Compound 102D-6 crystal form and preparation method thereof

Abstract

The invention discloses a compound 102D-6 crystal form and a preparation method thereof, and also discloses a pharmaceutical composition and antiviral application thereof.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to polymorphs of an anti-influenza virus drug, compound 102D-6, in particular, to crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V and crystal form VI of compound 102D-6 and a preparation method thereof. BACKGROUND

[0002] Influenza, commonly known as flu, is an acute respiratory infectious disease caused by influenza virus. The influenza virus is the pathogen causing influenza, belongs to the Orthomyxoviridae family, and is an RNA virus.

[0003] In Chinese invention patent CN 118496239A, a preparation method and antiviral use of compound 120D-6 and derivatives thereof are disclosed.

[0004] Drug crystal forms are important factors affecting drug quality. Different crystal forms of the same drug molecule will have significant differences in appearance, solubility, melting point, dissolution rate, biological effectiveness and other properties, thereby directly affecting the stability, bioavailability and efficacy of the drug. SUMMARY

[0005] Compound 102D-6 is ethyl (1R)-1-[[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepine-11-yl]-3,4,6,8,12,12a-hexahydro-6,8-dioxo-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxy]acetate, a compound as shown in formula (102D-6):

[0006]

[0007] Compound 102D-6 is an anti-influenza virus drug that can selectively inhibit cap-dependent endonuclease and prevent polymerase function and influenza virus mRNA replication.

[0008] Compound 102D-6 disclosed in Chinese invention patent CN 118496239A is in an amorphous state, has general stability and has strong hygroscopicity.

[0009] The present application provides a crystal form of compound 102D-6 and a preparation method thereof, in particular, the present application provides new crystal forms of compound 102D-6: crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V and crystal form VI.

[0010] The new crystal form of the present application is studied as described above, and it is found that the crystal form I, the crystal form II and the crystal form III have good performance in stability and the like, and can be used for preparing pharmaceutical preparations.

[0011] According to a first aspect of the present application, the present application provides a new crystal form of compound 102D-6, crystal form I, which is characterized in that the X-ray powder diffraction pattern thereof has diffraction peaks at at least one or more or all of the following 2θ (unit: degree, error ±0.2 degrees) angles: 7.0, 10.8, 15.2, 17.7, 20.6, 21.7, 25.1, 28.2, by using an X-ray powder diffractometer.

[0012] In some embodiments, the crystal form I has diffraction peaks at at least one or more or all of the following 2θ (unit: degree, error ±0.2 degrees) angles: 6.4, 7.0, 10.8, 14.0, 15.2, 17.7, 20.6, 21.7, 24.1, 25.1, 27.1, 28.2.

[0013] In some embodiments, the crystal form I has diffraction peaks at at least one or more or all of the following 2θ (unit: degree, error ±0.2 degrees) angles: 6.4, 7.0, 10.8, 14.0, 15.2, 17.7, 20.6, 21.7, 24.1, 25.1, 27.1, 28.2.

[0014] Table 1A Crystal form I

[0015]

[0016]

[0017] In some embodiments, the crystal form I has an X-ray powder diffraction pattern (XPRD pattern) substantially as shown in Figure 1 .

[0018] In some embodiments, the crystal form I has a differential scanning calorimetry curve with an endothermic peak at 203.8℃.

[0019] In some embodiments, the crystal form I has a differential scanning calorimetry curve (DSC pattern) substantially as shown in Figure 2 .

[0020] In some embodiments, the crystal form I has a thermogravimetric analysis curve showing that the weight loss of the sample is about 2.2%, and the sample is decomposed at 220℃.

[0021] In some embodiments, the crystal form I has a thermogravimetric analysis curve (TGA pattern) substantially as shown in Figure 3 .

[0022] According to a second aspect of the present application, the present application provides a new crystal form of compound 102D-6, crystal form II, which is characterized in that it has at least one or more or all of the following diffraction peaks at the following 2-theta (unit: degree, error ±0.2 degree) angles by using an X-ray powder diffractometer: 7.9, 9.9, 12.5, 16.0, 16.9, 19.7, 21.9.

[0023] In some embodiments, the crystal form II has at least one or more or all of the following diffraction peaks at the following 2-theta (unit: degree, error ±0.2 degree) angles: 7.9, 9.9, 12.5, 14.9, 16.0, 16.6, 16.9, 19.7, 20.6, 21.1, 21.9, 26.6.

[0024] In some embodiments, the crystal form II has diffraction peaks at the following 2-theta (unit: degree, error ±0.2 degree) angles:

[0025] Table IB Crystal form II

[0026]

[0027]

[0028] In some embodiments, the crystal form II has an X-ray powder diffraction pattern (XPRD pattern) substantially as shown in Figure 4 .

[0029] In some embodiments, the crystal form II has a differential scanning calorimetry curve with an endothermic peak at 200.3°C.

[0030] In some embodiments, the crystal form II has a differential scanning calorimetry curve (DSC pattern) substantially as shown in Figure 5 .

[0031] In some embodiments, the crystal form II has a thermogravimetric analysis curve showing that the sample loses about 1.5% weight, and the sample decomposes at 220°C.

[0032] In some embodiments, the crystal form II has a thermogravimetric analysis curve (TGA pattern) substantially as shown in Figure 6 .

[0033] According to a third aspect of the present application, the present application provides a new crystal form of compound 102D-6, crystal form III, which is characterized in that it has at least one or more or all of the following diffraction peaks at the following 2-theta (unit: degree, error ±0.2 degree) angles by using an X-ray powder diffractometer: 8.0, 10.7, 13.7, 14.3, 16.0, 16.5, 20.3, 22.1, 24.9.

[0034] In some embodiments, crystal form III has at least one or more or all of the following 2θ (unit: degrees, error ±0.2 degrees) angles: 8.0, 10.7, 11.7, 13.7, 14.3, 16.0, 16.5, 17.8, 19.1, 20.3, 22.1, 23.9, 24.9, 27.7.

[0035] In some embodiments, crystal form III has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles:

[0036] Table 1. Crystal Form III (C)

[0037]

[0038]

[0039] In some embodiments, crystal form III has substantially the following characteristics: Figure 7 The X-ray powder diffraction pattern (XPRD pattern) shown.

[0040] In some embodiments, the differential scanning calorimetry curve of crystal form III has an endothermic peak at 208.9°C.

[0041] In some embodiments, crystal form III has as follows Figure 8 The differential scanning calorimetry (DSC) curve is shown.

[0042] In some embodiments, the crystal form III has a thermogravimetric analysis curve showing that the sample does not lose weight and decomposes at 220°C.

[0043] In some embodiments, crystal form III has substantially the following characteristics: Figure 9 The thermogravimetric analysis curve (TGA spectrum) is shown.

[0044] According to a fourth aspect of the invention, a novel crystal form—crystal form IV—of compound 102D-6 is provided, characterized by having at least one or more or all of the following 2θ (unit: degrees, error ±0.2 degrees) diffraction peaks using an X-ray powder diffractometer: 6.7, 8.1, 10.5, 12.5, 15.7, 17.8, 18.4, 22.9.

[0045] In some embodiments, the crystal form IV has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 6.7, 8.1, 10.5, 11.6, 12.5, 13.4, 15.7, 17.8, 18.4, 20.1, 20.7, 22.9, 28.3.

[0046] In some embodiments, crystal form IV has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles:

[0047] Table 1D Crystal Form IV

[0048]

[0049] In some embodiments, the crystal form IV has substantially the following characteristics: Figure 10 The X-ray powder diffraction pattern (XPRD pattern) shown.

[0050] In some embodiments, the differential scanning calorimetry curve of crystal form IV has an endothermic peak at 210.4°C.

[0051] In some embodiments, the crystal form IV has as follows Figure 11 The differential scanning calorimetry (DSC) curve is shown.

[0052] In some embodiments, the crystal form IV has a thermogravimetric analysis curve showing a sample weight loss of approximately 3.0%, and the sample decomposes at 220°C.

[0053] In some embodiments, the crystal form IV has substantially the following characteristics: Figure 12 The thermogravimetric analysis curve (TGA spectrum) is shown.

[0054] According to a fifth aspect of the invention, the invention provides a novel crystal form V of compound 102D-6, characterized in that, by using an X-ray powder diffractometer, it has at least one or more or all of the following 2θ (unit: degrees, error ±0.2 degrees) angles: 9.0, 13.1, 18.1, 19.5, 20.7, 22.7, 32.0.

[0055] In some embodiments, the crystal form V has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles:

[0056] Table 1. Crystal form V

[0057]

[0058] In some embodiments, the crystal form V has substantially as follows Figure 13 The X-ray powder diffraction pattern (XPRD pattern) shown.

[0059] In some embodiments, the differential scanning calorimetry curve of crystal form V has an endothermic peak at 197.2°C.

[0060] In some embodiments, the crystal form V has as follows Figure 14 The differential scanning calorimetry (DSC) curve is shown.

[0061] In some embodiments, the crystal form V has a thermogravimetric analysis curve showing a weight loss of approximately 60.254% at around 210°C.

[0062] In some embodiments, the crystal form V has substantially as follows Figure 15 The thermogravimetric analysis curve (TGA spectrum) is shown.

[0063] According to a sixth aspect of the invention, the invention provides a new crystal form VI of compound 102D-6, characterized in that, by using an X-ray powder diffractometer, it has at least one or more or all of the following 2θ (unit: degrees, error ±0.2 degrees) angles: 7.1, 12.3, 17.2, 21.5, 22.3.

[0064] In some embodiments, the crystal form VI has at least one or more or all of the following 2θ (unit: degrees, error ±0.2 degrees) angles: 6.9, 7.1, 11.8, 12.3, 15.2, 17.2, 19.1, 20.7, 21.5, 22.3, 24.6, 25.9, 28.8.

[0065] In some embodiments, crystal form VI has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles:

[0066] Table 1F Crystal Form VI

[0067]

[0068]

[0069] In some embodiments, the crystal form VI has substantially the following characteristics: Figure 16 The X-ray powder diffraction pattern (XPRD pattern) shown.

[0070] In some embodiments, the differential scanning calorimetry curve of crystal form VI has an endothermic peak at 155.3°C.

[0071] In some embodiments, the crystal form VI has as follows Figure 17 The differential scanning calorimetry (DSC) curve is shown.

[0072] In some embodiments, the crystal form VI has a thermogravimetric analysis curve showing that the sample does not lose weight and decomposes at 220°C.

[0073] In some embodiments, the crystal form VI has substantially the following characteristics: Figure 18 The thermogravimetric analysis curve (TGA spectrum) is shown.

[0074] According to a seventh aspect of the present invention, the present invention provides a method for preparing crystal form I, comprising: adding compound 102D-6 to a certain volume of a good solvent, heating and stirring to dissolve the compound, directly cooling the compound or adding a poor solvent and then cooling the compound, stirring to crystallize the compound, filtering the mixture, and drying the mixture to obtain crystal form I.

[0075] In some embodiments, the good solvent may be one or more of methanol, ethanol, isopropanol, etc.

[0076] In some embodiments, the unsuitable solvent may be water.

[0077] In some embodiments, the heating and melting temperature can be 50–80°C.

[0078] In some embodiments, the crystallization temperature after cooling can be 0–30°C.

[0079] In some embodiments, the drying temperature can be 40-50°C, more preferably 40-45°C.

[0080] In some embodiments, the ratio of the good solvent to the solid compound 102D-6 can be 4 ml / g to 10 ml / g, more preferably 4 ml / g to 6 ml / g.

[0081] In some embodiments, the ratio of the poor solvent to the solid compound 102D-6 can be 4 ml / g to 10 ml / g, more preferably 4 ml / g to 6 ml / g.

[0082] According to an eighth aspect of the present invention, the present invention provides a method for preparing crystal form II, comprising: adding compound 102D-6 to a certain volume of a good solvent, stirring and dissolving it under controlled temperature, adding a poor solvent, stirring and crystallizing under controlled temperature, filtering, and drying to obtain crystal form II.

[0083] In some embodiments, the good solvent may be one or more of ethyl acetate, isopropyl acetate, methyl formate, ethyl formate, etc.

[0084] In some embodiments, the undesirable solvent may be one or more of n-hexane, cyclohexane, n-heptane, etc.

[0085] In some embodiments, water needs to be added.

[0086] In some embodiments, crystal type II seed crystals induce crystallization.

[0087] In some embodiments, the dissolution temperature can be 20–80°C, more preferably 50–60°C.

[0088] In some embodiments, the crystallization temperature can be 0–30°C, more preferably 0–10°C.

[0089] In some embodiments, the drying temperature can be 30–60°C, more preferably 50–60°C.

[0090] In some embodiments, the ratio of the good solvent to the solid compound 102D-6 can be 3 ml / g to 8 ml / g, more preferably 3 ml / g to 5 ml / g.

[0091] In some embodiments, the ratio of the poor solvent to solid compound 102D-6 can be 10 ml / g to 20 ml / g, more preferably 10 ml / g to 15 ml / g.

[0092] In some embodiments, the ratio of water to solid compound 102D-6 can be 0.01:1 to 0.1:1, more preferably 0.03:1 to 0.06:1.

[0093] In some embodiments, the ratio of the crystal type II seed crystal to the solid compound 102D-6 can be 0.001:1 to 0.01:1, more preferably 0.001:1 to 0.003:1.

[0094] According to a ninth aspect of the present invention, the present invention provides a method for preparing crystal form II, comprising: adding compound 102D-6 of crystal form I to a certain volume of n-heptane, stirring at a controlled temperature for a certain time, filtering, and drying to obtain crystal form II.

[0095] In some embodiments, the stirring temperature can be 40–85°C.

[0096] In some embodiments, the stirring time can be 4 to 24 hours.

[0097] In some embodiments, the drying temperature may be 50–60°C.

[0098] In some embodiments, the solid ratio of n-heptane to compound 102D-6 can be 5 ml / g to 20 ml / g, more preferably 10 ml / g to 15 ml / g.

[0099] According to a tenth aspect of the present invention, the present invention provides a method for preparing crystal form III, comprising: adding compound 102D-6 to a certain volume of a good solvent, heating and stirring to dissolve the compound, directly cooling to crystallize, or adding a poor solvent while maintaining the temperature and then cooling to crystallize, filtering, and drying to obtain crystal form III.

[0100] In some embodiments, the good solvent may be one or more of ethyl acetate, isopropyl acetate, etc.

[0101] In some embodiments, the undesirable solvent may be one or more of n-hexane, cyclohexane, n-heptane, etc.

[0102] In some embodiments, the defective solvent may be added all at once or in batches, more preferably in batches.

[0103] In some embodiments, the melting temperature can be 60–80°C, more preferably 60–70°C.

[0104] In some embodiments, the crystallization temperature can be 0–30°C, more preferably 0–10°C.

[0105] In some embodiments, the drying temperature can be 45–60°C, more preferably 50–60°C.

[0106] In some embodiments, the ratio of the good solvent to the solid compound 102D-6 can be 2 ml / g to 6 ml / g, more preferably 3 ml / g to 5 ml / g.

[0107] In some embodiments, the ratio of the poor solvent to the solid compound 102D-6 can be 3 ml / g to 20 ml / g, more preferably 10 ml / g to 15 ml / g.

[0108] According to an eleventh aspect of the present invention, the present invention provides a method for preparing crystal form III, comprising: adding an amorphous compound 102D-6 to a certain volume of solvent, stirring at a controlled temperature for a certain time, filtering, and drying to obtain crystal form III.

[0109] In some embodiments, the solvent may be one or more of n-heptane, isopropyl ether, etc.

[0110] In some embodiments, the stirring temperature can be 50–85°C, preferably 60–70°C.

[0111] In some embodiments, the stirring time can be 4 to 24 hours, preferably 15 to 20 hours.

[0112] In some embodiments, the drying temperature may be 50–60°C.

[0113] In some embodiments, the ratio of the solvent to solid compound 102D-6 can be 5 ml / g to 20 ml / g, more preferably 10 ml / g to 15 ml / g.

[0114] According to a twelfth aspect of the present invention, the present invention provides a method for preparing crystalline form IV, comprising: adding an amorphous compound 102D-6 to a certain volume of ethyl acetate, stirring at a controlled temperature of 20-30°C, filtering, and drying to obtain crystalline form IV.

[0115] In some embodiments, the ratio of ethyl acetate to solid compound 102D-6 can be 3 ml / g to 5 ml / g.

[0116] According to a thirteenth aspect of the present invention, the present invention provides a method for preparing crystal form IV, comprising: adding compound 102D-6 of crystal form VI to a certain volume of ethyl acetate, stirring at a controlled temperature of 20-30°C until dissolved, adding a certain volume of n-heptane, stirring at a controlled temperature of 20-30°C for 0.5 hours, adding a certain volume of n-heptane, stirring at a controlled temperature of 20-30°C, filtering, and drying to obtain crystal form IV.

[0117] In some embodiments, the ratio of ethyl acetate to solid compound 102D-6 can be 3 ml / g to 4 ml / g.

[0118] In some embodiments, the ratio of the first portion of n-heptane to the solid compound 102D-6 can be 3 ml / g to 4 ml / g.

[0119] In some embodiments, the ratio of the second portion of n-heptane to the solid compound 102D-6 can be 8 ml / g to 9 ml / g.

[0120] According to the fourteenth aspect of the present invention, the present invention provides a method for preparing crystal form V, comprising: adding compound 102D-6 of crystal form VI to a certain volume of n-heptane, heating and stirring for a certain time, cooling, stirring for a certain time, filtering, and drying to obtain crystal form V.

[0121] In some embodiments, the heating and stirring temperature can be 60–100°C, more preferably 80–90°C.

[0122] In some embodiments, the heating and stirring time can be 4 to 8 hours, more preferably 8 hours.

[0123] In some embodiments, the cooling and stirring temperature can be 0–30°C, more preferably 0–10°C.

[0124] In some embodiments, the drying temperature may be 50–60°C.

[0125] In some embodiments, the solid ratio of n-heptane to compound 102D-6 can be 10 ml / g to 20 ml / g.

[0126] According to the fifteenth aspect of the present invention, the present invention provides a method for preparing crystal form VI, comprising: adding compound 102D-6 to a certain volume of methanol, heating and stirring to dissolve, adding water and cooling, stirring to precipitate crystals, filtering, and drying to obtain crystal form VI.

[0127] In some embodiments, the heating and melting temperature can be 50–70°C, more preferably 60–65°C.

[0128] In some embodiments, the crystallization temperature after cooling can be 0–30°C, more preferably 20–30°C.

[0129] In some embodiments, the drying temperature can be 50-60°C, more preferably 55-60°C.

[0130] In some embodiments, the drying time can be 8 hours to 24 hours, more preferably 15 hours to 20 hours.

[0131] In some embodiments, the solid ratio of methanol to compound 102D-6 can be 4 ml / g to 8 ml / g, more preferably 5 ml / g to 7 ml / g.

[0132] In some embodiments, the ratio of water to solid compound 102D-6 can be 4 ml / g to 8 ml / g, more preferably 5 ml / g to 7 ml / g.

[0133] The "crystal form" described in this invention can exist in a sample at concentrations ranging from 0.0001% to 100%. Therefore, any sample containing even trace amounts of the "crystal form" described in this invention, such as greater than 0.0001%, 0.001%, or 0.01%, should be understood as falling within the scope of protection of this invention. To describe the various parameters of the "crystal form" described in this invention more clearly, this invention characterizes and identifies the crystal form by testing various parameters on samples containing a substantially pure "crystal form." The term "substantially pure" means that the sample is substantially composed of one main crystal form and substantially does not contain another or more other crystal forms or amorphous forms, with a main crystal form purity of at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%. The term "substantially free of one or more other crystalline or amorphous forms" means that the content of other crystalline or amorphous forms is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total weight of the sample.

[0134] In the context of this invention, all figures disclosed herein are approximate values, regardless of whether the words "approximately" or "about" are used. The value of each figure may vary by 1%, 2%, or 5%, etc.

[0135] Differential scanning calorimetry (DSC) of the crystal form has experimental errors. The position and peak value of the endothermic peak may vary slightly between one machine and another, and between one sample and another. The experimental error or difference may be less than or equal to 10°C, or less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute.

[0136] Those skilled in the art can adjust the amount of reagents used in the method of the present invention based on their knowledge and experience, including proportionally increasing or decreasing the amount of raw materials and adjusting the amount of solvent, and can also change the temperature of the method of the present invention. These adjustments are also included in the method of the present invention.

[0137] According to a sixteenth aspect of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-described crystal forms I to VI.

[0138] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described crystal form I with a crystal form purity of more than 90%.

[0139] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described crystal form II with a crystal form purity of more than 90%.

[0140] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described crystal form III with a crystal form purity of more than 90%.

[0141] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described crystal form IV with a crystal form purity of more than 90%.

[0142] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described crystal form V with a crystal form purity of more than 90%.

[0143] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described crystal form VI with a crystal form purity of more than 90%.

[0144] In some embodiments, the present invention provides a pharmaceutical composition comprising at least two of the following crystal forms with a therapeutically effective amount of crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, and crystal form VI with a crystal form purity of 90% or more.

[0145] In some embodiments, the present invention provides a pharmaceutical composition comprising at least three of the following crystal forms with a therapeutically effective amount of crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, and crystal form VI with a crystal form purity of 90% or more.

[0146] In some embodiments, the present invention provides a pharmaceutical composition comprising at least four of the following crystal forms with a therapeutically effective amount of crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, and crystal form VI with a crystal form purity of 90% or more.

[0147] In some embodiments, the pharmaceutical composition typically includes a pharmaceutically acceptable carrier, such as a pharmaceutically acceptable diluent, excipient, filler, binder, disintegrant, absorption enhancer, surfactant, lubricant, flavoring agent, sweetener, etc. The pharmaceutical composition can be in any suitable dosage form, specifically tablets, powders, capsules, granules, oral liquids, injections, powders, suppositories, pills, creams, pastes, gels, powders, inhalers, suspensions, dry suspensions, patches, lotions, nanoformulations, etc.

[0148] In some embodiments, the pharmaceutical composition may further comprise one or more therapeutic agents, which may be selected from neuraminidase inhibitors, nucleoside analogs, PB2 inhibitors, PB1 inhibitors, M2 inhibitors, or other anti-influenza drugs.

[0149] According to a seventeenth aspect of the present invention, the present invention provides a pharmaceutical composition comprising one of the crystal forms I to VI or comprising a therapeutically effective amount of at least one of the crystal forms I to VI, for use in the prevention and / or treatment of viral infectious diseases, optionally, said viral infectious disease being an infectious disease caused by an influenza virus, such as an infectious disease caused by influenza A virus or influenza B virus.

[0150] According to the eighteenth aspect of the present invention, the present invention provides the use of a pharmaceutical composition comprising one of the above-described crystal forms I to VI or containing a therapeutically effective amount of at least one of the above-described crystal forms I to VI in the preparation of a medicament for the prevention and / or treatment of viral infectious diseases, optionally, wherein the viral infectious disease is an infectious disease caused by an influenza virus, such as an infectious disease caused by influenza A virus or influenza B virus.

[0151] According to a nineteenth aspect of the present invention, the present invention provides a method for preventing and / or treating viral infectious diseases, the method comprising administering to an individual with a corresponding need a pharmaceutical composition of one of the crystal forms I to VI or containing a therapeutically effective amount of at least one of the crystal forms I to VI; optionally, the viral infectious disease is an infectious disease caused by an influenza virus, such as an infectious disease caused by influenza A virus or influenza B virus.

[0152] In this application, the structure of compound 102D-5 is as follows:

[0153]

[0154] In this application, the structure of compound 102D-6D is as follows:

[0155] Attached Figure Description

[0156] Figure 1 The XRPD pattern of compound 102D-6 of crystal form I provided by this invention;

[0157] Figure 2 The DSC spectrum of compound 102D-6 of crystal form I provided by this invention;

[0158] Figure 3 The TGA spectrum of compound 102D-6 of crystal form I provided by this invention;

[0159] Figure 4 The XRPD spectrum of compound 102D-6 of crystal form II provided by this invention;

[0160] Figure 5 The DSC spectrum of compound 102D-6 of crystal form II provided by this invention;

[0161] Figure 6 The TGA spectrum of compound 102D-6 of crystal form II provided by this invention;

[0162] Figure 7 The XRPD spectrum of compound 102D-6 of crystal form III provided by this invention;

[0163] Figure 8 The DSC spectrum of compound 102D-6 of crystal form III provided by this invention;

[0164] Figure 9 TGA spectrum of compound 102D-6 of crystal form III provided by this invention;

[0165] Figure 10The XRPD spectrum of the crystalline form IV compound 102D-6 provided by this invention;

[0166] Figure 11 The DSC spectrum of the crystalline form IV compound 102D-6 provided by this invention;

[0167] Figure 12 The TGA spectrum of the crystalline form IV compound 102D-6 provided by this invention;

[0168] Figure 13 The XRPD pattern of crystalline compound V 102D-6 provided by this invention;

[0169] Figure 14 The DSC spectrum of crystalline compound V, 102D-6, provided by this invention;

[0170] Figure 15 The TGA spectrum of crystalline compound V, 102D-6, provided by this invention;

[0171] Figure 16 The XRPD pattern of crystalline compound VI 102D-6 provided by this invention;

[0172] Figure 17 The DSC spectrum of crystalline compound VI 102D-6 provided by this invention;

[0173] Figure 18 The TGA spectrum of crystalline compound VI 102D-6 provided by this invention;

[0174] Figure 19 The XRPD spectrum of the existing amorphous compound 102D-6;

[0175] Figure 20 The DSC spectrum of the existing amorphous compound 102D-6;

[0176] Figure 21 The TGA spectrum of the existing amorphous compound 102D-6;

[0177] Figure 22 Liquid phase spectrum of amorphous 102D-6 after 0 days of stability testing;

[0178] Figure 23 Liquid phase spectrum of amorphous 102D-6 under high temperature conditions for 30 days during stability testing.

[0179] Figure 24 Liquid phase spectrum of amorphous 102D-6 under high humidity conditions for 30 days;

[0180] Figure 25Liquid phase spectrum of amorphous 102D-6 under accelerated stability test conditions for 30 days;

[0181] Figure 26 Liquid phase spectrum of 102D-6 stability test on day 0 for crystal form II;

[0182] Figure 27 Liquid phase spectrum of 102D-6 crystal form II under high temperature conditions for 30 days during stability testing.

[0183] Figure 28 Liquid phase spectrum of 102D-6 stability test under high humidity conditions for 30 days for crystal form II;

[0184] Figure 29 Liquid phase spectrum of 102D-6 stability test under accelerated conditions for crystal form II after 30 days;

[0185] Figure 30 Drug-time curves of 102D-6 with different crystal forms administered orally by gavage to SD rats after a single oral administration;

[0186] Figure 31 Drug-time curves after a single oral gavage administration of different crystalline forms of 102D-6 to cynomolgus monkeys;

[0187] Figure 32 Pharmacodynamic study of influenza virus in mice—body weight changes in mice in groups 1-5;

[0188] Figure 33 Pharmacodynamic study of influenza virus in mice—weight changes in mice in groups 6-10;

[0189] Figure 34 Pharmacodynamic study of influenza virus in mice—body weight changes in mice in groups 11-15;

[0190] Figure 35 Pharmacodynamics of influenza virus in mice—survival rate of mice in each group;

[0191] Figure 36 Pharmacodynamic study of influenza virus in ferrets—body temperature changes in ferrets of different groups;

[0192] Figure 37 Pharmacodynamic study of influenza virus in ferrets—clinical symptom scores of ferrets in different groups;

[0193] Figure 38 Pharmacodynamic study of influenza virus in ferrets—virus titers in nasal lavage fluid of ferrets in each group.

[0194] Figure 39 This is the mass spectrum of 102D-1;

[0195] Figure 40 This is the mass spectrum of 102D-2;

[0196] Figure 41 This is the mass spectrum of 102D-3;

[0197] Figure 42 This is the mass spectrum of 102D-4;

[0198] Figure 43 This is the mass spectrum of 102D-5;

[0199] Figure 44 This is the mass spectrum of 102D-5A. Detailed Implementation

[0200] The following specific examples illustrate the embodiments of the present invention. For those skilled in the art, these specific embodiments do not constitute a limitation on the scope of protection claimed by the present invention. Under the teachings of the present invention, obvious substitutions using techniques known in the art still fall within the scope of protection of the present invention.

[0201] The technical solution of the present invention will be further described in detail below through specific embodiments; however, the present invention is not limited to these embodiments.

[0202] abbreviation

[0203] DSC Differential Scan Calorimetry

[0204] TGA thermogravimetric analysis

[0205] T max Peak time

[0206] C max Maximum blood drug concentration

[0207] AUC 0-t Area under the blood drug concentration-time (0-t) curve

[0208] AUC 0-∞ Area under the plasma drug concentration-time (0-∞) curve

[0209] t 1 / 2 half life

[0210] CL / F apparent clearance rate

[0211] instrument

[0212] In an embodiment of the present invention, the high-performance liquid chromatography instrument is an Agilent 1200 liquid chromatograph.

[0213] Column: Inertsil™ ODS-3V 5um 4.6mm*250mm

[0214] Mobile phase A: 0.1% phosphoric acid solution

[0215] Mobile phase B: Acetonitrile-methanol (50:50)

[0216] UV detection wavelength: 210nm

[0217] Flow rate: 1.0 ml / min

[0218] Powder X-ray diffractometer:

[0219] D8 ADVANCE X-ray diffractometer, Bruker Corporation

[0220] Cu target, continuous scanning

[0221] Pipe voltage: 40kV

[0222] Pipe current: 25mA

[0223] Scan range: 5-60° (2θ)

[0224] Differential Scanning Calorimeter: PE Diamond DSC Differential Scanning Calorimeter (USA)

[0225] Thermogravimetric analyzer: PE Pyris1 TGA thermogravimetric analyzer

[0226] Test conditions: DSC Nitrogen atmosphere

[0227] TGA Nitrogen atmosphere

[0228] Example 1: Preparation method of compound 102D-6 of crystal form I

[0229] 0.9 g of compound 102D-6 was weighed into a single-necked flask, 4 ml of methanol was added, and the mixture was heated to reflux to dissolve. The temperature was then lowered to 20–30 °C, and after crystallization, 2 ml of methanol was added again. The mixture was kept at 20–30 °C and stirred for 1 hour. The mixture was filtered, and the filter cake was dried under vacuum at 40 °C to obtain 0.78 g of a white solid. Analysis confirmed that the crystal was of crystal form I, and its X-ray powder diffraction pattern was consistent with... Figure 1 Basically the same, its DSC spectrum is the same as Figure 2 Basically the same, its TGA spectrum is the same as Figure 3 Basically the same.

[0230] The X-ray powder diffraction pattern of crystal form I is shown below:

[0231]

[0232]

[0233] Example 2: Preparation method of compound 102D-6 of crystal form I

[0234] 1 g of compound 102D-6 was weighed into a single-necked flask, 6 ml of ethanol was added, and the mixture was heated to reflux to dissolve. The temperature was then lowered to 20–30 °C, and the mixture was stirred to induce crystallization overnight. The mixture was filtered, and the filter cake was dried under vacuum at 40 °C to obtain 0.85 g of an off-white solid. Analysis confirmed that the crystal was of crystal form I, and its X-ray powder diffraction pattern was consistent with... Figure 1 Basically the same, its DSC spectrum is the same as Figure 2 Basically the same, its TGA spectrum is the same as Figure 3 Basically the same.

[0235] Example 3: Preparation method of compound 102D-6 of crystal form I

[0236] 1 g of compound 102D-6 was weighed into a single-necked flask, 5 ml of methanol was added, and the mixture was heated to reflux to dissolve. 4 ml of water was added, and a solid precipitated. Another 4 ml of methanol was added, and the mixture was dissolved. The temperature was lowered to 0–5 °C, and the mixture was stirred to crystallize for 6 hours. The mixture was filtered, and the filter cake was dried under vacuum at 50 °C to obtain 0.89 g of an off-white solid. Analysis confirmed that the crystal was of crystal form I, and its X-ray powder diffraction pattern was consistent with... Figure 1 Basically the same, its DSC spectrum is the same as Figure 2 Basically the same, its TGA spectrum is the same as Figure 3 Basically the same.

[0237] Example 4: Preparation method of compound 102D-6 of crystal form I

[0238] 1 g of compound 102D-6 was weighed into a single-necked flask, 4 ml of ethanol was added, and the mixture was heated to reflux to dissolve. 7 ml of water was added, and a solid precipitated. 1 ml of ethanol was added to dissolve the solid, and the mixture was cooled to 0–5 °C. The mixture was stirred to allow crystallization for 1 hour, filtered, and the filter cake was dried under vacuum at 40 °C to obtain 0.92 g of a white solid. Analysis confirmed that the crystal was of crystal form I, and its X-ray powder diffraction pattern was consistent with… Figure 1 Basically the same, its DSC spectrum is the same as Figure 2 Basically the same, its TGA spectrum is the same as Figure 3 Basically the same.

[0239] Example 5: Preparation method of compound 102D-6 of crystal form I

[0240] 12g of compound 102D-6 was weighed into a single-necked flask, 60ml of methanol was added, and the mixture was heated to reflux to dissolve. The temperature was then lowered to 0-5℃, and the mixture was stirred to induce crystallization for 2 hours. The mixture was filtered, and the filter cake was dried under vacuum at 45℃ to obtain 10.1g of an off-white solid. Analysis confirmed that the crystal was of crystal form I, and its X-ray powder diffraction pattern was consistent with... Figure 1 Basically the same, its DSC spectrum is the same as Figure 2 Basically the same, its TGA spectrum is the same as Figure 3 Basically the same.

[0241] Example 6: Preparation method of compound 102D-6 of crystal form I

[0242] 5g of compound 102D-6 was weighed into a single-necked flask, 25ml of ethanol was added, and the mixture was heated to 55-60℃ to dissolve. 25ml of water was added, and the mixture was cooled to 20-30℃. The mixture was stirred to induce crystallization for 3 hours, filtered, and the filter cake was dried under vacuum at 50℃ to obtain 4.4g of a white solid. Analysis confirmed that the crystal was of crystal form I, and its X-ray powder diffraction pattern was consistent with... Figure 1 Basically the same, its DSC spectrum is the same as Figure 2 Basically the same, its TGA spectrum is the same as Figure 3 Basically the same.

[0243] Example 7: Preparation method of compound 102D-6 of crystal form II

[0244] 1 g of amorphous compound 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 5 ml of ethyl acetate and 5 ml of n-hexane were added, the mixture was heated to 70 °C to dissolve, and then cooled to 0–5 °C. After the solid precipitated, 5 ml of n-hexane was added, and the mixture was stirred to crystallize for 1 hour. The mixture was filtered, and the filter cake was dried under vacuum at 30 °C to obtain 0.91 g of a white solid. Analysis confirmed that the crystal was of crystal form II, and its X-ray powder diffraction pattern was consistent with... Figure 4 Basically the same, its DSC spectrum is the same as Figure 5 Basically the same, its TGA spectrum is the same as Figure 6 Basically the same.

[0245] Crystal Form II Characteristic Diffraction Data Table

[0246]

[0247] Example 8: Preparation method of compound 102D-6 of crystal form II

[0248] 1 g of amorphous compound 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 5.5 ml of ethyl formate and 14 ml of n-heptane were added, the mixture was heated to 55 °C to dissolve, cooled to 20–30 °C, stirred to induce crystallization for 1 hour, filtered, and the filter cake was dried under vacuum at 30 °C to obtain 0.92 g of off-white solid. Analysis confirmed that the crystal was of crystal form II, and its X-ray powder diffraction pattern was consistent with... Figure 4 Basically the same, its DSC spectrum is the same as Figure 5 Basically the same, its TGA spectrum is the same as Figure 6 Basically the same.

[0249] Example 9: Preparation method of compound 102D-6 of crystal form II

[0250] 0.7 g of amorphous compound 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 3 ml of isopropyl acetate was added, and the mixture was heated to 68 °C to dissolve. 5 ml of n-hexane was added, and a solid precipitated. Another 5 ml of isopropyl acetate was added, and the solid dissolved. The mixture was cooled to 0–5 °C, stirred, and crystallized for 1 hour. The mixture was filtered, and the filter cake was dried under vacuum at 40 °C to obtain 0.28 g of a white solid, yield: 40%. Analysis confirmed that the crystal was of crystal form II, and its X-ray powder diffraction pattern was consistent with... Figure 4 Basically the same, its DSC spectrum is the same as Figure 5 Basically the same, its TGA spectrum is the same as Figure 6 Basically the same.

[0251] Example 10: Preparation method of compound 102D-6 of crystal form II

[0252] 10g of compound 102D-6 (crystal form III, prepared according to the methods of Examples 17-24) was weighed into a single-necked flask, 50ml of ethyl formate was added, and the mixture was dissolved at 20-30°C. The solution was filtered, and the filtrate was heated to 50°C. 110ml of n-heptane was added, and the solution was cooled to 20-30°C. The filtrate was filtered again, and the filter cake was dried under vacuum at 55°C to obtain 9.3g of an off-white solid. Analysis confirmed that the crystal was crystal form II, and its X-ray powder diffraction pattern was consistent with... Figure 4 Basically the same, its DSC spectrum is the same as Figure 5 Basically the same, its TGA spectrum is the same as Figure 6 Basically the same.

[0253] Example 11: Preparation method of compound 102D-6 of crystal form II

[0254] 1 g of compound 102D-6 (prepared according to the methods of Examples 1-6) of crystal form I was weighed into a single-necked flask, 5 ml of ethyl acetate was added, and the mixture was dissolved at 20-30°C. 5 ml of n-heptane was added, and no solid precipitated. Crystal form II seed crystals (prepared according to the methods of Examples 7-10) were added, and the mixture was stirred at 20-30°C for 0.5 hours, resulting in the precipitation of a large amount of solid. 5 ml of n-heptane was added, and the mixture was stirred at 20-30°C for 0.5 hours. 5 ml of n-heptane was added again, and the mixture was stirred at 20-30°C for 1.5 hours. The mixture was filtered, and the filter cake was dried by forced air at 50°C to obtain 0.93 g of an off-white solid. Analysis confirmed that the crystal was crystal form II, and its X-ray powder diffraction pattern was consistent with... Figure 4 Basically the same, its DSC spectrum is the same as Figure 5 Basically the same, its TGA spectrum is the same as Figure 6 Basically the same.

[0255] Example 12: Preparation method of compound 102D-6 of crystal form II

[0256] 5g of compound 102D-6 of crystal form VI (prepared according to the methods of Examples 34-38) was weighed into a single-necked flask, 20ml of ethyl acetate and 0.25g of water were added, and the mixture was dissolved at 20-30°C. 5ml of n-heptane was added, along with 0.01g of crystal form II seed crystals (prepared according to the methods of Examples 7-11). The mixture was stirred at 20-30°C for 0.5 hours, then 25ml of n-heptane was added, and the mixture was stirred at 20-30°C for 0.5 hours. Then, 30ml of n-heptane was added, and the mixture was stirred at 20-30°C for 1 hour. The mixture was filtered, and the filter cake was dried by forced air at 50°C to obtain 4.8g of a white solid, with a yield of 96%. Analysis confirmed that the crystal was crystal form II, and its X-ray powder diffraction pattern was consistent with... Figure 4 Basically the same, its DSC spectrum is the same as Figure 5 Basically the same, its TGA spectrum is the same as Figure 6 Basically the same.

[0257] Example 13: Preparation method of compound 102D-6 of crystal form II

[0258] 5g of compound 102D-6 of crystal form VI (prepared according to the methods of Examples 34-38) was weighed into a single-necked flask, 20ml of ethyl acetate and 0.25g of water were added, the temperature was raised to 60-65°C, 10ml of n-heptane was added, and 0.005g of crystal form II seed crystals (prepared according to the methods of Examples 7-12) was added. The mixture was stirred at 60-65°C for 0.5 hours, 25ml of n-heptane was added, and the mixture was stirred at 60-65°C for 0.5 hours. The mixture was then cooled to 0-10°C and stirred at 0-10°C for 1 hour. The mixture was filtered, and the filter cake was dried by forced air at 50°C to obtain 4.64g of a white solid, with a yield of 92.8%. Analysis confirmed that the crystal was crystal form II, and its X-ray powder diffraction pattern was consistent with... Figure 4 Basically the same, its DSC spectrum is the same as Figure 5 Basically the same, its TGA spectrum is the same as Figure 6 Basically the same.

[0259] Example 14: Preparation method of compound 102D-6 of crystal form II

[0260] 10g of compound 102D-6 (prepared according to the methods of Examples 1-6) of crystal form I was weighed into a single-necked flask, 100ml of n-heptane was added, the temperature was raised to 40-45℃, and the mixture was stirred at 40-45℃ for 21 hours. After filtration, the filter cake was dried by forced air at 50℃ to obtain 9.6g of off-white solid. Analysis confirmed that the crystal was of crystal form II, and its X-ray powder diffraction pattern was consistent with... Figure 4 Basically the same, its DSC spectrum is the same as Figure 5 Basically the same, its TGA spectrum is the same as Figure 6 Basically the same.

[0261] Example 15: Preparation method of compound 102D-6 of crystal form II

[0262] 10g of compound 102D-6 (prepared according to the methods of Examples 1-6) of crystal form I was weighed into a single-necked flask, 150ml of n-heptane was added, the temperature was raised to 60-65℃, and the mixture was stirred at 60-65℃ for 8 hours. After filtration, the filter cake was dried by forced air at 50℃ to obtain 9.5g of off-white solid. Analysis confirmed that the crystal was of crystal form II, and its X-ray powder diffraction pattern was consistent with... Figure 4 Basically the same, its DSC spectrum is the same as Figure 5 Basically the same, its TGA spectrum is the same as Figure 6 Basically the same.

[0263] Example 16: Preparation method of compound 102D-6 of crystal form II

[0264] 10g of compound 102D-6 (prepared according to the methods of Examples 1-6) of crystal form I was weighed into a single-necked flask, 100ml of n-heptane was added, the temperature was raised to 80-85℃, and the mixture was stirred at 80-85℃ for 8 hours. After filtration, the filter cake was dried by forced air at 50℃ to obtain 9.4g of off-white solid. Analysis confirmed that the crystal was of crystal form II, and its X-ray powder diffraction pattern was consistent with... Figure 4 Basically the same, its DSC spectrum is the same as Figure 5 Basically the same, its TGA spectrum is the same as Figure 6 Basically the same.

[0265] Example 17: Preparation method of compound 102D-6 of crystal form III

[0266] 2g of amorphous compound 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 8ml of ethyl acetate was added, and the mixture was heated to 60-65℃ to dissolve. 10ml of n-hexane was added, and a solid precipitated. The mixture was cooled to 0-10℃ and stirred at 0-10℃ for 1 hour. After filtration, the filter cake was dried under vacuum at 45℃ to obtain 1.4g of an off-white solid. Analysis confirmed that the crystal was of crystal form III, and its X-ray powder diffraction pattern was consistent with... Figure 7 Basically the same, its DSC spectrum is the same as Figure 8 Basically the same, its TGA spectrum is the same as Figure 9 Basically the same.

[0267] Crystal Form III Characteristic Diffraction Data Table

[0268]

[0269]

[0270] Example 18: Preparation method of compound 102D-6 of crystal form III

[0271] 12g of amorphous compound 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 60ml of ethyl acetate was added, and the mixture was heated to 65-70℃ to dissolve. 60ml of n-hexane was added, and a solid precipitated. The mixture was cooled to 0-10℃ and stirred at 0-10℃ for 1 hour. After filtration, the filter cake was dried under vacuum at 45℃ to obtain 7.43g of an off-white solid, with a yield of 61.9%. Analysis confirmed that the crystal was of crystal form III, and its X-ray powder diffraction pattern was consistent with... Figure 7 Basically the same, its DSC spectrum is the same as Figure 8 Basically the same, its TGA spectrum is the same as Figure 9 Basically the same.

[0272] Example 19: Preparation method of compound 102D-6 of crystal form III

[0273] 10g of amorphous compound 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 50ml of ethyl acetate was added, and the mixture was heated to 65-70℃ to dissolve. 30ml of n-hexane was added, and a solid precipitated. The mixture was cooled to 0-10℃ and stirred at 0-10℃ for 1 hour. After filtration, the filter cake was dried under vacuum at 45℃ to obtain 4.5g of a white solid, yield: 45%. Analysis confirmed that the crystal was of crystal form III, and its X-ray powder diffraction pattern was consistent with... Figure 7 Basically the same, its DSC spectrum is the same as Figure 8 Basically the same, its TGA spectrum is the same as Figure 9 Basically the same.

[0274] Example 20: Preparation method of compound 102D-6 of crystal form III

[0275] 1 g of amorphous compound 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 5 ml of ethyl acetate was added, and the mixture was heated to 60–70 °C to dissolve. 5 ml of n-hexane was added, and the mixture was kept at 60–70 °C and stirred for 0.5 hours. 5 ml of n-hexane was added again, and the mixture was cooled to 0–10 °C and stirred for 1 hour. The mixture was filtered, and the filter cake was vacuum dried at 45 °C to obtain 0.8 g of an off-white solid. Analysis confirmed that the crystal was of crystal form III, and its X-ray powder diffraction pattern was consistent with... Figure 7 Basically the same, its DSC spectrum is the same as Figure 8 Basically the same, its TGA spectrum is the same as Figure 9 Basically the same.

[0276] Example 21: Preparation method of compound 102D-6 of crystal form III

[0277] 1 g of amorphous compound 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 5 ml of ethyl acetate was added, and the mixture was heated to 70–80 °C to dissolve. 5 ml of n-heptane was added, and the mixture was kept at 70–80 °C and stirred for 0.5 hours. 5 ml of n-heptane was added again, and the mixture was cooled to 0–10 °C and stirred for 1 hour. The mixture was filtered, and the filter cake was dried under vacuum at 50 °C to obtain 0.82 g of an off-white solid. Analysis confirmed that the crystal was of crystal form III, and its X-ray powder diffraction pattern was consistent with... Figure 7 Basically the same, its DSC spectrum is the same as Figure 8 Basically the same, its TGA spectrum is the same as Figure 9 Basically the same.

[0278] Example 22: Preparation method of compound 102D-6 of crystal form III

[0279] 5g of compound 102D-6 (prepared according to the methods of Comparative Examples 1 and 2) of crystal form VI was weighed into a single-necked flask, 10ml of ethyl acetate was added, the temperature was raised to 70-80℃ to dissolve, the temperature was lowered to 20-30℃ to crystallize, the mixture was filtered, and the filter cake was dried in a forced-air drying process at 50℃ to obtain 1.9g of off-white solid. Analysis confirmed that the crystal was of crystal form III, and its X-ray powder diffraction pattern was consistent with... Figure 7 Basically the same, its DSC spectrum is the same as Figure 8 Basically the same, its TGA spectrum is the same as Figure 9 Basically the same.

[0280] Example 23: Preparation method of compound 102D-6 of crystal form III

[0281] 1 g of amorphous compound 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 10 ml of n-heptane was added, the temperature was raised to 60–70 °C, and the mixture was stirred at 60–70 °C for 20 hours. The mixture was filtered, and the filter cake was dried by forced air at 50 °C to obtain a white solid. Analysis confirmed that the crystal was of crystal form III, and its X-ray powder diffraction pattern was consistent with… Figure 7 The values ​​are basically the same (0.87g), and their DSC spectra are similar. Figure 8 Basically the same, its TGA spectrum is the same as Figure 9 Basically the same.

[0282] Example 24: Preparation method of compound 102D-6 of crystal form III

[0283] 1 g of amorphous compound 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 20 ml of isopropyl ether was added, the temperature was raised to 60–70 °C, and the mixture was stirred at 60–70 °C for 15 hours. The mixture was filtered, and the filter cake was dried by forced air at 50 °C to obtain 0.6 g of a white solid. Analysis confirmed that the crystal was of crystal form III, and its X-ray powder diffraction pattern was consistent with… Figure 7 Basically the same, its DSC spectrum is the same as Figure 8 Basically the same, its TGA spectrum is the same as Figure 9 Basically the same.

[0284] Example 25: Preparation method of compound 102D-6 of crystal form IV

[0285] 5g of amorphous compound 102D-6 (prepared according to the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, and 15ml of ethyl acetate was added. The mixture was dissolved at 20-30℃, and a solid precipitated. The mixture was stirred at 20-30℃ for 1 hour, filtered, and the filter cake was dried in a forced-air drying process at 50℃ to obtain 1.8g of a white solid. Analysis confirmed that the crystal was of crystal form IV, and its X-ray powder diffraction pattern was consistent with... Figure 10 Basically the same, its DSC spectrum is the same as Figure 11 Basically the same, its TGA spectrum is the same as Figure 12 Basically the same.

[0286] Crystal form IV characteristic diffraction data table

[0287]

[0288] Example 26: Preparation method of compound 102D-6 of crystal form IV

[0289] 5g of amorphous compound 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, and 20ml of ethyl acetate was added. The mixture was dissolved at 20-30℃, and a solid precipitated. The mixture was stirred at 20-30℃ for 1 hour, filtered, and the filter cake was dried in a forced-air drying process at 50℃ to obtain 1.6g of an off-white solid. Analysis confirmed that the crystal was of crystal form IV, and its X-ray powder diffraction pattern was consistent with... Figure 10 Basically the same, its DSC spectrum is the same as Figure 11 Basically the same, its TGA spectrum is the same as Figure 12 Basically the same.

[0290] Example 27: Preparation method of compound 102D-6 of crystal form IV

[0291] 5g of amorphous compound 102D-6 (prepared according to the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, and 25ml of ethyl acetate was added. The mixture was dissolved at 20-30℃, and a solid precipitated. The mixture was stirred at 20-30℃ for 1 hour, filtered, and the filter cake was dried in a forced-air drying process at 50℃ to obtain 1.3g of an off-white solid. Analysis confirmed that the crystal was of crystal form IV, and its X-ray powder diffraction pattern was consistent with... Figure 10 Basically the same, its DSC spectrum is the same as Figure 11 Basically the same, its TGA spectrum is the same as Figure 12 Basically the same.

[0292] Example 28: Preparation method of compound 102D-6 of crystal form IV

[0293] 5g of compound 102D-6 (prepared according to the methods of Examples 34-38) of crystal form VI was weighed into a single-necked flask, 15ml of ethyl acetate was added, and the mixture was stirred and dissolved at 20-30℃. 15ml of n-heptane was added, and the mixture was stirred at 20-30℃ for 0.5 hours. 45ml of n-heptane was added, and the mixture was stirred at 20-30℃ for 1 hour. The mixture was filtered, and the filter cake was dried in a forced-air drying process at 55℃ to obtain 4.1g of an off-white solid. Analysis confirmed that the crystal was of crystal form IV, and its X-ray powder diffraction pattern was consistent with... Figure 10 Basically the same, its DSC spectrum is the same as Figure 11 Basically the same, its TGA spectrum is the same as Figure 12 Basically the same.

[0294] Example 29: Preparation method of compound 102D-6 of crystal form IV

[0295] 5g of compound 102D-6 (prepared according to the methods of Examples 34-38) of crystal form VI was weighed into a single-necked flask, 20ml of ethyl acetate was added, and the mixture was stirred and dissolved at 20-30℃. 20ml of n-heptane was added, and the mixture was stirred at 20-30℃ for 0.5 hours. 40ml of n-heptane was added, and the mixture was stirred at 20-30℃ for 1 hour. The mixture was filtered, and the filter cake was dried by forced air at 55℃ to obtain 3.7g of an off-white solid. Analysis confirmed that the crystal was of crystal form IV, and its X-ray powder diffraction pattern was consistent with... Figure 10 Basically the same, its DSC spectrum is the same as Figure 11 Basically the same, its TGA spectrum is the same as Figure 12 Basically the same.

[0296] Example 30: Preparation method of compound 102D-6 of crystal form IV

[0297] 5g of compound 102D-6 (prepared according to the methods of Examples 34-38) of crystal form VI was weighed into a single-necked flask, 15ml of ethyl acetate was added, and the mixture was stirred and dissolved at 20-30℃. 20ml of n-heptane was added, and the mixture was stirred at 20-30℃ for 0.5 hours. 40ml of n-heptane was added, and the mixture was stirred at 20-30℃ for 1 hour. The mixture was filtered, and the filter cake was dried in a forced-air drying process at 55℃ to obtain 4.3g of an off-white solid. Analysis confirmed that the crystal was of crystal form IV, and its X-ray powder diffraction pattern was consistent with... Figure 10 Basically the same, its DSC spectrum is the same as Figure 11 Basically the same, its TGA spectrum is the same as Figure 12 Basically the same.

[0298] Example 31: Preparation method of compound 102D-6 with crystal form V

[0299] 30g of compound 102D-6 (prepared according to the methods of Examples 34-38) of crystal form VI was weighed into a single-necked flask, 300ml of n-heptane was added, the temperature was raised to 60-70°C, and stirred at 60-70°C for 4 hours. The temperature was then lowered to 20-30°C, and stirred at 20-30°C for 1 hour. The mixture was filtered, and the filter cake was dried by forced air at 60°C to obtain 28g of off-white solid. Analysis confirmed that the crystal was of crystal form V, and its X-ray powder diffraction pattern was consistent with... Figure 13 Basically the same, its DSC spectrum is the same as Figure 14 Basically the same, its TGA spectrum is the same as Figure 15 Basically the same.

[0300] Crystal form V characteristic diffraction data table

[0301]

[0302] Example 32: Preparation method of compound 102D-6 with crystal form V

[0303] 10g of compound 102D-6 (prepared according to the methods of Examples 34-38) of crystal form VI was weighed into a single-necked flask, 150ml of n-heptane was added, the temperature was raised to 50-60°C, and stirred for 8 hours at 50-60°C. The temperature was then lowered to 20-30°C, and stirred for 1 hour at 20-30°C. The mixture was filtered, and the filter cake was dried by forced air at 50°C to obtain 9.4g of off-white solid. Analysis confirmed that the crystal was of crystal form V, and its X-ray powder diffraction pattern was consistent with... Figure 13 Basically the same, its DSC spectrum is the same as Figure 14 Basically the same, its TGA spectrum is the same as Figure 15 Basically the same.

[0304] Example 33: Preparation method of compound 102D-6 with crystal form V

[0305] 10g of compound 102D-6 of crystal form VI (prepared according to the methods of Examples 34-38) was weighed into a single-necked flask, 200ml of n-heptane was added, the temperature was raised to 95-100℃, and stirred for 4 hours at 95-100℃. The temperature was then lowered to 0-10℃, and stirred for 1 hour at 0-10℃. The mixture was filtered, and the filter cake was dried by forced air at 60℃ to obtain 9.5g of off-white solid. Analysis confirmed that the crystal was of crystal form V, and its X-ray powder diffraction pattern was consistent with... Figure 13 Basically the same, its DSC spectrum is the same as Figure 14 Basically the same, its TGA spectrum is the same as Figure 15 Basically the same.

[0306] Example 34: Preparation method of compound 102D-6 of crystal form VI

[0307] 206g of amorphous 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 1030ml of methanol was added, and the mixture was heated to 60-70℃ to dissolve. Then, 1060ml of water was added while maintaining the temperature at 50-70℃. The mixture was cooled to 20-30℃, stirred, and allowed to crystallize for 0.5 hours. The mixture was filtered, and the filter cake was dried in a forced-air dryer at 50℃ for 19 hours to obtain 196.27g of a white solid, with a yield of 95.3%. Analysis confirmed that the crystal was of crystal form VI, and its X-ray powder diffraction pattern was consistent with... Figure 16 Basically the same, its DSC spectrum is the same as Figure 17 Basically the same, its TGA spectrum is the same as Figure 18 Basically the same.

[0308] Crystal form VI characteristic diffraction data table

[0309]

[0310]

[0311] Example 35: Preparation method of compound 102D-6 of crystal form VI

[0312] Weigh 60g of amorphous 102D-6 (prepared by the methods of Comparative Examples 1 and 2) into a single-necked flask, add 360ml of methanol, heat to 60-70℃ to dissolve, add 360ml of water, cool to 0-10℃, stir to precipitate crystals for 1 hour, filter, and dry the filter cake at 50℃ for 8 hours to obtain 58g of off-white solid. Analysis confirmed that the crystal is crystal form VI, and its X-ray powder diffraction pattern is consistent with... Figure 16 Basically the same, its DSC spectrum is the same as Figure 17 Basically the same, its TGA spectrum is the same as Figure 18 Basically the same.

[0313] Example 36: Preparation method of compound 102D-6 of crystal form VI

[0314] Weigh 30g of amorphous 102D-6 (prepared by the methods of Comparative Examples 1 and 2) into a single-necked flask, add 150ml of methanol, heat to 60-65℃ to dissolve, control the temperature at 40-65℃ and add 210ml of water, cool to 20-30℃, stir to precipitate crystals for 1 hour, filter, and dry the filter cake at 60℃ for 8 hours to obtain 28g of off-white solid. Analysis confirmed that the crystal is crystal form VI, and its X-ray powder diffraction pattern is consistent with... Figure 16 Basically the same, its DSC spectrum is the same as Figure 17 Basically the same, its TGA spectrum is the same as Figure 18 Basically the same.

[0315] Example 37: Preparation method of compound 102D-6 of crystal form VI

[0316] Weigh 60g of amorphous 102D-6 (prepared by the methods of Comparative Examples 1 and 2) into a single-necked flask, add 420ml of methanol, heat to 60-65℃ to dissolve, control the temperature at 50-65℃ and add 420ml of water, cool to 0-10℃, stir to precipitate crystals for 2 hours, filter, and dry the filter cake at 50℃ for 20 hours to obtain 57g of off-white solid. Analysis confirmed that the crystal is crystal form VI, and its X-ray powder diffraction pattern is consistent with... Figure 16 Basically the same, its DSC spectrum is the same as Figure 17 Basically the same, its TGA spectrum is the same as Figure 18 Basically the same.

[0317] Example 38: Preparation method of compound 102D-6 of crystal form VI

[0318] 30g of amorphous 102D-6 (prepared by the methods of Comparative Examples 1 and 2) was weighed into a single-necked flask, 150ml of methanol was added, and the mixture was heated to 60-65℃ to dissolve. 120ml of water was added, and the mixture was cooled to 20-30℃ and stirred to induce crystallization for 0.5 hours. The mixture was filtered, and the filter cake was dried at 60℃ for 20 hours to obtain 27g of a white solid. Analysis confirmed that the crystal was of crystal form VI, and its X-ray powder diffraction pattern was consistent with... Figure 16 Basically the same, its DSC spectrum is the same as Figure 17 Basically the same, its TGA spectrum is the same as Figure 18 Basically the same.

[0319] Example 39

[0320] 200g of isoamyl alcohol and 130g of tetrahydrofuran were added sequentially to the reaction flask. Nitrogen was used to purge the mixture. 22g of sodium tert-butoxide and 50g of compound 102D-0 were added while maintaining room temperature. The reaction was carried out for 3 hours while maintaining room temperature. 300g of 8% citric acid monohydrate aqueous solution was added, followed by extraction and phase separation. The aqueous phase was discarded, and 32g of p-toluenesulfonic acid monohydrate and 100g of anhydrous sodium sulfate were added to the organic phase. The mixture was stirred for 1 hour, filtered, and the filtrate was concentrated under reduced pressure until no more droplets flowed out. The filtrate was heated to 50-60°C, and 850g of n-heptane was added. The mixture was cooled to 0-10°C and crystallized for 2 hours. The crystals were filtered, and the wet product was dried to constant weight to obtain 67.1g of off-white solid compound 102D-1, with a yield of 91.5%.

[0321]

[0322] 1 H NMR (400MHz, DMSO-d6) δ: 9.27 (s, 1H), 8.35 (d, J = 7.2Hz, 1H), 8.02 (d, J = 12.4Hz, 1H), 7.47 (d ,J=7.8Hz,2H),7.12(d,J=7.8Hz,2H),7.08(d,J=7.2Hz,1H),4.94~5.00(m,1H),4.19~4.03( m,5H),3.47(td,J=11.9,3.1Hz,1H),3.25(dd,J=11.5,9.9Hz,1H),3.01(ddd,J=13.7,12.1, 4.4Hz, 1H), 2.29 (s, 3H), 1.76 ~ 1.86 (m, 1H), 1.69 ~ 1.64 (m, 2H), 0.93 (dd, J = 6.7, 1.6Hz, 6H).

[0323] ESI: [M+H] + 308.3 (see) Figure 39 ).

[0324] Example 40

[0325] 215 g of isoamyl alcohol and 100 g of tetrahydrofuran were added sequentially to the reaction flask. Nitrogen was used to purge the mixture. 25 g of sodium tert-amyl alcohol and 50 g of compound 102D-0 were added while maintaining room temperature. The reaction was carried out for 5 hours while maintaining room temperature. 270 g of 8% citric acid monohydrate aqueous solution was added, followed by extraction and phase separation. The aqueous phase was discarded, and 32 g of p-toluenesulfonic acid monohydrate and 80 g of anhydrous sodium sulfate were added to the organic phase. The mixture was stirred for 1 hour, filtered, and the filtrate was concentrated under reduced pressure until no more droplets flowed out. The filtrate was heated to 50–60 °C, and 700 g of n-heptane was added. The mixture was cooled to 10–20 °C and crystallized for 2 hours. The crystals were filtered, and the wet product was dried to constant weight to obtain 65.3 g of off-white solid compound 102D-1, with a yield of 89.1%.

[0326] Example 41

[0327] 210 g of ethyl acetate, 70 g of cyclohexane, 60 g of compound 102D-1, 50 g of compound 102M1-D1, 160 g of ethyl acetate solution of T3P (propyl phosphoric anhydride), and 20 g of methanesulfonic acid were added sequentially to a reaction flask. The mixture was heated to 60–70 °C and reacted for 15 hours. After cooling to room temperature, 160 g of tetrahydrofuran and 120 g of water were added, followed by 150 g of 20% sodium hydroxide aqueous solution. The mixture was extracted, and the phases were separated. The aqueous phase was discarded, and 36 g of methanesulfonic acid was added to the organic phase. Crystallization was carried out at 0–10 °C for 2 hours. The mixture was filtered, and the wet product was dried to constant weight to obtain 69 g of off-white solid compound 102D-2, with a yield of 84.8%.

[0328]

[0329] 1 H NMR (400MHz, DMSO-d6) δ: 7.42 (dd, J=10.2, 6.4Hz, 2H), 7.33 (d, J=7.7Hz, 1H), 7.19~7.06 (m, 3H), 6.97 (dd, J=7.9, 1.5Hz, 1H), 6.82(td,J=7.4,1.4Hz,1H),5.86~5.77(m,2H),5.44(dd,J=14.3,2.4Hz,1H),4.51~4.42(m,2H),4.25(dt,J=9.1,6.7Hz,1H),4 .07(d,J=14.3Hz,1H),4.03~3.93(m,2H),3.66(dd,J=11.6,3.2Hz,1H),3.52(t,J=10.4Hz,1H),3.30(td,J=11.7,2.7Hz,1H),2 .94(ddd,J=14.8,11.9,3.4Hz,1H),2.37(s,3H),1.84(dt,J=13.4,6.7Hz,1H),1.67~1.60(m,2H),0.95(dd,J=6.7,5.2Hz,6H).

[0330] ESI: [M+H] + 554.2 (see) Figure 40 ).

[0331] Example 42

[0332] 270 g of ethyl acetate, 85 g of cyclohexane, 60 g of compound 102D-1, 50 g of compound 102M1-D1, 180 g of ethyl acetate solution of T4P (n-butylphosphine anhydride), and 24 g of methanesulfonic acid were added sequentially to a reaction flask. The mixture was heated to 70–80 °C and reacted for 10 hours. After cooling to room temperature, 180 g of tetrahydrofuran and 150 g of water were added, followed by 150 g of 20% sodium hydroxide aqueous solution. The mixture was extracted, and the phases were separated. The aqueous phase was discarded, and 36 g of methanesulfonic acid was added to the organic phase. Crystallization was carried out at 0–10 °C for 2 hours. The mixture was filtered, and the wet product was dried to constant weight to obtain 66 g of off-white solid compound 102D-2, with a yield of 81.2%.

[0333] Example 43

[0334] Add 60g of compound 102D-2 and 400g of dichloromethane to a reaction flask, start stirring, add 200g of 10% sodium bicarbonate aqueous solution dropwise, separate the phases, discard the aqueous phase, cool the organic phase to 0-10℃, add 20.6g of m-chloroperoxybenzoic acid, react at 0-10℃ for 1 hour, add 6g of sodium sulfite to quench the reaction, add 300g of water, separate the phases, discard the aqueous phase, add 300g of saturated sodium bicarbonate aqueous solution to the organic phase for extraction, separate the phases, discard the aqueous phase, add 30g of anhydrous sodium sulfate to the organic phase for drying for 1 hour, filter, concentrate the filtrate under reduced pressure to dryness to obtain 49.3g of compound 102D-3 yellow solid, yield 93.7%.

[0335]

[0336] 1 H NMR (400MHz, DMSO-d6) δ: 7.83 (dd, J=7.9, 1.3Hz, 1H), 7.62~7.41 (m, 4H), 7.31 (td, J=7.5, 1.4Hz, 1H), 7.21 (dd, J=7.9, 1.4Hz,1H),6.01(s,1H),5.75(dd,J=13.3,2.4Hz,1H),5.56(d,J=7.7Hz,1H),5.04(d,J=13.2Hz,1H),4.48(ddd,J=11. 7,7.1,2.7Hz,2H),4.24(dt,J=9.0,6.7Hz,1H),4.06~3.94(m,2H),3.67(dd,J=11.6,3.2Hz,1H),3.51(t,J=10.3Hz,1H ), 3.35~3.24(m,2H),2.92(ddd,J=13.4,11.6,3.4Hz,1H),1.92~1.74(m,1H),1.64(m,2H),0.95(dd,J=6.6,4.5Hz,6H).

[0337] ESI: [M+H] + 570.2 (see) Figure 41 ).

[0338] Example 44

[0339] Add 30g of compound 102D-2 and 200g of dichloromethane to a reaction flask, start stirring, add 100g of 5% sodium hydroxide aqueous solution dropwise, separate the phases, discard the aqueous phase, cool the organic phase to 0-10℃, add 5.8g of hydrogen peroxide, react at 0-10℃ for 1 hour, add 3g of sodium sulfite to quench the reaction, add 150g of water, separate the phases, discard the aqueous phase, add 150g of saturated sodium bicarbonate aqueous solution to the organic phase for extraction, separate the phases, discard the aqueous phase, add 15g of anhydrous sodium sulfate to the organic phase for drying for 1 hour, filter, concentrate the filtrate under reduced pressure to dryness to obtain 24.8g of compound 102D-3 yellow solid, yield 94.3%.

[0340] Example 45

[0341] 150 g of N-methylpyrrolidone, 47 g of compound 102D-3, 24.5 g of lithium chloride, and 3.8 g of methanesulfonic acid were added to a reaction flask. The mixture was heated to 80–90 °C and reacted for 15 hours. The temperature was then lowered to 40–50 °C, and 56 g of acetonitrile and 700 g of water were added. The mixture was then cooled to 0–10 °C and stirred for 1 hour. The mixture was filtered, and the wet product was dried to constant weight to obtain 31.7 g of off-white solid compound 102D-4, with a yield of 76.9%.

[0342]

[0343] 1 H NMR (400MHz, DMSO-d6) δ: 11.83 (s, 1H), 7.83 (dd, J=7.8, 1.3Hz, 1H), 7.58 (td, J=7.6, 1.4Hz, 1H), 7.5 3~7.40(m,3H),7.34(td,J=7.5,1.3Hz,1H),7.22(dd,J=7.8,1.4Hz,1H),5.99(s,1H),5.79~5.67(m, 1H), 5.48 (d, J = 7.7Hz, 1H), 5.07 (d, J = 13.2Hz, 1H), 4.57 (dd, J = 9.9, 3.0Hz, 1H), 4.45 (dd, J = 13.4, 2. 4Hz, 1H), 4.03 (dd, J = 10.7, 3.1Hz, 1H), 3.73 ~ 3.61 (m, 2H), 3.48 ~ 3.38 (m, 1H), 3.03 (t, J = 12.1Hz, 1H).

[0344] ESI: [M+H] + 500.2 (see) Figure 42).

[0345] Example 46

[0346] 120 g of N,N-dimethylacetamide, 40 g of compound 102D-3, 26.8 g of lithium chloride, and 3.2 g of methanesulfonic acid were added to a reaction flask. The mixture was heated to 90–100 °C and reacted for 10 hours. The temperature was then lowered to 40–50 °C, and 48 g of acetonitrile and 600 g of water were added. The mixture was then cooled to 10–20 °C and stirred for 1 hour. The mixture was filtered, and the wet product was dried to constant weight to obtain 25.7 g of off-white solid compound 102D-4, with a yield of 73.2%.

[0347] Example 47

[0348] 48 g of compound 102D-4, 26.4 g of potassium carbonate, 8.16 g of potassium iodide, and 636 g of dichloromethane were added to a reaction flask. The temperature was lowered to 10–20 °C, and 32.1 g of ethyl 1-bromoacetate was added. The reaction was carried out at 10–20 °C for 15 hours. 240 g of water was added for extraction, and the phases were separated. The aqueous phase was discarded, and 24 g of anhydrous sodium sulfate was added to the organic phase. The mixture was dried for 1 hour, filtered, and the filtrate was concentrated to dryness under reduced pressure. 112 g of acetonitrile was added to the concentrate, and the mixture was stirred at room temperature to crystallize for 1 hour. The mixture was filtered, and the filter cake was dried to constant weight to obtain 24.8 g of pale yellow compound 102D-5A solid, with a yield of 44%.

[0349] The filtrate of 102D-5A was concentrated to dryness under reduced pressure. 211g of toluene was added to the concentrate, and the mixture was stirred at room temperature for 1 hour to induce crystallization. The mixture was then filtered, and the wet product was dried to constant weight to give 22.4g of yellow 102D-5 compound solid, with a yield of 39.8%.

[0350]

[0351] 102D-5 11H NMR (400 MHz, DMSO-d6) δ 7.84 (dd, J = 7.8, 1.3 Hz, 1H), 7.60 (td, J = 7.6, 1.4 Hz, 1H), 7.56 - 7.41 (m, 3H), 7.32 (td, J = 7.5, 1.4 Hz, 1H), 7.14 (dd, J = 7.8, 1.4 Hz, 1H), 6.55 (q, J = 5.2 Hz, 1H), 5.76 (dd, J = 13.1, 2.4 Hz, 1H), 5.72 (s, 1H), 5.63 (d, J = 7.7 Hz, 1H), 5.01 (d, J = 13.2 Hz, 1H), 4.52 - 4.38 (m, 2H), 4.02 (dd, J = 10.7, 3.2 Hz, 1H), 3.67 (dd, J = 11.5, 3.2 Hz, 1H), 3.28 (dd, J = 11.7, 2.7 Hz, 1H), 2.95 (ddd, J = 14.8, 11.7, 3.4 Hz, 1H), 2.30 (s, 1H), 2.09 (s, 3H), 1.62 (d, J = 5.3 Hz, 3H).

[0352] of 102D-5A 1 1H NMR (400 MHz, DMSO-d6) δ 7.83 (dd, J = 7.8, 1.3 Hz, 1H), 7.58 (td, J = 7.6, 1.4 Hz, 1H), 7.54 - 7.41 (m, 3H), 7.35 (td, J = 7.5, 1.4 Hz, 1H), 7.23 (dd, J = 7.8, 1.4 Hz, 1H), 6.31 (q, J = 5.2 Hz, 1H), 5.94 (s, 1H), 5.73 (dd, J = 13.2, 2.4 Hz, 1H), 5.66 (d, J = 7.8 Hz, 1H), 5.01 (d, J = 13.2 Hz, 1H), 4.47 (dd, J = 9.8, 3.0 Hz, 1H), 4.42 (dd, J = 13.4, 2.4 Hz, 1H), 4.07 (dd, J = 10.6, 3.0 Hz, 1H), 3.69 (dd, J = 11.5, 3.2 Hz, 1H), 3.27 (td, J = 11.6, 2.6 Hz, 1H), 2.92 (ddd, J = 13.3, 11.7, 3.4 Hz, 1H), 2.08 (s, 1H), 1.95 (s, 3H), 1.68 (d, J = 5.3 Hz, 3H).

[0353] ESI of 102D-5: [M+H] + 586.2 (see Figure 43 ).

[0354] ESI of 102D-5A: [M+H] +586.2 (see) Figure 44 ).

[0355] Example 48

[0356] 20 g of compound 102D-4, 23.3 g of cesium carbonate, 1.7 g of potassium iodide, and 90 g of ethyl acetate were added to a reaction flask. The temperature was lowered to 0–10 °C, and 20.1 g of ethyl 1-bromoacetate was added. The reaction was carried out at 0–10 °C for 20 hours. 100 g of water was added for extraction, and the phases were separated. The aqueous phase was discarded, and 10 g of anhydrous sodium sulfate was added to the organic phase. The mixture was dried for 1 hour, filtered, and the filtrate was concentrated to dryness under reduced pressure. 31.2 g of acetonitrile was added to the concentrate, and the mixture was stirred at 0–10 °C for 1 hour to induce crystallization. The mixture was filtered, and the filter cake was dried to constant weight to obtain 9.1 g of off-white compound 102D-5A solid, with a yield of 38.9%.

[0357] The filtrate of 102D-5A was concentrated to dryness under reduced pressure. 88g of toluene was added to the concentrate, and the mixture was stirred at 0-10℃ for 1 hour to induce crystallization. The mixture was then filtered, and the wet product was dried to constant weight to obtain 8.3g of yellow 102D-5 compound solid, with a yield of 35.4%.

[0358] Example 49

[0359] 20 g of compound 102D-4, 12.1 g of triethylamine, 3.4 g of potassium iodide, and 265 g of dichloromethane were added to a reaction flask. The temperature was lowered to 10–20 °C, and 20.1 g of ethyl 1-bromoacetate was added. The reaction was carried out at 10–20 °C for 20 hours. 100 g of water was added for extraction, and the phases were separated. The aqueous phase was discarded, and 10 g of anhydrous sodium sulfate was added to the organic phase. The mixture was dried for 1 hour, filtered, and the filtrate was concentrated to dryness under reduced pressure. 24 g of acetonitrile was added to the concentrate, and the mixture was stirred at room temperature to crystallize for 1 hour. The mixture was filtered, and the filter cake was dried to constant weight to obtain 9.6 g of pale yellow compound 102D-5A solid, with a yield of 41%.

[0360] The filtrate of 102D-5A was concentrated to dryness under reduced pressure. 45g of toluene was added to the concentrate, and the mixture was stirred at room temperature for 1 hour to induce crystallization. The mixture was then filtered, and the wet product was dried to constant weight to give 8.7g of yellow 102D-5 compound solid, with a yield of 37.1%.

[0361] Example 50

[0362] 19 g of compound 102D-5, 16.9 g of sodium bisulfite, 4.2 g of iodine, and 281 g of chloroform were added to a reaction flask. The reaction was carried out at 10–20 °C for 15 hours. After filtration, 100 g of water was added to the filtrate for extraction. The phases were separated, the aqueous phase was discarded, and 10 g of anhydrous sodium sulfate was added to the organic phase. The mixture was dried for 1 hour, filtered, and the filtrate was concentrated to dryness under reduced pressure. 150 g of methanol was added to the concentrate, and the mixture was heated to dissolve. The temperature was then lowered to 0–10 °C to crystallize for 1 hour. After filtration, the wet product was dried to constant weight to obtain 16.1 g of white solid compound 102D-6, with a yield of 87.1%. Analysis confirmed that the crystal was of crystal form I, and its X-ray powder diffraction pattern was consistent with... Figure 1 Basically the same, its DSC spectrum is the same as Figure 2 Basically the same, its TGA spectrum is the same as Figure 3 Basically the same

[0363]

[0364] ESI: [M+H] + 570.2.

[0365] Example 51

[0366] 20 g of 102D-5, 10.7 g of sodium bisulfite, 2.6 g of iodine, and 265 g of dichloromethane were added to a reaction flask. The reaction was carried out at 0–10 °C for 20 hours. After filtration, 100 g of water was added to the filtrate for extraction. The phases were separated, and the aqueous phase was discarded. 10 g of anhydrous sodium sulfate was added to the organic phase and dried for 1 hour. After filtration, the filtrate was concentrated to dryness under reduced pressure. 125 g of ethanol was added to the concentrate, and the mixture was heated to dissolve. After cooling to 0–10 °C, crystals were precipitated for 1 hour. After filtration, the wet product was dried to constant weight to obtain 16.4 g of off-white 102D-6 compound solid, with a yield of 84.3%. Analysis confirmed that the crystal was of crystal form I, and its X-ray powder diffraction pattern was consistent with... Figure 1 Basically the same, its DSC spectrum is the same as Figure 2 Basically the same, its TGA spectrum is the same as Figure 3 Basically the same

[0367] Example 52

[0368] 10 g of compound 102D-5, 8.9 g of sodium bisulfite, 2.2 g of iodine, and 74 g of chloroform were added to a reaction flask. The reaction was carried out at 10–20 °C for 12 hours. After filtration, 50 g of water was added to the filtrate for extraction. The phases were separated, and the aqueous phase was discarded. 5 g of anhydrous sodium sulfate was added to the organic phase, and the mixture was dried for 1 hour. After filtration, the filtrate was concentrated to dryness under reduced pressure. 39 g of ethyl acetate was added to the concentrate, and the mixture was heated to 60–70 °C to dissolve it. 97 g of n-hexane was added, and the mixture was cooled to 0–10 °C to crystallize for 1 hour. After filtration, the wet product was dried to constant weight to obtain 7.8 g of white solid compound 102D-6, with a yield of 80.2%. Analysis confirmed that the crystal was of crystal form II, and its X-ray powder diffraction pattern was consistent with... Figure 4Basically the same, its DSC spectrum is the same as Figure 5 Basically the same, its TGA spectrum is the same as Figure 6 Basically the same

[0369] Example 53

[0370] 10 g of compound 102D-5, 8.9 g of sodium bisulfite, 2.2 g of iodine, and 74 g of chloroform were added to a reaction flask. The reaction was carried out at 20–30 °C for 10 hours. After filtration, 50 g of water was added to the filtrate for extraction. The phases were separated, and the aqueous phase was discarded. 5 g of anhydrous sodium sulfate was added to the organic phase, and the mixture was dried for 1 hour. After filtration, the filtrate was concentrated to dryness under reduced pressure. 44 g of isopropyl acetate was added to the concentrate, and the mixture was heated to 70–80 °C to dissolve it. 100 g of n-heptane was added, and the mixture was cooled to 0–10 °C to crystallize for 1 hour. After filtration, the wet product was dried to constant weight to obtain 7.65 g of off-white solid compound 102D-6, with a yield of 78.6%. Analysis confirmed that the crystal was of crystal form III, and its X-ray powder diffraction pattern was consistent with... Figure 7 Basically the same, its DSC spectrum is the same as Figure 8 Basically the same, its TGA spectrum is the same as Figure 9 Basically the same.

[0371] Example 54

[0372] Add 5g of compound 102D-5A, 4.45g of sodium bisulfite, 2.5g of iodine, and 37g of chloroform to a reaction flask. React at 10–20°C for 13 hours. Filter the mixture, add 25g of water to the filtrate for extraction, separate the phases, discard the aqueous phase, add 2g of anhydrous sodium sulfate to the organic phase and dry for 1 hour. Filter the mixture, concentrate the filtrate under reduced pressure to dryness, add 17.9g of acetonitrile to the concentrate, heat to dissolve, then cool to 0–10°C to crystallize for 1 hour. Filter the mixture, and dry the wet product to constant weight to obtain 4.1g of white solid compound 102D-6A, yield 84.3%.

[0373] ESI: [M+H]+570.2.

[0374] Example 55

[0375] Add 5g of compound 102D-5A, 4g of sodium bisulfite, 0.5g of iodine, and 66g of dichloromethane to a reaction flask. React at 20-30℃ for 10 hours. Filter, add 25g of water to the filtrate for extraction, separate the phases, discard the aqueous phase, add 2g of anhydrous sodium sulfate to the organic phase and dry for 1 hour. Filter, concentrate the filtrate under reduced pressure to dryness, add 20g of acetonitrile to the concentrate, heat to dissolve, then cool to 10-20℃ to crystallize for 1 hour. Filter, and dry the wet product to constant weight to obtain 3.8g of white compound 102D-6A solid, yield 78.1%.

[0376] Comparative Example 1: Preparation method of amorphous 102D-6

[0377] Amorphous 102D-6 was prepared according to the method disclosed in Chinese Invention Patent CN 118496239, and was determined to be amorphous by XRPD. The chromatogram is shown below. Figure 19 Its DSC spectrum and Figure 20 Basically the same, its TGA spectrum is the same as Figure 21 Basically the same.

[0378] Comparative Example 2: Preparation method of amorphous 102D-6

[0379] One or more of the following crystal forms, 102D-6 (I, II, III, IV, V, and VI), were dissolved in 10 times their volume of dichloromethane. The solution was concentrated under reduced pressure at 40–50 °C to obtain a foamy solid. XRPD analysis showed it to be amorphous, as shown in the chromatogram. Figure 19 .

[0380] Stability study of 102D-6 in amorphous, crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V and crystalline form VI

[0381] 1. Research Objectives

[0382] In accordance with ICH Q1A Stability Testing of New Drug Substances and Formulations and the guidelines for drug substances in the Chinese Pharmacopoeia, influencing factor tests (high temperature test and high humidity test) and accelerated tests were conducted on 102D-6 of amorphous, polymorph I, polymorph II, polymorph III, polymorph IV, polymorph V and polymorph VI to investigate the stability of different polymorphs.

[0383] 2. Stability assessment plan

[0384] 2.1 High temperature conditions: Take an appropriate amount of 102D-6 of each crystal form and place it in a constant temperature oven at 60℃. After 30 days, take out the sample for related substance testing.

[0385] 2.2 High humidity conditions: Take an appropriate amount of 102D-6 of each crystal form and place it in a constant temperature and humidity chamber at 25℃ / RH92.5%. After 30 days, take out the sample for related substance testing.

[0386] 2.3 Acceleration conditions: 102D-6 of each crystal form was placed in a constant temperature and humidity chamber at 40℃ / RH75% for 30 days. The sample was then taken out for related substance analysis.

[0387] 3. Stability test results

[0388] The results of the substance detection for the stability study of different crystal forms are shown in Table 1.

[0389] Table 1. Results of the stability of 102D-6 in each crystal form.

[0390]

[0391]

[0392] The HPLC chromatogram of amorphous 102D-6 on day 0 is attached. Figure 22 .

[0393] The HPLC chromatogram of 102D-6 of crystal form II on day 0 is attached. Figure 26 .

[0394] The results of related substance detection in Table 1 show that amorphous 102D-6 is the least stable under high temperature conditions. Its HPLC chromatogram after 30 days of high-temperature storage is shown in the appendix. Figure 23 Crystal form II of 102D-6 is the most stable under high temperature conditions; its HPLC chromatogram after 30 days of high-temperature storage is shown in the appendix. Figure 27 The stability of 102D-6 in different crystal forms under high temperature conditions, from highest to lowest, is as follows: crystal form II > crystal form III > crystal form I > crystal form V > crystal form VI > crystal form IV > amorphous.

[0395] The results of related substance detection in Table 1 show that amorphous 102D-6 is the least stable under high humidity conditions. Its HPLC chromatogram after 30 days of high humidity storage is shown in the appendix. Figure 24 Crystal form II 102D-6 is most stable under high humidity conditions; its HPLC chromatogram after 30 days of high humidity storage is attached. Figure 28 The stability of 102D-6 under high humidity conditions, from highest to lowest, is as follows: crystal form II > crystal form I > crystal form VI > crystal form III > crystal form V > crystal form IV > amorphous.

[0396] The results of related substance detection in Table 1 show that amorphous 102D-6 is the least stable under accelerated conditions. Its HPLC chromatogram after 30 days of storage is shown in the appendix. Figure 25 Crystal form II of 102D-6 is the most stable under accelerated conditions; its HPLC chromatogram after 30 days of storage is attached. Figure 29 The stability of 102D-6 under accelerated conditions, from highest to lowest, is as follows: crystal form II > crystal form I > crystal form III > crystal form VI > crystal form V > crystal form IV > amorphous.

[0397] Equilibrium solubility test of 102D-6 in crystal forms I, II, III, IV, V and VI

[0398] 1. Research Objectives

[0399] Referring to ICH M9: Bioequivalence Exemption Based on Biopharmaceutics Classification System, the equilibrium solubility of different crystalline active pharmaceutical ingredients in hydrochloric acid at pH 1.0, acetate buffer at pH 4.5, phosphate buffer at pH 6.8, and pure water was determined.

[0400] 2. Information on the test sample, reference standard, and other solvents and media.

[0401] 2.1 Test sample

[0402] 2.1.1 Name: Crystal Form I 102D-6 Batch Number: 20240423-1

[0403] 2.1.2 Name: Crystal Form II 102D-6 Batch Number: 20240425-1

[0404] 2.1.3 Name: Crystal Form III 102D-6 Batch Number: 20240423-3

[0405] 2.1.4 Name: Crystal Form IV 102D-6 Batch Number: 20241113-1

[0406] 2.1.5 Name: Crystal form V 102D-6 Batch number: 20241127-1

[0407] 2.1.6 Name: Crystal Form VI 102D-6 Batch Number: 20241126-1

[0408] 2.2 Solvent and Medium Information

[0409] 2.2.1 Name: Hydrochloric acid; Batch number: 20240723

[0410] 2.2.2 Name: Anhydrous Sodium Acetate Batch Number: 20240507

[0411] 2.2.3 Name: Glacial Acetic Acid Batch Number: 20240111

[0412] 2.2.4 Name: Sodium hydroxide Batch number: 20240408

[0413] 2.2.5 Name: Sodium dihydrogen phosphate Batch number: 20240221

[0414] 3. Testing Methods

[0415] 3.1 Preparation of Aqueous Media

[0416] pH 1.0 hydrochloric acid: Measure 991ml of purified water, add 9ml of hydrochloric acid, and stir well.

[0417] pH 4.5 acetate buffer: Measure 1000ml of purified water, add 1.8g of anhydrous sodium acetate, stir until completely dissolved, add 1.6ml of glacial acetic acid, stir well, and adjust the pH to 4.5±0.05 with sodium hydroxide solution or glacial acetic acid.

[0418] pH 6.8 buffer: Measure 1000ml of purified water, add 7.8g of sodium dihydrogen phosphate dihydrate and 0.9g of sodium hydroxide, stir until completely dissolved, and adjust the pH to 6.8±0.05 with sodium hydroxide solution or phosphoric acid.

[0419] 3.2 Testing Process

[0420] Take stoppered centrifuge tubes, add an appropriate amount of medium to each tube, then add an excess of different crystalline forms of the active pharmaceutical ingredient, and determine the initial pH value. Place the centrifuge tubes in a constant temperature water bath shaker at 37℃±0.5℃, set the speed to 100 rpm, and shake for 24 hours. Measure the pH value of the sample. Take an appropriate amount of sample, filter it through a 0.45μm filter membrane, and inject it to determine the content. Prepare three samples in parallel for each medium.

[0421] 4 Test Results

[0422] The equilibrium solubility of different crystal forms is shown in Table 2. The equilibrium solubility from high to low is as follows: crystal form II > crystal form III ≈ crystal form V > crystal form IV > crystal form I ≈ crystal form VI.

[0423] Table 2 Equilibrium solubility of raw materials with different crystal forms

[0424]

[0425]

[0426] *Note: pH 1.2 is the sum of the prodrug and the hydrolysis product.

[0427] Biological testing of 102D-6 in crystal form II, crystal form III and crystal form V - Rat PK study

[0428] 1. Research Objectives

[0429] SD rats were administered different crystalline drug forms via a single oral gavage. Plasma samples were collected at different time points after administration to detect drug levels, and the pharmacokinetic parameters of different crystalline drug forms in SD rats were calculated and compared.

[0430] 2. Information on the test sample, reference standard, and other solvents and media.

[0431] 2.1 Test sample

[0432] 2.1.1 Name: Crystal Form II 102D-6 Batch Number: 20240425-1

[0433] 2.1.2 Name: Crystal Form III 102D-6 Batch Number: 20240423-3

[0434] 2.1.3 Name: Crystal form V 102D-6 Batch number: 20241127-1

[0435] 2.2 Solvent and Medium Information

[0436] 2.2.1 Name: Sodium dodecyl sulfate Batch number: E2406220

[0437] 2.2.2 Name: Anhydrous Ethanol Batch Number: 161112194B

[0438] 3. Experimental System

[0439] 3.1 Animal grouping

[0440] Fifty-six SD rats, weighing 180g–220g, with an equal number of males and females, were randomly divided into three groups of eight rats each. The grouping information is as follows:

[0441] Table 3. Grouping and Identification of SD Rats

[0442]

[0443] 3.2 Drug administration and sample collection

[0444] SD rats were randomly divided into groups and fasted for at least 12 hours before administration, but were allowed free access to water. Water intake was prohibited 1 hour before and 1 hour after administration. Feeding was administered 4 hours after administration. Each group was administered a single oral gavage dose of 3.0 mg / kg (based on the active ingredient). Approximately 0.2 mL of blood was collected from the jugular vein of each animal at 0 h before administration and at 5 min, 10 min, 15 min, 30 min, 1, 2, 4, 6, 10, and 24 h after administration and placed in EDTA-K2 anticoagulant tubes.

[0445] 3.3 Biological Sample Analysis

[0446] Whole blood was collected and centrifuged at 4000 rpm for 10 min at 4°C to obtain plasma, which was then stored at -80°C for later analysis. The plasma drug concentration of each group of samples was determined by LC-MS / MS.

[0447] PK parameters were calculated using a non-compartmental model based on Phoenix Winnonlin 8.0. Data analysis included C. max T max AUC 0-t AUC 0-∞ t 1 / 2 Pharmacokinetic parameters such as CL / F.

[0448] 4. Test Results

[0449] 4.1 Observation near the cage

[0450] No obvious abnormalities were observed in any of the animals after administration of the drug and observation at their cages.

[0451] 4.2 Test Results

[0452] Table 4 shows the main pharmacokinetic parameters of each group of compounds after a single oral gavage administration (based on the active ingredient) to SD rats. The drug-time curves are shown in Table 4. Figure 30 As shown.

[0453] Table 4. Pharmacokinetic parameters of different drugs after a single oral gavage administration in SD rats.

[0454]

[0455] Note: (1) Compared with crystal form III ** P<0.005. (2) Compared with crystal form V, ## P<0.005.

[0456] Research Results

[0457] (1) After a single oral gavage administration of the same dose (based on the active ingredient) of the compound to SD rats, the bioavailability (C) of each group of rats was compared. max and AUC 0-t The crystal forms are sorted in descending order as follows: Crystal Form II > Crystal Form III > Crystal Form V.

[0458] (2) Compared with crystal form III and crystal form V, the bioavailability (C2) of compounds in crystal form II was significantly higher. max and AUC 0-t The level was significantly improved, with a statistically significant difference (P < 0.005).

[0459] Biological testing of 102D-6 in crystal form II, crystal form III and crystal form V - cynomolgus monkey PK study

[0460] 1. Research Objectives

[0461] Different crystalline drug forms were administered via single oral gavage to cynomolgus monkeys. Plasma samples were collected at different time points after administration to determine drug levels, and the pharmacokinetic parameters of different drug groups in the cynomolgus monkeys were calculated and compared.

[0462] 2. Information on the test sample, reference standard, and other solvents and media.

[0463] 2.1 Test sample

[0464] 2.1.1 Name: Crystal Form II 102D-6 Batch Number: 20240425-1

[0465] 2.1.2 Name: Crystal Form III 102D-6 Batch Number: 20240423-3

[0466] 2.1.3 Name: Crystal form V 102D-6 Batch number: 20241127-1

[0467] 2.2 Solvent and Medium Information

[0468] 2.2.1 Name: Sodium dodecyl sulfate Batch number: E2406220

[0469] 2.2.2 Name: Anhydrous Ethanol Batch Number: 161112194B

[0470] 3. Experimental System

[0471] 3.1 Animal grouping

[0472] Twenty-four cynomolgus macaques, aged 3-5 years and weighing 3-7 kg, were selected, with an equal number of males and females. They were randomly divided into three groups of eight animals each, based on their weight. The grouping information is as follows:

[0473] Table 5. Grouping and Identification of Crab-Eating Mammals

[0474]

[0475] 3.2 Drug administration and sample collection

[0476] After randomization into groups, cynomolgus monkeys were fasted for at least 12 hours before administration, but were allowed free access to water. Water intake was prohibited for 1 hour before and 1 hour after administration. Feeding was given 4 hours after administration. Each group was administered a single oral gavage dose of 5.0 mg / kg (based on the active ingredient). Approximately 1.0 mL of blood was collected from the jugular vein of each group at 0 h before administration and at 5 min, 10 min, 15 min, 30 min, 1, 2, 3, 4, 6, 8, 12, 24, and 48 h after administration (D2) and placed in EDTA-K2 anticoagulant tubes.

[0477] 3.3 Biological Sample Analysis

[0478] Whole blood was collected and centrifuged at 4000 rpm for 10 min at 4°C to obtain plasma, which was then stored at -80°C for later analysis. The plasma drug concentration of each group of samples was determined by LC-MS / MS.

[0479] PK parameters were calculated using a non-compartmental model based on Phoenix Winnonlin 8.0. Data analysis included C. max T max AUC 0-t AUC 0-∞ t 1 / 2 Pharmacokinetic parameters such as CL / F.

[0480] 4. Test Results

[0481] 4.1 Observation near the cage

[0482] No obvious abnormalities were observed in any of the animals after administration of the drug and observation at their cages.

[0483] 4.2 Test Results

[0484] Table 6 shows the main pharmacokinetic parameters of each group of compounds after a single oral gavage administration (based on the active ingredient) to cynomolgus monkeys. The drug-time curves are shown in Table 6. Figure 31 As shown.

[0485] Table 6. Pharmacokinetic parameters of different drug groups after a single oral gavage administration to cynomolgus monkeys.

[0486]

[0487] Note: (1) Compared with crystal form III ** P<0.005; *** P<0.001. (2) Compared with crystal form V, ## P<0.005; ### P<0.001.

[0488] Research findings:

[0489] (1) After a single oral gavage administration of the same dose (based on the active ingredient) of the compound to cynomolgus monkeys, the bioavailability (C0) of the compound in each group of cynomolgus monkeys was as follows: max and AUC 0-t The crystal forms are sorted in descending order as follows: Crystal Form II > Crystal Form III > Crystal Form V.

[0490] (2) Compared with crystal form III and crystal form V, the bioavailability (C2) of compounds in crystal form II was significantly higher. max and AUC 0-t The results showed a significant improvement, with statistical significance.

[0491] In summary, 102D-6 of crystal form II remains stable under high temperature, high humidity, and accelerated conditions; the equilibrium solubility of 102D-6 of crystal form II is superior to that of the other crystal forms; compared with crystal forms III and V, the bioavailability (C0) of compounds in crystal form II is significantly higher. max and AUC 0-t Significantly improved.

[0492] Pharmacodynamic study of crystal form II – mouse model of influenza infection

[0493] 1. Research Objectives

[0494] This study used a mouse model of influenza virus infection to evaluate the survival protection of crystalline type II compounds in influenza-infected mice.

[0495] Female BALB / c mice were infected nasally with a lethal dose of influenza A virus. Treatment with solvent (0.5% (w / v) methylcellulose + 0.5% polysorbate 80 + ultrapure water), crystal form II compound, and positive control (mabaloxavir) began at 24, 48, and 72 hours post-infection. Throughout the experiment, mouse weight, health status, and survival were monitored daily to assess the in vivo antiviral efficacy of the test substance.

[0496] 2. Information on the test sample, reference standard, and other solvents and media.

[0497] 2.1 Test sample

[0498] 2.1.1 Name: Crystal Form II 102D-6 Batch Number: 20240425-1

[0499] 2.1.2 Name: Marbaloxavir Batch Number: BLX-705-240403

[0500] 2.2 Solvent and Medium Information

[0501] 2.2.1 Name: Methylcellulose Batch Number: 230226-19

[0502] 2.2.2 Name: Polysorbate 80 Batch Number: F104C240501

[0503] 2.3 Virus strains

[0504] Influenza A virus, A / PR / 8 / 34 (H1N1), original strain purchased from ATCC, catalog number: VR1469. Titer: 7.15 E+07 PFU / mL.

[0505] 2.4 Animal Information

[0506] Female BALB / c mice, aged 6-8 weeks and weighing 18-20g, of specific pathogen-free grade, were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0507] 3. Experimental System

[0508] 3.1 Animal grouping

[0509] According to the experimental design, the animals were randomly divided into 15 groups, with 10 mice in each group.

[0510] 3.2 Virus inoculation

[0511] On day 0, mice were anesthetized by intraperitoneal injection of an anesthetic (5 mL / kg) and then inoculated with the virus via nasal drops. Each mouse received 830 PFU in an inoculation volume of 50 μL.

[0512] 3.3 Administration

[0513] Mice were treated with a solvent, a crystal form II compound, and a positive control (mabaloxavir) via gavage, twice daily for 7 consecutive days, with an 8 / 16-hour interval between the two daily doses. The first dose was administered 24 hours after viral inoculation for groups 1-5, 48 hours after viral inoculation for groups 6-10, and 72 hours after viral inoculation for groups 10-15. Detailed information is shown in Table 7.

[0514] Table 7. In vivo experimental design

[0515]

[0516]

[0517] 3.4 Evaluation Indicators

[0518] (1) Changes in body weight: During the experiment, the mice were observed and their body weight was recorded daily.

[0519] (2) Median survival: the survival time corresponding to a cumulative survival rate of 50%.

[0520] Note: According to the IACUC protocol, any mouse that loses more than 35% of its initial weight during the experiment, or / and exhibits signs of impending death, will be euthanized.

[0521] 3.5 Data Analysis

[0522] Statistical analysis was performed on the data using Prism 7, two-way ANOVA was used to analyze mouse weight changes, and the Log-rank (Mantel-cox) test was used to analyze mouse survival status.

[0523] 4. Test Results

[0524] The in vivo efficacy of the test compound in a mouse model of influenza A virus infection was evaluated by measuring changes in mouse body weight and survival rate.

[0525] 4.1 Protection of mouse body weight by the test substance in the model

[0526] For details on the weight changes of mice in groups 1-15 after virus inoculation, please refer to [link / reference]. Figures 32-34 .

[0527] In the solvent group, the body weight of mice in groups 1 (+24h), 6 (+48h), and 11 (+72h) began to decrease from day 3 and continued to decrease until death or euthanasia.

[0528] Mabaloxavir Group:

[0529] Group 2 (+24h): The body weight of mice in Group 2 decreased significantly from day 6, with an average maximum decrease of -13.6%, and recovered to normal levels from day 8. Compared with the solvent group, mabaloxavir significantly alleviated the weight loss caused by viral infection in mice from day 2 to day 9, with statistically significant differences (P<0.05); Group 7 (+48h): The body weight of mice in Group 7 decreased significantly from day 3, with an average maximum decrease of -24.7%, and recovered to normal levels from day 8. Compared with the solvent group, mabaloxavir significantly alleviated the weight loss caused by viral infection in mice from day 5 to day 8, with statistically significant differences (P<0.05); Group 12 (+72h): The body weight of mice in Group 12 decreased significantly from day 3, with an average maximum decrease of -32.6%, and the body weight of surviving animals recovered to normal levels from day 9. Compared with the solvent group, mabaloxavir significantly alleviated the weight loss in mice caused by viral infection on days 8-9, with statistically significant differences (P<0.05).

[0530] Crystal form II compound group (0.5 mpk):

[0531] In groups 3 (+24h) and 13 (+72h), mouse body weight began to decrease from day 3, with surviving mice recovering their weight from day 10. In group 8 (+48h), mouse body weight began to decrease from day 3, with surviving mice recovering their weight from day 9. Compared with the solvent group, compound II (0.5mpk, group 3) significantly alleviated the weight loss induced by viral infection in mice on day 6, with a statistically significant difference (P<0.05).

[0532] Crystal form II compound group (5mpk):

[0533] Group 4 (+24h): The body weight of mice in Group 4 began to decrease from day 6, with an average maximum decrease of -9.5%, and recovered to normal levels from day 8. Compared with the solvent group, compound II significantly alleviated the weight loss caused by viral infection in mice from day 2 to day 9, with statistically significant differences (P<0.05). Compared with mabaloxavir, compound II further alleviated the weight loss in mice from day 6 to day 8 and day 10, with statistically significant differences (P<0.05); Group 9 (+48h): The body weight of mice in Group 9 began to decrease from day 3, with an average maximum decrease of -23.0%, and recovered to normal levels from day 8. Compared with the solvent group, the crystal form II compound significantly alleviated the weight loss of mice caused by viral infection from day 5 to day 8, and the difference was statistically significant (P<0.05); Group 14 (+72h): The weight of mice in Group 14 began to decrease from day 3, and the weight of surviving animals began to recover to normal levels from day 9.

[0534] Crystal form II compound group (15 mpk):

[0535] Group 5 (+24h): The body weight of mice in Group 5 began to decrease from day 6, with an average maximum decrease of -8.7%, and recovered to normal levels from day 8. Compared with the solvent group, compound II significantly alleviated the weight loss caused by viral infection in mice from day 3 to day 9, with statistically significant differences (P<0.05); compared with mabaloxavir, compound II further alleviated the weight loss in mice from day 6 to day 7, with statistically significant differences (P<0.05); Group 10 (+72h): The body weight of mice in Group 10 began to decrease from day 3, with an average maximum decrease of -20.1%, and recovered to normal levels from day 8. Compared with the solvent group, compound II significantly alleviated the weight loss caused by viral infection in mice from day 4 to day 8 (P<0.05); compared with mabaloxavir, compound II further alleviated the weight loss in mice from day 4 to day 10 (P<0.05); Group 15 (+72h): The weight of mice in group 15 began to decrease from day 3, and the weight of surviving animals recovered to normal levels from day 9; compared with the solvent group, compound II significantly alleviated the weight loss caused by viral infection in mice from day 7 to day 9 (P<0.05); compared with mabaloxavir, compound II further alleviated the weight loss in mice from day 9 to day 10 and from day 13 to day 14 (P<0.05).

[0536] 4.2 Protection of mouse survival by the test compound in the model

[0537] The survival status of mice in each group after virus inoculation is summarized in... Figure 35 .

[0538] Solvent Groups: Mice in Group 1 (+24h) died on day 6, and all died on day 9, with a median survival of 7 days and a final survival rate of 0%; Mice in Group 6 (+48h) died on day 6, and all died on day 8, with a median survival of 7 days and a final survival rate of 0%; Mice in Group 11 (+72h) died on day 6, and all died on day 9, with a median survival of 8 days and a final survival rate of 0%; Mabaloxavir Groups: Mice in Groups 2 (+24h) and 7 (+48h) did not die, and the final survival rate was 100%; Mice in Group 12 (+72h) began to lose weight from day 7, reaching the set humane euthanasia threshold, and all dead animals were euthanized, with a final survival rate of 70%; Crystal Form II Compound Group (0.5mpk): Mice in Groups 3 (+24h) and 8 (+48h) died on day 6, and all died on day 9, with a median survival of 8 days and a final survival rate of 0%; Mice in groups +48h and 13 (+72h) died on day 7, with median survival of 9, 8, and 7.5 days, respectively, and a final survival rate of 10% for all groups. In the crystal form II compound group (5mpk), mice in groups 4 (+24h) and 9 (+48h) did not die, and the final survival rate was 100%. Mice in group 14 (+72h) began to lose weight on day 7, reaching the set humane euthanasia threshold, and all animals that died were euthanized, with a median survival of 8 days and a final survival rate of 10%. In the crystal form II compound group (15mpk), mice in groups 5 (+24h) and 10 (+48h) did not die, and the final survival rate was 100%. Mice in group 15 (+72h) died on day 7 (the animals reached the humane endpoint and were euthanized), with a final survival rate of 80%.

[0539] Pharmacodynamic study of crystal form II – ferret model of influenza infection

[0540] 1. Research Objectives

[0541] This study used an influenza virus ferret infection model to evaluate the survival protection of crystal form II compounds on influenza-infected mice.

[0542] Female *M. putorius* ferrets were infected with influenza A virus via nasal drops, treated with solvents, test compounds, and control compounds. During the experiment, the ferrets' weight, body temperature, and clinical symptoms were monitored daily to assess the protective effect of the test compounds. Nasal lavage fluid from the experimental ferrets was collected at 72 hours post-infection, and the viral titer was measured to assess the inhibitory effect of the test compounds on viral replication.

[0543] 2. Information on the test sample, reference standard, and other solvents and media.

[0544] 2.1 Test sample

[0545] 2.1.1 Name: Crystal Form II 102D-6 Batch Number: 20240425-1

[0546] 2.1.2 Name: Marbaloxavir Batch Number: BLX-705-240403

[0547] 2.2 Solvent and Medium Information

[0548] 2.2.1 Name: Methylcellulose Batch Number: 230226-19

[0549] 2.2.2 Name: Polysorbate 80 Batch Number: F104C240501

[0550] 2.3 Virus strains

[0551] Influenza A virus, A / PR / 8 / 34 (H1N1), original strain purchased from ATCC, catalog number: VR1469. Titer: 7.20 E+07 PFU / mL.

[0552] 2.4 Animal Information

[0553] Female, common grade, influenza negative ferret, 16-18 weeks old, 1-1.5kg, purchased from Wuxi Coral Reef Biotechnology Co., Ltd.

[0554] 3. Experimental System

[0555] 3.1 Animal grouping

[0556] According to the experimental design, the animals were randomly divided into 5 groups, with 6 ferrets in each group.

[0557] 3.2 Virus inoculation

[0558] On day 0, the experimental animals were deeply anesthetized by intramuscular injection of an anesthetic (2 mg / kg), and then inoculated with the virus via nasal drops, with an inoculation dose of 2.88 mg / animal. E+07 PFU, inoculation volume is 0.4 mL / ferret (0.2 mL / nostril).

[0559] 3.3 Administration

[0560] Ferrets were treated with solvent, mabaloxavir, or crystal form II compound by gavage, twice daily for 7 consecutive days, with an interval of 8 / 16 hours between the two daily doses. The first dose was given 2 hours after viral inoculation. See Table 8 for details.

[0561] Table 8. In vivo experimental design

[0562]

[0563] 3.4 Evaluation Indicators

[0564] (1) Health monitoring

[0565] During the experiment, the ferrets were observed daily, and their weight, body temperature, and clinical symptoms were scored*.

[0566] *Clinical symptom scoring: Activity level: 0 points for normal activity level, 1 point for reduced activity level, 2 points for inactivity or lethargy; Nasal discharge: 0 points for no nasal discharge, 1 point for nasal discharge; Sneezing: 0 points for no sneezing, 1 point for sneezing. Clinical symptoms should be observed 4 times daily (09:00-21:00) after infection, every 4 hours for 20 minutes each time.

[0567] (2) Virus titer

[0568] 72 hours after viral inoculation, the ferrets were deeply anesthetized, and 2 mL of DPBS was injected into the nasal cavity in a small volume (1 mL / nostril) to irrigate the nasal cavity. The ferrets were then stimulated to sneeze with a pipette tip, and secretions and sputum were collected in 2 mL sterile EP tubes and stored at -80°C until influenza virus titer testing was performed.

[0569] 3.5 Data Analysis

[0570] Statistical analysis was performed on the data using Prism 7. Two-way ANOVA was used to analyze changes in ferret weight, body temperature, and clinical symptoms; one-way ANOVA was used to analyze the viral titer in nasal lavage fluid.

[0571] 4. Test Results

[0572] The protective effect of the test compounds on ferrets in an influenza A virus infection model was evaluated by changes in ferret weight, body temperature, and clinical symptom scores, while the inhibitory effect on viral replication was evaluated by viral titer in nasal lavage fluid.

[0573] 4.1 Protection of ferret body temperature by the test compound in the model

[0574] Following virus inoculation, the body temperatures of the ferrets in each group were summarized as follows: Figure 36 .

[0575] In the solvent group, the ferrets' body temperature began to rise 24 hours after viral infection, reached its highest point of 40.2℃ at 36 hours, and began to recover after 60 hours.

[0576] Marbaloxavir: Ferrets maintained stable body temperature during the experiment, and marbaloxavir at the set dose protected ferrets from fever caused by viral infection. Twenty-four hours after viral inoculation, the body temperature of animals in the solvent group began to be significantly higher than that in the control group.

[0577] Crystal form II compound group (0.5 mpk): The ferret's body temperature began to rise 24 hours after viral infection, reached its highest point of 40.4°C at 36 hours, and began to recover 48 hours later.

[0578] Compound group II (5 mpk): The ferrets maintained stable body temperature during the experiment, and 102D-6 at the set dose protected the ferrets from fever caused by viral infection. 24 hours after viral inoculation, the body temperature of the solvent group animals began to be significantly higher than that of the control group.

[0579] Compound group II (15 mpk): The ferrets maintained stable body temperature during the experiment, and 102D-6 at the set dose protected the ferrets from fever caused by viral infection. 24 hours after viral inoculation, the body temperature of the solvent group animals began to be significantly higher than that of the control group.

[0580] 4.2 Protection of ferrets against clinical symptoms in the model by the test compound

[0581] The clinical symptom scores of ferrets in each group after virus inoculation were summarized in [the table / data]. Figure 37 .

[0582] The solvent group: Ferrets in the solvent group were affected by viral infection, and clinical observation showed a significant increase in drowsiness, nasal secretions, and the number of sneezes.

[0583] Marbaloxavir (5mpk): Compared with the solvent group, the ferrets showed some relief of clinical symptoms, with a significant reduction in the frequency of drowsiness, nasal discharge, and sneezing.

[0584] In the group of crystal form II compounds (0.5, 5 and 15 mpk): the clinical symptom scores of ferrets were lower than those in the solvent group, and the symptoms of drowsiness, nasal discharge and sneezing were significantly improved. Moreover, the clinical symptoms became milder with increasing dose.

[0585] 4.3 Effect of the test compound on influenza virus titer in the model

[0586] Nasal lavage fluid samples were collected 72 hours after viral inoculation. The IFV titers in the nasal lavage fluid of each ferret group were summarized in [the table below]. Figure 38 .

[0587] The average IFV viral titer in the nasal lavage fluid of ferrets in the solvent group on day 3 of the experiment was 3.292 Log(plaque# / mL nasal wash), while the average IFV viral titer in the nasal lavage fluid of ferrets in the mabaloxavir group on day 3 of the experiment was 2.120 Log(plaque# / mL nasal wash), which was significantly lower than that in the solvent group and was in line with the expected model.

[0588] Test compound group: Compared with the solvent group, the crystal form II compound, when administered 2 hours after infection at the set dose (0.5 mpk), failed to significantly reduce the IFV virus titer in the nasal lavage fluid of infected animals. Compared with the solvent group, the crystal form II compound, when administered 2 hours after infection at the set doses (5 mpk and 15 mpk), significantly reduced the IFV virus titer in the nasal lavage fluid of infected animals, with average reductions of 1.615 Log (P<0.001) and 1.702 Log (P<0.001), respectively, indicating that both compounds showed good in vivo anti-IFV efficacy under the set experimental conditions.

Claims

1. A crystalline Form I of compound 102D-6 characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern thereof has diffraction peaks at least at one or more or all of the following 2θ (unit: degree, error ±0.2 degree) angles: 7.0，10.8，15.2，17.7，20.6，21.7，25.1，28.2。 2. The crystalline Form I of claim 1, characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern thereof has diffraction peaks at least at one or more or all of the following 2θ (unit: degree, error ±0.2 degree) angles: 6.4，7.0，10.8，14.0，15.2，17.7，20.6，21.7，24.1，25.1，27.1，28.2。 3. The crystalline Form I of claim 2, characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern thereof has diffraction peaks at least at one or more or all of the following 2θ (unit: degree, error ±0.2 degree) angles: 6.4, 7.0, 10.8, 12.8, 14.0, 15.2, 17.1, 17.7, 19.5, 20.6, 21.7, 22.8, 24.1, 25.1, 27.1, 28.2, 28.7, 29.5, 30.4, 33.0; preferably as shown in Figure 1.

4. The crystalline Form I of any one of claims 1 to 3, the data of DSC; preferably as shown in Figure 2.

5. The crystalline Form I of any one of claims 1 to 4, the data of TGA; preferably as shown in Figure 3.

6. A crystalline form II of compound 102D-6 characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern thereof has diffraction peaks at least at one or more or all of the following 2θ (unit: degree, error ±0.2 degree) angles: 7.9，9.9，12.5，16.0，16.9，19.7，21.9。 7. The crystalline Form II of claim 6, characterized in that the X-ray powder diffraction pattern thereof has diffraction peaks at least at one or more or all of the following 2θ (unit: degree, error ±0.2 degree) angles: 7.9，9.9，12.5，14.9，16.0，16.6，16.9，19.7，20.6，21.1，21.9，26.6。 8. The crystalline Form II of claim 7, characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern thereof has diffraction peaks at least at one or more or all of the following 2θ (unit: degree, error ±0.2 degree) angles: 6.7, 7.9, 9.9, 11.1, 12.5, 14.9, 16.0, 16.6, 16.9, 19.7, 20.6, 21.1, 21.9, 22.6, 23.8, 24.2, 25.2, 26.6, 27.6, 28.9, 29.5, 30.1, 30.6, 32.9, 36.2; preferably as shown in Figure 4.

9. The crystalline Form II of any one of claims 6 to 8, the data of DSC; preferably as shown in Figure 5.

10. The crystalline Form II of any one of claims 6 to 9, the data of TGA; preferably as shown in Figure 6.

11. A crystalline form III of compound 102D-6 characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern thereof has diffraction peaks at least at one or more or all of the following 2θ (unit: degree, error ±0.2 degree) angles: 8.0，10.7，13.7，14.3，16.0，16.5，20.3，22.1，24.9。 12. The Form III of claim 11, characterized by: by using an X-ray powder diffractometer, the X-ray powder diffraction pattern thereof has diffraction peaks at least at one or more or all of the following 2θ (unit: degree, error ±0.2 degree) angles: 8.0，10.7，11.7，13.7，14.3，16.0，16.5，17.8，19.1，20.3，22.1，23.9，24.9，27.7。 13. The crystalline Form III of claim 12, characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern thereof has diffraction peaks at least at one or more or all of the following 2θ (unit: degree, error ±0.2 degree) angles: 8.0, 9.2, 10.7, 11.7, 12.3, 12.7, 13.7, 14.3, 16.0, 16.5, 17.8, 19.1, 20.3, 21.1, 22.1, 23.5, 23.9, 24.9, 25.2, 26.6, 27.1, 27.7, 28.0, 29.4, 32.5; preferably as shown in Figure 7.

14. The crystalline Form III according to any one of claims 11 to 13, having the data of DSC; preferably as shown in Figure 8.

15. The crystalline Form III according to any one of claims 11 to 14, having the data of TGA; preferably as shown in Figure 9.

16. A crystalline form IV of compound 102D-6 characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern of which has diffraction peaks at at least one or more or all of the following 2θ (unit: degree, error ±0.2 degrees) angles: 6.7，8.1，10.5，12.5，15.7，17.8，18.4，22.9。 17. The Form IV of claim 16, characterized by: by using an X-ray powder diffractometer, the X-ray powder diffraction pattern of which has diffraction peaks at at least one or more or all of the following 2θ (unit: degree, error ±0.2 degrees) angles: 6.7，8.1，10.5，11.6，12.5，13.4，15.7，17.8，18.4，20.1，20.7，22.9，28.3。 18. The Form IV of claim 17, characterized by: by using an X-ray powder diffractometer, the X-ray powder diffraction pattern of which has diffraction peaks at at least one or more or all of the following 2θ (unit: degree, error ±0.2 degrees) angles: 6.7, 8.1, 10.5, 11.6, 12.5, 13.4, 15.7, 16.3, 17.8, 18.4, 20.1, 20.7, 21.6, 22.9, 23.4, 24.3, 24.8, 26.6, 28.3, 29.5; preferably as shown in Figure 10.

19. A crystalline form V of compound 102D-6 characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern of which has diffraction peaks at at least one or more or all of the following 2θ (unit: degree, error ±0.2 degrees) angles: 9.0, 13.1, 18.1, 19.5, 20.7, 22.7, 32.0; preferably as shown in Figure 13.

20. A crystalline Form VI of compound 102D-6 characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern of which has diffraction peaks at at least one or more or all of the following 2θ (unit: degree, error ±0.2 degrees) angles: 7.1，12.3，17.2，21.5，22.3。 21. The crystalline Form VI of claim 20, characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern of which has diffraction peaks at at least one or more or all of the following 2θ (unit: degree, error ±0.2 degrees) angles: 6.9，7.1，11.8，12.3，15.2，17.2，19.1，20.7，21.5，22.3，24.6，25.9，28.8。 22. The crystalline Form VI of claim 21, characterized by, by using an X-ray powder diffractometer, the X-ray powder diffraction pattern of which has diffraction peaks at at least one or more or all of the following 2θ (unit: degree, error ±0.2 degrees) angles: 6.9, 7.1, 11.8, 12.3, 13.9, 15.2, 15.9, 17.2, 18.3, 19.1, 20.7, 21.5, 22.3, 22.8, 24.1, 24.6, 25.9, 28.0, 28.8; preferably as shown in Figure 16.

23. A method of preparing the crystalline Form I of any one of claims 1 to 5, comprising: The compound 102D-6 is added to a good solvent, after warming and stirring to dissolve, directly cooling or adding a poor solvent to cool, stirring to crystallize, filtering, and drying to obtain the crystalline Form I; optionally, the good solvent can be methanol, ethanol, isopropanol, etc.; the poor solvent can be water.

24. A method of preparing the crystalline Form II of any one of claims 6 to 10, comprising: Compound 102D-6 is added to a good solvent, stirred to dissolve, then a poor solvent is added, stirred to crystallize, filtered, and dried to obtain Form II; optionally, the good solvent can be ethyl acetate, isopropyl acetate, methyl formate, ethyl formate, etc.; the poor solvent can be n-hexane, cyclohexane, n-heptane, etc.

25. A method of preparing the crystalline Form III of any one of claims 11 to 15, comprising: Compound 102D-6 is added to a good solvent, stirred to dissolve, then a poor solvent is added, stirred to crystallize, filtered, and dried to obtain Form II; optionally, the good solvent can be ethyl acetate, isopropyl acetate, methyl formate, ethyl formate, etc.; the poor solvent can be n-hexane, cyclohexane, n-heptane, etc.

26. A method of preparing the crystalline Form IV of any one of claims 16-18, comprising: Amorphous compound 102D-6 is added to ethyl acetate, stirred at 20-30°C, filtered, and dried to obtain Form IV.

27. A method of preparing the crystalline Form V of claim 19, comprising: Compound 102D-6 of Form IV according to claims 16-18 is added to a certain volume of n-heptane, stirred at elevated temperature for a certain period of time, cooled, filtered after stirring for a certain period of time, and dried to obtain Form V.

28. A method of preparing the crystalline Form VI of any one of claims 20-22, comprising: Compound 102D-6 is added to a certain volume of methanol, stirred to dissolve at elevated temperature, cooled after adding water, stirred to crystallize, filtered, and dried to obtain Form VI.

29. A pharmaceutical composition comprising a therapeutically effective amount of at least one of Form I according to any one of claims 1-5, Form II according to any one of claims 6-10, Form III according to any one of claims 11-15, Form IV according to any one of claims 16-18, Form V according to claim 19, and Form VI according to any one of claims 20-22.

30. The pharmaceutical composition according to claim 29, which can further comprise one or more therapeutic agents, which can be selected from neuraminidase inhibitors, nucleoside drugs, PB2 inhibitors, PB1 inhibitors, M2 inhibitors, or other anti-influenza drugs, etc.

31. Use of at least one of Form I according to any one of claims 1-5, Form II according to any one of claims 6-10, Form III according to any one of claims 11-15, Form IV according to any one of claims 16-18, Form V according to claim 19, and Form VI according to any one of claims 20-22, or the pharmaceutical composition according to claim 29 or 30, in the preparation of a medicament for preventing and / or treating a viral infectious disease, which can be an infectious disease caused by an influenza virus, such as an infectious disease caused by an influenza A virus or an influenza B virus.

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