Salts and crystals of MNK inhibitor compounds, and methods for preparing them.

Abstract

The present invention relates to a salt of a compound as an MNK inhibitor, particularly a sulfate salt of the compound, and a crystal of the compound, as well as a method for preparing the same.

Description

Technical Field

[0001] The present invention relates to salts of a compound as an MNK inhibitor, in particular a sulfate salt of the above compound, a crystal of the above compound, and a method for preparing the same.

Background Art

[0002] In recent years, it has been found that the expression of serine / threonine-protein kinase (MNK) is strongly correlated with proliferative diseases, inflammatory diseases and neurodegenerative diseases. For example, International Publication No. WO2020155842 A1 discloses a class of MNK inhibitors that have potential therapeutic effects in the treatment of various conditions such as proliferative diseases, inflammatory diseases and neurodegenerative diseases, and can be used for preparing pharmaceutical compositions for treating diseases or conditions associated with MNK activity or MNK expression.

[0003] Among such MNK inhibitors, a preferred compound is "N-(12'-methyl-1',5'-dioxo-1',5',6',11'-tetrahydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5':1,6]pyrido[3,4-b][1,6]naphthyridin]-8'-yl)cyclopropanecarboxamide" represented by Chemical Formula 1. It is known that this compound has unique and highly efficient anti-tumor activity and immunomodulatory effect, exhibits excellent anti-tumor activity in various hematological tumor models and solid tumor models, and is a broad-spectrum anticancer agent with great potential. However, the chemical stability of this compound is relatively low, making it susceptible to oxidation or aromatization under ambient temperature, atmospheric pressure or light exposure. Furthermore, the low solubility of this compound affects the concentration of the active ingredient, thereby making the conditions for its production and storage considerably stringent.

Chem

[0004] Therefore, when used as an active ingredient in pharmaceutical compositions, it is necessary to convert it into a more structurally stable form to enable the maintenance of the active ingredient's concentration over a long period, reduce the requirements of process conditions, and achieve industrialization under relatively mild conditions. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] The object of the present invention is to provide a salt of "N-(12'-methyl-1',5'-dioxo-1',5',6',11'-tetrahydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5':1,6]pyrido[3,4-b][1,6]naphthyridine]-8'-yl)cyclopropanecarboxamide" (hereinafter referred to as "Compound 1") and its crystalline form. [Means for solving the problem]

[0006] In a first aspect of the present invention, a salt of the compound of chemical formula 1, [ka] The above salt includes a free base portion and an acid portion, The above free base portion has the structure of chemical formula 1, A salt is provided in which the acid portion is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, or formic acid.

[0007] Converting a compound into a salt can improve its solubility in solvents and enhance its stability. For example, when the acidic portion is an inorganic or organic acid, the salt of the compound exhibits improved solubility in water and / or organic solvents, reduced potential for oxidation or aromatization, and improved storage stability. These effects are particularly pronounced when the acidic portion is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, or formic acid.

[0008] In a preferred embodiment, the salt is in crystalline form.

[0009] In a preferred embodiment, the acid portion is sulfuric acid.

[0010] Through extensive experimental research, the inventors have found that when the acidic portion of the salt is sulfuric acid, the resulting salt exhibits optimal chemical stability and storage stability, better water solubility, and lower hygroscopicity, while simultaneously demonstrating a simple and highly reproducible salt preparation process. Therefore, salts with sulfuric acid as the acidic portion are considered to have significant potential for pharmaceutical development.

[0011] In a second aspect of the present invention, the sulfate crystal of the compound of chemical formula 1 is, The crystal is provided having the crystal structure of polymorph A, and the powder X-ray diffraction pattern of polymorph A shows characteristic peaks at 2θ values ​​of 7.44±0.2°, 15.72±0.2°, 20.05±0.2°, 24.10±0.2°, 24.57±0.2°, 25.55±0.2°, and 27.10±0.2°.

[0012] In a preferred embodiment, the powder X-ray diffraction pattern of polymorph A also has one or more characteristic peaks at 2θ values ​​selected from 12.33±0.2°, 13.50±0.2°, 14.83±0.2°, 18.33±0.2°, 19.70±0.2°, 21.30±0.2°, and 29.77±0.2°.

[0013] In a preferred embodiment, the powder X-ray diffraction pattern of polymorph A exhibits characteristic peaks at 2θ values ​​of 7.44±0.2°, 10.52±0.2°, 12.33±0.2°, 13.50±0.2°, 14.83±0.2°, 15.72±0.2°, 17.43±0.2°, 18.33±0.2°, 19.70±0.2°, 20.05±0.2°, 21.30±0.2°, 24.10±0.2°, 24.57±0.2°, 25.55±0.2°, 27.10±0.2°, 27.93±0.2°, and 29.77±0.2°.

[0014] In a preferred embodiment, the powder X-ray diffraction pattern of said polymorph A exhibits characteristic peaks at 2θ values of 7.44±0.2°, 10.52±0.2°, 11.23±0.2°, 12.33±0.2°, 13.50±0.2°, 14.83±0.2°, 15.34±0.2°, 15.72±0.2°, 17.43±0.2°, 18.33±0.2°, 18.81±0.2°, 19.70±0.2°, 20.05±0.2°, 21.30±0.2°, 22.31±0.2°, 23.20±0.2°, 24.10±0.2°, 24.57±0.2°, 25.05±0.2°, 25.55±0.2°, 26.04±0.2°, 27.10±0.2°, 27.93±0.2°, 29.77±0.2°, 30.33±0.2°, 30.99±0.2°, 32.10±0.2°, 32.75±0.2°, 33.69±0.2°, 34.83±0.2°, and 35.83±0.2°.

[0015] In a preferred embodiment, the crystal of said sulfate is a hydrate, particularly a dihydrate.

[0016] In a third aspect of the present invention, there is provided a method for preparing a crystalline sulfate of the compound of Chemical Formula 1, the method comprising the steps of: mixing said compound of Chemical Formula 1 with a solvent selected from water, alcohols, ketones, or mixtures thereof, adding a sulfuric acid solution to form a suspension; and stirring the suspension, followed by isolation to obtain crystals.

[0017] In a preferred embodiment, said solvent is a mixture of water and a ketone.

[0018] In a preferred embodiment, said solvent is a mixture of water and acetone.

[0019] In a preferred embodiment, the volume ratio of water to acetone is 1 / 99 to 30 / 70.

[0020] In a preferred embodiment, the volume ratio of water to acetone is 5 / 95 to 10 / 90.

[0021] In a preferred embodiment, 1.1 to 2.1 equivalents of a sulfuric acid solution is added.

[0022] In a fourth aspect of the present invention, there is provided a method for preparing crystals of a sulfate salt of a compound of Chemical Formula 1, comprising: mixing said compound of Chemical Formula 1 with a solvent selected from water, alcohols, ketones, or mixtures thereof; adding a sulfuric acid solution to form a suspension; adding polymorph A of the sulfate salt of said compound of Chemical Formula 1 as seed crystals to said suspension; and stirring said suspension followed by separation to obtain crystals.

[0023] In a preferred embodiment, said solvent is selected from water, methanol, ethanol, n-propanol, isopropanol, 1-butanol, tert-butanol, acetone, butanone, 2-pentanone, or mixtures thereof.

[0024] In a preferred embodiment, said solvent is selected from water, ethanol, acetone, or mixtures thereof.

[0025] In a fifth aspect of the present invention, there is provided a pharmaceutical composition comprising the salt according to the first aspect, or the crystal according to the second aspect, and a pharmaceutically acceptable excipient.

[0026] Converting the compound of Chemical Formula 1 into a salt form improves structural stability, so that it is less prone to undergo oxidation or aromatization to be converted into other components under environmental conditions of constant humidity and room temperature, thereby reducing the content of the active ingredient.

[0027] The more stable structure of the salt reduces the requirements for manufacturing process conditions and storage process conditions, and facilitates processing into pharmaceuticals and industrialization.

[0028] The sulfate crystal of the compound of Chemical Formula 1 prepared by the method of the present invention is characterized by optimal chemical and storage stability, better water solubility, lower hygroscopicity, etc., and the preparation process is simple, controllable and has good reproducibility, so the present component has great potential for pharmaceutical development.

[0029] Within the scope of the present invention, it should be understood that each of the above technical features of the present invention, and each of the technical features specifically described below (e.g., in the examples), can be combined with each other to constitute a new or preferred technical solution. For space reasons, they will not be repeated herein. [Brief explanation of the drawing]

[0030] [Figure 1] Figure 1 shows the powder X-ray diffraction (XRPD) pattern of polymorph I of compound 1 obtained in Comparative Example 1. [Figure 2] Figure 2 shows the powder X-ray diffraction (XRPD) pattern of polymorph A of the sulfate of compound 1 obtained in Example 1. [Figure 3] Figure 3 shows the thermogravimetric analysis (TGA) profile of polymorph A of the sulfate of compound 1 obtained in Example 1. [Figure 4] Figure 4 shows the differential scanning calorimetry (DSC) profile of polymorph A of the sulfate of compound 1 obtained in Example 1. [Figure 5] Figure 5 shows the powder X-ray diffraction (XRPD) pattern of polymorph B of the hydrochloride salt of compound 1 obtained in Example 2. [Figure 6] Figure 6 shows the powder X-ray diffraction (XRPD) pattern of polymorph B of the mesylate of compound 1 obtained in Example 3. [Figure 7] Figure 7 shows the powder X-ray diffraction (XRPD) pattern of polymorph A of the formate of compound 1 obtained in Example 4. [Figure 8] Figure 8 shows the powder X-ray diffraction (XRPD) pattern of polymorph B of the sulfate of compound 1 obtained in Example 7. [Figure 9] Figure 9 shows the powder X-ray diffraction (XRPD) pattern of polymorph C of the sulfate of compound 1 obtained in Example 8. [Figure 10] Figure 10 shows the powder X-ray diffraction (XRPD) pattern of polymorph D of the sulfate of compound 1 obtained in Example 9. [Figure 11]Figure 11 shows the powder X-ray diffraction (XRPD) pattern of polymorph E of the sulfate of compound 1 obtained in Example 10. [Figure 12] Figure 12 shows the powder X-ray diffraction (XRPD) pattern of polymorph F of the sulfate of compound 1 obtained in Example 11. [Figure 13] Figure 13 shows the powder X-ray diffraction (XRPD) pattern of polymorph G of the sulfate of compound 1 obtained in Example 12. [Figure 14] Figure 14 shows comparative powder X-ray diffraction patterns of polymorph A of compound 1 sulfate obtained in Example 1 after being left for one week under different temperature and humidity conditions. [Figure 15] Figure 15 shows comparative powder X-ray diffraction patterns of polymorph A of compound 1 sulfate obtained in Example 1 after being left for 4 weeks under different temperature and humidity conditions. [Figure 16] Figure 16 shows the dynamic water sorption (DVS) profile of polymorph A of the sulfate of compound 1 obtained in Example 1. [Modes for carrying out the invention]

[0031] The present invention will be further described below with reference to specific embodiments. It should be understood that the detailed description of the technical solutions of the present invention by the following embodiments will make the advantages and effects of the technical solutions of the present invention easier to understand. The embodiments do not limit the scope of protection of the present invention as defined by the claims.

[0032] In a first aspect of the present invention, a salt of the compound of chemical formula 1, [ka] The above salt includes a free base portion and an acid portion, The above free base portion has the structure of chemical formula 1, A salt is provided in which the acid portion is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, or formic acid.

[0033] Converting a compound into a salt can improve its solubility in solvents and enhance its stability. For example, when the acidic portion is an inorganic or organic acid, the salt of the compound exhibits improved solubility in water and / or organic solvents, reduced potential for oxidation or aromatization, and improved storage stability. These effects are particularly pronounced when the acidic portion is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, or formic acid.

[0034] In a preferred embodiment, the salt is in crystalline form.

[0035] Compound 1 in its free base form or its amorphous salt is known to be susceptible to oxidation or aromatization at room temperature and atmospheric pressure, which affects the chemical structure of the active ingredient and consequently impairs its pharmaceutical properties. Compound 1 in its crystalline salt form exhibits higher chemical stability than its free base form or amorphous salt form.

[0036] In a preferred embodiment, the acid portion is sulfuric acid.

[0037] Through extensive experimental research, the inventors have found that when the acidic portion of the salt is sulfuric acid, the resulting salt exhibits optimal chemical stability and storage stability, better water solubility, and lower hygroscopicity, while simultaneously demonstrating a simple and highly reproducible salt preparation process. Therefore, salts with sulfuric acid as the acidic portion are considered to have significant potential for pharmaceutical development.

[0038] In a second aspect of the present invention, the sulfate crystal of the compound of chemical formula 1 is, The crystal is provided having the crystal structure of polymorph A, and the powder X-ray diffraction pattern of polymorph A shows characteristic peaks at 2θ values ​​of 7.44±0.2°, 15.72±0.2°, 20.05±0.2°, 24.10±0.2°, 24.57±0.2°, 25.55±0.2°, and 27.10±0.2°.

[0039] In a preferred embodiment, the powder X-ray diffraction pattern of polymorph A also has one or more characteristic peaks at 2θ values ​​selected from 12.33±0.2°, 13.50±0.2°, 14.83±0.2°, 18.33±0.2°, 19.70±0.2°, 21.30±0.2°, and 29.77±0.2°.

[0040] In a preferred embodiment, the powder X-ray diffraction pattern of polymorph A exhibits characteristic peaks at 2θ values ​​of 7.44±0.2°, 10.52±0.2°, 12.33±0.2°, 13.50±0.2°, 14.83±0.2°, 15.72±0.2°, 17.43±0.2°, 18.33±0.2°, 19.70±0.2°, 20.05±0.2°, 21.30±0.2°, 24.10±0.2°, 24.57±0.2°, 25.55±0.2°, 27.10±0.2°, 27.93±0.2°, and 29.77±0.2°.

[0041] In a preferred embodiment, the powder X-ray diffraction patterns of polymorph A are 7.44±0.2°, 10.52±0.2°, 11.23±0.2°, 12.33±0.2°, 13.50±0.2°, 14.83±0.2°, 15.34±0.2°, 15.72±0.2°, 17.43±0.2°, 18.33±0.2°, 18.81±0.2°, 19.70±0.2°, 20.05±0.2°, 21.30±0.2°, 22.31±0.2°, Characteristic peaks are observed at 2θ values ​​of 23.20±0.2°, 24.10±0.2°, 24.57±0.2°, 25.05±0.2°, 25.55±0.2°, 26.04±0.2°, 27.10±0.2°, 27.93±0.2°, 29.77±0.2°, 30.33±0.2°, 30.99±0.2°, 32.10±0.2°, 32.75±0.2°, 33.69±0.2°, 34.83±0.2°, and 35.83±0.2°.

[0042] The powder X-ray diffraction patterns of polymorph A differ slightly due to subtle differences in crystal structure, which are mainly influenced by specific crystallization conditions. In a particular embodiment, the powder X-ray diffraction pattern of polymorph A is shown in Figure 2.

[0043] In a preferred embodiment, the sulfate crystals are hydrates, particularly dihydrates.

[0044] In pharmaceutical compositions, it is usually required to minimize residual organic solvents. If a solvate structure is present in the component, desolvation can occur under changes in temperature or pressure. Therefore, if the solvent is an organic solvent, the released solvent may cause safety issues in the use of the pharmaceutical. If the solvent is water, even if dehydration occurs, the safety of the pharmaceutical is still guaranteed.

[0045] In some embodiments, the salt has about 1.5 equivalents of hydrate relative to the salt. In some embodiments, the salt has about 2 equivalents of hydrate relative to the salt. In some embodiments, the salt has about 2.5 equivalents of hydrate relative to the salt. In some embodiments, the salt has about 3 equivalents of hydrate relative to the salt. Particularly preferably, the salt has about 2 equivalents of hydrate relative to the salt.

[0046] A third aspect of the present invention provides a method for preparing a sulfate crystal of a compound of chemical formula 1, comprising the steps of: mixing the compound of chemical formula 1 with a solvent selected from water, alcohol, ketone, or a mixture thereof; adding a sulfuric acid solution to form a suspension; and stirring the suspension and then separating it to obtain crystals.

[0047] The suspension can be formed by any method known in the art. In this invention, stirring and slurring are used to form the suspension.

[0048] The stirring process for forming the suspension is typically carried out at 20-60°C for 1-72 hours. To ensure a more complete reaction, a two-stage stirring process can be used, for example, stirring at 40-60°C for 1-2 hours, followed by stirring at 20-30°C for 1-24 hours.

[0049] Since the salt of the compound of chemical formula 1 according to the present invention is a polar substance, the salt can be better dispersed in the system by selecting a polar solvent. Water, alcohols, and ketones are all solvents with a certain polarity, and by selecting any of these solvents or mixtures thereof as needed, the appropriate polarity of the solvent can be achieved, thereby promoting better dispersion of the salt in the system.

[0050] In a preferred embodiment, the solvent is a mixture of water and a ketone.

[0051] In a preferred embodiment, the solvent is a mixture of water and acetone.

[0052] In a preferred embodiment, the volume ratio of water to acetone is 1 / 99 to 30 / 70.

[0053] In a preferred embodiment, the volume ratio of water to acetone is 5 / 95 to 10 / 90.

[0054] In a preferred embodiment, the amount of sulfuric acid solution added is preferably 1.1 to 2.1 equivalents.

[0055] Sulfuric acid solutions are typically selected as either aqueous solutions of sulfuric acid or organic solutions of sulfuric acid, depending on the polarity of the solvent added to form the suspension.

[0056] Those skilled in the art will recognize that, depending on the conditions (e.g., solvent, temperature) and the strength of the acid, an equilibrium exists between the sulfuric acid and the free base moiety, where protons may be present. For example, under certain conditions, sulfuric acid can form a weak interaction by donating one or more protons to the basic site of the free base, resulting in the sharing of protons between the acid and the free base. Adding a slightly excess amount of acid allows the sulfuric acid to react sufficiently with the free base moiety, completely converting the free base moiety into a salt. As the reaction progresses, some of the sulfuric acid is consumed, decreasing its concentration and reactivity, thus requiring an appropriate excess of sulfuric acid. However, excessive use of sulfuric acid generates more waste in subsequent processing, increasing processing costs. Therefore, it is preferable to add sulfuric acid solution in the range of 1.1 to 2.1 equivalents.

[0057] The crystal separation method disclosed in this invention may be any separation method known in the art, such as decantation, filtration, centrifugation, or gravity sedimentation, and generally an appropriate separation method is selected depending on the fluidity of the suspension and the particle size of the solid particles. Commonly used methods are filtration and centrifugation.

[0058] The solid obtained after separation is placed in a vacuum oven and dried at 30-60°C for 0.5-24 hours.

[0059] A fourth aspect of the present invention provides a method for preparing a sulfate crystal of a compound of chemical formula 1, comprising: mixing the compound of chemical formula 1 with a solvent selected from water, alcohol, ketone, and mixtures thereof; adding a sulfuric acid solution to form a suspension; adding polymorph A of the sulfate of the compound of chemical formula 1 as a seed crystal to the suspension; and stirring the suspension and then separating it to obtain crystals.

[0060] In preferred embodiments, the solvent is selected from water, methanol, ethanol, n-propanol, isopropanol, 1-butanol, tert-butanol, acetone, butanone, 2-pentanone, or mixtures thereof.

[0061] In preferred embodiments, the solvent is selected from water, ethanol, acetone, or a mixture thereof.

[0062] A fifth aspect of the present invention provides a pharmaceutical composition comprising the salt described in the first aspect or the crystal described in the second aspect and a pharmaceutically acceptable excipient. [Examples]

[0063] In the following examples, experimental methods where conditions are not specified are generally carried out under conventional conditions or according to the manufacturer's recommended procedures.

[0064] Unless otherwise specified, the raw materials or reagents used in the examples were purchased from Sinopharm Chemical Reagent Co., Ltd.

[0065] Unless otherwise specified, use the listed reagents directly without purification.

[0066] The following techniques are used to identify, characterize, or analyze crystals: chromatographic techniques such as powder X-ray diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), and HPLC.

[0067] The XRPD spectrum was acquired using a Bruker D8 ADVANCE diffractometer, and the method parameters for powder X-ray diffraction are as follows. X-ray reflection parameters: Cu, Kα Tube voltage: 40 kilovolts (kV) Tube current: 40 milliamperes (mA) Slits: 2# Scattering slit: 1°, 3# Anti-scattering slit: 1°, 4# Light-receiving slit: 0.3mm Scanning mode: Step Step angle: 0.02°, Sampling time: 0.2 seconds / step Scanning range: 3.0~40.0° TGA analysis method, equipment information: Model: TA DISCOVERY TGA 55 Manufacturer: TA Instruments Parameter settings Sample tray: Platinum HT Sample weight: 10 mg Heating rate: 10°C / min Temperature scanning range: RT-400℃ Balance purge gas flow rate: 40 mL / min Furnace purge gas flow rate: 60mL / min DSC analysis method, equipment information: Model: TA DISCOVERY DSC 250 Manufacturer: TA Instruments Parameter settings Sample tray: Tzero aluminum Cover: Yes Sample weight: 3-5 mg Heating rate: 10°C / min Temperature scanning range: 0~400℃ Nitrogen purge flow rate: 50 mL / min

[0068] Preparation of the compound of chemical formula 1 The compound of chemical formula 1 can be prepared according to the method described in International Publication No. 2020155842 (A1), or according to the exemplary preparation methods described below. [ka]

[0069] Step 1: Synthesis of Compound 4 [ka] In a three-necked flask, 4-amino-6-((2,4-dimethoxybenzyl)amino)ethyl nicotinate (compound 2, 45.0 g, prepared according to the synthesis of intermediate A described in International Publication No. 2020155842 (A1)), 6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (compound 3, 136.8 g, prepared according to the synthesis method of intermediate B described in International Publication No. 2020155842 (A1)), Pd2(dba)3 (7.44 g), xanthophos (9.42 g), and cesium carbonate (265.5 g) were added. The mixture was degassed and purged three times with nitrogen. 1,4-dioxane (2700 mL) was added, and the reaction mixture was heated under nitrogen for 22 hours under reflux. The reaction mixture was cooled to room temperature and poured into a mixture of water and ethyl acetate. The mixture was stirred at room temperature for 0.5 hours and then filtered. The filtered cake was dried at 60°C to obtain the desired compound 4 (204 g, purity 98.05%, yield 87.8%) as a gray solid. LCMS:(ESI)[M+H] + =562.3.

[0070] Step 2: Synthesis of Compound 5 [ka] 6-((2,4-dimethoxybenzyl)amino)-4-((8'-methyl-1',5'-dioxa-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-6'-yl)amino) nicotinate ethyl ester (compound 4, 203.3 g) was mixed with a mixture of ethanol and water (7.5 L), and lithium hydroxide (60 g) was added. The reaction mixture was heated and stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature and acidified to pH=3-4 by adding 6 M HCl dropwise. The mixture was stirred for 30 minutes and then filtered. The filtered cake was washed with ethanol:water = 1:1 and dried at 60°C. Target compound 5 (219.3 g, 100% yield) was obtained as a yellow solid. LCMS:(ESI)[M+H] + = 534.3.

[0071] Step 3: Synthesis of Compound 6 [ka] A mixed solution of polyphosphate (174 g) and trifluoromethanesulfonic acid (1740 mL) was heated to 130°C, and then 6-((2,4-dimethoxybenzyl)amino)-4-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-6'-yl)aminonicotinic acid (compound 5, 200 g) was added. The reaction mixture was heated and stirred at 130°C for 0.5 hours. After cooling the mixture to 15°C, the mixture was slowly added to ice water to adjust the pH to 7 and filtered. The filtered cake was washed with water and dried to obtain compound 6 (85 g, 62% yield) as a yellow solid. LCMS:(ESI)[M+H] + =366.2. 1 H NMR:(400 MHz,DMSO-d6)δ 11.49(s,1H),10.13(s,1H),8.78(s,1H),6.70(s,2H),6.59(s,1H),3.0 2-2.90(m,5H),1.79-1.60(m,5H),1.52-1.49(m,2H),1.28-1.20(m,1H).

[0072] Step 4: Synthesis of Compound 7 [ka] At room temperature, 8-amino-12-methyl-1H-spiro[cyclohexane-1,3-imidazo[1,5:1,6]pyrido[3,4-b][1,6]naphthyridine]-1,5,11'(2H,6H)-trione (compound 6, 75 g) was dissolved in Eaton's reagent (1125 mL), and cyclopropanecarboxylic acid (35.4 g) was added to the reaction mixture. The reaction mixture was heated and stirred at 50°C for 1 hour. The mixture was cooled to room temperature and slowly poured into ice water (58 times its volume). The mixture was stirred for 30 minutes and filtered. The solid obtained from filtration was dried at 60°C for 16 hours to obtain the crude product of target compound 7 (98.7 g, purity 95.95%) as a yellow solid. LCMS:(ESI)[M+H] + =434.2. 1 H NMR:(400 MHz,DMSO-d6)δ 12.09(s,1H),11.13(s,1H),10.21(s,1H),9.03(s,1H),8.54(s,1H),3.02-2.90(m,5H),2.0 2-2.36(m,1H),1.80-1.59(m,5H),1.52-1.49(m,2H),1.30-1.22(m,1H),0.85-0.87(m,4H).

[0073] Step 5: Synthesis of Compound 1 of Chemical Formula 1 [ka] N-(12-methyl-1,5,11-trioxo-2,5,6,11-tetrahydro-1H-spiro[cyclohexane-1,3-imidazo[1,5:1,6]pyrido[3,4-b][1,6]naphthopyridine]-8-yl)cyclopropanecarboxamide (compound 7, 70.0 g) was dissolved in acetic acid (1600 mL), and zinc powder (106 g) was added to the reaction mixture at 25°C. The reaction mixture was heated and stirred at 100°C for 2 hours. The reaction mixture was filtered, the filtered cake was washed with acetic acid, and dried at room temperature to obtain 100 g of crude product of compound 1. LCMS:(ESI)[M+H] + =440.2. 1 H NMR:(400 MHz,DMSO-d6)δ 10.45(s,1H),10.01(s,1H),9.01(s,1H),7.90(s,1H),7.78(s,1H),3.96(s,2H),3.10-2.93(m,2H),2.42 (s,3H),2.02-1.92(m,1H),1.79-1.56(m,5H),1.47-1.39(m,2H),1.280-1.23(m,1H),0.82-0.77(m,4H).

[0074] Comparative Example 1: Crystallization preparation of Compound 1 70 g of the crude product of compound 1 obtained by the above experimental method was taken and completely dissolved in dichloromethane (560 mL) at room temperature. Insoluble matter was removed by filtration. The solution was cooled to 0°C to precipitate the solid, which was then filtered and vacuum-dried to obtain 38.2 g of crystals of compound 1. The obtained crystals were sampled for analysis.

[0075] The powder X-ray diffraction spectrum of the obtained solid product was measured as shown in Figure 1. The powder X-ray diffraction pattern of the obtained crystal showed characteristic peaks at diffraction angles (2θ±0.20°) of 6.225°, 9.536°, 11.212°, 14.415°, 15.303°, 15.779°, 16.452°, 19.290°, 20.915°, 22.133°, 23.295°, 24.532°, 25.473°, 26.705°, 27.776°, 28.871°, 29.596°, and 30.353°. This crystalline form is defined as polymorph I of compound 1.

[0076] Example 1: Preparation of polymorph A of the sulfate of compound 1 In a 1 L round-bottom flask, 20 g of compound polymorph I obtained in Comparative Example 1 and 300 mL of an acetone / water mixture with an acetone / water (v / v) ratio of 95 / 5 were added. Then, under slow stirring, 1.1 equivalents of acetone sulfate solution (1.1 equivalents of concentrated sulfuric acid diluted 10-fold with acetone) were added dropwise to form a suspension. The suspension was stirred at 50°C for 1 hour, and then at 25°C for 18 hours. The suspension was filtered, and the filtered cake was vacuum-dried at 50°C for 18 hours. 24.4 g of yellow sulfate crystals were obtained. Ion chromatography analysis revealed that the molar ratio of compound 1 / sulfuric acid in the crystals was 1 / 1.0.

[0077] The obtained sulfate crystals of compound 1 were characterized by XRPD, and the powder X-ray diffraction pattern is shown in Figure 2, with diffraction angles of 7.439°, 10.519°, 12.329°, 13.503°, 14.825°, 15.723°, 17.430°, 18.334°, 19.700°, 20.048°, 21.302°, 24.099°, 24.567°, 25.551°, 27.096°, 27.933°, and 29.770°. The crystal had characteristic peaks at diffraction angles (2θ±0.20°), or further characteristic peaks at diffraction angles (2θ±0.20°) of 11.231°, 15.342°, 18.812°, 22.307°, 23.194°, 25.053°, 26.040°, 30.331°, 30.985°, 32.097°, 32.754°, 33.690°, 34.834°, and 35.833°. This crystal is defined as sulfate polymorph A. The analysis data of the XRPD pattern of sulfate polymorph A of compound 1 is shown in Table 1 below.

[0078] [Table 1]

[0079] The TGA pattern of the obtained polymorph A is shown in Figure 3. It was confirmed that sulfate polymorph A desolvates 6.6% of crystal water at 120°C, and it can be calculated that sulfate polymorph A contains two molecules of crystal water. The crystal is the dihydrate of sulfate polymorph A of compound 1.

[0080] The DSC pattern of the obtained polymorph A is shown in Figure 4. It can be confirmed that sulfate polymorph A begins to melt at 99°C, with a melting temperature of 127.67°C and a heat of fusion of 165.97 J / g.

[0081] Example 2 Preparation of polymorph B of the hydrochloride salt of compound 1 300 mg of polymorph I of the compound obtained in Comparative Example 1 and 7 mL of acetonitrile were added to a 40 mL vial. Then, 1.1 equivalents of hydrochloric acid acetonitrile solution (1.1 equivalents of concentrated hydrochloric acid diluted 10-fold with acetonitrile) were added dropwise under slow stirring to form a suspension. The suspension was stirred at 25°C for 72 hours. The suspension was separated by centrifugation, and the lower solid layer after centrifugation was vacuum-dried at 50°C for 0.5 hours. 330 mg of yellow hydrochloride crystals were obtained. Ion chromatography analysis revealed that the molar ratio of compound 1 / hydrochloric acid in the crystals was 1 / 1.1.

[0082] The obtained hydrochloride crystals of compound 1 were subjected to XRPD characterization, and the powder X-ray diffraction pattern is shown in Figure 5. Characteristic peaks were observed at diffraction angles (2θ±0.20°) of 4.648°, 8.214°, 8.689°, 9.174°, 11.177°, 13.774°, 16.284°, 17.289°, 18.752°, 20.376°, 23.015°, 24.732°, 25.508°, 25.797°, 26.813°, 29.698°, 32.638°, and 33.658°. This crystal is defined as polymorph B of the hydrochloride. The analysis data of the XRPD pattern of polymorph B of compound 1 is shown in Table 2 below.

[0083] [Table 2]

[0084] Example 3 Preparation of methanesulfonate polymorph B of compound 1 500 mg of compound polymorph I obtained in Comparative Example 1 and 10 mL of acetonitrile were added to a 40 mL vial. Then, 1.1 equivalents of methanesulfonic acid acetone solution (1.1 equivalents of methanesulfonic acid, diluted 10-fold with acetone) were added dropwise under slow stirring to form a suspension. The suspension was stirred at 50°C for 1 hour, and then at 25°C for 8 hours. The suspension was filtered, and the filtered cake was vacuum-dried at 50°C for 2 hours. 450 mg of yellow methanesulfonate crystals were obtained. By 1H-NMR analysis, the molar ratio of compound 1 / methanesulfonic acid in the crystals was 1 / 1.1.

[0085] The obtained methanesulfonate crystals of compound 1 were characterized by XRPD, and the powder X-ray diffraction pattern is shown in Figure 6. Characteristic peaks were observed at diffraction angles (2θ±0.20°) of 8.100°, 8.768°, 9.720°, 11.309°, 13.417°, 13.843°, 16.217°, 17.518°, 18.157°, 18.663°, 19.544°, 20.533°, 20.833°, 21.455°, 22.323°, 22.819°, 24.736°, and 26.954°. This crystal is defined as polymorph B of the mesylate. The analysis data of the XRPD pattern of polymorph B of compound 1 is shown in Table 3 below.

[0086] [Table 3]

[0087] Example 4 Preparation of polymorph A of the formate of compound 1 In a 5 mL vial, 100 mg of polymorph I of the compound obtained in Comparative Example 1 and 0.1 mL of formic acid were added, and the mixture was slowly stirred until compound 1 was completely dissolved. The solution was filtered, and 0.5 mL of deionized water was slowly added to the filtrate until the solid was completely dissolved. The solution was then filtered again, and the filtered cake was vacuum-dried at 30°C for 2 hours to obtain 80 mg of yellow formate crystals. Analysis of the 1H-NMR results showed that the molar ratio of compound 1 to formic acid in the crystals was 1 / 1.0.

[0088] The obtained formate crystals of compound 1 were characterized by XRPD, and the powder X-ray diffraction pattern is shown in Figure 7. The diffraction patterns are 5.880°, 9.276°, 9.632°, 11.681°, 12.460°, 14.096°, 14.459°, 14.756°, 15.088°, 17.186°, 17.621°, 18.084°, 18.564°, 19.496°, 19.986°, 20.740°, 21.288°, 21.775°, 22.367°, Characteristic peaks were observed at diffraction angles (2θ±0.20°) of 22.764°, 23.409°, 24.512°, 25.065°, 25.449°, 26.414°, 26.738°, 28.365°, 29.241°, 29.813°, 30.191°, 30.693°, 31.098°, 31.624°, 32.332°, 34.001°, 34.444°, 34.969°, 37.205°, and 37.654°. This crystal is defined as formate polymorph A. The analysis data of the XRPD pattern of formate polymorph A of compound 1 is shown in Table 4 below.

[0089] [Table 4]

[0090] Example 5 Preparation of polymorph A of the sulfate of compound 1 In a 500 mL round-bottom flask, 5 g of polymorph I of the compound obtained in Comparative Example 1 and 100 mL of an acetone / water mixture with an acetone / water (v / v) ratio of 95 / 5 were added. Then, 1.1 equivalents of acetone sulfate solution (1.1 equivalents of concentrated sulfuric acid diluted 10-fold with acetone) were added dropwise under slow stirring. 50 mg of sulfate polymorph A was added to the suspension as a seed crystal, and the suspension was stirred at 50°C for 1 hour, then transferred to 25°C and stirred for 24 hours. The suspension was filtered, and the filtered cake was vacuum-dried at 50°C for 18 hours. 6.1 g of highly crystalline yellow sulfate crystals were obtained. Ion chromatography analysis revealed that the molar ratio of compound 1 / sulfuric acid in the crystals was 1 / 1.0.

[0091] When the obtained sulfate crystals of compound 1 were characterized using XRPD, it was confirmed to be sulfate polymorph A.

[0092] Analysis revealed that the crystal was the dihydrate of polymorph A of the sulfate of compound 1.

[0093] Example 6 Preparation of sulfate polymorph A of compound 1 In a 5 mL vial, 100 mg of polymorph I of the compound obtained in Comparative Example 1 and 1 mL of ethanol were added. Then, under slow stirring, 1.1 equivalents of sulfuric acid-ethanol solution (1.1 equivalents of concentrated sulfuric acid diluted 10-fold with ethanol) was added dropwise to form a suspension. The suspension was stirred at 25°C for 48 hours. The suspension was centrifuged, and the lower solid layer was vacuum-dried at 50°C for 2 hours. 110 mg of yellow sulfate crystals were obtained. Ion chromatography analysis revealed that the molar ratio of compound to sulfuric acid in the crystals was 1 / 1.1.

[0094] When the obtained sulfate crystals of compound 1 were characterized using XRPD, it was confirmed to be sulfate polymorph A.

[0095] Analysis revealed that the crystal was the dihydrate of polymorph A of the sulfate of compound 1.

[0096] Example 7 Preparation of sulfate polymorph B of compound 1 In a 5 mL vial, 100 mg of polymorph I of the compound obtained in Comparative Example 1 and 1 mL of acetonitrile were added. Then, under slow stirring, 1.1 equivalents of acetonitrile sulfate solution (1.1 equivalents of concentrated sulfuric acid diluted 10-fold with acetonitrile) were added dropwise to form a suspension. The suspension was stirred at 25°C for 48 hours. The suspension was separated by centrifugation, and the lower solid layer after centrifugation was vacuum-dried at 50°C for 2 hours. 103 mg of yellow sulfate crystals were obtained. Ion chromatography analysis revealed that the molar ratio of compound to sulfuric acid in the crystals was 1 / 0.7.

[0097] The obtained sulfate crystals of compound 1 were characterized by XRPD, and the powder X-ray diffraction pattern is shown in Figure 8. The diffraction patterns are 7.133°, 7.913°, 8.298°, 8.638°, 10.471°, 10.784°, 11.633°, 12.279°, 13.093°, 14.346°, 15.016°, 15.799°, 16.267°, 17.671°, 18.578°, 19.316°, 19.691°, 2 Characteristic peaks were observed at diffraction angles (2θ±0.20°) of 0.710°, 21.656°, 21.995°, 22.552°, 23.353°, 23.784°, 24.296°, 24.589°, 25.363°, 26.292°, 28.403°, 29.149°, 30.146°, 30.922°, 31.751°, 35.260°, 38.358°, and 39.295°. This crystal is defined as sulfate polymorph B. The analysis data of the XRPD pattern of sulfate polymorph B of compound 1 is shown in Table 5 below.

[0098] [Table 5]

[0099] Analysis revealed that the crystal was the acetonitrile solvate of polymorph B of the sulfate of compound 1.

[0100] Example 8 Preparation of sulfate polymorph C of compound 1 500 mg of sulfate polymorph A, prepared according to Example 1, and 3 mL of acetonitrile were added to a 10 mL vial and suspended at 25°C for 3 days to form a slurry. The suspension was filtered, and the filtered cake was vacuum-dried at 40°C for 2 hours to obtain 278 mg of yellow sulfate crystals. Ion chromatography analysis revealed that the molar ratio of compound 1 / sulfuric acid in the crystals was 1 / 1.1.

[0101] The obtained sulfate crystals of compound 1 were characterized by XRPD, and the powder X-ray diffraction pattern is shown in Figure 9: 7.138°, 7.861°, 10.406°, 11.602°, 13.061°, 14.311°, 14.959°, 15.732°, 16.165°, 17.641°, 18.507°, 19.172°, 19.960°, Characteristic peaks were observed at diffraction angles (2θ±0.20°) of 20.637°, 21.926°, 22.481°, 23.292°, 23.689°, 24.262°, 24.525°, 25.216°, 26.247°, 28.351°, 29.149°, 30.089°, 30.844°, and 31.568°. This crystal is defined as sulfate polymorph C. The analysis data of the XRPD pattern of sulfate polymorph C of compound 1 is shown in Table 6 below.

[0102] [Table 6]

[0103] Analysis revealed that the crystals were the acetonitrile solvate of polymorph C of the sulfate of compound 1.

[0104] Example 9 Preparation of sulfate polymorph D of compound 1 50 mg of sulfate polymorph A, prepared according to Example 1, and 1 mL of DMF were added to a 5 mL vial, and the mixture was suspended at 25°C for 3 weeks to form a slurry. The suspension was filtered, and the filtered cake was vacuum-dried at 40°C for 2 hours to obtain 45 mg of yellow sulfate crystals. Ion chromatography analysis revealed that the molar ratio of compound 1 / sulfuric acid in the crystals was 1 / 1.0.

[0105] The obtained sulfate crystals of compound 1 were characterized by XRPD, and the powder X-ray diffraction pattern is shown in Figure 10: 6.424°, 8.272°, 10.796°, 12.922°, 13.458°, 13.920°, 15.220°, 15.856°, 16.467°, 16.814°, 17.786°, 19.201°, 19.680°, 19.901°, 20.302°, 20.867°, 21.570°, 22.068°. It exhibited characteristic peaks at diffraction angles (2θ±0.20°) of 22.863°, 23.436°, 24.264°, 24.850°, 25.330°, 25.633°, 26.355°, 27.190°, 27.923°, 28.650°, 29.742°, 30.510°, 31.462°, 31.752°, 32.544°, 32.811°, 34.607°, 35.751°, and 39.055°. This crystal is defined as sulfate polymorph D. The analysis data of the XRPD pattern of sulfate polymorph D of compound 1 is shown in Table 7 below.

[0106] [Table 7]

[0107] Analysis revealed that the crystal was the DMF solvate of polymorph D of the sulfate of compound 1.

[0108] Example 10 Preparation of sulfate polymorph E of compound 1 10 mg of sulfate polymorph A, prepared according to Example 1, and 0.8 mL of DMSO were added to a 10 mL vial and stirred slowly until completely dissolved. The solution was filtered, and 6 volumes of dichloromethane were slowly added to the filtrate until 100% solid was removed. The solution was then filtered again, and the filtrate cake was vacuum-dried at 40°C for 2 hours to obtain 8 mg of yellow sulfate crystals. Ion chromatography analysis revealed that the molar ratio of compound 1 / sulfuric acid in the crystals was 1 / 1.0.

[0109] The obtained sulfate crystals of compound 1 were characterized by XRPD, and the powder X-ray diffraction patterns are shown in Figure 11: 6.078°, 8.418°, 10.552°, 12.100°, 13.964°, 16.766°, 17.480°, 17.840°, 18.224°, 19.597°, 20.307°, 20.707°, 21.874°, 22.107°, 22. Characteristic peaks were observed at diffraction angles (2θ±0.20°) of 871°, 23.944°, 24.268°, 25.244°, 25.687°, 26.163°, 26.614°, 27.357°, 28.054°, 29.727°, 31.174°, 31.965°, 32.508°, 33.872°, 34.827°, and 36.183°. This crystal is defined as sulfate polymorph E. The analysis data of the XRPD pattern of sulfate polymorph E of compound 1 is shown in Table 8 below.

[0110] [Table 8]

[0111] Analysis revealed that the crystal was the DMSO solvate of polymorph E of the sulfate of compound 1.

[0112] Example 11 Preparation of polymorph F of the sulfate of compound 1 10 mg of sulfate polymorph A, prepared according to Example 1, and 0.8 mL of DMSO were added to a 10 mL vial and stirred slowly until completely dissolved. The solution was filtered, and 6 volumes of anisole were slowly added to the filtrate until 100% solid was removed. The solution was then filtered again, and the filtrate cake was vacuum-dried at 40°C for 2 hours to obtain 9 mg of yellow sulfate crystals. Ion chromatography analysis revealed that the molar ratio of compound 1 / sulfuric acid in the crystals was 1 / 1.0.

[0113] The obtained sulfate crystals of compound 1 were characterized by XRPD, and the powder X-ray diffraction pattern is shown in Figure 12. Characteristic peaks were observed at diffraction angles (2θ±0.20°) of 8.355°, 13.896°, 16.727°, 17.387°, 17.777°, 20.225°, 20.621°, 21.807°, 22.775°, 24.194°, 25.196°, 25.991°, 27.210°, 27.983°, 29.643°, 31.083°, 31.926°, 33.803°, 34.742°, 35.763°, and 38.545°. This crystal is defined as polymorph F of the sulfate. Table 9 below shows the analysis data of the XRPD pattern of polymorph F of the sulfate of compound 1.

[0114] [Table 9]

[0115] Analysis revealed that the crystals were the DMSO solvate of polymorph F of the sulfate of compound 1.

[0116] Example 12 Preparation of polymorph G of the sulfate of compound 1 10 mg of polymorph A of sulfate, prepared according to Example 1, and 0.8 mL of DMSO were added to a 10 mL vial and stirred slowly until completely dissolved. The solution was filtered, and 6 volumes of deionized water were slowly added to the filtrate until 10% solid was removed. The solution was filtered, and the filtrate cake was vacuum-dried at 40°C for 2 hours to obtain 9 mg of yellow sulfate crystals. Ion chromatography analysis revealed that the molar ratio of compound 1 / sulfuric acid in the crystals was 1 / 1.0.

[0117] The obtained sulfate crystals of compound 1 were characterized by XRPD, and the powder X-ray diffraction pattern is shown in Figure 13: 4.876°, 8.895°, 9.306°, 9.751°, 11.140°, 11.672°, 12.290°, 15.384°, 15.867°, 16.336°, 16.752°, 17.464°, 18.587°, 19.242°, Characteristic peaks were observed at diffraction angles (2θ±0.20°) of 19.556°, 19.977°, 22.805°, 23.488°, 24.619°, 25.158°, 25.449°, 26.020°, 27.471°, 27.650°, 28.598°, 29.236°, 31.558°, 35.224°, and 39.656°. This crystal is defined as sulfate polymorph G. The analysis data of the XRPD pattern of sulfate polymorph G of compound 1 is shown in Table 10 below.

[0118] [Table 10]

[0119] Analysis revealed that the crystal was the DMSO solvate of polymorph G of compound 1 sulfate.

[0120] The sulfate of compound 1 can be obtained in various crystalline forms (polymorphs A, B, C, D, E, F, and G: where polymorph A is the hydrate, polymorphs B and C are acetonitrile solvates, polymorph D is DMF solvate, and polymorphs E, F, and G are DMSO solvates). Polymorphs C, D, E, F, and G are all prepared by slurring polymorph A as a starting material in the corresponding solvent, or by adding a poor solvent. However, the inventors found that polymorphs B, C, D, E, F, and G of the sulfate of compound 1 are each converted to polymorph A after being left under atmospheric conditions for one week. Therefore, polymorph A of the sulfate of compound 1 is a favorable crystalline form among many sulfate crystalline forms and has better storage stability. Subsequent experiments were conducted on polymorph A of the sulfate of compound 1.

[0121] Example 13: Stability evaluation of polymorph I of compound 1 and its sulfate polymorph A. Polymorph I of Compound 1 obtained in Comparative Example 1 and polymorph A of the sulfate obtained in Example 1 were each placed in an airtight environment and stored for 1 week and 2 weeks at 2-8°C, 25°C, and 60°C, respectively. After storage, samples were taken and their chemical purity was examined by HPLC and their crystalline morphology by XRPD. The results are shown in Table 11.

[0122] [Table 11]

[0123] Characterization of the crystal structure revealed that polymorph I of compound 1 did not change significantly after two weeks of storage at low temperatures (2-8°C) or room temperature (25°C). However, when stored at high temperatures (60°C) for two weeks, the crystal structure changed, and the purity of the product decreased to some extent. This indicates the need to improve the stability of the substance under the aforementioned conditions, particularly at high temperatures.

[0124] Characterization of the crystal structure revealed that polymorph A of compound 1's sulfate salt did not change significantly after storage for one and two weeks at 2-8°C, 25°C, and 60°C, respectively, and that the chemical purity of polymorph A did not decrease significantly. This indicates that compound 1 can remain stable under different temperature conditions for at least two weeks after forming sulfate crystals.

[0125] Therefore, it can be concluded that compound 1 exhibits good physical and chemical stability after the formation of sulfate crystals, thereby significantly improving the structural stability of the original compound 1, which is useful for the stable storage of pharmaceuticals prepared from this compound and its salt forms.

[0126] Example 14 Evaluation of temperature and humidity stability of sulfate polymorph A The sulfate polymorph A obtained in Example 1 was left in an open environment under conditions of 25°C / 92.5%RH, 25°C / 60%RH, and 40°C / 75%RH, respectively, to test its temperature and humidity stability. After storing the samples for 1 week and 4 weeks, the purity of the samples was tested by HPLC, and the crystal morphology of the samples was examined by XRPD. The results are shown in Table 12.

[0127] The XRPD results for sulfate polymorph A after storage at 25°C / 92.5%RH, 25°C / 60%RH, and 40°C / 75%RH for 1 week and 4 weeks are shown in Figures 14 and 15.

[0128] [Table 12]

[0129] As shown in Table 12, Figure 14, and Figure 15, polymorph A of the sulfate of compound 1 exhibits high structural stability and can be stored stably under different humidity and temperature conditions.

[0130] Example 15: Water adsorption-desorption experiment using sulfate polymorph A The moisture adsorption-desorption characteristics of sulfate polymorph A obtained according to Example 1 were investigated by DVS. 16 mg of sulfate polymorph A was placed in a metal container and placed in an Intrinsic DVS instrument. A periodic humidity gradient of 40-95-0-40%RH was set at 25°C, and the sample was subjected to two consecutive adsorption-desorption cycles. There was a 10%RH difference between each step. The following equilibrium criteria were used at each stage: mass change dm / dt < 0.002% over 5 minutes, and minimum and maximum equilibrium times at each stage were 60 minutes and 360 minutes, respectively. The results are shown in Table 13 and Figure 16.

[0131] [Table 13]

[0132] The results of the hygroscopicity test showed that under conditions of 25°C, sulfate polymorph A adsorbed 1.2% of moisture in the range of 0%RH to 95%RH, indicating that sulfate polymorph A is slightly hygroscopic. This suggests that when the compound exists in the form of sulfate polymorph A, it can remain stable during the manufacture and storage of pharmaceuticals without strict humidity control. This reduces the requirements for pharmaceutical manufacturing processes and storage conditions.

[0133] Example 16 Solubility Experiment Polymorph I of Compound 1 obtained in Comparative Example 1 and sulfate polymorph A obtained in Example 1 were weighed into sample vials, and 1 mL each of pH=1.2 hydrochloric acid buffer, pH=4.5 acetate buffer, pH=6.8 phosphate buffer, and water were added. The suspensions were magnetically stirred at 25°C (1000 r / min). After 24 hours, samples were taken, centrifuged, and the supernatant was collected. Solubility was measured by HPLC. The results of the solubility evaluation of Compound 1 and its sulfate polymorph A are summarized in Table 14.

[0134] [Table 14]

[0135] The table above shows that the solubility of sulfate polymorph A in acetate buffer at pH=4.5, phosphate buffer at pH=6.8, and water can be significantly increased, which improves the drugability of the compound and helps increase the in vivo drug concentration, thereby promoting drug absorption. [Industrial applicability]

[0136] This invention provides salts of MNK inhibitors, particularly their sulfates and crystalline polymorphs, along with methods for their preparation. The prepared salts of the compounds can be applied as MNK inhibitors with potential therapeutic effects in the treatment of various diseases, including proliferative disorders, inflammatory diseases, and neurodegenerative diseases. Therefore, this invention is suitable for industrial use.

[0137] It should be noted that this application is not limited to the embodiments described above. The embodiments described above are merely illustrative, and any embodiment that has a configuration substantially consistent with the technical idea and achieves similar effects within the scope of the technical solutions of this application is included in the technical scope of this application. Furthermore, any modifications to the embodiments that a person skilled in the art could conceive of, as long as they do not depart from the spirit of this application, as well as other forms constructed by combining some of the components of the embodiments, are also included in the scope of this application.

Claims

1. A crystalline sulfate of the compound of chemical formula 1, 【Chemistry 1】 The crystal is characterized in that it has the crystal structure of polymorph A, and the powder X-ray diffraction pattern of polymorph A shows characteristic peaks at 2θ values ​​of 7.44±0.2°, 15.72±0.2°, 20.05±0.2°, 24.10±0.2°, 24.57±0.2°, 25.55±0.2°, and 27.10±0.2°.

2. The crystal according to claim 1, characterized in that the powder X-ray diffraction pattern of polymorph A further shows one or more characteristic peaks at 2θ values ​​selected from 12.33±0.2°, 13.50±0.2°, 14.83±0.2°, 18.33±0.2°, 19.70±0.2°, 21.30±0.2°, and 29.77±0.2°.

3. The crystal according to claim 1, characterized in that the powder X-ray diffraction pattern of polymorph A shows characteristic peaks at 2θ values ​​of 7.44±0.2°, 10.52±0.2°, 12.33±0.2°, 13.50±0.2°, 14.83±0.2°, 15.72±0.2°, 17.43±0.2°, 18.33±0.2°, 19.70±0.2°, 20.05±0.2°, 21.30±0.2°, 24.10±0.2°, 24.57±0.2°, 25.55±0.2°, 27.10±0.2°, 27.93±0.2°, and 29.77±0.2°.

4. The powder X-ray diffraction patterns of the above polymorph A are 7.44±0.2°, 10.52±0.2°, 11.23±0.2°, 12.33±0.2°, 13.50±0.2°, 14.83±0.2°, 15.34±0.2°, 15.72±0.2°, 17.43±0.2°, 18.33±0.2°, 18.81±0.2°, 19.70±0.2°, 20.05±0.2°, 21.30±0.2°, 22.31±0.2°, 23.20±0.2°, and 24.1 The crystal according to claim 1, characterized by exhibiting characteristic peaks at 2θ values ​​of 0±0.2°, 24.57±0.2°, 25.05±0.2°, 25.55±0.2°, 26.04±0.2°, 27.10±0.2°, 27.93±0.2°, 29.77±0.2°, 30.33±0.2°, 30.99±0.2°, 32.10±0.2°, 32.75±0.2°, 33.69±0.2°, 34.83±0.2°, and 35.83±0.2°.

5. The crystal according to any one of claims 1 to 4, characterized in that the sulfate crystals are hydrated.

6. A method for preparing crystals according to any one of claims 1 to 4, A method characterized by mixing the compound of chemical formula 1 with a solvent selected from water, alcohol, ketone, or a mixture thereof, adding a sulfuric acid solution to form a suspension, stirring the suspension, and then separating it to obtain the crystals.

7. The method according to claim 6, characterized in that the solvent is a mixture of water and a ketone.

8. The method according to claim 6, characterized in that the solvent is a mixture of water and acetone.

9. The method according to claim 6, characterized by adding 1.1 to 2.1 equivalents of sulfuric acid solution.

10. A method for preparing crystals according to any one of claims 1 to 4, A method characterized by: mixing the compound of chemical formula 1 with a solvent selected from water, alcohol, ketone, or a mixture thereof; adding a sulfuric acid solution to form a suspension; adding polymorph A of the sulfate salt of the compound of chemical formula 1 as a seed crystal to the suspension; and stirring the suspension and then separating it to obtain the crystals.

11. The method according to claim 10, characterized in that the solvent is selected from water, methanol, ethanol, n-propanol, isopropanol, 1-butanol, tert-butanol, acetone, butanone, 2-pentanone, or a mixture thereof.

12. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

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