Methanesulfonate crystal form of polycyclic compound, pharmaceutical composition and application

Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to different mesylate crystal forms of a polycyclic compound (E)-2-(3-(2-cyano-2-(6-methoxy-3H-imidazo [4, 5-c] pyridine-2-yl) vinyl)-2, 5-dimethyl-1H-pyrrole-1-yl)-5-methylthiophene-3-nitrile, a pharmaceutical composition containing the crystal forms, and an application of the crystal forms of the polycyclic compound (E)-2-(3-(2-cyano-2-(6-methoxy-3H-imidazo [4, 5-c] pyridine-2-yl) vinyl)-2, 5-dimethyl-1H-pyrrole-1-yl)-5-methylthiophene-3-nitrile. The purity, the water solubility, the chemical stability and the crystal form stability of the mesylate crystal form are better than those of other crystal forms.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and relates to different mesylate crystal forms of a polycyclic compound, namely (E)-2-(3-(2-cyano-2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)vinyl)-2,5-dimethyl-1H-pyrrol-1-yl)-5-methylthiophene-3-carbonitrile (hereinafter referred to as "compound of formula (I)"), and also relates to a pharmaceutical composition containing the crystal form and medical use. Background Art

[0002] DHX33 belongs to the RNA helicase protein family containing the DEAD / H box. DEAD / H stands for the amino acid abbreviation Asp-Glu-Ala-Asp / His. This sequence, together with several other conserved amino acid sequences, appears in the protein sequences of RNA helicase family members and is highly involved in nucleic acid substrate binding and ATP hydrolysis. Although these family members share these same sequences, each RNA helicase has its own specific specificity and unique biological function. The molecular weight of human DHX33 protein is 72kDa. It has the function of unwinding nucleic acids. It uses the bioenergy released by ATP hydrolysis to drive the change of the conformation of RNA and protein complexes, and then participates in a variety of RNA metabolic activities, specifically, a series of biological processes from RNA transcription, shearing, editing, translation to degradation. The function of DHX33 is not limited to the modification of RNA molecules. Studies have shown that in addition to unwinding RNA double strands, DHX33 protein is also involved in DNA metabolism. Specifically, DHX33 protein can unwind the double-stranded structure of DNA and play an important role in gene expression.

[0003] Studies have shown that DHX33 affects the methylation state of DNA by binding to the promoters of various cancer-related genes, thereby regulating the expression of various cancer genes and signal pathways related to tumor development at the genomic level, and plays a vital role in various cell activities such as cell growth, proliferation, migration, apoptosis, and metabolism. In addition, it was found that DHX33 can sense the invasion of foreign double-stranded RNA molecules and play an important role in the innate immunity of cells. As a very important cell growth regulatory gene, DHX33 is highly expressed in many cancers, such as lung cancer, lymphoma, glioblastoma, breast cancer, colon cancer, liver cancer, etc. The occurrence and development of many cancers depend on the high expression of DHX33 protein. Genetic knockout of DHX33 can significantly inhibit the occurrence and development of lung cancer driven by RAS oncogene; in vivo and in vitro experiments have confirmed that after inhibiting DHX33 protein, the occurrence and development of various cancers such as breast cancer, colon cancer, brain glioma, lymphoma, etc. are significantly inhibited. Since the protein function of DHX33 depends on its helicase activity, and the helicase activity-deficient mutant of DHX33 does not have the function of DHX33 protein, it cannot replace the function of the protein encoded by the wild-type DHX33 gene.

[0004] The applicant has discovered a variety of compounds that can inhibit the RNA helicase activity of DHX33 (for example, (E)-2-(3-(2-cyano-2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)vinyl)-2,5-dimethyl-1H-pyrrol-1-yl)-5-methylthiophene-3-carbonitrile), and verified that these compounds can significantly inhibit the growth and proliferation of cancer cells both in vitro and in vivo. Summary of the invention

[0005] The object of the present invention is to provide different mesylate salt forms of a polycyclic compound, namely (E)-2-(3-(2-cyano-2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)vinyl)-2,5-dimethyl-1H-pyrrol-1-yl)-5-methylthiophene-3-carbonitrile (hereinafter referred to as "compound of formula (I)"), a pharmaceutical composition containing the same and use thereof.

[0006] The structural formula of the compound of formula (I) is as follows:

[0007]

[0008] In a first aspect, the present invention provides a mesylate salt form 1 of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 4.6±0.2° and 18.3±0.2°.

[0009] In some embodiments, the X-ray powder diffraction pattern of the mesylate salt form 1 of the compound of formula (I) further has characteristic diffraction peaks at one or more of the following 2θ angles: 21.2±0.2°, 25.9±0.2° and 28.0±0.2°.

[0010] In some embodiments, the X-ray powder diffraction pattern of the mesylate salt form 1 of the compound of formula (I) also has characteristic diffraction peaks at one or more of the following 2θ angles: 4.1±0.2o, 19.8±0.2o, 24.1±0.2o and 26.3±0.2o.

[0011] The present invention also provides a method for preparing the mesylate salt crystal form 1 of the compound of formula (I), comprising: adding an organic solvent to the free state of the compound of formula (I), then adding methanesulfonic acid, stirring at room temperature for about 2-5 days, collecting the solid and then drying to obtain the mesylate salt crystal form 1. In a specific embodiment of the present invention, the organic solvent is isopropanol.

[0012] In an embodiment of the present invention, in the above preparation method, stirring may be performed at room temperature for about 1-4 days, for example, about 1, 1.5, 2, 2.5, 3, 3.5, 4 days.

[0013] In an embodiment of the present invention, in the above preparation method, drying can be carried out under vacuum at 40-95° C. for about 8-16 hours. In a specific embodiment, drying can be carried out under vacuum at 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95° C. for about 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16 hours.

[0014] In a third aspect, the present invention provides a pharmaceutical composition comprising at least one of the above-mentioned crystal forms and one or more pharmaceutically acceptable carriers. The composition can be used to treat and / or prevent diseases or conditions at least partially mediated by DHX33, such as cancer, viral infection and inflammation, and the cancer can be, for example, breast cancer, colon cancer, brain glioma, lymphoma, etc.

[0015] In a fourth aspect, the present invention provides use of the above-mentioned crystal form or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease or condition at least partially mediated by DHX33.

[0016] In a fifth aspect, the present invention provides a method for preventing and / or treating a disease or condition at least partially mediated by DHX33, comprising the following steps: administering a preventive and / or therapeutically effective amount of the above-mentioned crystalline form or the above-mentioned pharmaceutical composition to an individual in need thereof; preferably, the disease is selected from cancer, viral infection and inflammation mediated by DHX33.

[0017] The present invention is not to be limited to the particular embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing and not limiting the particular embodiments.

[0018] Definition of terms

[0019] Unless otherwise stated, the technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. If there is a contradiction, the definition provided in the present application shall prevail. When a certain amount, concentration or other value or parameter is expressed in the form of a range, a preferred range or a preferred upper numerical limit and a preferred lower numerical limit, it should be understood that it is equivalent to specifically revealing any range by combining any pair of upper range limits or preferred values ​​with any lower range limit or preferred values, without considering whether the scope is specifically disclosed. Unless otherwise stated, the numerical range listed herein is intended to include the endpoints of the range and all integers and fractions (decimals) within the range.

[0020] The term "about" when used with a numerical variable generally refers to the value of that variable and all values ​​of that variable are within experimental error (eg, within a 95% confidence interval for the mean) or within ±10% of the specified value, or wider.

[0021] The expression "comprising" or its synonymous similar expressions "including", "containing" and "having", etc., is open-ended and does not exclude additional unrecited elements, steps or ingredients. The expression "consisting of excludes any element, step or ingredient not specified. The expression "consisting essentially of means that the scope is limited to the specified elements, steps or ingredients, plus the optional elements, steps or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of".

[0022] The term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. An XRPD pattern is usually characterized by peak positions (abscissa) and / or peak intensities (ordinate).

[0023] The term "diffraction angle" or "2θ" refers to the peak position expressed in degrees (°) based on the setup in the X-ray diffraction experiment, and is usually the unit of the abscissa in the diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires that the reflected beam be recorded at an angle of 2θ. It should be understood that the specific 2θ value mentioned in this article for a specific crystal form is intended to represent the 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0024] It should be noted that in the powder X-ray diffraction spectrum, the position of the peak or the relative intensity of the peak may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, there may be an error in the position of the peak, and the measurement error of the 2θ value may be ±0.2°. Therefore, when determining each crystal form, this error should be taken into account, and the error is also within the scope of this application.

[0025] For the same crystal form, the position of the endothermic peak of DSC may be different due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, the position of the endothermic peak may have an error, which may be ±5°C or ±3°C. Therefore, when determining each crystal form, this error should be taken into account, and the error is also within the scope of this application.

[0026] For the same crystal form, the position of the weight loss temperature of TGA may be different due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, there may be an error in the position of the weight loss temperature, which may be ±5°C or ±3°C. Therefore, when determining each crystal form, this error should be taken into account, and the error is also within the scope of this application.

[0027] It should be understood that different types of equipment or using different test conditions may give slightly different XRPD patterns and characteristic peaks or different DSC patterns and characteristic peaks. The specific values ​​provided are not to be taken as absolute values.

[0028] The term "room temperature" refers to 20°C ± 5°C.

[0029] The term "prevention" refers to prophylactic administration to reduce the likelihood of, or delay the onset of, a disease or symptom.

[0030] The term "treatment" aims to alleviate or eliminate the disease state or condition being targeted. It should also be understood that the treatment of the disease state or condition includes not only complete treatment, but also less than complete treatment, but achieving some biological or medically relevant results.

[0031] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or crystal forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, and are commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable carrier" refers to an inert substance that is administered together with the active ingredient and is conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is acceptable for use in humans or animals (such as livestock) and approved by the State Food and Drug Administration.

[0032] The above-mentioned pharmaceutical compositions can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, percutaneous, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes or as inhalant administration.

[0033] The above-mentioned administration route can be achieved through a suitable dosage form. The dosage forms that can be used in the present invention include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, etc.

[0034] When administered orally, the pharmaceutical composition can be prepared into any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions, aqueous suspensions, and the like.

[0035] The term "disease or condition mediated at least in part by DHX33" refers to a disease whose pathogenesis at least partially involves factors related to DHX33, such as cancer, viral infection, and inflammation.

[0036] The term "effective amount" refers to a dose that can induce a biological or medical response in cells, tissues, organs or organisms (eg, individuals) and is sufficient to achieve the desired preventive and / or therapeutic effect.

[0037] The therapeutically effective amount of the crystalline form described in the present application is from about 0.0001-20 mg / Kg body weight / day, for example, from 0.001-10 mg / Kg body weight / day.

[0038] The dosage frequency of the crystal formation described in the present application can be determined by a physician according to the needs of individual patients, for example, once or twice a day, or more times a day. Administration can be intermittent, for example, wherein during a period of several days, the patient receives a daily dose of the crystal formation, and then during a period of several days or more days, the patient does not receive a daily dose of the crystal formation. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 is the X-ray powder diffraction (XRPD) pattern of the free base (amorphous) of the compound of formula (I).

[0040] Figure 2 is the free base of the compound of formula (I) 1 HNMR spectrum.

[0041] Figure 3 It is the X-ray powder diffraction (XRPD) pattern of sulfate salt form 1 of the compound of formula (I).

[0042] Figure 4 It is the X-ray powder diffraction (XRPD) pattern of sulfate crystal form 2 of the compound of formula (I).

[0043] Figure 5 It is the X-ray powder diffraction (XRPD) pattern of sulfate crystal form 4 of the compound of formula (I).

[0044] Figure 6 It is the sulfate crystal form 4 of the compound of formula (I) 1 HNMR spectrum.

[0045] Figure 7 It is the X-ray powder diffraction (XRPD) pattern of the mesylate salt form 1 of the compound of formula (I).

[0046] Figure 8 It is the X-ray powder diffraction (XRPD) pattern of the mesylate salt form 2 of the compound of formula (I).

[0047] Fig. 9 It is a thermogravimetric analysis (TGA) diagram of the mesylate salt form 1 of the compound of formula (I).

[0048] Fig.10 It is a differential scanning calorimetry (DSC) diagram of the mesylate salt form 1 of the compound of formula (I).

[0049] Fig.11 The mesylate salt of the compound of formula (I) is 1 H NMR spectra.

[0050] Fig.12 The figure is a comparison of the crystal forms of the mesylate salt form 1 of the compound of formula (I) in stability analysis.

[0051] Fig.13 It is a DVS test chart of the hygroscopicity of the mesylate salt form 1 of the compound of formula (I).

[0052] Fig.14 It is a comparison chart of XRPD of the mesylate salt form 1 of the compound of formula (I) before and after the DVS test. DETAILED DESCRIPTION

[0053] The intermediate compounds of the present application can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0054] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0055] The present application will be described in detail below through examples, which do not imply any limitation to the present application.

[0056] X-ray powder diffraction (XRPD)

[0057] XRPD Testing Parameters

[0058]

[0059] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0060] TGA and DSC test parameters

[0061]

[0062] H NMR spectrum ( 1 HNMR) 1 H NMR test parameters

[0063]

[0064] Ion Chromatography (IC)

[0065] IC Test Parameters

[0066]

[0067] High Performance Liquid Chromatography (HPLC) HPLC Test Parameters

[0068]

[0069]

[0070] Dynamic Water Sorption Analysis (DVS)

[0071] DVS test parameters

[0072]

[0073] Example 1: Synthesis and identification of compounds of formula (I)

[0074] 1.1 The synthetic route is as follows:

[0075]

[0076] Among them, R is

[0077] 1.2 Synthesis method:

[0078] 1.2.1. Preparation of Compound 2 (6-methoxypyridine-3,4-diamine)

[0079]

[0080] Compound 1 (2-methoxy-5-nitropyridine-4-amine) (3.0 g, 17.74 mmol, 1.0 eq.) was dissolved in methanol (30 mL) and a carbon-supported palladium catalyst (300 mg, 0.1 wt%) was added. The mixture was stirred at room temperature for 16 h in the presence of hydrogen. The solid was filtered and concentrated to give compound 2 (6-methoxypyridine-3,4-diamine) (2.6 g, yield: 100%) as a brown solid. MS (ESI) m / z: 140 [M+H] +; TLC: DCM: MeOH (10: 1); R f :(Compound 1) = 0.7; R f :(Compound 3)=0.5.

[0081] 1.2.2. Preparation of Compound 4 (2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)acetonitrile)

[0082]

[0083] Compound 2 (6-methoxypyridine-3,4-diamine) (1.5 g, 10.2 mmol, 1.0 eq.) and compound 3 (ethyl cyanoacetate) (3.5 g, 30.6 mmol, 3.0 eq.) were dissolved in dimethylformamide (6 mL) and stirred at 180 ° C for 5 h. The solvent was removed after cooling. The residue was purified by flash column chromatography (dimethylformamide: methanol = 200: 1 to 50: 1) to give compound 4 (2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)acetonitrile) (500 mg, yield: 26.0%) as a brown solid powder. MS (ESI) m / z: 188 [M+H] +; TLC: petroleum ether / ethyl acetate (1: 1); R f :(Compound 1) = 0.5; Rf :(Compound 3)=0.2.

[0084] 1.2.3. Synthesis of (E)-2-(3-(2-cyano-2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)vinyl)-2,5-dimethyl-1H-pyrrol-1-yl)-methylthiophene-3-carbonitrile (Compound A)

[0085]

[0086] Compound 4 (2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)acetonitrile) (80 mg, 0.42 mmol, 1.0 eq.) was dissolved in 1 mL of ethanol, and compound 5 (2-(3-formyl-2,5-dimethyl-1H-pyrrol-1-yl)-methylthiophene-3-carbonitrile) (103 mg, 0.42 mmol, 1.0 eq.) and piperidine (36 mg, 0.42 mmol, 1.0 eq.) were added. The mixture was heated to reflux and stirred for 1 h. After the reaction was completed, the reactant was cooled to room temperature and filtered. The solid was collected and dried to give compound AB24288 ((E)-2-(3-(2-cyano-2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)vinyl)-2,5-dimethyl-1H-pyrrol-1-yl)-methylthiophene-3-carbonitrile) (95 mg, yield: 13.6%) as a yellow powder.

[0087] 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),8.16(s,1H),7.31(s,1H),6.96(s,1H),6.89(s,1H),3.89(s,3H),2.51(s,3H),2.30(s,3H),2.08(s,3H).

[0088] The free form of the compound of formula (I) is in an amorphous state and has substantially the following Figure 1 XRPD pattern shown.

[0089] The free form of the compound of formula (I) 1 H NMR images Figure 2 shown.

[0090] In view of the poor aqueous solubility of the free weak base compound of formula (I), in order to improve the water solubility of the compound and facilitate its bioavailability, the present application uses two strong acids: sulfuric acid and methanesulfonic acid, to carry out a salt-forming reaction, which is intended to improve the physicochemical properties of the compound and facilitate the later formulation development.

[0091] Example 2: Sulfate salt of the compound of formula (I) and its preparation method

[0092] Preparation method of sulfate crystal form of compound of formula (I)

[0093] Small test: weigh about 20 mg of the free compound of formula (I) and a certain molar amount of the counter ion (1.1 eq.) into a 3.0 mL vial, add 1.0 mL of solvent (select isopropanol, acetone and ethyl acetate), stir magnetically at room temperature, separate the obtained solid after stirring for 2 days, and measure XRPD after air drying at 50°C. Three sulfate salt crystal forms 1 / 2 / 3 (weakly crystalline) were obtained, among which crystal form 1 was obtained using isopropanol as solvent ( Figure 3 ); Form 2 was obtained by using acetone as solvent ( Figure 4 ); Form 3 was obtained by using ethyl acetate as solvent, but due to its poor crystallinity, no XRPD pattern was provided. From the XRPD pattern, the cleanliness of sulfate form 1 was poor, so acetone was selected as solvent to enlarge the synthesis of sulfate form 2 of the compound of formula (I).

[0094] Scale-up synthesis: 199.92 mg of the free compound of formula (I) was weighed and added to 5 mL of acetone to form a suspension; 10 mL of acetone solution containing 29.0 μL of sulfuric acid (1.1 eq.) was added under stirring at room temperature; the system became turbid after 4 days of cyclic heating and cooling, centrifuged, and dried at 50°C for 2 hours; the solid was crushed and continued to be dried at 50°C overnight. Separation test XRPD, the crystal form 2 obtained in the small test was converted into sulfate crystal form 4.

[0095] Sulfate salt form 4 has substantially Figure 5 XRPD pattern shown.

[0096] The XRPD pattern of sulfate salt form 4 has characteristic diffraction peaks at the following 2θ angles, as shown in Table 1:

[0097] Table 1

[0098]

[0099] Sulfate Form 4 1 H-NMR spectrum Figure 6 As shown. Figure 6 It can be seen that the structure of this compound is no different from the free base compound.

[0100] The results of high performance liquid chromatography (HPLC) showed that during the drying process of sulfate, the HPLC purity decreased significantly and the solid state stability was poor. The HPLC purity data are shown in Table 2:

[0101] Table 2

[0102] Solid form HPLC purity Free base (amorphous) 96.20 Sulfate crystal form 4 75.10

[0103] Example 3: Preparation and characterization of the mesylate salt of the compound of formula (I)

[0104] Small test: weigh about 20 mg of the free compound of formula (I) and a certain molar amount of the counter ion (1.1 eq.) into a 3.0 mL vial, add 1.0 mL of solvent (select isopropanol, acetone), stir magnetically at room temperature, separate the obtained solid after stirring for 2 days, and measure XRPD after air drying at 50°C. Two mesylate salt forms 1 / 2 are obtained, of which form 1 is obtained by using isopropanol as solvent, and the mesylate salt form 1 has substantially the same Figure 7 XRPD pattern shown; Form 2 was obtained by using acetone as solvent ( Figure 8 ). From the XRPD spectrum, the crystallinity of the mesylate salt form 1 is slightly better. Later, isopropanol was selected as the solvent to amplify the synthesis of the mesylate salt form 1 of the compound of formula (I).

[0105] Amplified synthesis: Weigh 200.15 mg of free state (20221231) and add 5 mL of acetone to form a suspension; add 5 mL of acetone solution containing 34.4 μL of methanesulfonic acid (1.1 eq.) under stirring at room temperature; after 4 days of cyclic heating and cooling, the system becomes turbid, centrifuge, and air dry at 50°C for 2 hours; crush the solid and continue to air dry at 50°C overnight. (Cyclic heating and cooling program: 40°C (120 min) -> 40°C -> 5°C (0.1°C / min) -> 5°C (120 min) -> 40°C (0.1°C / min) -> 40°C (120 min) -> 5°C (0.1°C / min) -> 5°C (120 min), a total of 2 cycles, then heat to 25°C and stir at a constant temperature).

[0106] Methanesulfonate Form 1 has substantially Figure 7 The XRPD pattern of the crystal form 1 has characteristic diffraction peaks at the following 2θ angles, as shown in Table 3.

[0107] Table 3

[0108]

[0109]

[0110] like Fig. 9 As shown in the thermogravimetric analysis (TGA) curve of the mesylate salt crystal form 1, the sample weight loss is about 1.34% when the temperature rises to 120°C, and it has thermal stability. The mesylate salt crystal form 1 is anhydrous.

[0111] like Fig.10 As shown, the differential scanning calorimetry (DSC) curve of the mesylate salt form 1 has an endothermic peak at 215.58°C.

[0112] The molar ratio of the compound of formula (I) to hydrochloric acid in the methanesulfonic acid form 2 is about 1:1, which is a salt.

[0113] Methanesulfonic acid crystal form 2 1 H-NMR spectrum Fig.11 As shown in Figure 2, the crystal compound has no structural difference from the free base. The base-acid ratio is about 1:1 to form a salt, and there is no obvious organic solvent residue.

[0114] Example 3: 24-hour equilibrium solubility experiment in water

[0115] The 24-hour equilibrium solubility of the free base compound of formula (I) and the mesylate salt form 1 was tested. The specific steps are: weigh 10 mg of the sample and prepare it into a suspension in 1 mL of the corresponding solvent, stir it magnetically at 37±2°C, take a sample after 24 hours, centrifuge the sample, and filter the supernatant for solubility testing. The supernatant was filtered through a 0.22 μm PTFE filter membrane and then tested for solubility. The results are shown in Table 4. The water solubility of the free base compound of formula (I) is about 16.2 μg / mL, and the solubility of the mesylate salt form 1 is 43.07 μg / mL.

[0116] Table 4

[0117] Solid form Equilibrium solubility in water at 37℃ (μg / mL) Free base (amorphous) 16.2 Methanesulfonate Form 1 43.07

[0118] Example 4: One-week stability experiment

[0119] Free base and mesylate crystal form 1 and crystal form 2 samples were placed under 25°C / 60%RH (long term) and 40°C / 75%RH (accelerated) conditions for one week, and then tested for HPLC purity and crystal form change ( Fig.12 The results are shown in Table 5. After the mesylate salt crystal form 1 was placed under the two test conditions for one week, the HPLC purity and crystal form did not change significantly. The chemical stability and crystal form stability of the mesylate salt crystal form 1 were both good. Fig.12 shown.

[0120] Table 5

[0121]

[0122] Example 5: Hygroscopicity

[0123] To evaluate the stability risk of samples at 25°C with humidity changes, DVS test was performed on the mesylate form 1 with better solid stability ( Fig.13 ), collect the solid sample after testing for XRPD testing ( Fig.14 ).

[0124] The results are summarized in Table 6 and Fig.14As shown in the figure, the mesylate salt form 1 is slightly hygroscopic. After the test, the crystal forms of all samples did not change.

[0125] Table 6 Summary of hygroscopicity evaluation results

[0126]

[0127] *: The definition of hygroscopicity in the 2020 edition of the Chinese Pharmacopoeia: Under the conditions of 25°C / 80%RH, the weight gain of the sample is 0.2-2% (less than 2% but not less than 0.2%) and is slightly hygroscopic.

Claims

1. A mesylate crystalline form of a polycyclic compound, wherein the structural formula of the compound is as shown in formula (I):

2. The crystal form according to claim 1, which is a mesylate crystal form 1, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.6±0.2o and 18.3±0.2o; Preferably, its X-ray powder diffraction pattern also has characteristic diffraction peaks at one or more of the following 2θ angles: 21.2±0.2°, 25.9±0.2° and 28.0±0.2°; Preferably, its X-ray powder diffraction pattern also has characteristic diffraction peaks at one or more of the following 2θ angles: 4.1±0.2°, 19.8±0.2°, 24.1±0.2° and 26.3±0.2°. Preferably, the mesylate salt Form 1 has an XRPD pattern substantially as shown in FIG5 .

3. A pharmaceutical composition comprising the crystal form according to any one of claims 1 to 2 and a pharmaceutically acceptable carrier.

4. Use of the crystalline form according to any one of claims 1 to 2 or the pharmaceutical composition according to claim 3 in the preparation of a medicament for preventing and / or treating a disease or condition at least partially mediated by DHX33; preferably, the disease is selected from cancer, viral infection and inflammation mediated by DHX33.

5. The method for preparing the mesylate salt form 1 according to claim 2, comprising: An organic solvent is added to the free state of the compound of formula (I), and then methanesulfonic acid is added, stirred, and the solid is collected and then dried to obtain the mesylate salt form 1.

6. The method according to claim 5, characterized in that The organic solvent is isopropanol.

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