A hydrochloride salt crystalline form of a polycyclic compound, pharmaceutical compositions and uses thereof

Abstract

The application belongs to the field of pharmaceutical chemistry, and relates to different hydrochloride salt crystal forms of a polycyclic compound (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, pharmaceutical compositions containing the crystal forms and purposes. The purity, water solubility, chemical stability and crystal form stability of the hydrochloride salt crystal form are all better than those of other crystal forms.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to different hydrochloride 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 "the compound of formula (I)"), as well as pharmaceutical compositions containing the crystalline form and medical uses. Background Art

[0002] DHX33 belongs to the DEAD / H box-containing RNA helicase protein family. DEAD / H stands for the amino acid abbreviation Asp-Glu-Ala-Asp / His. This sequence, along with several other conserved amino acid sequences, is found in the protein sequences of RNA helicase family members and is highly involved in nucleic acid substrate binding and ATP hydrolysis. While these family members share these common sequences, each RNA helicase has unique specificity and biological functions. The human DHX33 protein has a molecular weight of 72 kDa and functions to unwind nucleic acids. It utilizes the bioenergy released by ATP hydrolysis to drive conformational changes in RNA and protein complexes, thereby participating in a variety of RNA metabolic activities, specifically, RNA transcription, splicing, editing, translation, and degradation. DHX33's functions are not limited to RNA modification. Research has shown that in addition to unwinding RNA duplexes, DHX33 also participates in DNA metabolism. Specifically, DHX33 can unwind the double-stranded structure of DNA and play a vital role in gene expression.

[0003] Research has shown that DHX33 binds to the promoters of various cancer-related genes, affecting DNA methylation. This in turn regulates the expression of numerous cancer genes and signaling pathways associated with tumor development at the genomic level, playing a crucial role in numerous cellular activities, including cell growth, proliferation, migration, apoptosis, and metabolism. Furthermore, DHX33 has been found to sense the intrusion of foreign double-stranded RNA molecules and play a crucial role in cellular innate immunity. As a crucial cell growth regulator, DHX33 is highly expressed in a variety of cancers, including lung cancer, lymphoma, glioblastoma, breast cancer, colon cancer, and liver cancer. The development and progression of many cancers depend on elevated DHX33 protein expression. Genetic knockout of DHX33 significantly inhibits the development and progression of RAS oncogene-driven lung cancer. In vitro and in vivo experiments have confirmed that inhibition of DHX33 significantly suppresses the development and progression of various cancers, including breast cancer, colon cancer, glioma, and lymphoma. 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 hydrochloride 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 "the compound of formula (I)"), a pharmaceutical composition containing the same, and uses.

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

[0007]

[0008] In a first aspect, the present invention provides a hydrochloride salt form 2 of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 4.0±0.2° and 13.2±0.2°.

[0009] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt form 2 of the compound of formula (I) further has characteristic diffraction peaks at one or more of the following 2θ angles: 8.3±0.2°, 13.6±0.2°, and 25.6±0.2°.

[0010] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt form 2 of the compound of formula (I) further has characteristic diffraction peaks at one or more of the following 2θ angles: 6.8±0.2°, 22.6±0.2°, and 27.5±0.2°.

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

[0012] In an embodiment of the present invention, in the above preparation method, stirring can be performed at room temperature for about 1-4 days, for example, about 1, 1.5, 2, 2.5, 3, 3.5, or 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 aforementioned crystalline forms and one or more pharmaceutically acceptable carriers. This composition can be used to treat and / or prevent diseases or conditions mediated at least in part by DHX33, such as cancer, viral infection, and inflammation. Cancers may include, for example, breast cancer, colon cancer, glioma, and lymphoma.

[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 preventively 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 DHX33-mediated cancer, viral infection and inflammation.

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

[0018] Definitions of terms

[0019] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. If there is a conflict between the definitions provided in this application and those provided in the art to which this application pertains, the definitions provided in this application control. When expressing a quantity, concentration, or other value or parameter of interest in the form of a range, a preferred range, or a preferred upper limit and a preferred lower limit, it is to be understood that every range of values, preferred or otherwise, between the stated lower limit and upper limit, inclusive of the lower and upper limits, is contemplated unless otherwise indicated. Numerical ranges listed herein are intended to include all integers and fractions within the range.

[0020] The term "about" when used before a numerical designator means that the numerical value of the variable and all values of the variable within experimental error (e.g., within 95% confidence interval for a mean value) or within ±10% of the stated numerical value, or within a broader range.

[0021] The recitation of "comprising" or analogous terms such as "comprises," "comprised of," "containing" or "containing" or "having" or the like are open-ended and do not exclude additional, unrecited elements, steps or ingredients. The recitation of "consisting essentially of" excludes any element, step or ingredient not specified, but does not exclude trace amounts of unrecited elements, steps or ingredients. The recitation of "consisting of excludes any element, step or ingredient not specified. It should be understood that the recitation of "comprising" is intended to be an open-ended recitation unless otherwise limited. The recitation of "consisting essentially of" is intended to be an open-ended recitation, unless otherwise limited. The recitation of "consisting of is intended to be a close-ended recitation, unless otherwise limited.

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

[0023] The term "diffraction angle" or "2Θ" refers to the peak position in degrees (°) as set up in an X-ray diffraction experiment and is typically the unit of abscissa in a diffraction pattern. If a reflection is diffracted when the incident beam forms an angle Θ with a certain lattice plane, the experimental setup requires that the reflected beam is recorded at a 2Θ angle. It should be understood that a particular 2Θ value mentioned herein for a particular polymorph is intended to mean the 2Θ value (in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0024] It should be noted that the positions or relative intensities of peaks in powder X-ray diffraction spectra may vary due to factors such as the measuring instrument, measurement method, and conditions. For any particular crystal form, the peak positions may have errors, and the measurement error of the 2θ value can be ±0.2°. Therefore, this error should be taken into account when determining each crystal form, and determinations within this error are within the scope of this application.

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

[0026] For the same crystal form, the location of the weight loss temperature on TGA may vary due to factors such as the measuring instrument, measurement method / conditions, etc. For any particular crystal form, the location of the weight loss temperature may have an error of ±5°C or even ±3°C. Therefore, this error should be taken into account when determining the weight loss temperature of each crystal form, and any error within this error is 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 numerical values ​​provided should not be regarded as absolute values.

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

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

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

[0031] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or crystalline forms that are suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. "Pharmaceutically acceptable carrier" refers to an inert substance that is administered together with the active ingredient and facilitates 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 (e.g., livestock) as approved by the State Food and Drug Administration.

[0032] Above-mentioned pharmaceutical composition can act systemically and / or act topically.For this purpose, they can be administered by suitable approach, for example by parenteral, local, intravenous, oral, subcutaneous, intraarterial, intradermal, percutaneous, rectal, intracranial, intraperitoneal, intranasal, intramuscular approach or as inhalant administration.

[0033] The above-mentioned route of administration can be achieved through suitable dosage forms. 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 herein 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 crystalline forms described herein can be determined by a physician based on the needs of the individual patient, for example, once or twice a day, or more times a day. Administration can be intermittent, for example, wherein the patient receives a daily dose of the crystalline form over a period of several days, followed by a period of several or more days in which the patient does not receive a daily dose of the crystalline form. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 is an X-ray powder diffraction (XRPD) pattern of Form 1 sulfate salt of the compound of Formula (I).

[0040] Figure 2 is an X-ray powder diffraction (XRPD) pattern of Form 2 sulfate salt of the compound of Formula (I). 1 HNMR pattern.

[0041] Figure 3 is an X-ray powder diffraction (XRPD) pattern of Form 1 hydrochloride salt of the compound of Formula (I).

[0042] Figure 4 is an X-ray powder diffraction (XRPD) pattern of Form 2 hydrochloride salt of the compound of Formula (I).

[0043] Figure 5 is an X-ray powder diffraction (XRPD) pattern of Form 3 hydrochloride salt of the compound of Formula (I).

[0044] Figure 6 is a thermogravimetric analysis (TGA) pattern of Form 2 hydrochloride salt of the compound of Formula (I). 1 HNMR pattern.

[0045] Figure 7 is an X-ray powder diffraction (XRPD) pattern of Form 1 hydrochloride salt of the compound of Formula (I).

[0046] Figure 8 is an X-ray powder diffraction (XRPD) pattern of Form 3 hydrochloride salt of the compound of Formula (I).

[0047] Figure 9 is an X-ray powder diffraction (XRPD) pattern of Form 2 hydrochloride salt of the compound of Formula (I).

[0048] Figure 10 is a thermogravimetric analysis (TGA) pattern of Form 2 hydrochloride salt of the compound of Formula (I).

[0049] Figure 11 is a differential scanning calorimetry (DSC) pattern of Form 2 hydrochloride salt of the compound of Formula (I).

[0050] Figure 12 is a differential scanning calorimetry (DSC) pattern of Form 2 hydrochloride salt of the compound of Formula (I). 1 HNMR pattern. DETAILED DESCRIPTION

[0051] The intermediate compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present application.

[0052] The chemical reactions of the specific embodiments of the present application are performed in solvents appropriate to the reactants and reagents used and the desired product, and which are readily identifiable by one skilled in the art. It is sometimes necessary to remove the protecting groups after the completion of the reaction or removal of the protecting groups can be carried out prior to the completion of the reaction. The removal of the protecting groups is carried out in accordance with the teachings of the art, or as commonly practiced in the art.

[0053] The present application will now be described in detail by way of reference only to the following examples, which are not meant to limit the present application in any way.

[0054] X-ray powder diffraction (XRPD)

[0055] XRPD test parameters

[0056]

[0057] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0058] TGA and DSC test parameters

[0059]

[0060] H NMR spectrum ( 1 HNMR)

[0061] 1 HNMR test parameters

[0062]

[0063] Ion chromatography (IC)

[0064] IC test parameters

[0065]

[0066] High performance liquid chromatography (HPLC) HPLC test parameters

[0067]

[0068] Dynamic vapour sorption analysis (DVS) DVS test parameters

[0069]

[0070]

[0071] Example 1: Synthesis and identification of compounds of formula (I)

[0072] 1.1 The synthetic route is as follows:

[0073]

[0074] Where R is

[0075] 1.2 Synthesis method:

[0076] 1.2.1. Preparation of Compound 2 (6-methoxypyridine-3,4-diamine)

[0077]

[0078] 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.

[0079] 1.2.2. Preparation of Compound 4 (2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)acetonitrile)

[0080]

[0081] 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. After cooling, the solvent was removed. The residue was purified by flash column chromatography (dimethylformamide: methanol = 200: 1 to 50: 1) to obtain 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; R f :(Compound 3)=0.2.

[0082] 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)

[0083]

[0084] 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. 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 hour. After completion of the reaction, the reactants were 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.

[0085] 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).

[0086] The free form of the compound of formula (I) is in an amorphous state and has substantially the following Figure 1 The XRPD pattern shown. 1 H NMR spectrum Figure 2 shown.

[0087] Given that the free weak base compound of formula (I) has poor aqueous solubility, in order to improve the water solubility of the compound and facilitate its bioavailability, the present application uses two commonly used strong acids: hydrochloric acid and sulfuric acid, to carry out a salt-forming reaction, with the intention of improving the physicochemical properties of the compound and facilitating subsequent formulation development.

[0088] Example 2: Sulfate salt of compound of formula (I) and its preparation method

[0089] Process for preparing a sulfate salt crystalline form of a compound of formula (I)

[0090] Small test: weigh about 20 mg of the free form of the 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) and stir magnetically at room temperature. After stirring for 2 days, separate the resulting solid and air dry it at 50°C before XRPD analysis. Three sulfuric acid crystal forms 1 / 2 / 3 (weakly crystalline) were obtained, of which 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 using ethyl acetate as the solvent. Due to its poor crystallinity, an XRPD pattern is not provided. The XRPD pattern indicates that the cleanliness of the sulfate salt Form 1 is poor, so acetone was later selected as the solvent for the amplified synthesis of the sulfate salt Form 2 of the compound of formula (I).

[0091] Scale-up Synthesis: 199.92 mg of the free form of the compound of formula (I) was weighed and added to 5 mL of acetone to form a suspension. Under stirring at room temperature, 10 mL of an acetone solution containing 29.0 μL of sulfuric acid (1.1 eq.) was added. After 4 days of cyclic heating and cooling with stirring, the solution became turbid. The solution was centrifuged and air-dried at 50°C for 2 hours. The solid was crushed and air-dried at 50°C overnight. XRPD analysis of the isolated Form 2 revealed that the sulfate salt Form 4 was converted to Form 2.

[0092] Sulfate Form 4 has substantially the following Figure 5 The XRPD pattern shown.

[0093] The XRPD pattern of sulfate salt form 4 has characteristic diffraction peaks at the following 2θ angles, as shown in Table 1:

[0094] Table 1

[0095]

[0096] 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 that of the free base compound.

[0097] The results of high performance liquid chromatography (HPLC) showed that the HPLC purity of sulfate decreased significantly during the drying process and the solid state stability was poor. The HPLC purity data are shown in Table 2:

[0098] Table 2

[0099] Solid form HPLC purity Free base (amorphous) 96.20 Sulfate salt crystalline form 4 75.10

[0100] Example 3: Preparation and Characterization of the Hydrochloride Crystalline Form of the Compound of Formula (I)

[0101] Small test: weigh about 20 mg of the free form of the 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 (selected from isopropanol, acetone and ethyl acetate), stir magnetically at room temperature, stir for 2 days, separate the resulting solid, air-dry at 50°C, and measure XRPD. Three salt crystal forms 1 / 2 / 3 were obtained, of which Form 1 was obtained using isopropanol as the solvent. The hydrochloride salt Form 1 has substantially the same Figure 7 XRPD pattern shown; Form 2 was obtained from acetone as solvent; Form 3 was obtained from ethyl acetate as solvent ( Figure 8 From the XRPD pattern, the crystallinity of hydrochloride crystal form 1 is slightly poor. Acetone and ethyl acetate were selected as solvents to amplify the synthesis of hydrochloride crystal form 2 of compound of formula (I) ( Figure 9 ) and Form 3 ( Figure 8 ). Hydrochloride salt form 3 has substantially the following Figure 8 The XRPD pattern shown.

[0102] Scale-up Synthesis: Weigh 199.85 mg of the free form of the compound of formula (I) and add 5 mL of acetone or ethyl acetate to form a suspension. Add 5 mL of an acetone solution containing 44.3 μL of concentrated hydrochloric acid (1.1 eq.) while stirring at room temperature. Cycle heating and stirring for 4 days until the solution becomes turbid. Centrifuge and air-dry at 50°C for 2 hours. Grind the solid and continue air-drying at 50°C overnight. (Cycling 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), for a total of 2 cycles, then raise the temperature to 25°C with constant stirring).

[0103] Hydrochloride Form 1 has substantially Figure 7 The XRPD pattern shown.

[0104] Hydrochloride Form 3 has substantially the following Figure 8 The XRPD pattern of hydrochloride salt form 2 has characteristic diffraction peaks at the following 2θ angles, as shown in Table 3.

[0105] Table 3

[0106]

[0107] like Figure 10 As shown in the thermogravimetric analysis (TGA) curve of hydrochloride salt form 2, the sample loses about 5.39% weight when the temperature is raised to 120° C. Hydrochloride salt form 2 is a hydrate or anhydrous form, but has water adsorbed on the surface.

[0108] like Figure 11As shown, the differential scanning calorimetry (DSC) curve of the hydrochloride salt Form 2 has endothermic peaks at about 46.39 °C and 194.73 °C.

[0109] The molar ratio of the compound of Formula (I) to hydrochloric acid in the hydrochloride salt Form 2 is about 1:1, which is a mono-salt.

[0110] The XRPD pattern of the hydrochloride salt Form 2 is shown in Figure 1. 1 The H-NMR spectrum is shown in Figure 2. Figure 12 As shown, the compound of this crystal form is structurally identical to the free base.

[0111] Example 3: 24-hour equilibrium solubility test in water

[0112] The 24-hour equilibrium solubility of the compound of Formula (I) in free base form and the hydrochloride salt Form 2 and Form 3 were tested. The specific steps are as follows: 10 mg of sample was weighed into 1 mL of the corresponding solvent to prepare a suspension, which was stirred magnetically at 37 ± 2 °C. After 24 hours, the sample was taken, centrifuged, and the supernatant was filtered and tested for solubility. The supernatant was filtered through a 0.22 μm PTFE filter membrane and tested for solubility. The results are shown in Table 4. The solubility of the compound of Formula (I) in free base form in water is about 16.2 μg / mL, the solubility of the hydrochloride salt Form 2 is 119.1 μg / mL, and the solubility of the hydrochloride salt Form 3 is 106.5 μg / mL.

[0113] Table 4

[0114] Solid form Equilibrium solubility in water at 37°C (pg / mL) Free base (amorphous) 16.2 Hydrochloride salt crystalline form 2 119.1 Hydrochloride salt crystalline form 3 106.5

[0115] Example 4: One-week stability test

[0116] After the free base and the hydrochloride salt Form 2 and Form 3 samples were placed at 25 °C / 60% RH (long-term) and 40 °C / 75% RH (accelerated) for one week, the HPLC purity and crystal form change were tested. The results are shown in Table 5. The hydrochloride salt Form 2 did not show significant changes in HPLC purity and crystal form after being placed under the two test conditions for one week, indicating that it has good chemical stability and crystal form stability.

[0117] Table 5

[0118]

Claims

1. A hydrochloride crystalline form of a polycyclic compound, wherein the structural formula of the compound is as shown in formula (I): ； Formula (I), in, The hydrochloride crystal form is hydrochloride crystal form 2, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.0±0.2 o , 13.2±0.2 o , 8.3±0.2 o , 13.6±0.2 o and 25.6±0.2 o .

2. The hydrochloride crystalline form according to claim 1, wherein Its X-ray powder diffraction pattern also has characteristic diffraction peaks at one or more of the following 2θ angles: 6.8±0.2 o , 22.6±0.2 o and 27.5±0.2 o .

3. The hydrochloride crystal form according to claim 1, wherein The hydrochloride salt Form 2 has an XRPD pattern substantially as shown in FIG5 .

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

5. Use of the crystalline form according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4 in the preparation of a medicament for preventing and / or treating a disease or condition at least partially mediated by DHX33.

6. The use according to claim 5, wherein The disease is selected from the group consisting of DHX33-mediated cancer, viral infection, and inflammation.

7. The method for preparing the hydrochloride salt form 2 according to claim 1, comprising: Acetone is added to the free state of the compound of formula (I), followed by hydrochloric acid, and the mixture is stirred. The solid is collected and then dried to obtain the hydrochloride salt form 2.

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