Crystalline forms of imidazopyrazine derivatives, their preparation methods and applications

Abstract

The present invention relates to the field of pharmaceutical technology, and more particularly to a crystalline form of an imidazopyrazine derivative represented by the following formula (I), as well as its preparation method and application. JPEG2025534133000014.jpg5049

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical technology, particularly to the crystalline form of imidazopyrazine derivatives and their preparation methods and applications. [Background technology]

[0002] The B-cell receptor (BCR) is a transmembrane receptor located on the surface of B lymphocytes, and BCR signaling is crucial for normal B cell development and acquired immunity. Abnormal BCR signaling can lead to impaired B cell activation and / or the formation of pathogenic autoantibodies, resulting in various B cell malignancies, autoimmune diseases, and inflammatory diseases. B cell malignancies include chronic lymphocytic leukemia, small lymphocytic lymphoma, diffuse large B cell lymphoma, follicular lymphoma, multiple myeloma, marginal zone lymphoma, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Autoimmune and inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis.

[0003] Bruton tyrosine kinase (BTK), a member of the TEC family of non-receptor tyrosine kinases, plays a key role in the activation of the BCR signaling pathway and is a key regulator of early B cell formation and the activation and survival of mature B cells. BTK plays an important role in regulating B cell proliferation and apoptosis. Therefore, inhibition of BTK can be used to treat tumors, such as B cell lymphoma and leukemia, as well as immune and inflammatory diseases.

[0004] Prior art WO2020063012A1 discloses an imidazopyrazine derivative that is a BTK inhibitor, with the chemical name 4-(8-amino-3-(4-(2-morpholylacetamido)bicyclo[2.2.1]hept-1-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (hereinafter referred to as compound of formula (I)), whose structural formula is as follows:

[0005] [ka]

[0006] The prior art discloses a preparation method thereof, but does not disclose any information regarding the crystalline form. In the research and development process of drugs, the study of crystalline form is very important, and different substance forms have significant differences in terms of physicochemical properties, biological activity, bioavailability, formulation, production, etc. The present inventors have conducted polymorphic research on this compound in order to obtain an excellent crystalline form that is safe, efficient, quality-controllable, stable, and advantageous for pharmaceutical use. Summary of the Invention

[0007] To achieve the above objectives, the present invention provides the following technical solutions:

[0008] The present invention provides crystalline Form I of compound of formula (I), which has characteristic peaks at 11.4±0.2°, 13.6±0.2°, 15.3±0.2°, 16.1±0.2°, 18.3±0.2°, and 20.7±0.2° in powder X-ray diffraction using Cu-Kα radiation at 2θ angles.

[0009] [ka]

[0010] In some embodiments, the crystalline form I further has at least one characteristic peak at 12.3±0.2°, 19.4±0.2°, 19.9±0.2°, 21.2±0.2°, and 24.9±0.2° in powder X-ray diffraction analysis using Cu-Kα radiation at 2θ angles.

[0011] The present invention further provides a process for preparing crystalline Form I of compound of formula (I), which comprises the steps of:

[0012] The compound of formula (I) is dissolved in diphenyl ether at a temperature of 240°C to 260°C, and the temperature is lowered to obtain Crystal Form I.

[0013] In some embodiments, the dose of the diphenyl ether is 1 to 35 times (eg, 5 to 35 times) the volume of the compound of formula (I).

[0014] The present invention further provides crystalline Form II of compound of formula (I), which has characteristic peaks at 7.8±0.2°, 10.6±0.2°, 10.9±0.2°, 14.7±0.2°, 15.1±0.2° and 19.7±0.2° in powder X-ray diffraction using Cu-Kα radiation at 2θ angles.

[0015] [ka]

[0016] In some embodiments, the crystalline form II further has at least one characteristic peak at 12.7±0.2°, 17.0±0.2°, 18.0±0.2°, and 21.0±0.2° in powder X-ray diffraction analysis using Cu-Kα radiation at 2θ angles.

[0017] In some embodiments, the crystalline form II further has at least one characteristic peak at 23.0±0.2°, 23.6±0.2°, and 25.6±0.2° in powder X-ray diffraction measured at 2θ angles using Cu-Kα radiation.

[0018] The present invention further provides a process for preparing crystalline Form II of compound of formula (I), which comprises the steps of:

[0019] The compound of formula (I) is placed in a solvent and reacted until reflux to obtain crystalline form II of the compound of formula (I), wherein the solvent is selected from one or more of a benzene solvent, an ether solvent, an ester solvent, and water.

[0020] In some embodiments, a method for preparing crystalline Form II of the compound of Formula (I) comprises the steps of: The compound of formula (I) is placed in an alcoholic solvent and reacted at a temperature ranging from 45°C to reflux to obtain crystalline form II of the compound of formula (I).

[0021] In some embodiments, in the method for preparing Crystalline Form II, the alcohol solvent is selected from at least one of methanol, ethanol, isopropanol, and n-butanol; the benzene solvent is selected from toluene and / or xylene; the ether solvent is selected from tetrahydrofuran and / or 2-methyltetrahydrofuran; and the ester solvent is selected from ethyl acetate and / or isopropyl acetate.

[0022] In some embodiments, in the above method for preparing Crystalline Form II, the solvent is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, aqueous methanol, aqueous ethanol, and aqueous isopropanol, and the alcoholic solvent is selected from one or more of methanol, ethanol, isopropanol, and n-butanol.

[0023] In some embodiments, in the method for preparing crystalline Form II, the solvent is selected from toluene, 2-methyltetrahydrofuran, aqueous methanol, and ethyl acetate, and the alcoholic solvent is selected from methanol and ethanol.

[0024] In some embodiments, the above-mentioned aqueous methanol solution, aqueous ethanol solution, and aqueous isopropanol solution refer to mixed solvents in which methanol, ethanol, and isopropanol are mixed with water, respectively.

[0025] In some embodiments, the volume ratio of alcohol to water in the aqueous methanol solution, aqueous ethanol solution, or aqueous isopropanol solution is greater than 1, preferably greater than 1 and less than 100, more preferably greater than 4 and less than 100, and most preferably greater than 30 and less than 100.

[0026] In some embodiments, the amount of the solvent is 1 to 35 times (eg, 5 to 35 times) the volume of the compound of formula (I).

[0027] In some examples, the reflux temperature refers to the boiling point temperature of the solvent used.

[0028] In some embodiments, the range of 45°C to reflux temperature may be 45°C to 120°C, or 50°C to 120°C, or 45°C to 70°C, or 45°C to 85°C.

[0029] In some embodiments, the alcoholic solvent is selected from one or more of methanol, ethanol, isopropanol, and n-butanol.

[0030] In some embodiments, the alcoholic solvent is selected from methanol.

[0031] In some embodiments, the amount of the alcoholic solvent is 1 to 30 times the volume of the compound of formula (I).

[0032] The present invention further provides crystalline Form III of compound of formula (I), which has characteristic peaks at 5.9±0.2°, 10.4±0.2°, 11.8±0.2°, 15.7±0.2° and 18.8±0.2° in powder X-ray diffraction using Cu-Kα radiation at 2θ angles.

[0033] [ka]

[0034] In some embodiments, the crystalline form III further has at least one characteristic peak at 17.5±0.2°, 20.1±0.2°, and 21.4±0.2° in powder X-ray diffraction measured at 2θ angles using Cu-Kα radiation.

[0035] The present invention further provides a process for preparing crystalline Form III of compound of formula (I), which comprises the steps of: The compound of formula (I) is placed in ethyl acetate and slurried at room temperature for 10 to 36 hours to obtain crystalline Form III.

[0036] The present invention further provides a pharmaceutical composition comprising any one of the above crystalline Form I, any one of the above crystalline Form II, or any one of the above crystalline Form III, and a pharmaceutically acceptable pharmaceutical carrier.

[0037] The present invention further provides a pharmaceutical formulation comprising any one of the above crystalline Form I, any one of the above crystalline Form II, or any one of the above crystalline Form III, and a pharmaceutically acceptable pharmaceutical carrier.

[0038] In embodiments of the present invention, the pharmaceutical compositions and pharmaceutical preparations may contain one or more pharmaceutical carriers. The pharmaceutical carrier may be one or more solid or liquid fillers suitable for human use. The pharmaceutical carrier preferably has sufficient purity and low toxicity, is compatible with the compounds provided by the present invention, and does not significantly reduce the efficacy of the compounds. For example, the pharmaceutical carrier may be a filler, adhesive, disintegrant, lubricant, aqueous or non-aqueous solvent, etc.

[0039] The pharmaceutical preparations according to the present invention can be prepared into any pharmaceutically acceptable dosage form, and a therapeutically effective amount of the crystalline Form I, Form II, or Form III of the compound of formula (I) is administered to a patient or examinee in need of such treatment by any suitable administration route, such as oral, parenteral, rectal, or pulmonary administration. For oral administration, the preparations can be prepared into tablets, capsules, pills, granules, etc. For parenteral administration, the preparations can be prepared into injection solutions, sterile powders for injection, etc.

[0040] The present invention further provides a use of any one of the above crystalline Form I, any one of the above crystalline Form II, any one of the above crystalline Form III, the pharmaceutical composition, or the pharmaceutical formulation in the preparation of a medicament for the prevention and / or treatment of B-cell malignancies, autoimmune diseases, and inflammatory diseases.

[0041] Details of the invention The term "room temperature" as used herein refers to the room temperature, which is usually 10°C to 30°C, or may be 15°C to 25°C.

[0042] The term "double volume" as used herein refers to the volume (mL) of a solvent required to dissolve 1 g of a substance. For example, if 20 mL of a solvent is required to dissolve 1 g of the compound of formula (I), it is referred to as 20-fold volume.

[0043] The "therapeutically effective amount" according to the present invention refers to the amount of crystalline Forms I, II, and III of the compound of formula (I) in the composition or pharmaceutical formulation, which, when administered to a patient, is capable of at least alleviating the symptoms of the patient's disease. The actual amount, including the "therapeutically effective amount," will vary depending on several factors, including, but not limited to, the specific disease being treated, the severity of the disease, the patient's physical condition and health, and the route of administration. A skilled physician can easily determine the appropriate amount using methods known in the medical field.

[0044] Beneficial Effects of the Invention Research has shown that the crystalline forms I, II, and III provided by the present invention have significantly improved solubility compared with amorphous forms, which can promote the absorption of drugs into the body and increase their bioavailability, thereby enhancing the efficacy of the drugs.The higher solubility allows for a reduction in dosage while maintaining therapeutic efficacy, thereby reducing drug side effects and improving safety.At the same time, the crystalline forms I, II, and III have excellent pharmacokinetic properties.

[0045] The present invention further demonstrates that crystalline Forms I and II have better stability under influential conditions, and can avoid the effects of unapproved or harsh conditions such as high temperature, high humidity, and light exposure due to seasonal variations, climatic differences, or weather factors that occur during the production, transportation, and storage of the drug, thereby ensuring the therapeutic efficacy and safety of the drug.

[0046] The present invention further demonstrates that crystalline Form II has relatively low hygroscopicity, which can overcome the drawbacks of highly hygroscopic drug substances, such as the difficulty in determining the content of drug substance components due to weight change caused by moisture adsorption, the tendency for moisture-absorption aggregation to occur, which affects the particle size distribution of samples and the uniformity of the drug substance in the formulation process, and further affects the dissolution and bioavailability of the drug substance, and the high hygroscopic drug substance also imposes high requirements on storage conditions, packaging and quality control, which increases production costs.

[0047] The present invention further demonstrates that crystalline Form II has good long-term stability, which is advantageous for drug storage. [Brief explanation of the drawings]

[0048] [Figure 1] 1 is an amorphous X-ray powder diffraction (XRPD) pattern of compound of formula (I). [Figure 2] 1 is a differential scanning calorimetry (DSC) pattern of an amorphous form of compound of formula (I). [Figure 3] 1 is a powder X-ray diffraction (XRPD) pattern of crystalline Form II of compound of formula (I). [Figure 4] 1 is a differential scanning calorimetry (DSC) pattern of crystalline Form II of compound of formula (I). [Figure 5] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline Form I of compound of formula (I). [Figure 6] 1 is a differential scanning calorimetry (DSC) pattern of crystalline Form I of compound of formula (I). [Figure 7] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline Form III of compound of formula (I). [Figure 8] 1 is a differential scanning calorimetry (DSC) pattern of crystalline Form III of compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0049] The above content of the present invention will be described in more detail below with reference to specific embodiments, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology realized based on the above content of the present invention belongs to the scope of the present invention.

[0050] The compound of formula (I) used in the following examples was prepared by the method described in WO2020063012A1, and upon testing, the compound was found to be amorphous, with an XRPD analysis shown in Figure 1 and a differential scanning calorimetry (DSC) pattern shown in Figure 2.

[0051] Example 1 Preparation of Crystalline Form II of Compound of Formula (I)

[0052] 180 g of the compound of formula (I) was dispersed in 270 mL of methanol, heated to 50° C. and stirred, allowed to cool to room temperature, filtered by suction, and dried at 50° C. to obtain crystalline form II.

[0053] XRPD analysis using Cu-Kα radiation was as shown in FIG.

[0054] The melting temperature of crystalline Form II was measured by differential scanning calorimetry to be about 235°C to 239°C, as shown in Figure 4.

[0055] Example 2 Preparation of Crystalline Form II of Compound of Formula (I)

[0056] 10 mL of 2-methyltetrahydrofuran was added to a recovery flask and heated to reflux. 0.96 g of the compound of formula (I) was then added. The compound gradually dissolved and a solid precipitated. Crystalline Form II was obtained by suction filtration. When Cu-Kα radiation was used, the powder X-ray diffraction pattern was essentially as shown in Figure 3.

[0057] Example 3 Preparation of Crystalline Form II of Compound of Formula (I)

[0058] 10 mL of toluene was added to a recovery flask and heated to reflux. 0.3 g of the compound of formula (I) was then added. The toluene gradually dissolved and a solid precipitated. Crystalline Form II was obtained by suction filtration. When Cu-Kα radiation was used, the powder X-ray diffraction pattern was essentially as shown in Figure 3.

[0059] Example 4 Preparation of Crystalline Form II of Compound of Formula (I)

[0060] 10 mL of ethyl acetate was added to a recovery flask and heated to reflux. 0.4 g of the compound of formula (I) was then added. The compound gradually dissolved and a solid precipitated. Crystalline Form II was obtained by suction filtration. When Cu-Kα radiation was used, the powder X-ray diffraction pattern was essentially as shown in Figure 3.

[0061] Example 5 Preparation of Crystalline Form II of Compound of Formula (I)

[0062] 10 mL of ethanol was added to a recovery flask and heated to reflux. 0.8 g of the compound of formula (I) was then added. The compound gradually dissolved and a solid precipitated. Crystalline Form II was obtained by suction filtration. When Cu-Kα radiation was used, the powder X-ray diffraction pattern was essentially as shown in Figure 3.

[0063] Example 6 Preparation of Crystalline Form II of Compound of Formula (I)

[0064] 15 mL of methanol and 10 mL of water were added to a recovery flask and heated to reflux. 1.5 g of compound of formula (I) was then added, and the mixture gradually dissolved, resulting in the precipitation of a solid. Crystalline Form II was obtained by suction filtration. Using Cu-Kα radiation, the powder X-ray diffraction pattern was essentially as shown in Figure 3.

[0065] Example 7 Preparation of Crystalline Form I of Compound of Formula (I)

[0066] 15 mL of diphenyl ether was added to a recovery flask and heated to 250°C. 2.5 g of the compound of formula (I) was then added and gradually dissolved. During the natural cooling process, a solid precipitated. The solution was filtered by suction at 30°C to obtain crystalline Form I.

[0067] XRPD analysis using Cu-Kα radiation was as shown in FIG.

[0068] The melting temperature of crystalline form I was measured by differential scanning calorimetry to be about 258°C to 260°C, as shown in Figure 6.

[0069] Example 8 Preparation of Crystalline Form III of Compound of Formula (I)

[0070] 10 g of the compound of formula (I) was dispersed in 100 mL of ethyl acetate, slurried at room temperature for about 16 hours, filtered by suction, and dried by blowing air at 50° C. to obtain crystalline Form III.

[0071] XRPD analysis using Cu-Kα radiation was as shown in FIG.

[0072] The melting temperature of crystalline Form III was measured by differential scanning calorimetry to be about 134°C to 141°C, as shown in Figure 8.

[0073] The present invention can be better understood by the following experimental examples. However, it will be readily understood by those skilled in the art that the contents described in the experimental examples are merely for the purpose of illustrating the present invention and should not, and do not, limit the present invention as specifically described in the claims.

[0074] Experimental Example 1: Solubility Test of Crystalline Forms I, II, III and Compound of Formula (I) in pH 4.5 Acetate Buffer

[0075] Crystalline forms I, II, III and compound of formula (I) were weighed out in appropriate amounts, placed in 15 mL centrifuge tubes, and each centrifuge tube was added with pH 4.5 acetate buffer to prepare saturated solutions, which were then sealed and placed in a water bath thermostatic oscillator, shaken at 37 ℃ and 200 rpm for 24 hours, centrifuged, and the supernatant was taken and diluted to the appropriate number of times to determine the concentration.The detection basis was the 2020 edition of the Chinese Pharmacopoeia, and the results were as shown in Table 1.

[0076] Table 1. Solubility of crystalline forms I, II, III and compound of formula (I) in pH 4.5 acetate buffer

[0077] [Table 1]

[0078] As can be seen from the results, compared to the amorphous form, crystalline forms I, II, and III all had higher solubility in pH 4.5 acetate buffer.

[0079] Experimental Example 2: Pharmacokinetic evaluation test of crystalline forms I, II, and III in rats

[0080] Animals: SD male rats Animal administration and sample collection: Form I, Form II, and Form III were all dissolved in a 20% PEG400 + 80% (20% Captisol in 0.5% MC) formulation to prepare suspensions. Each formulation was intragastrically administered to SD rats at a dose of 100 mg / kg. Blood samples were taken at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 48 h, 72 h, and 96 h.

[0081] The day before dosing, a jugular catheter was inserted into the animals, and approximately 300 μL of blood was collected from the jugular vein after dosing. The collected blood was then placed in an anticoagulant tube containing EDTA-K2. Plasma samples were obtained by centrifugation at 8000 rpm for 10 min at 4°C. Plasma was prepared within 30 min of blood collection. Plasma was stored in a -80°C freezer prior to testing.

[0082] How to analyze the sample: Form I and Form III: Remove the sample to be tested from the -80°C freezer, allow it to thaw at room temperature, and then swirl for 5 minutes. 20 μL of the 20-fold diluted plasma sample was accurately aspirated into a 1.5 mL centrifuge tube, and 300 μL of 10 ng / mL internal standard working solution was added. Mix thoroughly, swirl for 5 minutes, and then centrifuge at 12,000 rpm for 5 minutes. 50 μL of the supernatant was precisely aspirated into a 96-well plate containing 150 μL of water per well, and mixed uniformly by swirling for 5 minutes before carrying out LC-MS / MS analysis.

[0083] Crystalline Form II: The samples to be tested were removed from the -80°C freezer, allowed to thaw at room temperature, and then swirled for 5 minutes. 2 μL of the plasma sample was accurately aspirated into a 1.5 mL centrifuge tube, and 28 μL of blank plasma was added to the 1.5 mL centrifuge tube. 450 μL of a 100 ng / mL internal standard working solution (tolbutamide in acetonitrile) was added and mixed uniformly. After swirling for 5 minutes, the tubes were centrifuged at 12,000 rpm for 5 minutes. 50 μL of the supernatant was accurately aspirated into a 96-well plate containing 150 μL of water per well, swirled for 5 minutes to mix uniformly, and then used for LC-MS / MS analysis.

[0084] Data processing methods: The concentrations of the test substances were determined using the results output by Analyst 1.7.1 from AB. Microsoft Excel was used to calculate parameters such as the mean, standard deviation, and coefficient of variation, and PK parameters were calculated using Pharsight Phoenix 8.2 software NCA (T max is the median).

[0085] The results are shown in Table 2.

[0086] Table 2. PK parameters of crystalline forms I, II, and III in SD rats (po: 100 mg / kg, Mean, male, n=3)

[0087] [Table 2]

[0088] As can be seen from Table 2, all of crystalline forms I, II, and III had excellent pharmacokinetic properties.

[0089] Experimental example 3: Stability evaluation with influencing factors Appropriate amounts of crystalline Forms I, II, III and compound of formula (I) were taken and placed bare under conditions of 60°C, RH 92.5%, and RH 75% with light irradiation, respectively. After 30 days, samples were taken and the purity and changes in XRPD of the samples were examined. The detection basis was the 2020 edition of the Chinese Pharmacopoeia. The results are shown in Table 3.

[0090] Table 3. 30-day test results of influencing factors of crystalline forms I, II, III and compound of formula (I)

[0091] [Table 3]

[0092] As can be seen from Table 3, the purity of crystalline forms I and II decreased by 0.5% only under light irradiation. After 30 days under all influencing factor conditions, the measured XRPD of crystalline form I was essentially as shown in Figure 5, and the measured XRPD of crystalline form II was essentially as shown in Figure 3, indicating that the crystalline form remained unchanged. The purity of crystalline form III decreased by 11% under light irradiation conditions, and by 4.2% under the high temperature condition of 60°C. The purity of compound of formula (I) decreased by 11.5% under light irradiation conditions. It has been found that crystalline forms I and II of the present invention have higher stability than amorphous forms and are advantageous for pharmaceutical use.

[0093] Experimental Example 4: Long-term stability test

[0094] An appropriate amount of crystalline Form II was taken and packaged in a low-density polyethylene bag and an aluminum foil bag. The bag was then placed under conditions of 25°C / 60%RH (relative humidity) and 30°C / 65%RH (relative humidity). Sampling was performed at 1M, 2M, 3M, 6M, 9M, 12M, 18M, and 40°C / 75%RH (relative humidity) at 1M, 2M, 3M, and 6M. The changes in properties, total impurities, content, moisture, and crystalline form (3M, 6M, 12M) were observed and compared with the results for day 0. The results are shown in Table 4.

[0095] Table 4 Long-term stability test results

[0096] [Table 4]

[0097] Results analysis: Form II was stored at 40°C / 75%RH for 6 months, and at 25°C / 60%RH and 30°C / 65%RH for 18 months. The properties, total impurities, content, and moisture content did not show any significant changes. The XRPD data were basically as shown in Figure 3, indicating that Form II has good stability.

[0098] Experimental Example 5: Hygroscopicity test

[0099] The experimental procedures were in accordance with the drug hygroscopicity test guidelines of the 2020 Chinese Pharmacopoeia. 1. Take a dry stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) and place it in a suitable thermostatic oven (saturated ammonium chloride solution placed at the bottom) at 25°C ± 1°C on the day before the test. After 24 hours, take it out and accurately weigh its weight m1.

[0100] 2. Take an appropriate amount of crystalline Form II and place it in the weighing bottle. The thickness is usually about 1 mm. Accurately measure the weight (m2). 3. The weighing bottle was opened and placed with the lid under the above constant temperature and humidity conditions for 24 hours.

[0101] 4. The lid of the weighing bottle was securely closed and the weight (m3) was accurately measured. Weight increase percentage=100%×(m3-m2) / (m2-m1)

[0102] 5. Description of hygroscopic characteristics and definition of hygroscopic weight gain: Deliquescence: Absorbs enough water to form a liquid Extremely hygroscopic: Weight increase by more than 15% Hygroscopic: The weight gain due to moisture absorption is less than 15% but more than 2%. Slightly hygroscopic: The weight gain upon absorbing moisture is less than 2% but not more than 0.2%. No or little moisture absorption: Weight increase upon moisture absorption is less than 0.2%.

[0103] Table 5. Moisture absorption of crystalline form II

[0104] [Table 5]

[0105] The results of the hygroscopicity test showed that the 24-hour weight gain percentage of crystalline form II was 0.34%<2%, so crystalline form II has some hygroscopicity, but the hygroscopicity is relatively small.

[0106] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of the claims of the present invention.

Claims

1. The powder X-ray diffraction pattern measured at 2θ angles using Cu-Kα radiation has characteristic peaks at 11.4±0.2°, 13.6±0.2°, 15.3±0.2°, 16.1±0.2°, 18.3±0.2°, and 20.7±0.2°. Crystalline Form I of the compound of formula (I). 【Chemical 1】

2. The powder X-ray diffraction pattern measured at 2θ angles using Cu-Kα radiation further has at least one characteristic peak at 12.3±0.2°, 19.4±0.2°, 19.9±0.2°, 21.2±0.2°, and 24.9±0.2°. Crystalline form I according to claim 1.

3. The powder X-ray diffraction pattern, measured at 2θ angles using Cu-Kα radiation, has characteristic peaks at 7.8±0.2°, 10.6±0.2°, 10.9±0.2°, 14.7±0.2°, 15.1±0.2°, and 19.7±0.2°. Crystalline Form II of the compound of formula (I). 【Chemistry 2】

4. The powder X-ray diffraction pattern measured at 2θ angles using Cu-Kα radiation further has at least one characteristic peak at 12.7±0.2°, 17.0±0.2°, 18.0±0.2°, and 21.0±0.2°. Crystalline Form II according to claim 3.

5. The powder X-ray diffraction pattern, measured at 2θ angles using Cu-Kα radiation, further has at least one characteristic peak at 23.0±0.2°, 23.6±0.2°, and 25.6±0.2°. Crystalline Form II according to claim 4.

6. A process for preparing crystalline form II of compound of formula (I), comprising the steps of: The compound of formula (I) is placed in a solvent and reacted until reflux to obtain crystalline form II of the compound of formula (I), wherein the solvent is selected from one or more of a benzene-based solvent, an ether-based solvent, an ester-based solvent, and water; or The compound of formula (I) is placed in an alcoholic solvent and reacted at a temperature ranging from 45°C to reflux to obtain crystalline form II of the compound of formula (I), Preparation method.

7. the alcohol-based solvent is selected from at least one of methanol, ethanol, isopropanol, and n-butanol, the benzene-based solvent is selected from toluene and / or xylene, the ether-based solvent is selected from tetrahydrofuran and / or 2-methyltetrahydrofuran, and the ester-based solvent is selected from ethyl acetate and / or isopropyl acetate, 7. A method for preparing crystalline form II according to claim 6.

8. the solvent is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, an aqueous methanol solution, an aqueous ethanol solution, and an aqueous isopropanol solution, and the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, and n-butanol, 7. A method for preparing crystalline form II according to claim 6.

9. The powder X-ray diffraction pattern, measured at 2θ angles using Cu-Kα radiation, has characteristic peaks at 5.9±0.2°, 10.4±0.2°, 11.8±0.2°, 15.7±0.2°, and 18.8±0.2°. Crystalline Form III of the compound of formula (I). 【Chemistry 3】

10. The powder X-ray diffraction pattern shown at 2θ angles using Cu-Kα radiation further has at least one characteristic peak at 17.5±0.2°, 20.1±0.2°, and 21.4±0.2°.

10. Crystalline Form III according to claim 9.

11. 10. A pharmaceutical composition comprising crystalline form I according to claim 1 or 2, crystalline form II according to any one of claims 3 to 5, or crystalline form III according to claim 9 or 10, and a pharmaceutically acceptable pharmaceutical carrier. Drug composition.

12. 10. A pharmaceutical composition comprising crystalline form I according to claim 1 or 2, crystalline form II according to any one of claims 3 to 5, or crystalline form III according to claim 9 or 10, and a pharmaceutically acceptable pharmaceutical carrier. Drug formulations.

13. In the preparation of a drug for the prevention and / or treatment of B-cell malignancies, autoimmune diseases and inflammatory diseases, comprising crystalline form I according to claim 1 or 2, crystalline form II according to any one of claims 3 to 5, crystalline form III according to claim 9 or 10, a drug composition according to claim 11, or a drug formulation according to claim 12. Purpose.

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