A solid form of an imidazotriazine compound, its preparation method and uses

Abstract

This application discloses a solid form of an imidazotriazine compound, its preparation method, and its use. Specifically, it discloses the solid form of 2-fluoro-N-methyl-4-[7-[(quinoline-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide dihydrochloride, its preparation method, pharmaceutical compositions comprising it, and its use in the preparation of medicaments for the prevention and / or treatment of cancer diseases.

Description

Technical Field

[0001] This invention relates to a solid form of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazin-2-yl]benzamide dihydrochloride (also known as carmatinib hydrochloride), a method for preparing said solid form, a pharmaceutical composition comprising said solid form, and the use of said solid form. Background Technology

[0002] Carmatinib, developed by Novartis in Switzerland, was approved for marketing in the United States in May 2020 for the treatment of metastatic non-small cell lung cancer (NSCLC) with METex14 mutations in adults. This drug is the first selective MET inhibitor approved by the FDA, offering advantages such as good efficacy and manageable safety. Its chemical name is 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazin-2-yl]benzamide, with its dihydrochloride monohydrate as the active ingredient in clinical products. Its structure is shown below.

[0003]

[0004] Currently, Chinese patent CN200980123120.8 discloses carmatinib dihydrochloride crystals and dibenzenesulfonate crystals. Different crystal forms of the same drug may exhibit significant differences in stability and bioavailability, thus affecting the drug's efficacy. Therefore, developing and obtaining new stable crystal forms of compounds to facilitate drug processing and use in pharmaceutical compositions, and to provide more qualitative and quantitative information for efficacy studies of solid drugs, is of great significance and an urgent need in the drug development process. Summary of the Invention

[0005] Overview

[0006] The present invention provides 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide dihydrochloride (hereinafter referred to as compound 1) in solid form.

[0007]

[0008] In one aspect, the present invention provides crystal I of compound 1, wherein the X-ray powder diffraction (XRPD) pattern of crystal I includes characteristic peaks at diffraction angles (2θ) of 5.18±0.2°, 7.43±0.2°, 8.74±0.2°, 12.56±0.2°, 15.00±0.2° and 16.12±0.2°.

[0009] A second aspect of the present invention provides a crystal II of compound 1, wherein the X-ray powder diffraction (XRPD) pattern of said crystal II includes characteristic peaks at diffraction angles (2θ) of 6.62±0.2°, 7.09±0.2°, 9.49±0.2°, 14.32±0.2°, 15.65±0.2° and 25.15±0.2°.

[0010] A third aspect of the present invention provides a crystal III of compound 1, wherein the X-ray powder diffraction pattern of the crystal III includes characteristic peaks at diffraction angles (2θ) of 6.36±0.2°, 10.39±0.2°, 13.79±0.2°, 22.94±0.2°, 24.64±0.2° and 28.17±0.2°.

[0011] A fourth aspect of the present invention provides a method for preparing crystals I, II and / or III of compound 1 of the present invention.

[0012] A fifth aspect of the present invention provides a pharmaceutical composition comprising crystal I, crystal II and / or crystal III of compound 1 of the present invention, and one or more pharmaceutically acceptable carriers.

[0013] The sixth aspect of the present invention provides the use of crystals I, II, III and / or pharmaceutical compositions of the present invention in the preparation of medicaments for the prevention or treatment of tumor diseases.

[0014] The seventh aspect of the present invention provides a method for preventing and / or treating tumor diseases, comprising administering an effective amount of crystal I, crystal II, crystal III and / or pharmaceutical composition of the compound 1 of the present invention to an individual in need thereof. Detailed description of the invention

[0015] definition

[0016] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0017] The terms “comprising,” “including,” “having,” “containing,” or “involving,” as used herein, and their other variations thereof, are inclusive or open-ended and do not exclude other unlisted elements or method steps, although such other unlisted elements or method steps may not necessarily exist (i.e., these terms also cover the terms “consistently consisting of” and “comprises of”).

[0018] As used herein, the term “about” means that a person skilled in the art would consider the value to be within an acceptable standard error, such as ±0.05, ±0.1, ±0.2, ±0.3, ±0.5, ±1, ±2, or ±3.

[0019] As used herein, the term "solid form" includes all solid forms of compound 1, such as crystalline forms.

[0020] As used in this article, the term "crystal form" or "crystal" refers to any solid material exhibiting a three-dimensional arrangement, which, in contrast to amorphous solid materials, produces characteristic XRPD patterns with clearly defined peaks.

[0021] As used in this article, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or the parameters, data, or values ​​derived from it. XRPD patterns are typically characterized by peak position (x-axis) and / or peak intensity (y-axis).

[0022] As used herein, the term "2θ" refers to the peak position in degrees (°) based on the setup of an X-ray diffraction experiment, and is typically the horizontal axis unit in a diffraction pattern. If the incident beam is diffracted when it forms an angle θ with a lattice plane, the experimental setup requires recording the reflected beam at a 2θ angle. It should be understood that specific 2θ values ​​for a particular crystal form mentioned herein are intended to represent 2θ values ​​(in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0023] As used in this article, the term “differential scanning calorimetry (DSC) spectrum” refers to a curve recorded by a differential scanning calorimeter.

[0024] As used in this article, the term "thermogravimetric analysis (TGA) curve" refers to the curve recorded by a thermogravimetric analyzer.

[0025] As used herein, the term "substantially identical" means taking into account variations in representative peak position and / or intensity. For example, for X-ray diffraction peaks, those skilled in the art will understand that peak position (2θ) will show some variation, typically up to 0.1–0.2 degrees, and that the instrument used to measure diffraction will also cause some variation. Furthermore, those skilled in the art will understand that relative peak intensities will vary due to differences between instruments, as well as the degree of crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to those skilled in the art.

[0026] Crystal and preparation method

[0027] In a first aspect, the present invention provides crystal I of compound 1, characterized in that the X-ray powder diffraction pattern of said crystal I includes characteristic peaks at diffraction angles (2θ) of 5.18±0.2°, 7.43±0.2°, 8.74±0.2°, 12.56±0.2°, 15.00±0.2° and 16.12±0.2°;

[0028]

[0029] In some embodiments, the XRPD pattern of crystal I of compound 1 includes characteristic peaks at diffraction angles (2θ) of 5.18±0.2°, 7.43±0.2°, 8.74±0.2°, 12.56±0.2°, 15.00±0.2°, 15.73±0.2°, 16.12±0.2°, 19.70±0.2° and 22.52±0.2°.

[0030] In some preferred embodiments, the XRPD pattern of crystal I of compound 1 includes characteristic peaks at diffraction angles (2θ) of 5.18±0.2°, 7.43±0.2°, 8.74±0.2°, 12.56±0.2°, 15.00±0.2°, 15.73±0.2°, 16.12±0.2°, 19.70±0.2°, 22.52±0.2°, 26.83±0.2°, 27.51±0.2°, and 28.15±0.2°.

[0031] In some preferred embodiments, the XRPD pattern of crystal I of compound 1 includes characteristic peaks at the following diffraction angles (2θ), wherein the error range of the 2θ value is ±0.2°:

[0032]

[0033]

[0034] In a more preferred embodiment, the XRPD pattern of crystal I of compound 1 includes... Figure 1The peaks shown are at essentially the same diffraction angle (2θ). In the most preferred embodiment, the XRPD pattern of crystal I of compound 1 is as follows: Figure 1 As shown.

[0035] In some embodiments, the differential scanning calorimetry (DSC) spectrum of crystal I of compound 1 shows an endothermic peak at 250±5℃ (starting temperature).

[0036] In a more preferred embodiment, the DSC spectrum of crystal I includes, as shown below: Figure 2 The characteristic peaks shown are at essentially the same temperature.

[0037] In a more preferred embodiment, the DSC spectrum of crystal I is as follows: Figure 2 As shown.

[0038] In a second aspect, the present invention provides crystal II of compound 1, characterized in that the X-ray powder diffraction pattern of said crystal II includes characteristic peaks at diffraction angles (2θ) of 6.62±0.2°, 7.09±0.2°, 9.49±0.2°, 14.32±0.2°, 15.65±0.2° and 25.15±0.2°.

[0039] In some embodiments, the XRPD pattern of crystal II of compound 1 includes characteristic peaks at diffraction angles (2θ) of 6.62±0.2°, 7.09±0.2°, 9.49±0.2°, 11.71±0.2°, 12.26±0.2°, 14.32±0.2°, 15.65±0.2°, 20.27±0.2°, and 25.15±0.2°.

[0040] In some preferred embodiments, the XRPD pattern of crystal II of compound 1 includes characteristic peaks at diffraction angles (2θ) of 6.62±0.2°, 7.09±0.2°, 9.49±0.2°, 11.71±0.2°, 12.26±0.2°, 14.32±0.2°, 15.65±0.2°, 20.27±0.2°, 22.65±0.2°, 23.15±0.2°, 25.15±0.2°, 26.94±0.2°, 28.00±0.2°, and 29.11±0.2°.

[0041] In some preferred embodiments, the XRPD pattern of crystal II of compound 1 includes characteristic peaks at the following diffraction angles (2θ), wherein the error range of the 2θ value is ±0.2°:

[0042] 2θ(°)±0.2° strength% 2θ(°)±0.2° strength% 6.62 29.39 24.64 16.61 7.09 12.33 25.15 100.00 9.49 9.04 25.55 9.58 10.03 5.23 26.19 2.61 11.71 7.34 26.94 43.79 12.26 11.27 27.65 11.16 13.63 2.61 28.00 35.05 14.32 63.02 28.97 21.13 14.87 5.70 29.11 31.45 15.10 7.20 30.13 21.91 15.43 13.54 30.65 17.97 15.65 52.36 30.95 5.16 16.08 7.81 31.26 2.19 18.29 8.77 31.57 9.36 18.45 10.57 32.12 3.92 18.90 2.56 32.71 6.13 20.27 20.75 33.14 2.65 20.50 5.90 33.98 2.29 21.10 3.74 34.70 6.32 21.34 6.11 35.17 3.96 21.69 19.73 35.92 0.96 21.86 17.66 36.55 5.56 22.30 2.44 37.16 1.59 22.65 19.49 37.54 1.05 23.15 21.22 38.11 1.45 23.81 4.74 38.61 2.89 23.99 13.22 39.54 2.24 24.25 4.15 / /

[0043] In a more preferred embodiment, the XRPD pattern of crystal II of compound 1 includes the same as... Figure 3 The peaks shown are at essentially the same diffraction angle (2θ). In the most preferred embodiment, the XRPD pattern of crystal II of compound 1 is as follows: Figure 3 As shown.

[0044] In some embodiments, the differential scanning calorimetry (DSC) spectrum of crystal II of compound 1 shows an endothermic peak at 174±5℃ (starting temperature).

[0045] In a more preferred embodiment, the DSC spectrum of crystal II includes, as follows: Figure 4 The characteristic peaks shown are at essentially the same temperature.

[0046] In a more preferred embodiment, the DSC spectrum of crystal II is as follows: Figure 4 As shown.

[0047] Thirdly, the present invention provides crystal III of compound 1, characterized in that the X-ray powder diffraction pattern of said crystal III includes characteristic peaks at diffraction angles (2θ) of 6.36±0.2°, 10.39±0.2°, 13.79±0.2°, 22.94±0.2°, 24.64±0.2° and 28.17±0.2°.

[0048] In some embodiments, the XRPD pattern of crystal III of compound 1 includes characteristic peaks at diffraction angles (2θ) of 6.36±0.2°, 8.16±0.2°, 10.39±0.2°, 13.79±0.2°, 22.94±0.2°, 24.15±0.2°, 24.64±0.2°, 26.91±0.2°, and 28.17±0.2°.

[0049] In some preferred embodiments, the XRPD pattern of crystal III of compound 1 includes characteristic peaks at diffraction angles (2θ) of 6.36±0.2°, 8.16±0.2°, 10.39±0.2°, 13.50±0.2°, 13.79±0.2°, 16.48±0.2°, 16.66±0.2°, 17.89±0.2°, 18.25±0.2°, 22.94±0.2°, 24.15±0.2°, 24.64±0.2°, 26.91±0.2°, and 28.17±0.2°.

[0050] In some preferred embodiments, the XRPD pattern of crystal III of compound 1 includes characteristic peaks at the following diffraction angles (2θ), wherein the error range of the 2θ value is ±0.2°:

[0051]

[0052]

[0053] In a more preferred embodiment, the XRPD pattern of crystal III of compound 1 includes... Figure 5 The peaks shown are at essentially the same diffraction angle (2θ). In the most preferred embodiment, the XRPD pattern of crystal III of compound 1 is as follows: Figure 5 As shown.

[0054] A fourth aspect of the present invention provides a method for preparing crystal I of the above-described compound 1, the method comprising the following steps:

[0055] Compound 1 was placed in a suitable solvent and heated to a suitable temperature to dissolve it. Then, a crystallization solvent was added dropwise to precipitate the solid. The solid was centrifuged and dried to obtain crystal I of compound 1.

[0056] In some embodiments, the first suitable solvent is selected from one or more of methanol, ethanol, n-propanol, and n-butanol; preferably methanol.

[0057] In some embodiments, the volume (ml) to mass (mg) ratio of the first suitable solvent to compound 1 is 2:(80-100).

[0058] In some embodiments, the crystallization solvent is selected from one or more of ethyl acetate, acetone, toluene, methyl tert-butyl ether, and n-heptane; preferably, the crystallization solvent is selected from ethyl acetate and acetone.

[0059] In some embodiments, the volume (ml) to mass (mg) ratio of the crystallization solvent to compound 1 is 20:(80-100).

[0060] In some embodiments, the heating to a suitable temperature is 40 to 50°C.

[0061] In some embodiments, the present invention provides a method for preparing crystal II of the above-described compound 1, the method comprising the following steps:

[0062] Compound 1 was placed in a second suitable solvent and heated to a suitable temperature to dissolve it. Then, a crystallization solvent was added to precipitate the solid. The solid was centrifuged and dried to obtain crystal II of compound 1.

[0063] In some embodiments, the second suitable solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, and n-butanol; preferably methanol.

[0064] In some embodiments, the volume (ml) to mass (mg) ratio of the second suitable solvent to compound 1 is 2:(80-100).

[0065] In some embodiments, the crystallization solvent is acetonitrile.

[0066] In some embodiments, the volume (ml) to mass (mg) ratio of the crystallization solvent to compound 1 is 20:(80-100).

[0067] In some embodiments, the heating to a suitable temperature is 40 to 50°C; preferably, the heating to a suitable temperature is 45°C.

[0068] In some embodiments, the present invention provides a method for preparing crystal III of the above-mentioned compound 1, the method comprising the following steps:

[0069] Compound 1 was placed in a third suitable solvent and heated to a suitable temperature to dissolve it. Then, a crystallization solvent was added to precipitate the solid. The solid was centrifuged and dried to obtain crystal III of compound 1.

[0070] In some embodiments, the third suitable solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, and n-butanol; preferably methanol.

[0071] In some embodiments, the volume (ml) to mass (mg) ratio of the third suitable solvent to compound 1 is 2:(80-200).

[0072] In some embodiments, the crystallization solvent is one or more of toluene, tetrahydrofuran, 1,4-dioxane, and methanol; preferably, the crystallization solvent is a mixture of toluene, or methanol and tetrahydrofuran.

[0073] In some embodiments, the volume (ml) to mass (mg) ratio of the crystallization solvent to compound 1 is 20:(80-200).

[0074] In some embodiments, the heating to a suitable temperature is 40 to 60°C; preferably, the heating to a suitable temperature is 60°C.

[0075] Pharmaceutical compositions and treatment methods

[0076] A fifth aspect of the present invention provides a pharmaceutical composition comprising crystal I, crystal II and / or crystal III of compound 1 of the present invention, and one or more pharmaceutically acceptable carriers.

[0077] The term "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with the therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0078] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes, such as by injection, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal administration; or by oral, sublingual, nasal, transmucosal, topical, ophthalmic formulations, or inhalation administration.

[0079] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0080] The dosage form may be a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form, including but not limited to tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, and syrups.

[0081] The sixth aspect of the present invention provides the use of crystals I, II, III of compound 1 and / or the pharmaceutical compositions of the present invention in the preparation of a medicament for the prevention or treatment of tumor diseases; preferably, the tumor diseases include, but are not limited to, non-small cell lung cancer (NSCLC).

[0082] A seventh aspect of the present invention provides a method for preventing and / or treating tumor diseases, the method comprising administering to an individual in need an effective amount of crystal I, crystal II, crystal III of compound 1 of the present invention and / or the pharmaceutical composition of the present invention. Preferably, the tumor disease includes, but is not limited to, non-small cell lung cancer (NSCLC).

[0083] The crystal form of Compound 1 provided by this invention not only exhibits excellent efficacy in the prevention and / or treatment of tumor diseases, but also demonstrates good chemical stability, physical stability, and pharmacokinetic properties. For example, the crystalline form of Compound 1 of this invention has good solubility, low hygroscopicity, and thermal stability, thus making it more advantageous for subsequent formulation preparation and maintaining sufficient biological activity. It also maintains reliability during transportation and storage, thereby effectively ensuring the quality and safety of the drug; moreover, it has good photostability, eliminating the need for special packaging treatments to prevent light exposure, thereby reducing costs and improving the safety and long-term efficacy of the drug. Attached Figure Description

[0084] Figure 1 XRPD pattern of crystal I of compound 1.

[0085] Figure 2 DSC spectrum of crystal I of compound 1.

[0086] Figure 3 XRPD pattern of crystal II of compound 1.

[0087] Figure 4 DSC spectrum of crystal II of compound 1.

[0088] Figure 5 XRPD pattern of crystal III of compound 1. Example

[0089] The present invention will be further illustrated by the following embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of the present invention. Those skilled in the art can make some non-essential improvements and adjustments, which still fall within the protection scope of the present invention.

[0090] Information on the testing instruments and methods used in the experiment:

[0091] X-ray powder diffraction (XRPD):

[0092] The X`Pert3 Powder Diffractometer was used, which employs Cu target irradiation and absolute scanning at room temperature. The detection range was 3.5° to 40°, with a step size of 0.013, a dwell time of 50 s, and one scan.

[0093] The differential scanning calorimetry (DSC) instrument used is a DSC1 (METTLER TOLEDO). The test temperature range is 35℃ to 250℃, and the heating rate is 10K / min.

[0094] Preparation Example: Preparation of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide dihydrochloride (Compound 1)

[0095]

[0096] Step 1: Preparation of 2-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamide

[0097] Add 11.60 g of 4-bromo-2-fluoro-N-methylbenzamide, 15.24 g of pinacol diborate, 31.10 g of Pd2(dba)3, 0.80 g of tricyclohexylphosphine, and 14.72 g of potassium acetate to the reaction flask, followed by 116 ml of 1,4-dioxane. After purging with nitrogen three times, the mixture was heated to 80 °C and stirred for 2 hours, during which time TLC was used to monitor the reaction progress. When the reactants were found to be essentially completely reacted, the reaction system was cooled to room temperature, and insoluble impurities were removed by filtration with diatomaceous earth. The resulting filtrate was concentrated to dryness under reduced pressure, and 100 ml of ethyl acetate was added until completely dissolved. The organic phase was then washed twice with 100 ml of purified water, separated, and the organic phases were combined and dried over anhydrous sodium sulfate. After drying, the solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. Then, it was recrystallized in hexane to give 10.31 g of crude 2-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamide, with a yield of 73.9%.

[0098] Step 2: Preparation of 4-(3-amino-1,2,4-triazin-6-yl)-2-fluoro-N-methylbenzamide

[0099] 14.37 g of crude 2-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamide and 74 ml of 1,4-dioxane were added to the reaction flask. After dissolving the mixture by stirring at room temperature, 6.15 g of 3-amino-6-bromo-1,2,4-triazine, an aqueous solution of potassium carbonate (19.42 g of potassium carbonate dissolved in 37 ml of water), and 0.61 g of PdCl2(dppf)2 were added. After purging the reaction system with nitrogen, the temperature was raised to 80 °C and the reaction was stirred for 2 hours. During this time, the reaction progress was monitored by TLC. When the reactants had basically reacted completely, the reaction system was placed in an ice-water bath to cool to below 10 °C, and 117 ml of hydrochloric acid aqueous solution was added dropwise. After the addition was complete, the reaction system was raised to room temperature and stirred for 1 hour. The mixture was then filtered, and the filtrate was washed with ethyl acetate, and the aqueous phase was collected. The aqueous phase was placed in an ice-water bath, and 120 ml of a 50% sodium hydroxide aqueous solution was added dropwise. After the addition was complete, a large amount of solid precipitated out. After stirring at this temperature for 2 hours, the mixture was filtered, and the filter cake was washed with purified water. After drying, the resulting filter cake yielded 6.95 g of 4-(3-amino-1,2,4-triazine-6-yl)-2-fluoro-N-methylbenzamide, with a yield of 80.1%.

[0100] Step 3: Preparation of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide

[0101] 2.80 g of 4-(3-amino-1,2,4-triazin-6-yl)-2-fluoro-N-methylbenzamide, 4.31 g of 1-(2-chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione, and 28 ml of ethylene glycol were added to the reaction flask. After purging the reaction system with nitrogen, the temperature was raised to 120 °C and stirred for 2 hours, during which the reaction progress was monitored by TLC. When the reactants had basically reacted completely, the reaction system was cooled to room temperature, and 60 ml of purified water was added dropwise. After the addition was complete, a large amount of solid precipitated out. The mixture was kept at room temperature and stirred for 0.5 hours, then filtered to obtain an orange-yellow filter cake. The filter cake was then placed in a reaction flask, and 60 ml of a DMF / MTBE mixed solvent (DMF:MTBE = 1:5) was added. The mixture was refluxed and stirred for 1 hour, then cooled to room temperature and filtered. The resulting filter cake was washed with MTBE. After drying, the resulting filter cake yielded 2.97 g of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide, with a yield of 63.8%.

[0102] Step 4: Preparation of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide dihydrochloride

[0103] 2.14 g of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazin-2-yl]benzamide was added to a reaction flask, followed by 30 mL of anhydrous methanol. The mixture was heated to 55 °C and stirred for 0.5 hours. Then, 2.1 mL of concentrated hydrochloric acid was added to the reaction system. After stirring for another 0.5 hours, 30 mL of MTBE was added dropwise, and the mixture was stirred at this temperature for 1 hour. The reaction system was then slowly cooled to room temperature, filtered, and washed with MTBE. The resulting filter cake was dried to give 2.41 g of the target compound, with a yield of 81.1%. 1 H NMR(400MHz, DMSO-d6)δ9.52(s,1H),9.29-9.27(dd,J=8,4Hz,1H),9.18-9.15(d,J=12Hz,1H),8.55-5.54(m,1H),8.52-8.50(d,J=8Hz,1H),8 .38(s,1H),8.30(s,1H),8.27-8.24,(dd,J=8,4Hz,1H),8.12-8.06(m,3H),7.84-7.80(t,J=8Hz,1H),4.82(s,2H),2.81-2.80(d,J=4Hz,3H).

[0104] Example 1: Preparation of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide dihydrochloride (crystal I of compound 1)

[0105] 100 mg of compound 1 was weighed and added to 2 mL of methanol. The solution was heated to 50 °C and then added dropwise to 20 mL of ethyl acetate. A solid precipitated out. After 1 h, the solution was centrifuged and dried at 40 °C to obtain the solid. XRPD analysis was performed on the solid, and the resulting XRPD spectrum is shown below. Figure 1 The image shown is Crystal I.

[0106] Example 2: Preparation of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide dihydrochloride (crystal I of compound 1)

[0107] 80 mg of compound 1 was weighed and added to 2 mL of methanol. The solution was heated to 45 °C and then added dropwise to 20 mL of acetone, precipitating a solid. After 1 h, the solid was centrifuged and dried at 40 °C to obtain the solid. XRPD analysis was performed on the solid, and the obtained XRPD spectrum was consistent with... Figure 1 The diagrams shown are consistent, indicating that this is crystal I.

[0108] Example 3: Preparation of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide dihydrochloride (crystal II of compound 1)

[0109] 100 mg of compound 1 was weighed and added to 2 mL of methanol. The solution was heated to 45 °C and then poured into 20 mL of acetonitrile. A solid precipitated, and after 1 h, it was centrifuged and dried at 40 °C to obtain the solid. XRPD analysis was performed on the solid, and the resulting XRPD spectrum is shown below. Figure 3 The image shown is Crystal II.

[0110] Example 4: Preparation of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide dihydrochloride (crystal III of compound 1)

[0111] 100 mg of compound 1 was weighed and added to 1 mL of methanol. The solution was heated to 60 °C and then slowly added dropwise to 1 mL of a mixed solvent (300 μL methanol + 700 μL tetrahydrofuran) at room temperature. A solid precipitated, and after 1 h, it was centrifuged and dried at 40 °C to obtain the solid. XRPD analysis was performed on the solid, and the obtained XRPD spectrum is shown below. Figure 5 The image shown is crystal III.

[0112] Example 5: Preparation of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide dihydrochloride (crystal III of compound 1)

[0113] 100 mg of compound 1 was weighed and added to 1 mL of methanol. The solution was heated to 60 °C and then poured into 2 mL of toluene, precipitating a solid. The mixture was subjected to cyclic heating and cooling at 20 °C-40 °C for 4 hours, followed by centrifugation and drying at 40 °C to obtain the solid. XRPD analysis was performed on the solid, and the resulting XRPD spectrum is shown below. Figure 5 The image shown is crystal III.

[0114] Example 6: Stability Study of Different Crystal Forms of 2-Fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide dihydrochloride (Compound 1)

[0115] The crystal forms of the samples were investigated and analyzed by XRPD and HPLC after 5 days and 10 days of storage in open containers under illumination (4500 lx ± 500 lx), 60 °C, and RH 92.5%. The results are shown in Tables 1-3.

[0116] Table 1. Results of photostability studies for crystal forms I, II, and III of the compounds.

[0117]

[0118] Table 2. Results of high-temperature (60℃) stability studies for crystal forms I, II, and III of the compounds.

[0119]

[0120] Table 3. Results of high-humidity (92.5%) stability studies for crystal forms I, II, and III.

[0121]

[0122] Example 7: Solubility test of various crystal forms of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazin-2-yl]benzamide dihydrochloride (compound 1)

[0123] The solubility of crystal forms I, II, and III was determined by HPLC external standard method in different media at 25℃. The pH 7.4 buffer solution was prepared as follows: Take one tablet of Invitrogen... TM Dissolve and bring the solution to a final volume of 100 ml in Phosphate Buffer Salin (PBS). The results are shown in Table 4.

[0124] Table 4. Solubility test results of compound 1 in crystal forms I, II, and III.

[0125]

[0126] Crystal forms I, II, and III all exhibit good solubility in the three solvents mentioned above, and their solubility in 0.1N HCl aqueous solution is only slightly different from that in pH 7.4 buffer solution, thus avoiding the risk of drug precipitation after entering intestinal fluid and improving drug bioavailability.

[0127] Example 8: Pharmacokinetic studies of various crystal forms of 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazin-2-yl]benzamide dihydrochloride (Compound 1) in rats.

[0128] Experimental Methods: Nine SD rats were randomly divided into three groups (n=3) according to their body weight, designated as groups A, B, and C. Each group received a single oral gavage dose of crystalline form I, crystalline form II, and crystalline form III, respectively, at a dose of 20 mg / kg (day of administration was designated as 0d). Blood samples of 0.25 ml were collected venously before administration and at 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, and 1d (24 h) on the day of administration, and plasma was separated. The collected plasma was stored at -80℃ for analysis. The plasma concentration was determined by LC-MS / MS using the protein precipitation method, and pharmacokinetic parameters were calculated by fitting pharmacokinetic curves. The results are shown in the table below.

[0129]

[0130]

[0131] The experimental data show that the crystal forms I, II, and III provided in this application have good pharmacokinetic properties in rats after oral administration.

[0132] The solid form of Compound 1 and its preparation method disclosed in this application can be implemented by those skilled in the art by appropriately modifying the raw materials, process parameters, and other aspects, based on the content of this application. The methods and products of this application have been described through preferred embodiments. Those skilled in the art can obviously modify or appropriately change and combine the methods and products described herein without departing from the content, spirit, and scope of this application to achieve the technology of this application. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the spirit, scope, and content of this application.

Claims

1. Crystalline Form I of Compound 1 characterized by, The X-ray powder diffraction pattern of said crystal I comprises characteristic peaks at diffraction angles (2θ) of 5.18±0.2 o , 7.43±0.2 o , 8.74±0.2 o , 12.56±0.2 o , 15.00±0.2 o and 16.12±0.2 o , Compound 1.

2. The crystal I according to claim 1, characterized by The X-ray powder diffraction pattern of said crystal I comprises characteristic peaks at diffraction angles (2 theta) of 5.18 ± 0.2 o , 7.43 ± 0.2 o , 8.74 ± 0.2 o , 12.56 ± 0.2 o , 15.00 ± 0.2 o , 15.73 ± 0.2 o , 16.12 ± 0.2 o , 19.70 ± 0.2 o , and 22.52 ± 0.2 o .

3. The crystal I according to claim 1, characterized by, The X-ray powder diffraction pattern of said crystal I comprises characteristic peaks at diffraction angles (2θ) of 5.18±0.2 o , 7.43±0.2 o , 8.74±0.2 o , 12.56±0.2 o , 15.00±0.2 o , 15.73±0.2 o , 16.12±0.2 o , 19.70±0.2 o , 22.52±0.2 o , 26.83±0.2 o , 27.51±0.2 o , and 28.15±0.2 o .

4. The crystal I according to claim 1, characterized by, The XRPD pattern of said crystal I comprises characteristic peaks at the following diffraction angles (2Θ), wherein the error range for the 2Θ values is ±0.2 o : 。 5. The crystal I of claim 1, wherein The XRPD pattern of the crystal I comprises peaks at substantially the same diffraction angles (2 theta) as shown in Figure 1.

6. The crystal I of claim 1, wherein The X-ray powder diffraction pattern of the crystal I is shown in Figure 1.

7. The crystal I according to any one of claims 1 to 6, characterized by The DSC pattern of the crystal I comprises an endothermic peak at 250±5°C.

8. The crystal I according to any one of claims 1 to 6, characterized by The DSC pattern of the crystal I comprises characteristic peaks at substantially the same temperatures as shown in Figure 2.

9. The crystal I according to any one of claims 1 to 6, characterized by The DSC pattern of the crystal I is shown in Figure 2.

10. Crystalline Form II of Compound 1 characterized by, The X-ray powder diffraction pattern of said crystal II comprises characteristic peaks at diffraction angles (2 theta) of 6.62 ± 0.2 o , 7.09 ± 0.2 o , 9.49 ± 0.2 o , 14.32 ± 0.2 o , 15.65 ± 0.2 o , and 25.15 ± 0.2 o .

11. The crystal II according to claim 10, characterized by, The X-ray powder diffraction pattern of said crystal II comprises characteristic peaks at diffraction angles (2 theta) of 6.62 ± 0.2 o , 7.09 ± 0.2 o , 9.49 ± 0.2 o , 11.71 ± 0.2 o , 12.26 ± 0.2 o , 14.32 ± 0.2 o , 15.65 ± 0.2 o , 20.27 ± 0.2 o , and 25.15 ± 0.2 o .

12. The crystal II according to claim 10, characterized by, The X-ray powder diffraction pattern of said crystal II comprises characteristic peaks at diffraction angles (2 theta) of 6.62 ± 0.2 o , 7.09 ± 0.2 o , 9.49 ± 0.2 o , 11.71 ± 0.2 o , 12.26 ± 0.2 o , 14.32 ± 0.2 o , 15.65 ± 0.2 o , 20.27 ± 0.2 o , 22.65 ± 0.2 o , 23.15 ± 0.2 o , 25.15 ± 0.2 o , 26.94 ± 0.2 o , 28.00 ± 0.2 o and 29.11 ± 0.2 o .

13. The crystal II according to claim 10, characterized by, The XRPD pattern of said crystalline II comprises characteristic peaks at the following diffraction angles (2Θ), wherein the error range for the 2Θ values is ± 0.2 o : 。 14. The crystal II according to claim 10, characterized by, The XRPD pattern of the crystal II comprises peaks at substantially the same diffraction angles (2 theta) as shown in Figure 3.

15. The crystal II according to claim 10, characterized by, The X-ray powder diffraction pattern of the crystal II is shown in Figure 3.

16. The crystal II according to any one of claims 10 to 15, characterized by The differential scanning calorimetry (DSC) pattern of the crystal II comprises an endothermic peak at 174±5°C.

17. The crystal II according to any one of claims 10-15, characterized by, The DSC pattern of the crystal II comprises characteristic peaks at substantially the same temperatures as shown in Figure 4.

18. The crystal II according to any one of claims 10-15, characterized by, The DSC pattern of the crystal II is shown in Figure 4.

19. A process for preparing crystalline Form I of Compound 1 of any one of claims 1-9, characterized in that, comprising the following steps: Compound 1 is dissolved in a first suitable solvent, heated to a suitable temperature to dissolve, then a crystallization solvent is added dropwise to precipitate a solid, centrifuged, and dried to obtain the crystal I of Compound 1; The first suitable solvent is selected from one or more of the following: methanol, ethanol, n-propanol, n-butanol; The crystallization solvent is selected from one or more of the following: ethyl acetate, acetone, toluene, methyl tert-butyl ether, n-heptane.

20. The method of claim 19, wherein the first suitable solvent is methanol.

21. A process for preparing crystalline Form II of Compound 1 of any one of claims 10-18, characterized in that, comprising the following steps: Compound 1 is dissolved in a second suitable solvent, heated to a suitable temperature to dissolve, then a crystallization solvent is added to precipitate a solid, centrifuged, and dried to obtain the crystal II of Compound 1; The second suitable solvent is selected from one or more of the following: methanol, ethanol, n-propanol, isopropanol, n-butanol; and the crystallization solvent is acetonitrile.

22. The method of claim 21, wherein the second suitable solvent is methanol.

23. A pharmaceutical composition comprising the crystal I of any one of claims 1-9, and / or the crystal II of any one of claims 10-18, and one or more pharmaceutically acceptable carriers.

24. Use of the crystal I of any one of claims 1-9, the crystal II of any one of claims 10-18, and / or the pharmaceutical composition of claim 23 in the manufacture of a medicament for preventing or treating a tumor disease.

25. The use according to claim 24, wherein, The tumor disease is non-small cell lung cancer (NSCLC).

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