[1,2,4] Triazole[4,3-b] Pyridazine Compounds: Crystalline Forms, Preparation Methods, and Uses

Abstract

[1,2,4]Triazole[4,3-b]pyridazine compound crystalline form, method of preparation thereof, and use. The crystalline form is a free base crystalline form and can be used for the treatment of neoplastic diseases, and crystalline form B exhibits storage stability. Furthermore, because crystalline form B has a low initial melting temperature, when used in a hot-melt extrusion process, it has a low content of related substances and impurities in the sample, which helps to improve the quality of pharmaceuticals.

Description

Detailed Description of the Invention , ,

[0004]

[0001] Technical Field The present invention relates to the field of chemical pharmaceuticals, and particularly to the crystal form of a [1,2,4]triazole[4,3-b]pyridazine compound which is a c-Met inhibitor, its preparation method and use.

[0002] Background Art Hepatocyte growth factor receptor (c-Met) is a transmembrane protein encoded by the MET gene, belongs to the tyrosine kinase receptor superfamily, and is mainly expressed in epithelial cells. Hepatocyte growth factor (HGF), also called scatter factor (SF), is the only high-affinity ligand for c-Met, is widely distributed in various human tissues and organs, and is mainly expressed in mesenchymal cells. When HGF and c-Met bind in the extracellular domain, it induces the dimerization of c-Met and promotes the phosphorylation transfer of Tyr1234 and Tyr1235, which are two catalytic active sites in the c-Met activation loop. Thereby, autophosphorylation of the terminal sites Tyrl349 and Tyr1356 is caused, various downstream cell effectors and effector molecules are recruited, and downstream signaling pathways such as PI3K-Akt, Ras-MAPK, STAT and Wnt / β-catenin are activated. c-Met / HGF plays an important role in promoting cell proliferation, cell growth, cell migration, vascular invasion and angiogenesis. c-Met gene abnormalities mainly include three types: MET14 exon skipping mutation, MET gene amplification, and c-Met protein overexpression. c-Met gene abnormalities can cause abnormal activation of the c-Met pathway, lead to overactivation of downstream pathways, and may induce cancer.

[0003] Currently, in the research on methods for inhibiting the c-Met / HGF signaling pathway, the most widely studied and most promising method is a c-Met small molecule kinase inhibitor. Small molecule kinase inhibitors can act on the intracellular catalytic domain, inhibit protein phosphorylation, and inhibit signal transduction, thereby realizing targeted cancer treatment. <0*********2><0*********3><0*********4>6-(1-cyclopropyl-1-hydroxypyrazole-4-yl)-3-(difluoro(6-fluoro-2-methyl-(dihydro-indazole-5-yl)methyl)-[1,2,4]triazole[4,3-b]pyridazine is a highly selective c-Met inhibitor for the treatment of cancers caused by c-Met gene mutations. This drug has been designated a Breakthrough Therapy by the National Medical Products Administration of China (NMPA) for the treatment of non-small cell lung cancer patients with c-Met exon 14 mutations. Its structural formula is shown in formula (I):

[0005] [ka]

[0006] At present, no publicly available reports regarding the free base crystalline form of the compound represented by formula (I) have been found. Summary of the Invention This invention provides a crystalline form of the c-Met inhibitor [1,2,4]triazole[4,3-b]pyridazine compound, a method for producing the same, and its use, in order to overcome the shortcomings of the prior art. The crystalline form of this invention is a free base crystalline form and is used in the treatment of neoplastic diseases. The crystalline form of this invention has good chemical and physical stability, low hygroscopicity, is less susceptible to the effects of heat, humidity, and light, and has excellent storage properties. Most importantly, because crystalline form B of this invention has a low initial melting temperature, sample preparation in the hot melt extrusion process is facilitated, and the content of related substances and impurities in the resulting solid dispersion is low, contributing to the improvement of pharmaceutical quality.

[0007] The present invention provides crystalline form A of the compound 6-(1-cyclopropyl-1-hydroxy-pyrazole-4-yl)-3-(difluoro(6-fluoro-2-methyl-(dihydro-indazole-5-yl)methyl)-[1,2,4]triazole[4,3-b]pyridazine, represented by formula (I). When irradiated with Cu-Kα rays, crystalline form A exhibits characteristic peaks in the X-ray powder diffraction pattern, represented by a 2θ angle, at 2θ values ​​of 7.47°, 10.30°, 12.47°, 14.18°, 17.19°, 24.25°, and 25.43°, with an error range of ±0.2° for 2θ.

[0008] [ka]

[0009] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form A exhibits characteristic peaks at 2θ values ​​of 7.47°, 10.30°, 12.47°, 14.18°, 17.19°, 17.54°, 17.85°, 18.15°, 20.39°, 24.25°, 25.43°, 25.97°, and 26.43°, with an error range of ±0.2° for 2θ.

[0010] In some embodiments of the present invention, the crystalline form A X-ray powder diffraction pattern is shown in Figure 1. In some embodiments of the present invention, the characteristic peak 2θ values ​​in the X-ray powder diffraction pattern of crystal form A are shown in the table below, and the error range of 2θ is ±0.2°.

[0011] [Table 1]

[0012] In some embodiments of the present invention, the thermogravimetric analysis curve of crystal form A does not show weight loss from room temperature to the melting point. In some embodiments of the present invention, the TGA spectrum of crystal form A is shown in Figure 2.

[0013] In some embodiments of the present invention, the differential scanning calorimetry curve of crystal form A has a peak value of an endothermic peak at 222.27°C. In some embodiments of the present invention, the DSC spectrum of crystal form A is shown in Figure 3.

[0014] The present invention provides a method for preparing crystalline form A, comprising dissolving a compound represented by formula (I) in a good solvent A1 at 0°C to 70°C, filtering the solution, and adding the resulting clarified solution dropwise to a poor solvent A2 to obtain crystalline form A.

[0015] Preferably, the good solvent A1 is acetic acid. Preferably, the poor solvent A2 is ethanol. Preferably, the volume ratio of the good solvent A1 to the poor solvent A2 is 1 / 6 to 1 / 1, and more preferably 1 / 4 or 1 / 3.

[0016] In order to dissolve the compound shown in formula (I) clearly in the good solvent A1, the temperature at which the compound shown in formula (I) is dissolved in the good solvent A1 is preferably 20°C to 40°C, and preferably 35°C.

[0017] Alternatively, the compound shown in formula (I) is dissolved in good solvent A1, filtered, and poor solvent A2 is added dropwise to the resulting clarified solution to obtain crystalline form A. Preferably, the good solvent A1 is acetic acid.

[0018] Preferably, the poor solvent A2 is ethanol. Preferably, the volume ratio of the good solvent A1 to the poor solvent A2 is 1 / 6 to 1 / 1, and more preferably 1 / 4 or 1 / 3.

[0019] Preferably, the temperature at which the compound represented by formula (I) dissolves in good solvent A1 is 20°C to 50°C, and more preferably 35°C. Alternatively, the compound shown in formula (I) is dissolved in a certain amount of solvent or mixed solvent, heated until completely dissolved, filtered, and slowly cooled to obtain crystalline form A.

[0020] Preferably, the temperature is 20°C to 70°C, more preferably 50°C. Preferably, the solvent is acetonitrile, methanol or acetic acid. Preferably, the mixed solvent is a mixture of acetic acid and ethanol.

[0021] Preferably, the volume ratio of the mixed solvent is 1 / 6 to 1 / 1, more preferably 1 / 4 or 1 / 3. The present invention further provides crystal form B of the compound 6-(1-cyclopropyl-1-hydroxy-pyrazol-4-yl)-3-(difluoro(6-fluoro-2-methyl-(dihydro-indazol-5-yl)methyl)-[1,2,4]triazolo[ [4,3-b]pyridazine shown in formula (I). When the crystal form B is irradiated with Cu-Kα rays, in the X-ray powder diffraction pattern represented by the 2θ angle, characteristic peaks are present at 2θ values of 8.38°, 15.99°, 18.73°, 24.86°, 28.96°, 29.83°, and the error range of 2θ is ±0.2°.

[0022]

Chemical formula

[0023] In some embodiments of the present invention, in the X-ray powder diffraction pattern of the crystal form B, characteristic peaks are present at 2θ values of 8.38°, 15.57°, 15.99°, 18.73°, 24.86°, 25.30°, 28.96°, 29.83°, and the error range of 2θ is ±0.2°.

[0024] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form B is shown in FIG. 5. In some embodiments of the present invention, the characteristic peak 2θ values in the X-ray powder diffraction pattern of the crystal form B are shown in the following table, and the error range of 2θ is ±0.2°. <*

[0025]

Table 2

[0026] In some embodiments of the present invention, the thermogravimetric analysis curve of crystal form B shows a weight loss of 0.50% from room temperature to 200°C. In some embodiments of the present invention, the TGA spectrum of crystal form B is shown in Figure 6.

[0027] In some embodiments of the present invention, the differential scanning calorimetry curve of crystal form B has a peak value of an endothermic peak at 203.00°C. In some embodiments of the present invention, the DSC spectrum of crystal form B is shown in Figure 7.

[0028] In some embodiments of the present invention, the crystalline form B is granular. In some embodiments of the present invention, the particle size D90 of crystal form B is 50 to 150 μm.

[0029] The present invention further provides a method for preparing crystalline form B, comprising adding the compound represented by formula (I) to a mixture of a good solvent B1 and a poor solvent B2, heating until dissolved, filtering, cooling, crystallizing, adding the poor solvent B2, and cooling to 0°C to obtain crystalline form B.

[0030] Preferably, the good solvent B1 is acetone. Preferably, the poor solvent B2 is water. Preferably, the heating temperature is between 0°C and 60°C, and preferably 60°C.

[0031] Preferably, the cooling temperature before crystallization is 40°C to 0°C, and preferably 30°C. Preferably, in the mixture of the good solvent B1 and the poor solvent B2, the volume ratio of the good solvent B1 to the poor solvent B2 is 4 / 1 to 1 / 1, preferably 3 / 1. Alternatively, the compound shown in formula (I) is added to the mixture of the good solvent B1 and the poor solvent B2, heated until dissolved, filtered, cooled, and crystalline form B is obtained.

[0032] Preferably, the good solvent B1 is acetone. Preferably, the poor solvent B2 is water. Preferably, the heating temperature is between 0°C and 60°C, and preferably 60°C.

[0033] Preferably, the cooling temperature is 0°C to 30°C, and more preferably 0°C to 10°C. Preferably, in the mixture of the good solvent B1 and the poor solvent B2, the volume ratio of the good solvent B1 to the poor solvent B2 is 3 / 1 to 4 / 1, and preferably 4 / 1.

[0034] The present invention further provides a pharmaceutical preparation or pharmaceutical composition comprising one or more of the crystalline forms A and B. According to the present invention, the pharmaceutical preparation or pharmaceutical composition may further contain pharmaceutically acceptable carriers and / or excipients.

[0035] Optionally, the above-mentioned pharmaceutical preparation or pharmaceutical composition may be a tablet, capsule, pill, granule, powder, suppository, injection, liquid, suspension, ointment, patch, lotion, drop, liniment, or spray.

[0036] The present invention further provides the use of the aforementioned crystalline form A or crystalline form B, or the aforementioned drug formulation or pharmaceutical composition, in the preparation of therapeutic agents for diseases mediated by c-Met abnormalities.

[0037] In some embodiments of the present invention, the disease mediated by the c-Mett abnormality is a tumor-related disease. Preferably, the tumor-related diseases include head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma esophageal cancer, renal cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic adenocarcinoma, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

[0038] The present invention further provides a method for treating diseases mediated by c-Met abnormalities, comprising administering the aforementioned crystalline form B or crystalline form A, or a drug formulation or pharmaceutical composition thereof, to a person in need.

[0039] Preferably, the disease mediated by the c-Met abnormality is a tumor-related disease. Preferably, the tumor-related diseases include head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma esophageal cancer, renal cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic adenocarcinoma, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

[0040] Technical effects The crystalline form in this invention possesses good chemical and physical stability, low hygroscopicity, and is less susceptible to the effects of heat, humidity, and light, thus exhibiting stable storage properties. Furthermore, because crystalline form B of the present invention has a low initial melting temperature, when used in a hot-melt extrusion molding process, it results in low levels of related substances and impurities in the prepared sample, contributing to improved pharmaceutical quality. In addition, because crystalline form B is granular, uniform mixing with additives is facilitated, friction during mixing is reduced, and the smoothness of the solid dispersion preparation process is enhanced.

[0041] Definition and description Unless otherwise specified, the terms and phrases used herein have the following meanings:

[0042] The term "chemical stability" refers to the degree to which the crystalline form provided by the present invention undergoes decomposition reactions under specific temperature, humidity, and light conditions. The term "physical stability" refers to the degree to which the crystalline form provided by the present invention undergoes a change in its solid form under high temperature, high humidity, and polishing conditions.

[0043] The term "good solvent" refers to a solvent in which the compound shown in formula (I) of this application dissolves well, and examples include one or more of acetic acid, tetrahydrofuran, acetone, acetonitrile, dichloromethane, methanol, dimethyl sulfoxide, and dimethylformamide. The term "poor solvent" refers to a solvent in which the compound shown in formula (I) of this application dissolves poorly, and examples include one or more of water, n-hexane, pentane, methyl tert-butyl ether, toluene, ethyl acetate, butyl acetate, ethanol, n-propanol, and 2-methyltetrahydrofuran.

[0044] The term "pharmaceutical composition" refers to a mixture of the crystalline form of the compound of the present invention with other chemical components such as pharmaceutically acceptable carriers, excipients, or diluents. The purpose of the pharmaceutical composition is to facilitate administration to animals. Pharmaceutical compositions may include pharmaceutically acceptable pH adjusters, buffers, and other excipients to mimic physiological conditions, as well as toxic modifiers such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate.

[0045] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, component, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or potting material, that serves to fill or deliver the active compound of the present invention from one site, body fluid, tissue, organ (internal or external), or body part to another site, body fluid, organ (internal or external), or body part. A pharmaceutically acceptable carrier may be a medium, diluent, excipient, or other substance that does not have excessive toxicity or side effects and can be brought into contact with animal tissue.

[0046] The following substances are considered pharmaceutically acceptable carriers: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as carmellose sodium, ethylcellulose, and cellulose acetate; (4) tragacanth gum powder; (5) maltose; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) p (11) Diols such as propyl glycol; (12) Polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (13) Lipids such as ethyl oleate and ethyl laurate; (14) Agaropectin; (15) Buffers such as magnesium hydroxide and aluminum hydroxide; (16) Alginic acid; (17) Sterile pyrogen-free distilled water; (18) Physiological saline; (19) Ringer's solution; (10) Alcohols such as ethanol and propanol; (11) Phosphate buffer; (22) Other non-toxic substances compatible with formulations, such as acetone.

[0047] Each pharmaceutically acceptable carrier should be compatible with other components, such as forming formulations with the compounds provided in the present invention, and should not cause excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications in biological tissues or organs, and should have a reasonable benefit-risk ratio.

[0048] The drug components can be formulated into any suitable dosage form, such as solid dosage forms (e.g., tablets, capsules, powders, granules, etc.) and liquid dosage forms (e.g., aqueous solutions, emulsions, elixirs, syrups, etc.). Methods for preparing pharmaceutical compositions are well known and can be carried out according to conventional methods, such as those described in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000). [Brief explanation of the drawing]

[0049] [Figure 1] Figure 1 shows the XRPD spectrum of compound crystalline form A, represented by formula (I). [Figure 2] Figure 2 shows the TGA curve diagram for compound crystal form A represented by formula (I). [Figure 3] Figure 3 shows the DSC curve of compound crystal form A represented by formula (I). [Figure 4] Figure 4 shows the XRPD overlay diagram of solid samples prepared by preparation methods 1 and 2 for compound crystal form A shown in formula (I). [Figure 5] Figure 5 shows the XRPD spectrum of compound crystal form B represented by formula (I). [Figure 6] Figure 6 shows the TGA curve for compound crystal form B represented by formula (I). [Figure 7] Figure 7 shows the DSC curve of compound crystal form B represented by formula (I). [Figure 8] Figure 8 shows the PLM diagram of crystal form A obtained by crystallizing the compound shown in formula (I) at 30°C using the poor solvent method. Here, Figure A shows the initial stage of precipitation, Figure B shows half the amount added, Figure C shows the completion of the addition, Figure D shows incubation for 1 hour, Figure E shows incubation for 3 hours, and Figure F shows the state before filtration. [Figure 9] Figure 9 shows the PLM diagram of crystal form A obtained by crystallization at 20°C using the compound poor solvent method shown in formula (I), where Figure A shows the initial stage of precipitation, Figure B shows half the amount added, and Figure C shows the completed addition. [Figure 10] Figure 10 shows the PLM diagram of compound crystalline form B represented by formula (I), where Figure A shows the initial precipitation stage, Figure B shows the completed crystallization stage, Figure C shows half the water droplets added, Figure D shows the completed water droplet addition stage, Figure E shows the completed incubation stage, and Figure F shows the state before filtration. [Figure 11] Figure 11 shows the XRPD superposition diagrams at each time point during vacuum drying at 40°C for compound crystal form B represented by formula (I). [Figure 12] Figure 12 shows the XRPD superposition diagrams at each time point during vacuum drying at 60°C for compound crystal form B represented by formula (I). [Figure 13]Figure 13 shows the XRPD superposition diagrams at various time points during drying of compound crystalline form B, represented by formula (I), under room temperature and nitrogen gas protection. [Figure 14] Figure 14 shows the XRPD superposition diagrams at each time point during drying of compound crystalline form B, represented by formula (I), at 40°C under nitrogen gas protection. [Figure 15] Figure 15 shows the XRPD overlay diagrams of the stability samples of compound crystal form A, represented by formula (I), under each test condition. [Figure 16] Figure 16 shows the XRPD overlay diagrams of the stability samples of compound crystal form B, represented by formula (I), under each test condition. [Figure 17] Figure 17 shows the solid XRPD superposition diagram of compound crystalline form A represented by formula (I) after 24 hours of storage in each medium. [Figure 18] Figure 18 shows the solid XRPD superposition diagram of compound crystalline form B represented by formula (I) after 24 hours of storage in each medium. [Modes for carrying out the invention]

[0050] The present invention will be described in more detail below, in accordance with the examples. These examples are used solely to illustrate the content of the present invention and do not limit the scope of the invention.

[0051] Equipment and analytical methods 1. XRPD: X-ray Powder Diffraction Crystal form analysis of the samples was performed using a Bruker D8 ADVANCE or Bruker D8 Focus X-ray powder diffractometer. The 2θ scanning angle of the samples was 3° to 42°, the scanning step width was 0.02°, and the scanning time was 0.05 seconds, 0.1 seconds, or 0.2 seconds / step. The photocell voltage and photocell current were 40kV and 40mA, respectively. When preparing the samples, an appropriate amount of sample was placed on the sample tray and flattened using a slide glass or other instrument to ensure that the surface was smooth and flat.

[0052] 2.TGA: Thermogravimetric analysis Samples were analyzed using a TA Instruments Discovery TGA Q500. The samples were placed on tare-weighted aluminum trays, and the system automatically measured their weight. Next, under nitrogen protection, the samples were heated to a specified temperature at a rate of 10°C / min.

[0053] 3. DSC: Differential Scanning Calorimetry Samples were analyzed using the TA Instruments Discovery DSC 25. Samples ranging from 2 to 10 mg were weighed, placed on an aluminum tray, and heated to the specified temperature at a rate of 10°C / min under nitrogen gas protection (50 mL / min).

[0054] 4. PLM: Microscopic examination The samples were analyzed using a LEICA DM750P microscope. A small amount of sample was placed on a glass slide, a drop of cedarwood oil was added to disperse it, a coverslip was placed on the microscope stage, and an image of the sample was taken at an appropriate magnification.

[0055] 5. HPLC: High-Performance Liquid Chromatography Solubility and stability were measured using Agilient 1260 HPLC. Column: ZORBAX Eclipse Plus Cl8 4.6*100mm 3.5-Micron; Flow rate: 1 mL / min; Column temperature: 35°C; Injection volume: 10 μL; Mobile phase: Mobile phase A: 0.02 mol / L sodium dihydrogen phosphate; Mobile phase B: ACN; Analysis time: 40 minutes; Detector: UV at 210 nm; Diluent: ACN; Injection concentration: 0.2 mg / mL; Elution procedure is shown in the table below.

[0056] [Table 3]

[0057] 6.Particle size D90 Particle size was measured using the dry method. A Malvern 3000 laser particle size distribution analyzer was equipped with an Aero S input device, the compressor air pressure exceeded 6 Bar, and the funnel slit was 1.0-1.5 mm. Approximately 200 mg of the sample was added to the dispersion unit of the Areo S input device funnel, and the start button was pressed to begin the sample measurement.

[0058] Each sample was measured three times, and the average of the three measurements, D90 (μm), was reported. If D90 was 10 μm or greater, the relative standard deviation RSD% (n=3) was considered to be 15% or less. If D90 was less than 10 μm, the relative standard deviation RSD% (n=3) was considered to be 30% or less.

[0059] Example 1: Preparation of compound crystalline form A shown in formula (I) 1. Preparation method 1: At 35°C, 3 g of the compound shown in formula (I) (crude product prepared according to the synthesis method of CN103122000A Example 44) was dissolved in 7.8 mL (2.6 vol) of acetic acid in reaction vessel 1 and kept warm. At 35°C, 31.2 mL (12 vol) of ethanol was added to reaction vessel 2 and kept warm. The saturated solution in reaction vessel 1 was slowly added to reaction vessel 2, and after the addition was complete, the mixture was kept warm at 30°C for 3 hours, filtered, and the filtered cake was washed with ethanol by the rinse method and dried at 40°C. The obtained solid was characterized by XRPD, TGA, and DSC tests. The results are shown in Figures 1, 2, and 3.

[0060] As shown in Figure 1, characteristic peaks are observed in the X-ray powder diffraction pattern of crystal form A at 2θ values ​​of 7.47°, 10.30°, 12.47°, 14.18°, 17.19°, 17.54°, 17.85°, 18.15°, 20.39°, 24.25°, 25.43°, 25.97°, and 26.43°. The 2θ error range was ±0.2°. As shown in Figure 2, the TGA curve did not show weight loss before raw material melting. As shown in Figure 3, the DSC curve showed that the melting point peak had a melting start temperature of 221.16°C, a peak temperature of 222.27°C, and an enthalpy of 156.10 J / g.

[0061] Combining the TGA characterization in Figure 2 and the DSC characterization in Figure 3, it was shown that crystal form A is a non-solvent crystal, is non-hygroscopic, and highly stable. 2. Preparation method 2: At 20°C, 2 g of the compound shown in formula (I) (crude product prepared according to the synthesis method of CN103122000A Example 44) was dissolved in 8 mL (4 vol) of acetic acid in reaction vessel 1 and kept warm. At 35°C, 24 mL (12 vol) of ethanol was added to reaction vessel 2 and kept warm. The saturated solution in reaction vessel 1 was slowly added to reaction vessel 2, crystallized for 30 minutes, and then further added dropwise. After the dropwise addition was complete, the mixture was kept warm at 35°C for 3 hours, cooled to 0°C, and left overnight. The mixture was filtered, the filtered cake was washed with ethanol by the rinse method, and dried at 40°C. The obtained solid was characterized by XRPD. The results are shown in Figure 4.

[0062] As shown in Figure 4, when the XRPD diagram of the solid obtained by preparation method 2 and the XRPD diagram of crystal form A obtained by manufacturing method 1 are superimposed, the crystal form obtained by manufacturing method 2 matches the crystal form obtained by manufacturing method 1, indicating that both are crystal form A. Example 2: Preparation and Stability of Compound Crystal Form B Shown in Formula (I) At room temperature, 12 g of the compound shown in formula (I) (crude product prepared according to the synthesis method of CN103122000A Example 44) and 156 mL (3 / 1 (v / v), 13 vol) of acetone / water mixed solvent were added to the reaction vessel and heated to 60°C until the mixed solution became clear. The mixture was cooled to 35°C at 1°C / min, and a very small amount of solid was observed in the reaction system. When cooled to 30°C, crystallization occurred for 1 hour, after which 78 mL (6.5 vol) of water was added over 2.5 hours. After the dropwise addition was complete, the mixture was incubated at 30°C for 3 hours, then cooled to 0°C at 10°C / hour, incubated overnight, filtered, and a pale yellow solid was obtained. The mixture was dried at 40°C to obtain a white crystalline powder. The obtained solid was characterized by XRPD, TGA, and DSC tests, as shown in Figures 5, 6, and 7.

[0063] As shown in Figure 5, characteristic peaks were observed in the X-ray powder diffraction pattern of crystal form B at 2θ values ​​of 8.38°, 15.57°, 15.99°, 18.73°, 24.86°, 25.30°, 28.96°, and 29.83°, with an error range of ±0.2° for 2θ. As shown in Figure 6, the TGA curve showed a 0.50% weight loss of the sample from room temperature to 200°C, indicating that the sample structure does not contain crystal water or crystallization solvent. As shown in Figure 7, the DSC curve showed an endothermic peak in the sample from 201.23°C, with a peak temperature of 203.00°C and an enthalpy of 13.626 J / g. This endothermic peak was due to the melting of the sample. A heat dissipation peak appeared in the sample from 205.31°C, with a peak temperature of 206.67°C and an enthalpy of 7.6334 J / g. This heat dissipation peak was due to heat dissipation associated with the crystallization of the sample. An endothermic peak appeared from 223.03°C, with a peak temperature of 224.15°C and an enthalpy of 94.995 J / g. This endothermic peak was due to the endothermic melting of the sample.

[0064] The TGA characteristic evaluation results in Figure 6 and the DSC characteristic evaluation results in Figure 7 indicate that the sample structure does not contain crystal water or crystallization solvent. Example 3: Consideration of the crystal habits of compound crystal forms A and B shown in formula (I) Consideration of the crystal habit of compound crystal form A shown in formula (I): Crystal form A was prepared according to the method of Preparation Method 1 in Example 1. The PLM was measured by sampling 5 minutes after the addition of saturated solution, when half of the saturated solution was added, after the addition of saturated solution was completed, after incubation at 30°C for 1 hour, after incubation at 30°C for 3 hours, and before filtration. The results are shown in Figure 8.

[0065] As shown in the PLM diagram in Figure 8, crystals grew uniformly during the dropping process, and the final product was short rod-shaped. The particle size distribution of the product was uniform during the experiment and before filtration, and the particle size D90 of the final product was 20-60 μm.

[0066] Consideration of the crystal habit of compound crystal form A shown in formula (I): Crystal form A was prepared according to the method of preparation method 2 in Example 1. After 4 minutes of adding the saturated solution, and after half of the saturated solution had been added, samples were taken and the PLM was measured. This is shown in Figure 9.

[0067] As shown in the PLM diagram in Figure 9, spontaneous crystallization occurred during back-droplet addition, resulting in the presence of numerous solids in the reaction system. Crystals grew uniformly during the addition process, and the final product was short, rod-shaped with a uniform particle size distribution. The particle size (D90) of the final product was 20-50 μm.

[0068] Consideration of the crystal habit of compound crystal form B shown in formula (I): Crystal form B was prepared according to the method of Example 2, and samples were taken during crystallization at 30°C for 15 minutes, at 30°C for 1 hour, when half of the water was added dropwise, after the addition of water was complete, after incubation at 30°C for 3 hours, and before filtration, and the PLM was measured. The results are shown in Figure 10.

[0069] As shown in the PLM diagram of Figure 10, crystals grew uniformly during the dropwise addition process, and the final product was granular. The particle size distribution of the product was uniform during the experiment and before filtration, and the particle size D90 of the final product was 50–150 μm.

[0070] Example 4: Consideration of the effect of drying conditions on the compound crystal form B shown in formula (I) on stability. Crystal form B was prepared according to the method of Example 2. Four 3g wet samples were placed in four 40×25mm watch glasses, and each was dried in a vacuum drying oven at 40°C or 60°C, or at room temperature or under a nitrogen atmosphere at 40°C. Samples were taken at 0 hours, 8 hours, 12 hours, 24 hours, or 48 hours, and characterization was performed by XRPD. The results are shown in Figures 11-14.

[0071] As shown in Figures 11-14, no crystal forms other than crystal form B appeared during the drying process, indicating that crystal form B was stable during the drying process. Example 5 Evaluation of thermal and humidity stability of crystal forms A and B Certain amounts of the compound represented by formula (I), crystalline form A (prepared according to preparation method 1 of Example 1) and crystalline form B (prepared according to the method of Example 2), were placed in a stability tester, removed after a certain period of time, and measured by HPLC and XRPD.

[0072] Test conditions: Measurements were taken by HPLC and XRPD under open air conditions at 25°C and 60% RH humidity (25°C / 60% RH), or under open air conditions at 40°C and 75% RH humidity (40°C / 75% RH), for 1 week, 2 weeks, 1 month, and 2 months, respectively. Measurements were also taken by HPLC and XRPD under sealed air conditions at 80°C for 1 day and under sealed air conditions with irradiation for 10 days. The test results are shown in Table 1 and Figures 15-16.

[0073] [Table 4]

[0074] As shown in Table 1, crystal forms A and B hardly decomposed under the test conditions. As shown in the XRPD overlay diagrams in Figures 1 and 16, the crystal forms of crystal forms A and B did not change under the test conditions. The above results indicate that crystal forms A and B have good stability, are less prone to crystallization, and can be used as active pharmaceutical ingredients for drug manufacturing.

[0075] Example 6: Evaluation of the stability of crystalline forms A and B in an aqueous medium. Two mL suspensions of crystalline form A (prepared according to preparation method 1 of Example 1) and crystalline form B (prepared according to the method of Example 2) were prepared, each at a concentration of 5 mg / mL. The samples of crystalline form A and crystalline form B were added to FaSSIF, FeSSIF, SGF, water, and buffer solutions of pH 1.2 (potassium chloride), pH 3.0 (potassium bitartrate), pH 4.5 (sodium acetate trihydrate), pH 6.8 (potassium dihydrogen phosphate), and pH 7.4 (potassium dihydrogen phosphate), respectively, and stirred in a 37°C water bath. After 24 hours, the pH of the sample filtrate was measured, and the XRPD of the solid sample was measured. The test results are shown in Table 2 and Figures 17-18.

[0076] [Table 5]

[0077] As shown in Table 2 and Figures 17-18, in different pH buffers and water, crystalline form A changed to crystalline form B after 24 hours, but the crystalline form did not change in the simulated biological culture medium. Crystallized form B remained unchanged in all culture media.

[0078] Example 7: Effect of different crystal forms on the preparation of solid dispersions The content of related substance D1 in solid dispersions prepared from crystalline form A (prepared according to Method 1 of Example 1) and crystalline form B (prepared according to Method 2 of Example 2), respectively, under the same hot-melt extrusion molding conditions was investigated. The structure of related substance D1 is shown in formula (II).

[0079] [ka]

[0080] Preparation of solid dispersions by hot-melt extrusion: The active pharmaceutical ingredient in crystalline form A (prepared according to preparation method 1 of Example 1) or crystalline form B (prepared according to the method of Example 2) and polyvinylpyrrolidone K30 were weighed and mixed in a 1:3 ratio. After the temperature of each hot-melt extrusion zone reached 130°C, 150°C, 180°C, 195°C, 200°C, 200°C, 200°C, and 200°C respectively, and equilibrium was maintained for 15 minutes, the mixture was fed into the extruder's supply hopper, the resulting solid was recovered and allowed to cool at room temperature, and the content of related substance D1 was measured. The results are shown in Table 3.

[0081] [Table 6]

[0082] As shown in Table 3, solid dispersions were prepared using the hot-melt extrusion method with crystal forms A and B, respectively. While there was no significant difference in the active pharmaceutical ingredient content of the resulting samples, differences in impurity content were observed in the prepared samples due to the difference in crystal forms. The sample prepared using crystal form B had a lower content of related substance D1 than the sample prepared using crystal form A. Therefore, crystal form B is superior to crystal form A in sample preparation.

[0083] Example 8: Effect of different crystal forms on the sample preparation process The active pharmaceutical ingredient in crystalline form A (prepared according to preparation method 1 of Example 1) or crystalline form B (prepared according to the method of Example 2) and polyvinylpyrrolidone K30 were weighed and mixed in a 1:3 ratio. The temperature of each hot melt extrusion zone reached 130°C, 150°C, 180°C, 195°C, 200°C, 200°C, 200°C, and 200°C, respectively. After maintaining equilibrium for 15 minutes, the mixture was fed into the extruder's feed hopper, the resulting solid was collected, and allowed to cool at room temperature. The phenomena of the entire process were observed. The results are shown in Table 4.

[0084] [Table 7]

[0085] As shown in Table 4, in the sample preparation process using crystal form A, clumps formed during input, the input speed was slow, and clogging occurred, resulting in unacceptable samples. When using crystal form B, the premix raw materials were dispersed, the input speed was fast, there was no clogging, samples could be prepared continuously, and it was possible to prepare acceptable samples that could withstand long-term continuous hot melt extrusion.

[0086] Example 9: Hygroscopic weight increase test of crystalline form B 2.6 g of crystal form B (prepared according to the method of Example 2) was weighed and placed in an open weighing bottle, and the sample was spread uniformly (layer thickness ≤ 3 mm). The above procedure was repeated to prepare a total of six samples. The samples were placed under temperature and humidity control conditions of 25±2℃ / 75±5%RH and 25±2℃ / 90±5%RH on days 0, 20, and 25, respectively. All samples were weighed on day 30, and the increase in weight due to moisture absorption (%) was calculated. The results are shown in Figure 5.

[0087] Weight increase (%)=(m3-m2) / (m2-m1)*100%

[0088] [Table 8]

[0089] As shown in Table 5, the increase in moisture-absorbing weight of crystalline form B was approximately 1% after storage for 5, 10, and 30 days, respectively, under high humidity conditions. The increase in moisture-absorbing weight was less than 2%, indicating that crystalline form B is slightly hygroscopic.

[0090] As described above, the free alkali crystal forms A and B of this application exhibit good stability and slight hygroscopicity, making them advantageous for storage. The resulting crystal forms have uniform particle size, facilitating mixing with additives. Furthermore, the melting points of crystal forms A and B are approximately 222°C and 203°C, respectively, with crystal form B having a lower melting point than crystal form A. Compared to crystal form A, free alkali crystal form B of this application is more suitable for sample preparation using a hot-melt extrusion process, yielding a solid dispersion with fewer related substances and impurities, contributing to the improvement of pharmaceutical quality. Moreover, crystal form B is granular, facilitating uniform mixing with additives, reducing friction during mixing, and improving the smoothness of the solid dispersion preparation process. Therefore, crystal form B has clear advantages over crystal form A.

Claims

1. When irradiated with Cu-Kα rays, the X-ray powder diffraction pattern, represented by the 2θ angle, shows characteristic peaks at 2θ values ​​of 8.38°, 15.99°, 18.73°, 24.86°, 28.96°, and 29.83°, with a 2θ error range of ±0.2°, and is the crystalline form B of compound 6-(1-cyclopropyl-1-hydroxypyrazole-4-yl)-3-(difluoro(6-fluoro-2-methyl-(dihydro-indazole-5-yl)methyl)-[1,2,4]triazole[4,3-b]pyridazine, represented by formula (I). 【Chemistry 1】

2. In the X-ray powder diffraction pattern of crystal form B, characteristic peaks are observed at 2θ values ​​of 8.38°, 15.57°, 15.99°, 18.73°, 24.86°, 25.30°, 28.96°, and 29.83°, with a 2θ error range of ±0.2°. Preferably, the crystal form B according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal form B is shown in Figure 5.

3. The thermogravimetric analysis curve of the aforementioned crystal form B shows a weight loss of 0.50% from room temperature to 200°C. Preferably, the TGA spectrum of the crystal form B is shown in Figure 6, Preferably, the differential scanning calorimetry curve of the crystal form B has a peak value of the endothermic peak at 203.00°C. Preferably, the crystal form B according to claim 1 or 2, characterized in that the DSC spectrum of the crystal form B is shown in Figure 7.

4. The compound shown in formula (I) is added to a mixture of good solvent B1 and poor solvent B2, heated until dissolved, filtered, cooled, and crystallized. The poor solvent B2 is then added, and the mixture is cooled to 0°C to obtain crystalline form B. Preferably, the good solvent B1 is acetone. Preferably, the poor solvent B2 is water. Preferably, the heating temperature is 0°C to 60°C, and preferably 60°C. Preferably, the cooling temperature before crystallization is 40°C to 0°C, preferably 30°C. Preferably, in the mixture of the good solvent B1 and the poor solvent B2, the volume ratio of the good solvent B1 to the poor solvent B2 is 4 / 1 to 1 / 1, preferably 3 / 1, or the substance shown in formula (I) is added to the mixture of the good solvent B1 and the poor solvent B2, heated until dissolved, filtered, cooled, and crystalline form B is obtained. Preferably, the good solvent B1 is acetone. Preferably, the poor solvent B2 is water. Preferably, the heating temperature is 0°C to 60°C, and preferably 60°C. Preferably, the cooling temperature is 0°C to 30°C, and more preferably 0°C to 10°C. A method for preparing crystalline form B according to any one of claims 1 to 3, preferably comprising a method in which the volume ratio of the good solvent B1 to the poor solvent B2 in a mixture of the good solvent B1 and the poor solvent B2 is 3 / 1 to 4 / 1, preferably 4 / 1.

5. When irradiated with Cu-Kα rays, the X-ray powder diffraction pattern, represented by the 2θ angle, shows characteristic peaks at 2θ values ​​of 7.47°, 10.30°, 12.47°, 14.18°, 17.19°, 24.25°, and 25.43°, with a 2θ error range of ±0.2°, for the crystalline form A of compound 6-(1-cyclopropyl-1-hydroxypyrazole-4-yl)-3-(difluoro(6-fluoro-2-methyl-(dihydro-indazole-5-yl)methyl)[1,2,4]triazole[4,3-b]pyridazine, represented by formula (I). 【Chemistry 2】

6. In the X-ray powder diffraction pattern of crystal form A, characteristic peaks are observed at 2θ values ​​of 7.47°, 10.30°, 12.47°, 14.18°, 17.19°, 17.54°, 17.85°, 18.15°, 20.39°, 24.25°, 25.43°, 25.97°, and 26.43°, with an error range of ±0.2° for 2θ. Preferably, the crystal form A according to claim 5, characterized in that the X-ray powder diffraction pattern of the crystal form A is shown in Figure 1.

7. The thermogravimetric analysis curve of crystal form A above does not show a loss of weight from room temperature to the melting point. Preferably, the TGA spectrum of the crystal form A is shown in Figure 2, Preferably, the differential scanning calorimetry curve of the crystal form A has a peak value of the endothermic peak at 222.27°C. Preferably, the crystal form A according to claim 5 or 6, characterized in that the DSC spectrum of the crystal form A is shown in Figure 3.

8. The compound shown in formula (I) is dissolved in a good solvent A1 at 0°C to 70°C, filtered, and the resulting clarified solution is added dropwise to a poor solvent A2 to obtain crystalline form A. Preferably, the good solvent A1 is acetic acid. Preferably, the poor solvent A2 is ethanol. Preferably, the volume ratio of the good solvent A1 to the poor solvent A2 is 1 / 6 to 1 / 1, more preferably 1 / 4 or 1 / 3. Preferably, in order to clearly dissolve the compound shown in formula (I) in the good solvent A1, preferably the temperature at which the compound shown in formula (I) is dissolved in the good solvent A1 is 20°C to 40°C, preferably 35°C, or the compound shown in formula (I) is dissolved in the good solvent A1, filtered, and the poor solvent A2 is added dropwise to the resulting clarified solution to obtain crystalline form A. Preferably, the good solvent A1 is acetic acid. Preferably, the poor solvent A2 is ethanol. Preferably, the volume ratio of the good solvent A1 to the poor solvent A2 is 1 / 6 to 1 / 1, more preferably 1 / 4 or 1 / 3. Preferably, the temperature at which the compound represented by formula (I) is dissolved in a good solvent A1 is 20°C to 50°C, more preferably 35°C, or the compound represented by formula (I) is dissolved in a certain amount of solvent or mixed solvent, heated until completely dissolved, filtered, and slowly cooled to obtain crystalline form A. Preferably, the temperature is 20°C to 70°C, and more preferably 50°C. Preferably, the solvent is acetonitrile, methanol, or acetic acid. Preferably, the mixed solvent is a mixture of acetic acid and ethanol. A method for preparing crystalline form A according to any one of claims 5 to 7, preferably comprising a method in which the volume ratio of the mixed solvent is 1 / 6 to 1 / 1, more preferably 1 / 4 or 1 / 3.

9. A pharmaceutical preparation or pharmaceutical composition comprising crystal form B according to any one of claims 1 to 3, or crystal form A according to any one of claims 5 to 7, and one or more pharmaceutically acceptable carriers and / or excipients, Preferably, the pharmaceutical preparation or pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, injection, liquid, suspension, ointment, patch, lotion, drop, liniment, or spray.

10. The use of crystalline form B according to any one of claims 1 to 3, or crystalline form A according to any one of claims 5 to 7, or a pharmaceutical preparation or pharmaceutical composition according to claim 9, in the preparation of a therapeutic agent for a disease mediated by c-Met abnormalities, Preferably, the disease mediated by the c-Met abnormality is a tumor-related disease. Preferably, the use includes, the tumor-related disease being head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma esophageal cancer, renal cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic adenocarcinoma, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

11. A method for treating a disease mediated by c-Meth abnormalities, comprising administering to a person in need of the crystalline form B described in any one of claims 1 to 3, or the crystalline form A described in any one of claims 5 to 7, or the pharmaceutical preparation or pharmaceutical composition described in claim 9, Preferably, the disease mediated by the c-Met abnormality is a tumor-related disease. Preferably, the method wherein the tumor-related disease includes head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma esophageal cancer, renal cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic adenocarcinoma, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

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