Crystal form of compound containing tricyclic heteroaryl, and preparation method therefor and use thereof

Abstract

Provided in the present invention are a crystal form I of compound I, and a preparation method therefor and the use thereof. The crystal form I provided in the present invention has low hygroscopicity, good stability and powder properties, is suitable for industrial production, and is suitable for being used as a raw material agent for production, storage and use.

Description

A crystal form of a compound containing a tricyclic heteroaryl group, and its preparation method and use Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a crystal form of a compound containing a tricyclic heteroaryl group, a preparation method and uses thereof. Background Art

[0002] JAK (Janus kinase) is a non-transmembrane, non-receptor tyrosine kinase that includes four subtypes: JAK1, JAK2, JAK3, and TYK2 (Tyrosine kinase 2). JAK inhibitors specifically inhibit the JAK-STAT (Signal transducers and activators of transcription) signaling pathway, blocking the cascade of cytokines and participating in immune regulation.

[0003] SYK (Spleen tyrosine kinase), i.e. spleen tyrosine kinase, is a non-receptor tyrosine kinase, present in the cell matrix. SYK is widely expressed in hematopoietic cells, lymphocytes, fibroblasts, vascular endothelial cells, is highly expressed in B lymphocytes, and plays an important role in tumors and autoimmune diseases. The SYK gene can inhibit the proliferation and migration of malignant tumor cells such as breast cancer, melanoma and liver cancer. At present, SYK inhibitors have been used in clinical II / III phase experiments for rheumatoid arthritis, chronic lymphocytic leukemia, etc. Recent studies have shown that using SYK inhibitors or interfering with the expression of SYK genes can effectively slow down the process of liver fibrosis / sclerosis, with a good therapeutic effect (see CN105664178A).

[0004] Compound I is a highly selective dual-target inhibitor of JAK kinase and SYK kinase, disclosed in CN110734454A, and has a structural formula shown in Formula I below:

[0005] There is no research on the crystal form of Compound I in the prior art. Summary of the Invention

[0006] Through extensive experimental research on the crystal form of Compound I, the inventors finally obtained a crystal form with low hygroscopicity, good stability (under high temperature, high humidity and light conditions) and powder properties that is suitable for industrial production and is suitable for production, storage and use as a raw material pharmaceutical.

[0007] In a first aspect, the present invention provides a crystalline form I of compound I, characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 7.7±0.2°, 8.9±0.2°, 11.7±0.2°, 16.0±0.2°, 21.6±0.2°,

[0008] In some embodiments of the present invention, the crystalline form I is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 7.7±0.2°, 8.9±0.2°, 11.7±0.2°, 16.0±0.2°, 19.2±0.2°, and 21.6±0.2°.

[0009] In some embodiments of the present invention, the crystalline form I is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 7.7±0.2°, 8.9±0.2°, 11.7±0.2°, 13.8±0.2°, 16.0±0.2°, 19.2±0.2°, and 21.6±0.2°.

[0010] In some embodiments of the present invention, the crystalline form I is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 7.7±0.2°, 8.9±0.2°, 11.7±0.2°, 13.8±0.2°, 16.0±0.2°, 18.7±0.2°, 19.2±0.2°, and 21.6±0.2°.

[0011] In some embodiments of the present invention, the crystalline form I is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 7.7±0.2°, 8.9±0.2°, 11.7±0.2°, 13.8±0.2°, 16.0±0.2°, 18.7±0.2°, 19.2±0.2°, 20.6±0.2°, and 21.6±0.2°.

[0012] In some embodiments of the present invention, the crystalline form I is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 7.7±0.2°, 8.9±0.2°, 11.7±0.2°, 13.2±0.2°, 13.8±0.2°, 16.0±0.2°, 18.7±0.2°, 19.2±0.2°, 20.6±0.2°, and 21.6±0.2°.

[0013] In some embodiments of the present invention, the crystalline form I is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 7.7±0.2°, 8.9±0.2°, 11.7±0.2°, 13.2±0.2°, 13.8±0.2°, 16.0±0.2°, 18.7±0.2°, 19.2±0.2°, 20.6±0.2°, 21.6±0.2°, and 23.0±0.2°.

[0014] In some embodiments of the present invention, the crystalline form I is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 7.7±0.2°, 8.9±0.2°, 11.7±0.2°, 13.2±0.2°, 13.8±0.2°, 16.0±0.2°, 18.7±0.2°, 19.2±0.2°, 20.6±0.2°, 21.6±0.2°, 23.0±0.2°, and 25.0±0.2°.

[0015] In the present invention, the powder X-ray diffraction pattern of the crystalline form I (using Cu-Kα radiation, expressed in 2θ angles (°)) shows a double peak at 13.2±0.2°, wherein the difference between the peak positions of the two peaks is between 0.1° and 0.4°, for example, between 0.2° and 0.3°, and the intensity of the peak is greater than 10%, for example, greater than 15% or greater than 20%.

[0016] In some embodiments of the present invention, the crystalline form I has a powder X-ray diffraction pattern substantially as shown in FIG1 or FIG2 using Cu-Kα radiation.

[0017] In a second aspect, the present invention provides a method for preparing the above-mentioned crystalline form I, which comprises: dissolving a crude compound I in a dissolving solvent (solvent 1, or a mixed solvent of solvent 1 / solvent 2); optionally adding seed crystals and solvent 3; crystallizing; optionally adding solvent 4 to the obtained solid for slurry washing; separating; obtaining crystalline form I, wherein the solvent 2 is not present, and the solvent 1 is acetone or acetonitrile; or the dissolving solvent is selected from one of the following mixed solvents (solvent 1 / solvent 2): acetone / ethyl acetate, trifluoroethanol / water, ethanol / dichloromethane, wherein, when solvent 2 is selected from water, the water accounts for no more than 10% of the total volume of solvent 1 and solvent 2; the solvent 3 is selected from n-heptane; the solvent 4 is selected from acetone, ethyl acetate, acetone-isopropyl acetate (preferably a volume ratio of 3:1), acetone-methanol (preferably a volume ratio of 1:3) or ethanol.

[0018] In some embodiments of the present invention, in the above-mentioned preparation method, the volume mass ratio (mL / g) of the solvent 1 to the crude compound I is (5-500):1, preferably (5-350):1, more preferably (5-200):1, further preferably (7-70):1, and further preferably (10-30):1, and the volume mass ratio (mL / g) of the solvent 2 to the crude compound I is (0-200):1, more preferably (0-150):1, further preferably (0-50):1, and further preferably (15-50):1.

[0019] In some embodiments of the present invention, in the above-mentioned preparation method, the volume ratio of solvent 1 to solvent 2 is (1-20):(0-50), preferably (1-15):(0-30), more preferably (1-15):(0-10), further preferably (1-15):(0-5), and even more preferably (1-3):(0-5).

[0020] In some embodiments of the present invention, in the above preparation method, the dissolving solvent is acetone, acetonitrile, acetone / ethyl acetate (preferably, the volume ratio is 5:1), trifluoroethanol / water (preferably, the volume ratio is 10:1), ethanol / dichloromethane (preferably, the volume ratio is (1-3): (1.5-5)); the solvent 3 is preferably n-heptane; the solvent 4 is acetone, ethyl acetate, acetone-isopropyl acetate (preferably the volume ratio is 3:1), acetone-methanol (preferably the volume ratio is 1:3) or ethanol.

[0021] In some embodiments of the present invention, in the above preparation method, the solvent 2 does not exist, and the solvent 1 is the dissolving solvent acetone (preferably, the crystallization temperature is 4°C), or acetonitrile (preferably, the crystallization temperature is 4°C), or the dissolving solvent is selected from one of the following mixed solvents (solvent 1 / solvent 2): acetone / ethyl acetate (preferably, the volume ratio is 5:1, and / or the crystallization temperature is 4°C), trifluoroethanol / water (preferably, the volume ratio is 10:1, and / or the crystallization temperature is 4°C), ethanol / dichloromethane (preferably, the volume ratio is (1-3): (1.5-5), and / or the crystallization temperature is room temperature); the solvent 3 is preferably n-heptane; the solvent 4 is acetone, ethyl acetate, acetone-isopropyl acetate (preferably the volume ratio is 3:1), acetone-methanol (preferably the volume ratio is 1:3) or ethanol.

[0022] In some embodiments of the present invention, in the above preparation method, the solvent 1 is preferably ethanol; the solvent 2 is preferably dichloromethane; the solvent 3 is preferably n-heptane; and the solvent 4 is preferably acetone.

[0023] In some embodiments of the present invention, in the above preparation method, a base is optionally added in the dissolving step. The base can be an inorganic base or an organic base, preferably an organic base, and more preferably an organic amine, such as triethylamine.

[0024] In some embodiments of the present invention, in the above preparation method, seed crystals are preferably added before crystallization.

[0025] In some embodiments of the present invention, in the above preparation method, the crystallization temperature is -50°C to 50°C, preferably 0°C to 45°C; more preferably room temperature or 4°C.

[0026] In some embodiments of the present invention, in the above preparation method, the pulping is carried out at room temperature.

[0027] In some embodiments of the present invention, in the above preparation method, the separation step comprises separating the obtained Form I from the crystallization solution by using a suitable method such as filtration and centrifugation.

[0028] In some embodiments of the present invention, the above preparation method, in order to remove the free solvent in the product, further includes a drying step after the separation step. The drying method can adopt any suitable known method, preferably reduced pressure (vacuum drying). Specific drying conditions are, for example, preferably a temperature of 30-70°C, more preferably 35-60°C, and more preferably 40-50°C; and a drying time of 4-20 hours, more preferably 8-16 hours. Regardless of the drying method used, it is preferable that the residual solvent content in the obtained product meets the quality standards.

[0029] The crude compound I described in the present invention can be prepared using the known method disclosed in CN110734454A, or any other known method disclosed in the prior art. In particular, "crude compound I" herein refers to a solid prepared according to Example 29 of CN110734454A or its equivalent (in terms of purity).

[0030] In a third aspect, the present invention further provides a pharmaceutical composition comprising the above-mentioned Form I and optionally a pharmaceutically acceptable carrier.

[0031] The pharmaceutical composition is prepared into a clinically acceptable formulation, such as an oral formulation, an injectable formulation, a topical formulation, or an external formulation, with oral formulations being preferred. The oral formulation is preferably a solid formulation, such as a tablet, capsule, or granule. These formulations can be prepared using corresponding excipients known to those skilled in the art and using corresponding known pharmaceutical preparation techniques.

[0032] In a fourth aspect, the present invention further provides uses of the above-mentioned Form I or the above-mentioned pharmaceutical composition for:

[0033] (a) preparing a drug for treating a disease associated with protein kinase activity or expression;

[0034] (b) preparing protein kinase targeted inhibitors; and / or

[0035] (c) non-therapeutic inhibition of protein kinase activity in vitro;

[0036] Wherein, the protein kinase is selected from the following group but not limited to: SYK, JAK, or a combination thereof.

[0037] In some embodiments of the present invention, the disease associated with protein kinase activity or expression is selected from the group consisting of: autoimmune diseases, hematological malignancies, and solid tumors;

[0038] Preferably, the disease associated with protein kinase activity or expression is selected from the group consisting of breast cancer, melanoma, rheumatoid arthritis, chronic lymphocytic leukemia, monocytic leukemia, splenomegaly, eosinophilic syndrome, essential thrombocytopenia, systemic giant cell disease, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, liver fibrosis / cirrhosis, allergic asthma, myelofibrosis, B-cell lymphoma, psoriasis, atopic dermatitis, lupus erythematosus, cytokine release syndrome, or systemic inflammatory response syndrome-related diseases.

[0039] Preferably, the psoriasis is selected from: psoriasis vulgaris, pustular psoriasis, erythrodermic psoriasis or arthritic psoriasis.

[0040] Preferably, the lupus erythematosus is selected from the group consisting of: discoid lupus erythematosus, subacute cutaneous lupus erythematosus, systemic lupus erythematosus, profundal lupus erythematosus, neonatal lupus erythematosus, and drug-induced lupus erythematosus.

[0041] Preferably, the cytokine release syndrome or systemic inflammatory response syndrome-related diseases are selected from: ① cytokine release syndrome or systemic inflammatory response syndrome caused by infection, ② cytokine release syndrome or systemic inflammatory response syndrome caused by non-infectious factors such as trauma, burns, surgery or ischemia-reperfusion, ③ cytokine release syndrome or systemic inflammatory response syndrome caused by hemorrhagic shock, ischemia, tissue damage, multiple trauma, acute pancreatitis, burns, poisoning, drug fever, ④ cytokine release syndrome and / or systemic inflammatory response syndrome caused by immunotherapy; the infection is caused by bacteria, viruses, fungi, etc., such as respiratory tract infection, biliary tract infection, abdominal infection, traumatic infection, etc. infection, etc.; the viruses are preferably: coronavirus, influenza virus, Ebola virus, hepatitis C virus, dengue virus, etc.; the coronavirus is preferably: SARS virus, novel coronavirus (COVID-19), MERS virus; the influenza virus is preferably: influenza A virus, influenza B virus; preferably, the cytokine release syndrome or systemic inflammatory response syndrome related diseases are: pneumonia, novel coronavirus pneumonia or acute lung injury requiring oxygen supplementation, pneumonia, novel coronavirus pneumonia or acute lung injury requiring non-invasive or invasive mechanical ventilation, hospitalized pneumonia, novel coronavirus pneumonia or acute lung injury requiring extracorporeal membrane oxygenation; the immunotherapy is CART treatment.

[0042] The aforementioned "patient" includes all members of the animal kingdom, including but not limited to mammals (eg, mice, rats, cats, monkeys, dogs, etc.) and humans.

[0043] Definition and Description

[0044] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commercial active ingredient.

[0045] Unless otherwise specified, the "2θ, 2θ angle or 2θ angle" mentioned in the present invention refers to the diffraction angle, with the unit being ° or degree.

[0046] Unless otherwise specified, the "crystallization temperature and drying temperature" mentioned in the present invention are expressed in degrees Celsius, and the error range may be ±10, ±5, ±4, ±3, ±2 or ±1°C.

[0047] The term "substantially as shown in the accompanying drawings" refers to a substantially pure crystalline form in which at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in the powder X-ray diffraction pattern, DSC pattern, or crystal shape diagram of the crystalline particles appear in the given pattern. Furthermore, as the content of a crystalline form in a product gradually decreases, some diffraction peaks attributable to that crystalline form in its powder X-ray diffraction pattern may become less due to factors such as the detection sensitivity of the instrument. In addition, for any given crystalline form, the positions of peaks may have slight errors, which is also well known in the art of crystallography. For example, the positions of peaks can shift due to temperature changes, sample movement, or instrument calibration during sample analysis, and the measurement error of 2θ values ​​is generally approximately ±0.2°. Therefore, this error should be taken into account when determining each crystalline structure, and the term "substantially" or "substantially as shown in the accompanying drawings" is also intended to cover such differences in diffraction peak positions.

[0048] Herein, room temperature refers to 10-30°C, preferably, 20-30°C.

[0049] The present invention will be described in detail below through examples.

[0050] The solvent used in the present invention is commercially available.

[0051] Technical Effects

[0052] The crystal form obtained by the present invention has the following beneficial effects:

[0053] (1) The crystal form of the present invention has low hygroscopicity.

[0054] (2) The crystal form of the present invention has excellent stability. On the one hand, the crystal form of the present invention has good physical stability and remains unchanged after airflow pulverization. On the other hand, the crystal form of the present invention has good thermodynamic stability. When the crystal form of the present invention is placed under high temperature, high humidity and light conditions, the content of the sample under investigation does not change significantly, and the crystal form does not change, making it more suitable for storage and use as a raw material drug.

[0055] (3) The crystal form of the present invention has good powder properties and is suitable for preparing pharmaceutical preparations, especially oral pharmaceutical preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1: XRPD spectrum of Form I of Compound 1 obtained in Example 1.

[0057] Figure 2: XRPD spectrum of Form I of Compound 1 obtained in Example 3.

[0058] Figure 3: XRPD spectrum of Form II of Compound I obtained in Example 5.

[0059] Figure 4: XRPD spectrum of Form I after airflow grinding. DETAILED DESCRIPTION

[0060] X-ray powder diffractometer (XRPD)

[0061] Instrument model (Examples 5-7, Comparative Example): Bruker D8 Advance X-ray Diffractometer

[0062] Target: Cu (40kV, 40mA)

[0063] Step angle: 0.02°

[0064] Scanning range: 3°-40° 2θ

[0065] Scanning speed: 0.02° / 0.2s; or

[0066] Instrument model (Examples 1-4, Test Examples 3-4): Bruker D2 PHASER X-ray diffractometer Target: Cu (30 kV, 10 mA)

[0067] Step angle: 0.02°

[0068] Scanning range: 3°-40° 2θ

[0069] Scanning speed: 0.02° / 0.3s.

[0070] Preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings. These embodiments are provided to better illustrate the present invention, but are not intended to limit the present invention to these embodiments. Non-essential improvements and adjustments to the embodiments made by those skilled in the art based on the above-described invention remain within the scope of protection of the present invention.

[0071] Preparation Example: Preparation of crude compound I

[0072] A crude product of Compound I was prepared as a pale yellow solid by referring to Example 29 of CN110734454A. The obtained solid sample was subjected to X-ray powder diffraction analysis, which showed that it was amorphous.

[0073] Example 1: Preparation of Form I of Compound I

[0074] 3 g of crude Compound I was added to a reaction flask, followed by 500 mL of acetone and 100 mL of ethyl acetate. The mixture was heated to 50°C to dissolve, stirred at the same temperature for 10 minutes, and then cooled to 4°C and stirred for 3 hours to yield 2.55 g of white crystals with an HPLC purity of 99.87%. Powder X-ray diffraction analysis of a sample revealed Form I (see Figure 1 for the spectrum and Table 1 for the data). TGA analysis of a sample also revealed an anhydrous crystalline form.

[0075] Table 1: Powder X-ray diffraction peak data of Form I sample of Example 1

[0076] Example 2: Preparation of Form I of Compound I

[0077] Referring to the preparation method of Example 1, the crystallization solvent was changed, and the results were as follows:

[0078] Example 3: Preparation of Form I of Compound I

[0079] 10 g of crude Compound I was added to a reaction flask, followed by 100 mL of ethanol, 200 mL of dichloromethane, and 3 mL of triethylamine. The mixture was stirred at room temperature to dissolve. The Form I sample obtained in Example 1 was seeded with 249 mL of n-heptane. The mixture was stirred at room temperature to crystallize, yielding approximately 8.1 g of white crystals. The wet white crystals were slurry-washed in acetone to obtain Form I with an HPLC purity of 99.98%. Powder X-ray diffraction of the sample revealed Form I. The spectrum is shown in Figure 2, and the data are shown in Table 2.

[0080] Table 2: Example 3 Form I sample powder - X-ray diffraction peak data

[0081] After investigation, it was found that Form I could be obtained in the range of 10-30 v / w ethanol: 15-50 v / w dichloromethane (Note: v / w is the volume mass ratio of solvent to crude product mL / g).

[0082] Example 4: Investigation of Preparation Conditions of Form I of Compound I

[0083] Referring to the preparation method of Example 3, the slurry washing solvent was changed, and the obtained crystal forms were as follows:

[0084] Example 5: Preparation of Form II of Compound I

[0085] Approximately 300 mg of the sample from Preparation Example 1 was added to 30 mL of acetonitrile and 10 mL of water. The mixture was heated to dissolve, filtered, and left to evaporate to dryness at 40°C. This yielded 290 mg of a solid, with a yield of 96.7% and an HPLC purity of 99.96%. Powder X-ray diffraction analysis of the sample revealed Form II (see Figure 3 for the spectrum and Table 3 for the data). TGA analysis of the sample also revealed the dihydrate form.

[0086] Table 3: Powder-X-ray characteristic peak data of Form II of Example 5

[0087] Form II can also be obtained by replacing the solvent with tetrahydrofuran / water (2.0 / 1.0) and evaporating to dryness at room temperature.

[0088] Example 6: Preparation of Form II of Compound I

[0089] 30 mg of crude compound I was added to a reaction flask, and the following solvents 1 and 2 were added, heated to 50°C for dissolution, and then cooled to 4°C for stirring and crystallization to obtain Form II.

[0090] Example 7: Preparation of Form II of Compound I

[0091] Referring to the preparation of Form I of Compound I, Form II was obtained under the following conditions.

[0092] Test Example 1: Crystal Solubility Test

[0093] Appropriate amounts of the amorphous sample of the preparation example, the Form I sample of Example 3, and the Form II sample of Example 5 were weighed and solubility tests were performed in water respectively. The results showed that the solubility of the above three substances was at the same solubility level as defined in the "Pharmacopoeia of the People's Republic of China" (Part II, 2020 Edition).

[0094] Test Example 2: Crystal Hygroscopicity Test

[0095] Appropriate amounts of the amorphous sample from the Preparation Example, Form I sample from Example 3, and Form II sample from Example 5 were placed in a suitable constant-temperature desiccator at 25°C ± 1°C (with a saturated solution of ammonium chloride or ammonium sulfate placed in the lower chamber) for 24 hours to test the hygroscopicity of the crystal forms in accordance with the "Guidelines for Hygroscopicity Testing of Pharmaceuticals." The results showed that the Form I sample had an average weight gain of 0.8%, indicating slight hygroscopicity; the Form II sample had an average weight gain of 47.9%, indicating strong hygroscopicity; and the amorphous sample had an average weight gain of 3.0%, indicating hygroscopicity.

[0096] Test Example 3: Crystal stability test

[0097] Take appropriate amounts of the amorphous sample of the preparation example, the Form I sample of Example 3, and the Form II sample of Example 5, and place them under high temperature (60°C), high humidity (25°C / 75% RH), and light (4500±500lux) conditions for 5 days and 10 days, respectively. The experimental results are compared with the 0-day data. See Table 4.

[0098] Table 4: Stability test results of amorphous, crystalline form I and crystalline form II

[0099] The results showed that Form I showed little change in properties, related substances, and crystal form after exposure to high temperature (60°C), high humidity (25°C / 75% RH), and light (4500±500 lux) for 5 and 10 days, respectively. Form II showed little change in properties and related substances after exposure to high temperature (60°C), high humidity (25°C / 75% RH), and light (4500±500 lux) for 5 and 10 days, respectively. However, the crystal form underwent transformation under high temperature and light conditions (Note: XRPD analysis revealed characteristic peaks other than Form II). The amorphous form degraded under these conditions, with degradation being particularly pronounced at high temperature.

[0100] Test Example 4: Determination of the crushing stability of Form I

[0101] An appropriate amount of the Form I sample of Example 3 was taken and pulverized using an experimental airflow mill with a feed rate of 6-7 bar and a pulverization pressure of 6-7 bar. The pulverized sample was subjected to XRPD detection, and the crystal form did not change. The spectrum is shown in Figure 4, and the data results are shown in Table 5.

[0102] Table 5: Powder-X-ray diffraction peak data of Form I after airflow crushing

[0103] Test Example 5: Powder Science Testing

[0104] The sample of Form I of Example 3 was subjected to powder science testing, and the test results are as follows:

[0105] Comparative Example:

[0106] During the research and development process, the inventors discovered that Compound I failed to precipitate into a crystalline solid using various crystal analysis methods and experimental conditions, resulting in only oils, solutions, emulsions, or amorphous forms. Alternatively, under various experimental conditions, only mixed crystals were obtained. Exemplary solutions include, but are not limited to, the following comparative examples:

[0107] Comparative Example 1

[0108] About 30 mg of the sample from Preparation Example 1 was weighed and added to 12 mL of trifluoroethanol, stirred and dissolved, and the resulting solution was concentrated to dryness under reduced pressure to obtain an oily substance.

[0109] Comparative Example 2: Antisolvent Crystallization

[0110] Positive addition: weigh about 30 mg of the sample from Preparation Example 1, add solvent 1 at 40°C, and filter the solution. Add solvent 2 dropwise to solvent 1, and stir at room temperature for crystallization.

[0111] Back addition: Weigh about 50 mg of the sample from Preparation Example 1, add solvent 1 at 40°C, filter the solution, and add solvent 1 dropwise to solvent 2, stirring at room temperature for crystallization.

[0112] Comparative Example 3: Cooling Crystallization Method

[0113] Weigh about 30 mg of the sample from Preparation Example 1, add the solvent, heat to 50°C to dissolve, filter, and stir at 4°C to crystallize.

[0114] Comparative Example 4: Slurry Crystallization Method

[0115] About 30 mg of the sample of Preparation Example 1 was weighed, and after adding a solvent, the mixture was placed at a corresponding temperature for crystallization for 5 days.

[0116] Comparative Example 5: Volatile Crystallization Method

[0117] About 30 mg of the sample of Preparation Example 1 was weighed, and the corresponding solvent was added. The sample was dissolved by ultrasonication and then exposed to the corresponding temperature to evaporate to dryness.

Claims

1. Polymorph Ⅰ of Compound I, characterized in that, Using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 7.7 ± 0.2°, 8.9 ± 0.2°, 11.7 ± 0.2°, 16.0 ± 0.2°, 21.6 ± 0.2°, 2. The crystalline form 1 of compound I as described in claim 1, characterized in that, Using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic peaks at the following positions: 7.7 ± 0.2°, 8.9 ± 0.2°, 11.7 ± 0.2°, 16.0 ± 0.2°, 19.2 ± 0.2°, 21.6 ± 0.2°; Alternatively, its powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 7.7 ± 0.2°, 8.9 ± 0.2°, 11.7 ± 0.2°, 13.8 ± 0.2°, 16.0 ± 0.2°, 19.2 ± 0.2°, 21.6 ± 0.2°; Alternatively, its powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 7.7 ± 0.2°, 8.9 ± 0.2°, 11.7 ± 0.2°, 13.8 ± 0.2°, 16.0 ± 0.2°, 18.7 ± 0.2°, 19.2 ± 0.2°, 21.6 ± 0.2°; Alternatively, its powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 7.7 ± 0.2°, 8.9 ± 0.2°, 11.7 ± 0.2°, 13.8 ± 0.2°, 16.0 ± 0.2°, 18.7 ± 0.2°, 19.2 ± 0.2°, 20.6 ± 0.2°, 21.6 ± 0.2°; Alternatively, its powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 7.7 ± 0.2°, 8.9 ± 0.2°, 11.7 ± 0.2°, 13.2 ± 0.2°, 13.8 ± 0.2°, 16.0 ± 0.2°, 18.7 ± 0.2°, 19.2 ± 0.2°, 20.6 ± 0.2°, 21.6 ± 0.2°; Alternatively, its powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 7.7 ± 0.2°, 8.9 ± 0.2°, 11.7 ± 0.2°, 13.2 ± 0.2°, 13.8 ± 0.2°, 16.0 ± 0.2°, 18.7 ± 0.2°, 19.2 ± 0.2°, 20.6 ± 0.2°, 21.6 ± 0.2°, 23.0 ± 0.2°; Alternatively, its powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 7.7 ± 0.2°, 8.9 ± 0.2°, 11.7 ± 0.2°, 13.2 ± 0.2°, 13.8 ± 0.2°, 16.0 ± 0.2°, 18.7 ± 0.2°, 19.2 ± 0.2°, 20.6 ± 0.2°, 21.6 ± 0.2°, 23.0 ± 0.2°, 25.0 ± 0.2°; Alternatively, its powder X-ray diffraction pattern is substantially as shown in Figure 1 or Figure 2.

3. A pharmaceutical composition, characterized in that, It contains crystalline form I of compound I as described in claim 1 or 2 and optionally a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, wherein The pharmaceutical composition is made into a clinically acceptable preparation, and the preparation includes oral preparations, injection preparations, topical administration preparations, external preparations, etc.; preferably an oral preparation, and further preferably tablets, capsules and granules.

5. Use of polymorph I of compound I as described in claim 1 or 2, or the pharmaceutical composition as described in claim 3 or 4, in the preparation of a medicament for the treatment of diseases (a), (b), (c): (a) in the preparation of a medicament for the treatment of diseases related to protein kinase activity or expression level; (b) in the preparation of a protein kinase-targeted inhibitor; and / or (c) in vitro non-therapeutically inhibiting the activity of protein kinase; Preferably, the protein kinase is selected from the group consisting of but not limited to: SYK, JAK, or a combination thereof.

6. The use according to claim 5, characterized in that, The diseases related to protein kinase activity or expression level are selected from: autoimmune diseases, hematological malignancies, solid tumors; Preferably, the diseases related to protein kinase activity or expression level are selected from: breast cancer, melanoma, rheumatoid arthritis, chronic lymphocytic leukemia, monocytic leukemia, splenomegalic erythrocytosis, eosinophilic leukocytosis syndrome, idiopathic thrombocytopenia, systemic cytomegalic disease, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, prostate cancer, glioblastoma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, renal cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, liver fibrosis / cirrhosis, allergic asthma, myelofibrosis, B-cell lymphoma, psoriasis, atopic dermatitis, lupus erythematosus, cytokine release syndrome or diseases related to systemic inflammatory response syndrome.

7. A method for preparing polymorph I of compound I as described in claim 1 or 2, the method comprising: Dissolve the crude compound I in solvent 1 and solvent 2; optionally add seed crystals and solvent 3; crystallize; optionally wash the obtained solid with solvent 4; Separate to obtain polymorph I, wherein: Solvent 2 is absent, and solvent 1 is acetone or acetonitrile; or the mixed solvent of solvent 1 / solvent 2 is selected from one of the following mixed solvents: acetone / ethyl acetate, trifluoroethanol / water, ethanol / dichloromethane, wherein when solvent 2 is selected from water, the volume content of water in the total volume of solvent 1 and solvent 2 does not exceed 10%; Solvent 3 is selected from n-heptane; Solvent 4 is selected from acetone, ethyl acetate, acetone-isopropyl acetate (preferably with a volume ratio of 3:1), acetone-methanol (preferably with a volume ratio of 1:3) or ethanol.

8. The preparation method according to claim 7, characterized in that, The volume-mass ratio (mL / g) of solvent 1 to the crude compound I is (5 - 500):1, preferably (5 - 350):1, more preferably (5 - 200):1, further preferably (7 - 70):1, still further preferably (10 - 30):1, and the volume-mass ratio (mL / g) of solvent 2 to the crude compound I is (0 - 200):1, more preferably (0 - 150):1, further preferably (0 - 50):1, still further preferably (15 - 50):

1.

9. The preparation method according to claim 7, characterized in that, The volume ratio of solvent 1 to solvent 2 is (1 - 20):(0 - 50), preferably (1 - 15):(0 - 30), more preferably (1 - 15):(0 - 10), further preferably (1 - 15):(0 - 5), still further preferably (1 - 3):(0 - 5).

10. The preparation method according to claim 7, characterized in that, The solvent 1 is ethanol; the solvent 2 is dichloromethane; the solvent 3 is n-heptane; the solvent 4 is acetone.

11. The preparation method according to claim 7, characterized in that, An alkali can be optionally added in the dissolution step, and the alkali can be an inorganic alkali or an organic alkali, preferably an organic alkali, more preferably an organic amine such as triethylamine.

12. The preparation method according to claim 7, characterized in that, Seeds are added before crystallization.

13. The preparation method according to claim 7, characterized in that, The crystallization temperature is from -50°C to 50°C, preferably from 0°C to 45°C; more preferably at room temperature or 4°C.

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