example 9 Solubility Study of Compound A Free Base and Crystalline Salt in Different Solvents

[0639] The solubility and stability of Compound A Form I, Compound A maleate Form I, and Compound A acetate Form I were studied in water, SGF (artificial gastric fluid), FaSSIF (artificial intestinal fluid in the fasted state), and FeSSIF (artificial intestinal fluid in the fed state). The specific results are listed in Table 9.

[0640] Table 9 Solubility of compound A free base and crystalline salt in different solvents

[0641]

[0642] The results showed that compound A crystal form I had good solubility in SGF biolysin (>5 mg / mL), poor solubility in water, FaSSIF and FeSSIF biolysin (<3 mg / mL), and the crystal form in water did not change. In FaSSIF and FeSSIF biolysin, the crystallinity decreased and approached amorphous form. Figure 45 , indicating that compound A crystalline form I did not precipitate solids in FaSSIF and FeSSIF biolysins over time and always remained in a solution state.

[0643] Compound A maleate salt crystal form I has good solubility in water and SGF biolysin (> 5 mg / mL), and poor solubility in FaSSIF and FeSSIF biolysin (< 3 mg / mL). The crystal form in water does not change. The crystallinity of the maleate salt in FaSSIF and FeSSIF decreases after 24 hours and approaches the amorphous form. Figure 46 , indicating that the maleate crystal form I of compound A did not precipitate solids in FaSSIF and FeSSIF biolysins over time and always remained in a solution state.

[0644] Compound A acetate salt form I has good solubility in SGF biolysin (>5 mg / mL), but poor solubility in water, FaSSIF and FeSSIF biolysin (<3 mg / mL). The crystallinity of the acetate salt in water, FaSSIF and FeSSIF decreases to be close to amorphous, such as Figure 47 , indicating that the acetate salt form I of compound A did not precipitate solids in FaSSIF and FeSSIF biolysins over time and always remained in a solution state.

[0645] The solubility of compound A maleate and acetate in water was significantly improved compared with the free base, from less than 0.2 mg / mL to greater than 0.8 mg / mL (maleate even greater than 6 mg / mL); in the biorelevant medium FaSSIF, the solubility of maleate was significantly improved compared with the free base.

[0646] Example 10 Single crystal X-ray structure and absolute stereochemistry of compound A

[0647] An attempt was made to grow single crystals of Compound A using a slow volatilization method at room temperature. The experiment was carried out in a 1.5 mL vial (a frequently used liquid phase analysis vial), and approximately 100 mg of Compound A Form I was dissolved in acetone, ethyl acetate, isopropyl acetate, and ethanol, respectively. The antisolvent n-heptane was added to the clear solution until the solution became slightly turbid, and 1-2 drops of solvent were added or the temperature was raised until the solution became clear again. The bottle cap was loosened, and the vial was placed at room temperature for slow volatilization. A single crystal was obtained one day later in a mixed solvent of ethyl acetate and n-heptane.

[0648] The collection and analysis of single crystal structure data were completed by the Crystal Laboratory of Peking University. Using Agilent's SuperNova XRD diffraction system, single crystal diffraction data of the sample were collected at 180K using the Cu target Kα spectrum (λ = 1.54178A). The data were trimmed and corrected for absorption using the CrysAlisPro program, and the structure was solved using the dual space algorithm using the SHELXT program. Non-hydrogen atoms may be located in different Fourier spectra, and hydrogen atoms are geometrically filled into their parent atoms. Using the SHELXL program, based on the F 2 The final structure was refined using the full-matrix least squares method.

[0649] The refined single crystal structure of compound A is shown in Figure 48 The crystal structure parameters obtained by analysis are listed in Table 10. The single crystal is a bulk crystal with the structural formula C 21 H 16 D3FN6O2 belongs to the monoclinic crystal system and P21 space group.

[0650] The single crystal sample was subjected to XRPD test and compared with the calculated value. Figure 49 As shown, all characteristic peaks of XRPD can correspond to the simulation values and are consistent with the XRPD of Compound A Form I, indicating that it is a single crystal of Compound A Form I.

[0651] Table 10 Crystal structure parameters of compound A

[0652]

[0653] Example 11 Representative Tablet Formulation of Compound A Form I

[0654] 5 mg and 25 mg doses of oral film-coated tablets were prepared using a powder direct compression process. The composition of the tablets is provided in Table 11-1.

[0655] Table 11-1 Composition of unit dose tablet products

[0656]

[0657] Note: *Purified water 1 is used as a wetting agent during the granulation process and is removed during the drying process and is not included in the material balance. The typical usage of purified water is 35% by weight, but the actual amount can be adjusted according to the actual wet granulation conditions.

[0658] **Opadry II 85F620077** ingredients are titanium dioxide, polyvinyl alcohol, talc, polyethylene glycol, and iron oxide yellow.

[0659] ***Purified water 2 is used as a solvent in the preparation of the coating solution and is removed during the coating process and is not included in the material balance.

[0660] This product, available in 5mg and 25mg tablet strengths, is formulated in equal proportions, using the same batch of masterbatch material and then compressed into tablets of different strengths. For example, a batch of 20,000 5mg tablets and a batch of 30,000 25mg tablets are produced. The batch formulation information is shown in Table 11-2.

[0661] Table 11-2 5mg / 25mg GMP batch prescription information

[0662]

[0663] Note: *Purified water 1 is used as a wetting agent during the granulation process and is removed during the drying process and is not included in the material balance. The typical usage of purified water is 35% by weight, but the actual amount can be adjusted according to the actual wet granulation conditions.

[0664] **Opadry II 85F620077** ingredients are titanium dioxide, polyvinyl alcohol, talc, polyethylene glycol, and iron oxide yellow.

[0665] ***Purified water 2 is used as a solvent in the preparation of the coating solution and is removed during the coating process and is not included in the material balance.

[0666] The method for preparing tablets is as follows:

[0667] 1. Weighing

[0668] Weigh the API Compound A Crystal Form I and excipients according to the prescribed amount.

[0669] 2. Sieve

[0670] Compound A Form I was passed through a 120-mesh sieve (the LDPE bag containing the API was rinsed with about 1 / 4 of the total amount of mannitol 50C and 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.

[0671] 3. Wet granulation

[0672] Mixing: Add microcrystalline cellulose 102, Compound A Form I, mannitol 50C, croscarmellose sodium, and hydroxypropylcellulose EXF to a wet granulation kettle and premix. Use a stirring paddle speed of 250 rpm, a shear rate of 400 rpm, and a mixing time of 10 min.

[0673] Spraying: After mixing, set the stirring paddle speed to 200 rpm, the shear rate to 1000 rpm, and the peristaltic pump speed to 241.7 rpm, and spray the prescribed amount of purified water into the material pot of the wet granulator. The spraying time is about 3 minutes.

[0674] Granulation: Granulate for 2 min after spraying, with a stirring paddle speed of 200 rpm and a shear speed of 1000 rpm.

[0675] Wet granulation: The granulated material is placed in a granulator for granulation at a granulation speed of 1500 rpm and a sieve aperture of 6×6 mm.

[0676] Drying: Set the fluidized bed air inlet temperature to 50-70°C and the air inlet volume to 35-120m 3 / h, filter bag shaking time 0.5s, bag shaking interval 3-5s, after preheating, the wet particles are dried to the material moisture <2% w / w.

[0677] Dry granulation: The dried material is placed in a granulator for granulation at a granulation speed of 1500 rpm and a sieve aperture of 1.0 mm.

[0678] 4. Total Mixing

[0679] The dried granulated material was added to a hopper mixer, and magnesium stearate was added for total mixing. The mixing speed was 20 rpm, the mixing time was 5 min, and samples were taken to detect the overall mixing uniformity.

[0680] 5. Tablet pressing

[0681] The punch for 5mg tablets is a 6.0mm shallow concave round punch, and the punch for 25mg tablets is a 10.0mm shallow concave round punch. After the equipment is debugged, formal production begins. Tablet weight, hardness, and friability are monitored online to ensure they meet the following standards:

[0682] Table 11-3 Tablet compression standards for the preparation process of Compound A Form I tablets

[0683]

[0684] 6. Coating

[0685] Prepare a fresh 12% Opadry coating solution in purified water.

[0686] Preheating: Set the air inlet temperature to 50-60℃ and the coating pan speed to 2rpm for preheating.

[0687] Spraying: When the coating pan is preheated to the exhaust temperature of 42℃, spray the coating.

[0688] Equipment parameters: Set the air inlet temperature to 50-70℃, the pot speed to 5-12rpm, and the air inlet volume to 300±100m 3 / h. Pump flow rate 8ml / min~80ml / min, atomization pressure 1.5±1bar, atomization angle control pressure 5mg specification: 1±0.5bar; 25mg specification: 2.5±1bar.

[0689] Monitor coating parameters and coating weight gain, and stop spraying when the coating weight gain reaches the target range of 3.0±0.5%.

[0690] Drying: Stop heating, adjust the coating pan speed to 5rpm, and the air volume to 200-500m 3 / h, and discharge the material after drying for 5 minutes.

[0691] 7. Packaging

[0692] The packaging materials for 5mg tablets and 25mg tablets are 45mL and 75mL oral solid pharmaceutical high-density polyethylene bottles, respectively, with 30 tablets per bottle.

[0693] 8. Label

[0694] Apply bottle labels to product bottles, one label per bottle.

[0695] Preferably, the present invention relates to the following technical solutions:

[0696] 1. Crystalline Form I of the compound of formula (A):

[0697]

[0698] It is characterized by: using CuK α The X-ray powder diffraction pattern obtained by radiation includes at least characteristic peaks located at the following °2θ: 16.175±0.2, 17.299±0.2 and 21.218±0.2.

[0699] 2. The crystalline form I of the compound of formula (A) of technical solution 1 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located at the following °2θ: 9.637±0.2, 12.555±0.2, 14.343±0.2 and 19.366±0.2.

[0700] 3. The crystalline form I of the compound of formula (A) of technical solution 2 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0701] Angle °2θ±0.2°2θ Relative strength % 9.637 38.2 12.555 38.1 14.343 34.5 16.175 100 17.299 68.5 19.366 34.7 21.218 54.1 .

[0702] 4. The crystalline form I of the compound of formula (A) of technical solution 2 or 3, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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.

[0703] 5. The crystalline form I of the compound of formula (A) of technical solution 1 is characterized in that: it has substantially Figure 1 The X-ray powder diffraction pattern is shown.

[0704] 6. The crystalline form I of the compound of formula (A) according to any one of technical solutions 1 to 5 is further characterized in that it has an endothermic peak at 232±2°C in differential scanning calorimetry analysis.

[0705] 7. The crystalline form I of the compound of formula (A) according to any one of technical solutions 1-6 is further characterized in that: in thermogravimetric analysis, there is essentially no weight loss before 150°C.

[0706] 8. Form I of the compound of formula (A), characterized in that it has the following parameters:

[0707]

[0708]

[0709] 9. The crystalline form I of the compound of formula (A) in any one of technical solutions 1-8 is characterized in that: its infrared absorption spectrum is below cm -1 The absorption peaks are 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.

[0710] 10. The crystalline form I of the compound of formula (A) of technical solution 9 is further characterized in that: it has substantially Figure 14 Infrared spectrum shown.

[0711] 11. The crystalline form I of the compound of formula (A) according to any one of technical solutions 1 to 10 is further characterized in that its UV spectrum has absorption peaks at the following nm: 206±2 and 317±2.

[0712] 12. The crystalline form I of the compound of formula (A) of technical solution 11 is further characterized in that: it has substantially Figure 15 UV spectrum shown.

[0713] 13. Crystalline form II of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation includes at least characteristic peaks located at the following degrees 2θ: 7.591±0.2, 12.081±0.2 and 23.364±0.2.

[0714] 14. The crystal form II of the compound of formula (A) of technical solution 13 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes 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.

[0715] 15. The crystal form II of the compound of formula (A) of technical solution 14 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0716] Angle °2θ±0.2°2θ Relative strength % 7.591 100 12.081 24.7 14.577 12.9 15.595 10.2 16.948 14.2 17.615 14.4 20.448 14.6 23.364 17.4 .

[0717] 16. The crystalline form II of the compound of formula (A) of technical solution 13 is characterized in that: it has substantially Figure 17 The X-ray powder diffraction pattern is shown.

[0718] 17. The crystalline form II of the compound of formula (A) according to any one of technical solutions 13 to 16 is further characterized in that it has an endothermic peak at 230±2° C. in differential scanning calorimetry analysis.

[0719] 18. The crystalline form II of the compound of formula (A) according to any one of technical solutions 13-17 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 6.69% before 160°C.

[0720] 19. Form III of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation includes at least a characteristic peak expressed at the following °2θ: 23.149±0.2.

[0721] 20. The crystal form III of the compound of formula (A) of technical solution 19, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes 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.

[0722] 21. The crystalline form III of the compound of formula (A) of technical solution 20 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0723] Angle °2θ±0.2°2θ Relative strength % 11.429 22.2 13.027 21.7 14.542 21.3 17.949 19.1 23.149 100 26.994 20.4 .

[0724] 22. The crystalline form III of the compound of formula (A) of technical solution 20 or 21, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes 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.

[0725] 23. The crystalline form III of the compound of formula (A) of technical solution 19 is characterized in that: it has substantially Figure 18 The X-ray powder diffraction pattern is shown.

[0726] 24. The crystalline form III of the compound of formula (A) according to any one of technical solutions 19 to 23 is further characterized in that it has an endothermic peak at 226±2° C. in differential scanning calorimetry analysis.

[0727] 25. The crystalline form III of the compound of formula (A) according to any one of technical solutions 19-24 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 5.31% before 165°C.

[0728] 26. Form IV of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation includes at least a characteristic peak located at the following °2θ: 10.113±0.2.

[0729] 27. The crystalline form IV of the compound of formula (A) of technical solution 26 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes 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.

[0730] 28. The crystalline form IV of the compound of formula (A) of technical solution 27 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0731] Angle °2θ±0.2°2θ Relative strength % 10.113 100 11.583 31 11.768 35.2 12.098 25.9 17.143 46.2 19.267 26.6 .

[0732] 29. The crystalline form IV of the compound of formula (A) of technical solution 27 or 28, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes 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.

[0733] 30. The crystalline form IV of the compound of formula (A) of technical solution 26 is characterized in that: it has substantially Figure 19 The X-ray powder diffraction pattern is shown.

[0734] 31. The crystalline form IV of the compound of formula (A) according to any one of technical solutions 26 to 30 is further characterized in that it has an endothermic peak at 232±2° C. in differential scanning calorimetry analysis.

[0735] 32. The crystalline form IV of the compound of formula (A) according to any one of technical solutions 26-31 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 0.28% before 200°C.

[0736] 33. Form V of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation includes at least characteristic peaks located at the following °2θ: 6.939±0.2, 16.276±0.2 and 17.494±0.2.

[0737] 34. The crystalline form V of the compound of formula (A) of technical solution 33 is characterized in that: αThe X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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.

[0738] 35. The crystalline form V of the compound of formula (A) of technical solution 34 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0739] Angle °2θ±0.2°2θ Relative strength % 4.912 28.1 6.939 100 9.774 30.1 12.709 41.4 14.246 29.4 14.482 33.4 16.276 55.9 17.242 42.4 17.494 76.9 18.519 25.7 19.425 34.7 21.001 27.3 21.317 29.5 22.734 26.7 25.218 28.2 29.688 26.1 .

[0740] 36. The crystalline form V of the compound of formula (A) of technical solution 34 or 35, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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.

[0741] 37. The crystalline form V of the compound of formula (A) of technical solution 33 is characterized in that: it has substantially Figure 20 The X-ray powder diffraction pattern is shown.

[0742] 38. The crystalline form V of the compound of formula (A) according to any one of technical solutions 33 to 37 is further characterized in that it has an endothermic peak at 232±2° C. in differential scanning calorimetry analysis.

[0743] 39. The crystalline form V of the compound of formula (A) according to any one of technical solutions 33-38 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 0.22% before 200°C.

[0744] 40. Crystalline form VI of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation includes at least characteristic peaks located at the following degrees 2θ: 10.247±0.2, 12.198±0.2 and 17.258±0.2.

[0745] 41. The crystalline form VI of the compound of formula (A) of technical solution 40 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes 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.

[0746] 42. The crystal form VI of the compound of formula (A) of technical solution 41, characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0747] Angle °2θ±0.2°2θ Relative strength % 10.247 100 12.198 70.6 12.514 42.8 17.258 53.8 17.596 44.5 19.406 27.9 21.888 30.3 27.599 27.5 .

[0748] 43. The crystalline form VI of the compound of formula (A) of technical solution 41 or 42, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes 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.

[0749] 44. The crystalline form VI of the compound of formula (A) of technical solution 40 is characterized in that: it has substantially Figure 21 The X-ray powder diffraction pattern is shown.

[0750] 45. The crystalline form VI of the compound of formula (A) according to any one of technical solutions 40-44 is further characterized in that it has an endothermic peak at 233±2°C in differential scanning calorimetry analysis.

[0751] 46. The crystalline form VI of the compound of formula (A) according to any one of technical solutions 40-45 is further characterized in that: in thermogravimetric analysis, there is almost no weight loss before 200°C.

[0752] 47. Form VII of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation at least includes characteristic peaks located at the following °2θ: 7.138±0.2 and 9.876±0.2.

[0753] 48. The crystalline form VII of the compound of formula (A) of technical solution 47, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located at the following °2θ: 12.572±0.2, 12.945±0.2, 14.675±0.2 and 17.16±0.2.

[0754] 49. The crystalline form VII of the compound of formula (A) of technical solution 48, characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0755] Angle °2θ±0.2°2θ Relative strength % 7.138 100 9.876 51.2 12.572 31.6 12.945 38.5 14.675 30.3 17.16 26.2 .

[0756] 50. The crystalline form VII of the compound of formula (A) of technical solution 47 is characterized in that: it has substantially Figure 22 The X-ray powder diffraction pattern is shown.

[0757] 51. The crystalline form VII of the compound of formula (A) according to any one of technical solutions 47-50 is further characterized in that it has an endothermic peak at 232±2°C in differential scanning calorimetry analysis.

[0758] 52. The crystalline form VII of the compound of formula (A) according to any one of technical solutions 47-51 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 0.35% before 200°C.

[0759] 53. The maleate salt (1:1) crystalline form I of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation includes at least characteristic peaks located at the following degrees 2θ: 9.737±0.2, 12.241±0.2 and 23.08±0.2.

[0760] 54. The maleate (1:1) crystalline form I of the compound of formula (A) of technical solution 53 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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.

[0761] 55. The maleate (1:1) crystalline form I of the compound of formula (A) of technical solution 54 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0762] Angle °2θ±0.2°2θ Relative strength % 9.737 80 11.982 41 12.241 100 13.601 28 16.495 32 17.186 25 19.625 38 23.08 98 24.527 36 .

[0763] 56. The maleate (1:1) crystalline form I of the compound of formula (A) of technical solution 54 or 55, characterized in that: αThe X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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.

[0764] 57. The maleate (1:1) crystalline form I of the compound of formula (A) of technical solution 53 is characterized in that: it has substantially Figure 25 The X-ray powder diffraction pattern is shown.

[0765] 58. The maleate salt (1:1) crystalline form I of the compound of formula (A) according to any one of technical solutions 53-57 is further characterized in that it has an endothermic peak at 209±2°C in differential scanning calorimetry analysis.

[0766] 59. The maleate salt (1:1) crystalline form I of the compound of formula (A) according to any one of technical solutions 53-58 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 0.44% before 175°C.

[0767] 60. Acetate (1:1) crystalline form I of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation includes at least characteristic peaks located at the following °2θ: 12.866±0.2 and 23.129±0.2.

[0768] 61. Acetate (1:1) crystalline form I of the compound of formula (A) of technical solution 60, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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.

[0769] 62. The acetate (1:1) crystalline form I of the compound of formula (A) of technical solution 61, characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0770]

[0771]

[0772] 63. Acetate (1:1) crystalline form I of the compound of formula (A) of technical solution 61 or 62, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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.

[0773] 64. The acetate (1:1) crystalline form I of the compound of formula (A) of technical solution 60 is characterized in that: it has substantially Figure 28 The X-ray powder diffraction pattern is shown.

[0774] 65. The acetate (1:1) crystalline form I of the compound of formula (A) according to any one of technical solutions 60-64 is further characterized in that it has an endothermic peak at 232±2°C in differential scanning calorimetry analysis.

[0775] 66. The acetate (1:1) crystalline form I of the compound of formula (A) according to any one of technical solutions 60-65 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 0.67% before 140°C.

[0776] 67. The p-toluenesulfonate (1:1) crystalline form I of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation includes at least characteristic peaks located at the following °2θ: 10.583±0.2 and 21.674±0.2.

[0777] 68. The p-toluenesulfonate (1:1) crystalline form I of the compound of formula (A) of technical solution 67 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located at the following °2θ: 12.968±0.2 and 14.503±0.2.

[0778] 69. The p-toluenesulfonate (1:1) crystalline form I of the compound of formula (A) of technical solution 68, characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0779] Angle °2θ±0.2°2θ Relative strength % 10.583 100 12.968 29.6 14.503 38.6 21.674 51.3 .

[0780] 70. The p-toluenesulfonate (1:1) crystalline form I of the compound of formula (A) of technical solution 68 or 69, characterized in that: αThe X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located at the following °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.

[0781] 71. The p-toluenesulfonate (1:1) crystalline form I of the compound of formula (A) of technical solution 67 is characterized in that: it has substantially Figure 31 The X-ray powder diffraction pattern is shown.

[0782] 72. The p-toluenesulfonate (1:1) crystalline form I of the compound of formula (A) according to any one of technical solutions 67-71 is further characterized in that it has an endothermic peak at 269±2°C in differential scanning calorimetry analysis.

[0783] 73. The p-toluenesulfonate (1:1) crystalline form I of the compound of formula (A) according to any one of technical solutions 67-72 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 0.6% before 220°C.

[0784] 74. The oxalate (1:1) crystalline form I of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation at least includes characteristic peaks located at the following °2θ: 4.32±0.2 and 6.642±0.2.

[0785] 75. The oxalate (1:1) crystalline form I of the compound of formula (A) of technical solution 74, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located at the following °2θ: 5.54±0.2, 10.366±0.2, 10.98±0.2 and 13.242±0.2.

[0786] 76. The oxalate (1:1) crystalline form I of the compound of formula (A) of technical solution 75, characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0787] Angle °2θ±0.2°2θ Relative strength % 4.32 31.2 5.54 27.5 6.642 100 10.366 18.1 10.98 15 13.242 19.6 .

[0788] 77. The oxalate (1:1) crystalline form I of the compound of formula (A) of technical solution 74 is characterized in that: it has substantially Figure 34 The X-ray powder diffraction pattern is shown.

[0789] 78. The oxalate (1:1) crystalline form I of the compound of formula (A) of any one of technical solutions 74-77 is further characterized in that it has an endothermic peak at 209±2°C in differential scanning calorimetry analysis.

[0790] 79. The oxalate (1:1) crystalline form I of the compound of formula (A) of any one of technical solutions 74-78 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 0.86% before 130°C.

[0791] 80. The sulfate salt crystal form I of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation at least includes characteristic peaks located at the following degrees 2θ: 15.763±0.2 and 23.266±0.2.

[0792] 81. The sulfate crystal form I of the compound of formula (A) of technical solution 80 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes 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.

[0793] 82. The sulfate crystal form I of the compound of formula (A) of technical solution 81 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0794] Angle °2θ±0.2°2θ Relative strength % 11.604 33.5 13.318 37.9 14.74 30.9 15.763 96.3 15.961 28.5 18.385 45.4 19.228 28.6 21.413 44.1 22.361 44.3 23.266 100 23.936 27.4 24.958 28.3 .

[0795] 83. The sulfate crystal form I of the compound of formula (A) of technical solution 81 or 82, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes 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.

[0796] 84. The sulfate crystalline form I of the compound of formula (A) of technical solution 80 is characterized in that: it has substantially Figure 35 X-ray powder diffraction pattern of .

[0797] 85. The sulfate crystal form I of the compound of formula (A) according to any one of technical solutions 80-84 is further characterized in that it has an endothermic peak at 251±2°C in differential scanning calorimetry analysis.

[0798] 86. The sulfate crystal form I of the compound of formula (A) according to any one of technical solutions 80-85 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 2.95% before 90°C.

[0799] 87. The hydrobromide salt of the compound of formula (A) in form I, characterized in that: α The X-ray powder diffraction pattern obtained by radiation includes at least characteristic peaks located at the following degrees 2θ: 13.206±0.2, 23.995±0.2 and 24.941±0.2.

[0800] 88. The hydrobromide salt crystal form I of the compound of formula (A) of technical solution 87 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes 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.

[0801] 89. The hydrobromide salt crystal form I of the compound of formula (A) of technical solution 88 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0802] Angle °2θ±0.2°2θ Relative strength % 9.222 25.3 11.905 39.8 13.206 100 19.937 28 23.995 83.3 24.941 60.9 26.773 33.3 27.5 45.1 .

[0803] 90. The hydrobromide salt crystalline form I of the compound of formula (A) of technical solution 88 or 89, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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.

[0804] 91. The hydrobromide salt crystalline form I of the compound of formula (A) of technical solution 87 is characterized in that: it has substantially Figure 36 X-ray powder diffraction pattern of .

[0805] 92. The hydrobromide salt crystalline form I of the compound of formula (A) according to any one of technical solutions 87-91 is further characterized in that it has an endothermic peak at 241±2°C in differential scanning calorimetry analysis.

[0806] 93. The hydrobromide salt crystalline form I of the compound of formula (A) according to any one of technical solutions 87-92 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 8.18% before 150°C.

[0807] 94. The hydrochloride crystal form I of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation includes at least characteristic peaks located at the following °2θ: 12.079±0.2, 13.319±0.2 and 24.093±0.2.

[0808] 95. The hydrochloride crystal form I of the compound of formula (A) of technical solution 94 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located at the following °2θ: 9.38±0.2, 12.749±0.2, 24.92±0.2 and 27.559±0.2.

[0809] 96. The hydrochloride crystal form I of the compound of formula (A) of technical solution 95 is characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0810] Angle °2θ±0.2°2θ Relative strength % 9.38 35.3 12.079 52 12.749 26.8 13.319 100 24.093 59.9 24.92 47 27.559 25.7 .

[0811] 97. The hydrochloride crystal form I of the compound of formula (A) of technical solution 95 or 96, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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.

[0812] 98. The hydrochloride crystalline form I of the compound of formula (A) of technical solution 94 is characterized in that: it has substantially Figure 37 X-ray powder diffraction pattern of .

[0813] 99. The hydrochloride crystal form I of the compound of formula (A) according to any one of technical solutions 94-98 is further characterized in that it has an endothermic peak at 221±2°C in differential scanning calorimetry analysis.

[0814] 100. The hydrochloride crystalline form I of the compound of formula (A) according to any one of technical solutions 94-99 is further characterized in that: in thermogravimetric analysis, there is a weight loss of about 1.67% before 125°C and a weight loss of about 3.84% at 125-230°C.

[0815] 101. The methanesulfonate (1:1) crystalline form I of the compound of formula (A), characterized in that: α The X-ray powder diffraction pattern obtained by radiation includes at least a characteristic peak located at the following °2θ: 8.338±0.2.

[0816] 102. The methanesulfonate (1:1) crystalline form I of the compound of formula (A) of technical solution 101, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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.

[0817] 103. The methanesulfonate (1:1) crystalline form I of the compound of formula (A) of technical solution 102, characterized in that: α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks:

[0818] Angle °2θ±0.2°2θ Relative strength % 8.338 100 11.706 91.7 13.932 80.9 14.738 56.7 18.341 82.2 21.148 50.3 21.588 72 22.597 51 25.732 69.4 .

[0819] 104. The methanesulfonate (1:1) crystalline form I of the compound of formula (A) of technical solution 102 or 103, characterized in that: α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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.

[0820] 105. The mesylate (1:1) crystalline form I of the compound of formula (A) of technical solution 101 is characterized in that: it has substantially Figure 40X-ray powder diffraction pattern of .

[0821] 106. A pharmaceutical composition comprising the crystal form of any one of technical solutions 1-105, and a pharmaceutically acceptable excipient.

[0822] 107. A pharmaceutical composition comprising the following ingredients:

[0823] (i) the crystal form of any one of technical solutions 1-105,

[0824] (ii) a diluent,

[0825] (iii) disintegrants,

[0826] (iv) a binder, and

[0827] (v) Lubricants.

[0828] 108. The pharmaceutical composition of technical solution 107, wherein the weight percentage of the crystalline form in the total weight of the pharmaceutical composition is 1-30%, preferably 2-20%, preferably 3-15%, more preferably about 4%, 5%, 6%, 7%, 8%, 9% or 10%, calculated based on the weight of the free base of the compound; preferably, the content of the crystalline form in a unit dose is 1-100 mg, preferably 2-50 mg, preferably 3-40 mg, preferably about 5, 10, 15, 20, 25, 30, 35 or 40 mg.

[0829] 109. The pharmaceutical composition of any one of technical solutions 107-108, wherein the weight percentage of the diluent in the total weight of the pharmaceutical composition is 65-95%, preferably 70-90%, preferably about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%; preferably, the content of the diluent in a unit dose is 50-380 mg, preferably 60-360 mg, preferably 70-350 mg, for example, about 70 mg or 350 mg.

[0830] 110. A pharmaceutical composition according to any one of technical solutions 107-109, wherein the diluent is selected from microcrystalline cellulose, anhydrous calcium hydrogen phosphate and mannitol, such as microcrystalline cellulose 102, mannitol 100SD and mannitol 50C, and mixtures thereof; preferably, when microcrystalline cellulose 102 and mannitol 50C are present at the same time, the weight ratio of microcrystalline cellulose 102 to mannitol 50C is 5:1 to 1:5, preferably 3:1 to 1:2, preferably about 2:1.

[0831] 111. The pharmaceutical composition of any one of technical solutions 107-110, wherein the weight percentage of the disintegrant in the total weight of the pharmaceutical composition is 1-5%, preferably 2-4%, preferably about 2%, 2.5%, 3%, 3.5% or 4%; preferably, the content of the disintegrant in a unit dose is 1-20 mg, preferably 2-16 mg, preferably about 2, 2.5, 3, 6, 9 or 12 mg.

[0832] 112. The pharmaceutical composition of any one of technical solutions 107-111, wherein the disintegrant is cross-linked carboxymethyl cellulose sodium or cross-linked polyvinylpyrrolidone XL-10, preferably cross-linked carboxymethyl cellulose sodium.

[0833] 113. A pharmaceutical composition according to any one of technical solutions 107-112, wherein the weight percentage of the adhesive in the total weight of the pharmaceutical composition is 1-5%, preferably 2-4%, preferably about 2%, 2.5%, 3%, 3.5% or 4%; preferably, the content of the adhesive in a unit dose is 1-20 mg, preferably 2-16 mg, preferably about 2, 2.5, 3, 6, 9 or 12 mg.

[0834] 114. The pharmaceutical composition of any one of technical solutions 107-113, wherein the binder is hydroxypropylcellulose EXF or povidone K30, preferably hydroxypropylcellulose EXF.

[0835] 115. The pharmaceutical composition of any one of technical solutions 107-114, wherein the weight percentage of the lubricant to the total weight of the pharmaceutical composition is 0.1-5%, preferably 0.5-2%, preferably about 1%; preferably, the content of the lubricant in a unit dose is 0.1-20 mg, preferably 0.5-8 mg, preferably about 0.5, 1, 2, 3, 4, 5, 6, 7 or 8 mg.

[0836] 116. The pharmaceutical composition of any one of technical solutions 107-115, wherein the lubricant is magnesium stearate or sodium stearyl fumarate PRUV, preferably magnesium stearate.

[0837] 117. The pharmaceutical composition of any one of technical solutions 107-116, comprising the following ingredients:

[0838] (i) 1-30% by weight of Compound A, Form I,

[0839] (ii) 65-95% by weight of microcrystalline cellulose 102 and mannitol 50C (weight ratio of about 2:1),

[0840] (iii) 2-4% by weight of cross-linked sodium carboxymethyl cellulose,

[0841] (iv) 2-4% by weight of hydroxypropylcellulose EXF, and

[0842] (v) 0.1-5% by weight of magnesium stearate.

[0843] 118. The pharmaceutical composition of technical solution 117, wherein the unit dose comprises the following components:

[0844] (i) about 5 mg of Compound A Form I,

[0845] (ii) about 45 mg of microcrystalline cellulose 102 and about 25 mg of mannitol 50C,

[0846] (iii) about 2.5 mg croscarmellose sodium,

[0847] (iv) about 2.5 mg of hydroxypropylcellulose EXF, and

[0848] (v) about 1 mg magnesium stearate.

[0849] 119. The pharmaceutical composition of technical solution 117, wherein the unit dose comprises the following components:

[0850] (i) about 25 mg of Compound A Form I,

[0851] (ii) about 230 mg lactose monohydrate and about 120 mg microcrystalline cellulose,

[0852] (iii) about 12 mg croscarmellose sodium,

[0853] (iv) about 12 mg of hydroxypropylcellulose EXF, and

[0854] (v) about 4 mg magnesium stearate.

[0855] 120. The pharmaceutical composition of any one of technical solutions 107-119, which is a tablet, preferably a coated tablet; preferably, the coating agent is Opadry II 85F620077.

[0856] 121. Use of the crystal form of any one of technical solutions 1-105 or the pharmaceutical composition of any one of technical solutions 106-120 in the preparation of a drug for treating and / or preventing diseases mediated by ALK and ROS1 kinases and their mutants.

[0857] 122. Use of the crystal form of any one of technical solutions 1-105 or the pharmaceutical composition of any one of technical solutions 106-120 in the preparation of a medicament for treating and / or preventing the following diseases: cell proliferative diseases, inflammation, infection, immune diseases, organ transplantation, 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, gastric cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease or cystic fibrosis.

Claims

1. Crystalline Form I of the compound of formula (A): Its characteristics are: When using CuK α The X-ray powder diffraction pattern obtained by radiation includes at least characteristic peaks located at the following °2θ: 16.175±0.2, 17.299±0.2 and 21.218±0.

2.

2. The crystalline form I of the compound of formula (A) according to claim 1, characterized in that: When using CuK α The X-ray powder diffraction pattern obtained by radiation also includes 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. The crystalline form I of the compound of formula (A) according to claim 2, characterized in that: When using CuK α The X-ray powder diffraction pattern obtained by radiation has the following characteristic peaks: 。 4. The crystalline form I of the compound of formula (A) according to claim 2 or 3, characterized in that: When using CuK α The X-ray powder diffraction pattern obtained by radiation also includes characteristic peaks located 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. The 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 FIG1 .

6. The crystalline form I of the compound of formula (A) according to any one of claims 1 to 5, further characterized in that: In differential scanning calorimetry analysis, the compound showed an endothermic peak at 232±2°C.

7. The crystalline form I of the compound of formula (A) according to any one of claims 1 to 6, further characterized in that: In thermogravimetric analysis, there was essentially no weight loss before 150°C.

8. Form I of the compound of formula (A), characterized in that: It has the following parameters:

9. The crystalline form I of the compound of formula (A) according to any one of claims 1 to 8, characterized in that: Its infrared absorption spectrum is below cm -1 The absorption peaks are 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. The crystalline form I of the compound of formula (A) according to claim 9, further characterized in that: It has an infrared spectrum substantially as shown in FIG14.

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