Crystal form of compound 102d-6 and preparation method therefor, and preparation method for acyl ethyl ester polycyclic compound

Abstract

The present application discloses a crystal form of a compound 102D-6 and a preparation method therefor, and also discloses a pharmaceutical composition and an antiviral use thereof. The present application also discloses an industrial preparation method for an acyl ethyl ester polycyclic compound and an intermediate compound thereof, the intermediate compound being as shown in formula (II), see description for definitions of substituents. The preparation method not only obtains a product having high purity and low cost, but also has a process that is more suitable for industrial production.

Description

Compound 102D-6 crystal form, preparation method thereof and preparation method of acetoxy ester polycyclic compound

[0001] The present application claims priority to the Chinese patent application No. 202411252134.2, filed on September 7, 2024, and entitled "Industrial preparation method of acetoxy ester polycyclic compound and intermediate compound thereof", the content of which is understood to be incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to, but is not limited to, the technical field of medicinal chemistry, and relates to polymorphs of an anti-influenza virus drug, compound 102D-6, in particular, relates 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 preparation methods thereof; the present application also relates to an industrial preparation method of a drug raw material, acetoxy ester polycyclic compound, and an intermediate compound. BACKGROUND

[0003] Influenza, commonly known as flu, is an acute respiratory infectious disease caused by influenza virus. Influenza virus is the pathogen causing influenza, which belongs to Orthomyxoviridae and is an RNA virus.

[0004] In Chinese invention patent CN 118496239A, a preparation method and antiviral use of compound 120D-6 and its derivatives are disclosed.

[0005] Drug crystal form is an important factor affecting the quality of drug. 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

[0006] In the present application, the chemical name of compound 102D-6 is (1R)-1-[[(12aR)-12-[(11S)-7,8-fluoro-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]acetic acid ethyl ester, which is a compound as shown in formula (102D-6):

[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] The compound 102D-6 disclosed in the Chinese invention patent CN 118496239A is in an amorphous state, has general stability and strong moisture absorption.

[0009] The present application provides a compound 102D-6 crystal form 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 forms described in the present application are studied, 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, i.e. crystal form I, and the crystal form I is 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: 7.0, 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 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.

[0013] In some embodiments, the crystal form I has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angles:

[0014] Table 1A Crystal Form I

[0015] In some embodiments, the crystal form I has an X-ray powder diffraction pattern (XPRD pattern) substantially as shown in FIG. 1.

[0016] In some embodiments, the crystal form I has a differential scanning calorimetry curve with an endothermic peak at 203.8°C.

[0017] In some embodiments, the crystal form I has a differential scanning calorimetry curve (DSC pattern) as shown in FIG. 2.

[0018] 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°C.

[0019] In some embodiments, the crystal form I has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 3.

[0020] 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 by having 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.

[0021] 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.

[0022] In some embodiments, the crystal form II has diffraction peaks at the following 2-theta (unit: degree, error ±0.2 degree) angles:

[0023] Table IB Crystal form II

[0024] In some embodiments, the crystal form II has an X-ray powder diffraction pattern (XPRD pattern) substantially as shown in Figure 4.

[0025] In some embodiments, the crystal form II has a differential scanning calorimetry curve with an endothermic peak at 200.3°C.

[0026] In some embodiments, the crystal form II has a differential scanning calorimetry curve (DSC pattern) as shown in Figure 5.

[0027] 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.

[0028] In some embodiments, the crystal form II has a thermogravimetric analysis curve (TGA pattern) substantially as shown in Figure 6.

[0029] 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 by having 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.

[0030] In some embodiments, the Form III has diffraction peaks at least one or more or all of the following 2-theta (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.

[0031] In some embodiments, the Form III has diffraction peaks at least one or more or all of the following 2-theta (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.

[0032] Table 1C Form III

[0033] In some embodiments, the Form III has an X-ray powder diffraction pattern (XPRD pattern) substantially as shown in Figure 7.

[0034] In some embodiments, the Form III has a differential scanning calorimetry curve (DSC pattern) substantially as shown in Figure 8.

[0035] In some embodiments, the Form III has a differential scanning calorimetry curve (DSC pattern) substantially as shown in Figure 8.

[0036] In some embodiments, the Form III has a thermogravimetric analysis curve (TGA pattern) substantially as shown in Figure 9.

[0037] In some embodiments, the Form III has a thermogravimetric analysis curve (TGA pattern) substantially as shown in Figure 9.

[0038] According to a fourth aspect of the present application, the present application provides a new crystal form of compound 102D-6, Form IV, which is characterized by having diffraction peaks at least one or more or all of the following 2-theta (unit: degree, error ±0.2 degree) angles: 6.7, 8.1, 10.5, 12.5, 15.7, 17.8, 18.4, 22.9, using an X-ray powder diffractometer.

[0039] In some embodiments, the Form IV has diffraction peaks at least one or more or all of the following 2-theta (unit: degree, error ±0.2 degree) 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.

[0040] In some embodiments, the Form IV has diffraction peaks at least one or more or all of the following 2-theta (unit: degree, error ±0.2 degree) 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.

[0041] Table 1D Form IV In some embodiments, the Form IV has a differential scanning calorimetry curve (DSC pattern) substantially as shown in Figure 10.

[0042] In some embodiments, the Form IV has an X-ray powder diffraction pattern (XPRD pattern) substantially as shown in FIG. 10.

[0043] In some embodiments, the Form IV has a differential scanning calorimetry curve with an endothermic peak at 210.4 °C.

[0044] In some embodiments, the Form IV has a differential scanning calorimetry curve (DSC pattern) as shown in FIG. 11.

[0045] In some embodiments, the Form IV has a thermogravimetric analysis curve showing that the sample loses about 3.0% weight, and the sample decomposes at 220 °C.

[0046] In some embodiments, the Form IV has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 12.

[0047] According to a fifth aspect of the present application, the present application provides a new crystal form of compound 102D-6, Form V, which is characterized by having at least one or more or all of the following 2-theta (unit: degree, error ±0.2 degree) angles having diffraction peaks by using an X-ray powder diffractometer: 9.0, 13.1, 18.1, 19.5, 20.7, 22.7, 32.0.

[0048] In some embodiments, the Form V has diffraction peaks at the following 2-theta (unit: degree, error ±0.2 degree) angles:

[0049] Table 1E Form V

[0050] In some embodiments, the Form V has an X-ray powder diffraction pattern (XPRD pattern) substantially as shown in FIG. 13.

[0051] In some embodiments, the Form V has a differential scanning calorimetry curve with an endothermic peak at 197.2 °C.

[0052] In some embodiments, the Form V has a differential scanning calorimetry curve (DSC pattern) as shown in FIG. 14.

[0053] In some embodiments, the Form V has a thermogravimetric analysis curve showing that the sample loses weight at about 210 °C, and the weight loss is about 60.254%.

[0054] In some embodiments, the Form V has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 15.

[0055] According to a sixth aspect of the present application, the present application provides a new crystal form of compound 102D-6, crystal form VI, which is characterized in that it has diffraction peaks at at least one or more or all of the following 2 theta (unit: degree, error ±0.2 degrees) angles by using an X-ray powder diffractometer: 7.1, 12.3, 17.2, 21.5, 22.3.

[0056] In some embodiments, the crystal form VI has diffraction peaks at at least one or more or all of the following 2 theta (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.

[0057] In some embodiments, the crystal form VI has diffraction peaks at at least one or more or all of the following 2 theta (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.

[0058] Table 1F Crystal form VI

[0059] In some embodiments, the crystal form VI has an X-ray powder diffraction pattern (XPRD pattern) substantially as shown in Figure 16.

[0060] In some embodiments, the crystal form VI has a differential scanning calorimetry curve with an endothermic peak at 155.3°C.

[0061] In some embodiments, the crystal form VI has a differential scanning calorimetry curve (DSC pattern) as shown in Figure 17.

[0062] In some embodiments, the crystal form VI has a thermogravimetric analysis curve showing that the sample does not lose weight, and the sample decomposes at 220°C.

[0063] In some embodiments, the crystal form VI has a thermogravimetric analysis curve (TGA pattern) substantially as shown in Figure 18.

[0064] According to a seventh aspect of the present application, the present application provides a method for preparing crystal form I, comprising: adding compound 102D-6 into a certain volume of a good solvent, stirring to dissolve, then directly cooling or adding a poor solvent to cool, stirring to crystallize, filtering, and drying to obtain crystal form I.

[0065] In some embodiments, the good solvent can be one or more of methanol, ethanol, isopropanol, etc.

[0066] In some embodiments, the poor solvent can be water.

[0067] In some embodiments, the temperature for dissolution can be 50-80°C.

[0068] In some embodiments, the temperature for crystallization after cooling can be 0-30°C.

[0069] In some embodiments, the temperature for drying can be 40-50°C, more preferably 40-45°C.

[0070] In some embodiments, the ratio of good solvent to compound 102D-6 solid can be 4 ml / g-10 ml / g, more preferably 4 ml / g-6 ml / g.

[0071] In some embodiments, the ratio of poor solvent to compound 102D-6 solid can be 4 ml / g-10 ml / g, more preferably 4 ml / g-6 ml / g.

[0072] According to an eighth aspect of the present application, a method for preparing crystal form II is provided, comprising: adding compound 102D-6 to a volume of good solvent, stirring to dissolve, then adding poor solvent, stirring to crystallize, filtering, and drying to obtain crystal form II.

[0073] In some embodiments, the good solvent can be one or more of ethyl acetate, isopropyl acetate, methyl formate, ethyl formate, etc.

[0074] In some embodiments, the poor solvent can be one or more of n-hexane, cyclohexane, n-heptane, etc.

[0075] In some embodiments, water needs to be added.

[0076] In some embodiments, crystal form II seed is used to induce crystallization.

[0077] In some embodiments, the temperature for dissolution can be 20-80°C, more preferably 50-60°C.

[0078] In some embodiments, the temperature for crystallization can be 0-30°C, more preferably 0-10°C.

[0079] In some embodiments, the temperature for drying can be 30-60°C, more preferably 50-60°C.

[0080] In some embodiments, the ratio of good solvent to compound 102D-6 solid can be 3 ml / g-8 ml / g, more preferably 3 ml / g-5 ml / g.

[0081] In some embodiments, the ratio of the poor solvent to the compound 102D-6 solid can be 10 ml / g to 20 ml / g, more preferably 10 ml / g to 15 ml / g.

[0082] In some embodiments, the ratio of the water to the compound 102D-6 solid can be 0.01:1 to 0.1:1, more preferably 0.03:1 to 0.06:1.

[0083] In some embodiments, the ratio of the crystal form II seed to the compound 102D-6 solid can be 0.001:1 to 0.01:1, more preferably 0.001:1 to 0.003:1.

[0084] According to a ninth aspect of the present application, the present application provides a method for preparing the crystal form II, comprising: adding the compound 102D-6 in the crystal form I into a certain volume of n-heptane, stirring at a controlled temperature for a certain time, filtering, and drying to obtain the crystal form II.

[0085] In some embodiments, the stirring temperature can be 40 to 85°C.

[0086] In some embodiments, the stirring time can be 4 to 24 hours.

[0087] In some embodiments, the drying temperature can be 50 to 60°C.

[0088] In some embodiments, the ratio of the n-heptane to the compound 102D-6 solid can be 5 ml / g to 20 ml / g, more preferably 10 ml / g to 15 ml / g.

[0089] According to a tenth aspect of the present application, the present application provides a method for preparing the crystal form III, comprising: adding the compound 102D-6 into a certain volume of a good solvent, stirring at a raised temperature until the solution is clear, and then directly lowering the temperature to induce crystallization, or adding a poor solvent after incubation and then lowering the temperature to induce crystallization, filtering, and drying to obtain the crystal form III.

[0090] In some embodiments, the good solvent can be one or more of ethyl acetate, isopropyl acetate, and the like.

[0091] In some embodiments, the poor solvent can be one or more of n-hexane, cyclohexane, n-heptane, and the like.

[0092] In some embodiments, the poor solvent can be added at one time or in batches, more preferably in batches.

[0093] In some embodiments, the dissolution temperature can be 60 to 80°C, more preferably 60 to 70°C.

[0094] In some embodiments, the temperature of the crystallization can be 0-30°C, more preferably 0-10°C.

[0095] In some embodiments, the temperature of the drying can be 45-60°C, more preferably 50-60°C.

[0096] In some embodiments, the ratio of the good solvent to the compound 102D-6 solid can be 2-6 ml / g, more preferably 3-5 ml / g.

[0097] In some embodiments, the ratio of the poor solvent to the compound 102D-6 solid can be 3-20 ml / g, more preferably 10-15 ml / g.

[0098] According to an eleventh aspect of the present application, the present application provides a method for preparing the crystal Form III, which comprises: adding amorphous compound 102D-6 into a certain volume of solvent, stirring at a controlled temperature for a certain time, filtering, and drying to obtain the crystal Form III.

[0099] In some embodiments, the solvent can be one or more of n-heptane, isopropyl ether, and the like.

[0100] In some embodiments, the stirring temperature can be 50-85°C, preferably 60-70°C.

[0101] In some embodiments, the stirring time can be 4-24 hours, preferably 15-20 hours.

[0102] In some embodiments, the drying temperature can be 50-60°C.

[0103] In some embodiments, the ratio of the solvent to the compound 102D-6 solid can be 5-20 ml / g, more preferably 10-15 ml / g.

[0104] According to a twelfth aspect of the present application, the present application provides a method for preparing the crystal Form IV, which comprises: adding amorphous compound 102D-6 into a certain volume of ethyl acetate, stirring at a controlled temperature of 20-30°C, filtering, and drying to obtain the crystal Form IV.

[0105] In some embodiments, the ratio of the ethyl acetate to the compound 102D-6 solid can be 3-5 ml / g.

[0106] According to the thirteenth aspect of the present application, the present application provides a method for preparing Form IV, comprising: adding compound 102D-6 of Form VI into a certain volume of ethyl acetate, stirring at 20-30°C until the solution is clear, adding a certain volume of n-heptane, stirring at 20-30°C for 0.5 hours, adding a certain volume of n-heptane, stirring at 20-30°C, filtering, and drying to obtain Form IV.

[0107] In some embodiments, the ratio of ethyl acetate to compound 102D-6 solid can be 3-4 ml / g.

[0108] In some embodiments, the ratio of the first portion of n-heptane to compound 102D-6 solid can be 3-4 ml / g.

[0109] In some embodiments, the ratio of the second portion of n-heptane to compound 102D-6 solid can be 8-9 ml / g.

[0110] According to the fourteenth aspect of the present application, the present application provides a method for preparing Form V, comprising: adding compound 102D-6 of Form VI into a certain volume of n-heptane, stirring at a certain temperature for a certain time, cooling, stirring for a certain time, filtering, and drying to obtain Form V.

[0111] In some embodiments, the stirring temperature can be 60-100°C, more preferably 80-90°C.

[0112] In some embodiments, the stirring time can be 4-8 hours, more preferably 8 hours.

[0113] In some embodiments, the stirring temperature can be 0-30°C, more preferably 0-10°C.

[0114] In some embodiments, the drying temperature can be 50-60°C.

[0115] In some embodiments, the ratio of n-heptane to compound 102D-6 solid can be 10-20 ml / g.

[0116] According to the fifteenth aspect of the present application, the present application provides a method for preparing Form VI, comprising: adding compound 102D-6 into a certain volume of methanol, stirring at a certain temperature until the solution is clear, adding water, cooling, stirring to crystallize, filtering, and drying to obtain Form VI.

[0117] In some embodiments, the stirring temperature can be 50-70°C, more preferably 60-65°C.

[0118] In some embodiments, the temperature for the post-cooling crystallization can be 0-30°C, more preferably 20-30°C.

[0119] In some embodiments, the drying temperature can be 50-60°C, more preferably 55-60°C.

[0120] In some embodiments, the drying time can be 8-24 hours, more preferably 15-20 hours.

[0121] In some embodiments, the ratio of methanol to compound 102D-6 solid can be 4-8 ml / g, more preferably 5-7 ml / g.

[0122] In some embodiments, the ratio of water to compound 102D-6 solid can be 4-8 ml / g, more preferably 5-7 ml / g.

[0123] The "crystal form" described herein can exist in a sample in an amount of 0.0001% to 100%, and therefore, as long as a sample contains even a trace amount, for example, more than 0.0001%, more than 0.001%, more than 0.01%, of the "crystal form" described herein, it should be understood to fall within the scope of the present application. In order to more clearly describe the various parameters of the "crystal form" described herein, the present application tests various parameters of a sample containing substantially pure form of a certain "crystal form" and characterizes and identifies the "crystal form". The term "substantially pure" means that the sample is substantially composed of one major crystal form, and is substantially free of another or additional crystal form(s) or amorphous, and the purity of the major crystal form is 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 another or additional crystal form(s) or amorphous" means that the content of the other crystal form(s) or amorphous 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.

[0124] In the context of the present application, all of the numbers disclosed herein are approximations. The numerical value, of each can vary by 1%, 2%, or 5%.

[0125] The differential scanning calorimetry (DSC) of the crystal form can have experimental errors, and the position and peak value of the endothermic peak can be slightly different between one machine and another machine and between one sample and another sample, the value of the experimental error or difference can 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 value of the peak position or peak value of the DSC endothermic peak cannot be considered absolute.

[0126] The amount of reagent used in the method of the present application can be adjusted by those of ordinary skill in the art according to their knowledge and experience, including scaling up or down the amount of raw materials and adjusting the amount of solvent, and the temperature of the method of the present application can be changed. These adjustment schemes are also included in the method of the present application.

[0127] According to a sixteenth aspect of the present application, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned crystal form I to crystal form VI.

[0128] In some embodiments, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned crystal form I with a crystal form purity of more than 90%.

[0129] In some embodiments, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned crystal form II with a crystal form purity of more than 90%.

[0130] In some embodiments, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned crystal form III with a crystal form purity of more than 90%.

[0131] In some embodiments, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned crystal form IV with a crystal form purity of more than 90%.

[0132] In some embodiments, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned crystal form V with a crystal form purity of more than 90%.

[0133] In some embodiments, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned crystal form VI with a crystal form purity of more than 90%.

[0134] In some embodiments, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of at least two of the above-mentioned crystal form I with a crystal form purity of more than 90%, the above-mentioned crystal form II with a crystal form purity of more than 90%, the above-mentioned crystal form III with a crystal form purity of more than 90%, the above-mentioned crystal form IV with a crystal form purity of more than 90%, the above-mentioned crystal form V with a crystal form purity of more than 90%, and the above-mentioned crystal form VI with a crystal form purity of more than 90%.

[0135] In some embodiments, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of at least three of the above Form I with more than 90% purity, the above Form II with more than 90% purity, the above Form III with more than 90% purity, the above Form IV with more than 90% purity, the above Form V with more than 90% purity, and the above Form VI with more than 90% purity.

[0136] In some embodiments, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of at least four of the above Form I with more than 90% purity, the above Form II with more than 90% purity, the above Form III with more than 90% purity, the above Form IV with more than 90% purity, the above Form V with more than 90% purity, and the above Form VI with more than 90% purity.

[0137] In some embodiments, the pharmaceutical composition generally comprises 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 take any suitable dosage form, which can be a tablet, powder, capsule, granule, oral solution, injection, powder, suppository, pill, cream, paste, gel, powder, inhalant, suspension, dry suspension, patch, lotion, nano-preparation, etc.

[0138] In some embodiments, the pharmaceutical composition can further comprise one or more therapeutic agents, which can be selected from a neuraminidase inhibitor, a nucleoside drug, a PB2 inhibitor, a PB1 inhibitor, a M2 inhibitor, or other anti-influenza drugs, etc.

[0139] According to a seventeenth aspect of the present application, the present application provides one of the above Form I to Form VI or a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above Form I to Form VI for use in 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.

[0140] According to an eighteenth aspect of the present application, the present application provides use of one of the above Form I to Form VI or a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above Form I to Form VI 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.

[0141] According to a nineteenth aspect of the present application, the present application provides a method for preventing and / or treating a viral infectious disease, which comprises administering one of the above-mentioned crystalline forms I to VI or a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned crystalline forms I to VI to an individual in need thereof; optionally, the viral infectious disease is an infectious disease caused by an influenza virus, such as an infectious disease caused by an influenza A virus or an influenza B virus.

[0142] According to a twentieth aspect of the present application, the present application provides an industrialized preparation method of acyl acetal polycyclic compounds.

[0143] The preparation method not only has high product purity and low cost, but also is more suitable for industrial production.

[0144] The present application provides an industrialized preparation method of acyl acetal polycyclic compounds, wherein the acyl acetal polycyclic compound is as shown in formula (I-1) or as shown in formula (I-2):

[0145] R1, R2, R3, R4, R5, R6 and R7 in formula (I-1) or formula (I-2) are each independently selected from hydrogen and deuterium;

[0146] The preparation method at least comprises the following steps:

[0147] The compound of formula (II-1) or formula (II-2) is subjected to a reduction reaction with a reducing agent to obtain the compound of formula (I-1) or formula (I-2):

[0148] wherein the definitions of R1, R2, R3, R4, R5, R6 and R7 in formula (II-1) or formula (II-2) are the same as those in formula (I-1) or formula (I-2).

[0149] In an embodiment of the present application, the preparation method further comprises the following steps: subjecting the compound of formula (102D-4) to an etherification reaction with the compound of formula (III) to obtain a mixture of the compound of formula (II-1) and the compound of formula (II-2); and then subjecting the mixture to recrystallization to obtain the compound of formula (II-1) or formula (II-2);

[0150] wherein the definitions of R1, R2, R3, R4, R5, R6 and R7 in formula (III) are the same as those in formula (I-1) or formula (II-2); and X in formula (III) is iodine, bromine, chlorine or sulfonate.

[0151] In some embodiments of the present application, the preparation method further comprises the following step: the compound of formula (IV) is subjected to a dehydroxyl substituent reaction to obtain a compound of formula (102D-4);

[0152] Y in formula (IV) is C1-C 10 alkyl, optionally selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, heptyl, octyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 3-methyl-1-pentyl and 4-methyl-1-pentyl.

[0153] In some embodiments of the present application, the preparation method further comprises the following step: the compound of formula (V) is subjected to a reaction with an oxidant to obtain a compound of formula (IV);

[0154] wherein Y in formula (V) is defined the same as in formula (IV).

[0155] In some embodiments of the present application, the preparation method further comprises the following step: the compound of formula (VI) is subjected to a condensation reaction with a compound of formula (102M2-D1) to obtain a compound of formula (V);

[0156] wherein Y in formula (VI) is defined the same as in formula (V).

[0157] In some embodiments of the present application, the preparation method further comprises the following step: the compound of formula (102D-0) is subjected to a reaction with a compound of formula (VII) to obtain a compound of formula (VI);

[0158] wherein Bn in formula (102D-0) is benzyl; Y in formula (VII) is defined the same as in formula (VI).

[0159] In some embodiments of the present application, the present application provides an industrialized preparation method of acyl ethyl ester polycyclic compounds, which comprises the following steps:

[0160] the compound of formula (102D-4) is subjected to an etherification reaction with a compound of formula (III) to obtain a mixture of a compound of formula (II-1) and a compound of formula (II-2); and then recrystallization is performed to obtain a compound of formula (II-1) or a compound of formula (II-2);

[0161] the compound of formula (II-1) or the compound of formula (II-2) is subjected to a reduction reaction with a reducing agent to obtain a compound of formula (I-1) or a compound of formula (I-2):

[0162] wherein R1, R2, R3, R4, R5, R6and R7in formula (III), formula (II-1), formula (II-2), formula (I-1) or formula (I-2) are each independently selected from hydrogen and deuterium; X in formula (III) is iodo, bromo, chloro or sulfonate.

[0163] In some embodiments of the present application, R1, R2, R3, R4, R5, R6and R7in formula (I-1), formula (I-2), formula (II-1), formula (II-2) and formula (III) are all hydrogen.

[0164] In some embodiments of the present application, R1, R2and R3in formula (I-1), formula (I-2), formula (II-1), formula (II-2) and formula (III) are all deuterium, and R4, R5, R6and R7are all hydrogen.

[0165] In some embodiments of the present application, X in formula (III) is bromo or chloro; in an embodiment of the present application, X in formula (III) is bromo.

[0166] In some embodiments of the present application, Y in formula (IV), formula (V), formula (VI) and formula (VII) is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, heptyl, octyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 3-methyl-1-pentyl or 4-methyl-1-pentyl; in an embodiment of the present application, Y in formula (IV), formula (V), formula (VI) and formula (VII) is pentyl or isopentyl.

[0167] In an embodiment of the present application, R1, R2, R3, R4, R5, R6and R7in formula (I-2) are all hydrogen, i.e. the compound of formula (I-2) is a compound of formula (102D-6).

[0168] In an embodiment of the present application, the present application provides a preparation method of acyloxyester polycyclic compound as shown in formula (102D-6) or formula (102D-6A), which comprises the following steps:

[0169] (i) etherification reaction of a compound of formula (102D-4) with a compound of formula (102M1-C0) to obtain a mixture of a compound of formula (102D-5) and a compound of formula (102D-5A); recrystallization to obtain the compound of formula (102D-5) or the compound of formula (102D-5A) respectively;

[0170] (ii) reaction of the compound of formula (102D-5) with a reducing agent to obtain a compound of formula (102D-6);

[0171] Alternatively, the compound of formula (102D-5A) is reacted with a reducing agent to obtain a compound of formula (102D-6A);

[0172] In some embodiments of the present application, the etherification reaction is carried out in the presence of a base, which can be an inorganic base or an organic base, the inorganic base can be selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, and the organic base can be selected from triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, preferably potassium carbonate or triethylamine. In some examples, the reaction is carried out in a reaction solvent, which can be selected from dichloromethane, ethyl acetate, chloroform, etc., preferably dichloromethane; in some examples, the etherification reaction temperature is selected from -10°C to 30°C, preferably 10°C to 20°C.

[0173] In some embodiments of the present application, the solvent for recrystallization after the etherification reaction is acetonitrile or a mixed solvent of acetonitrile and methyl tert-butyl ether, and optionally, the volume ratio of acetonitrile to methyl tert-butyl ether is any value selected from 1:20 to 50:1.

[0174] In some embodiments of the present application, the solvent for recrystallization after the etherification reaction is toluene or a mixed solvent of toluene and methyl tert-butyl ether, and optionally, the volume ratio of toluene to methyl tert-butyl ether is any value selected from 1:5 to 50:1.

[0175] In some embodiments of the present application, the reducing agent is one or more of sodium bisulfite / iodine, sodium iodide / boron trifluoride etherate, and potassium iodide / trichloroisocyanuric acid.

[0176] In an embodiment of the present application, the present application provides a method for preparing an acetoxy poly cyclic compound as shown in formula (102D-6) or formula (102D-6A), which comprises the following steps:

[0177] (1) the compound of formula (102D-0) is reacted with isoamyl alcohol to obtain a compound of formula (102D-1), wherein TsOH is p-toluenesulfonic acid;

[0178] (2) the compound of formula (102D-1) is subjected to a condensation reaction with a compound of formula (102M2-D1) to obtain a compound of formula (102D-2), wherein MsOH is methanesulfonic acid;

[0179] (3) the compound of formula (102D-2) is reacted with an oxidizing agent to obtain a compound of formula (102D-3);

[0180] (4) the compound of formula (102D-3) is de-isopentyled in the presence of lithium chloride to obtain a compound of formula (102D-4);

[0181] (5) the compound of formula (102D-5) and the compound of formula (102D-5A) are obtained by etherification reaction of the compound of formula (102D-4) and the compound of formula (102M1-C0); the compound of formula (102D-5) and the compound of formula (102D-5A) are obtained by recrystallization, respectively;

[0182] (6) the compound of formula (102D-6) is obtained by reaction of the compound of formula (102D-5) with a reducing agent;

[0183] or, the compound of formula (102D-6A) is obtained by reaction of the compound of formula (102D-5A) with a reducing agent;

[0184] In some embodiments, the step (1) is: isopentyl alcohol, tetrahydrofuran, a base are put into a reactor, the compound of formula (102D-0) is added, after the addition, the reaction is carried out at room temperature for 1-5 h; after the reaction is completed, the reaction is quenched by adding an aqueous citric acid solution, the phases are separated, the aqueous phase is discarded, p-toluenesulfonic acid monohydrate is added to the organic phase to form a salt, anhydrous sodium sulfate is added for drying, filtration is carried out, the filtrate is concentrated under reduced pressure to dryness, the filtrate is warmed to 50-60 °C, normal heptane is added, after the addition, the temperature is lowered to induce crystallization, filtration is carried out, and the wet product is dried to constant weight to obtain the compound of formula (102D-1); in some embodiments, the base in the step (1) can be selected from sodium tert-butoxide and / or sodium tert-amylate, and preferably sodium tert-butoxide; the molar ratio of the compound of formula (102D-0), isopentyl alcohol and the base is 1:10-20:1-2, and preferably the ratio is 1:15:1.5; the crystallization temperature is selected from 0 °C to 30 °C, and preferably 10 °C to 20 °C.

[0185] In some embodiments, the step (2) is: the compound of formula (102D-1) obtained in step (1), the compound of formula (102M2-D1), ethyl acetate, cyclohexane, a condensing agent, methanesulfonic acid are put into a reactor, and the reaction is carried out at elevated temperature for 10-30 h; after the reaction is completed, tetrahydrofuran and water are added, an aqueous sodium hydroxide solution is added for extraction, the phases are separated, the aqueous phase is discarded, methanesulfonic acid is added to the organic phase to form a salt, filtration is carried out, and the wet product is dried to constant weight to obtain the compound of formula (102D-2); in some embodiments, the condensing agent in the step (2) can be selected from propyl phosphonic anhydride solution or n-butyl phosphonic anhydride solution, and preferably propyl phosphonic anhydride solution; the molar ratio of the compound of formula (102D-1), the compound of formula (102M2-D1) and the condensing agent is 1:1-2:1-3, and preferably the ratio is 1:1.5:2; the reaction temperature is selected from 50 °C to 80 °C, and preferably 60 °C to 70 °C.

[0186] In some embodiments, the step (3) is: reacting the compound of formula (102D-2) obtained in step (2) with dichloromethane and aqueous base, separating the phases, discarding the aqueous phase, adding an oxidizing agent to the organic phase, stirring the reaction at a controlled temperature for 0.1-2 hours; after the reaction is complete, quenching the reaction with sodium sulfite, extracting with water, separating the phases, and discarding the aqueous phase; adding saturated aqueous sodium carbonate to the organic phase, extracting, separating the phases, discarding the aqueous phase, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain the compound of formula (102D-3); in some embodiments, the base used in the step (3) can be selected from sodium hydroxide, sodium bicarbonate, or sodium carbonate, etc.; the oxidizing agent can be selected from meta-chloroperoxybenzoic acid, hydrogen peroxide, sodium hypochlorite pentahydrate, or potassium hydrogen persulfate, etc., and is preferably meta-chloroperoxybenzoic acid; the molar ratio of the compound of formula (102D-2) to the oxidizing agent is 1:1-1.2, and is preferably 1:1.1; the reaction temperature is selected from -10°C to 30°C, and is preferably 0°C to 10°C.

[0187] In some embodiments, the step (4) is: adding the compound of formula (102D-3) obtained in step (3), lithium chloride, methanesulfonic acid, and a reaction solvent into a reaction bottle in sequence, stirring the reaction at a controlled temperature for 10-20 hours; after the reaction is complete, adding acetonitrile and water to the reaction solution, filtering, and drying the wet product to constant weight to obtain the compound of formula (102D-4); in some embodiments, the reaction solvent used in the step (4) can be selected from N-methylpyrrolidone or N,N-dimethylacetamide, and is preferably N-methylpyrrolidone; the molar ratio of the compound of formula (102D-3) to lithium chloride is 1:5-10, and is preferably 1:7; the reaction temperature is selected from 70°C to 110°C, and is preferably 80°C to 90°C; the crystallization temperature is selected from 0°C to 30°C, and is preferably 0°C to 10°C.

[0188] In some embodiments, the step (5) or step (i) is: adding the compound of formula (102D-4) obtained in step (4), a base, potassium iodide, a reaction solvent into a reaction flask, adding the compound of formula (102M1-C0), stirring for 10-20 hours; adding water, stirring for half an hour, separating the phases, discarding the aqueous phase, adding saturated aqueous sodium bicarbonate solution into the organic phase, extracting, separating the phases, discarding the aqueous phase, adding anhydrous sodium sulfate into the organic phase, drying for 1 hour, filtering, concentrating the filtrate under reduced pressure to dryness, adding acetonitrile into the concentrate, stirring to crystallize, filtering, drying the filter cake to constant weight to obtain the compound of formula (102D-5A); concentrating the filtrate of 102D-5A under reduced pressure to dryness, adding toluene into the concentrate, stirring to crystallize, filtering, drying the wet product to constant weight to obtain the compound of formula (102D-5); in some embodiments, the base used in the etherification reaction of the step (5) or step (i) can be an inorganic base or an organic base, the inorganic base can be selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, the organic base can be selected from triethylamine, N-methylmorpholine, N,N-di-isopropylethylamine, preferably potassium carbonate or triethylamine; the reaction solvent can be selected from dichloromethane, ethyl acetate, chloroform, etc., preferably dichloromethane; the molar ratio of the compound of formula (102D-4), the compound of formula (102M1-C0), the base is 1:1.5-3:1.5-3, preferably 1:2:2; the reaction temperature is selected from -10℃ to 30℃, preferably 10℃ to 20℃.

[0189] In some embodiments, the step (6) or step (ii) is: adding the compound of formula (102D-5) obtained in step (5), a reaction solvent, sodium bisulfite, iodine into a reactor, controlling the temperature to react for 10-20 hours. After the reaction is completed, filtering, adding water into the filtrate to extract, separating the phases, discarding the aqueous phase, adding anhydrous sodium sulfate into the organic phase, drying for 1 hour, filtering, concentrating the filtrate under reduced pressure to dryness, recrystallizing the concentrate with a single or mixed solvent, drying the wet product to constant weight to obtain the compound of formula (102D-6); the reaction solvent used in the step (6) or step (ii) can be selected from dichloromethane, chloroform, etc., preferably chloroform; the molar ratio of the compound of formula (102D-5), sodium bisulfite, iodine is 1:3-6:0.5-1, preferably the ratio is 1:5:0.5; the reaction temperature is selected from -10℃ to 30℃, preferably 10℃ to 20℃; the single solvent used in recrystallization can be selected from methanol, ethanol or acetonitrile; the mixed solvent can be selected from methanol-water, ethanol-water, ethyl acetate-n-hexane, ethyl acetate-n-heptane, isopropyl acetate-n-hexane, isopropyl acetate-n-heptane, dimethyl sulfoxide-water, etc.

[0190] In some embodiments, the step (6) or step (ii) is: putting the compound of formula (102D-5A) obtained in step (5), a reaction solvent, sodium bisulfite, iodine into a reactor, and reacting for 10-20 hours at a controlled temperature. After the reaction is completed, filtering, adding water into the filtrate to extract, separating the phases, discarding the aqueous phase, adding anhydrous sodium sulfate into the organic phase to dry for 1 hour, filtering, and concentrating the filtrate under reduced pressure to dryness, recrystallizing the concentrate with acetonitrile, and drying the wet product to constant weight to obtain the compound of formula (102D-6A); the reaction solvent in the step (6) or step (ii) can be selected from dichloromethane, chloroform, etc., and chloroform is preferred; the molar ratio of the compound of formula (102D-5A), sodium bisulfite, and iodine is 1:3-6:0.5-1, and the preferred ratio is 1:5:0.5; and the reaction temperature is selected from -10°C to 30°C, and preferably 10°C to 20°C.

[0191] According to a twenty-first aspect of the present application, the present application provides a compound as shown in formula (II):

[0192] wherein R1, R2, R3, R4, R5, R6, and R7 are each independently selected from hydrogen and deuterium.

[0193] In an embodiment, the compound of formula (II) is a compound of formula (II-1):

[0194] In an embodiment, the compound of formula (II) is a compound of formula (II-2):

[0195] In an embodiment, the compound of formula (II) is a mixture of a compound of formula (II-1) and a compound of formula (II-2):

[0196] In some embodiments of the present application, R1, R2, R3, R4, R5, R6, and R7 in the compound of formula (II), formula (II-1), or formula (II-2) are all hydrogen; or the compound of formula (II-2) is a compound of formula (102D-5); or the compound of formula (II-1) is a compound of formula (102D-5A); or the compound of formula (II) is a compound of formula (102D-5), a compound of formula (102D-5A), or a mixture of a compound of formula (102D-5) and a compound of formula (102D-5A).

[0197] In some embodiments of the present application, R1, R2, and R3 in the compound of formula (II), formula (II-1), or formula (II-2) are all deuterium, and R4, R5, R6, and R7 are all hydrogen.

[0198] According to a twenty-second aspect of the present application, the present application provides a use of the compound shown in the above formula (II) as an intermediate compound for preparing a compound of formula (I-1) or a compound of formula (I-2).

[0199] According to a twenty-third aspect of the present application, the present inventors have found that 102M2-D1 is oxidized into a sulfoxide first and then condensed with a compound of formula (VI), and attempts of T3P, guangyan reaction and the like all fail to generate a compound of formula (IV).

[0200] In some embodiments, the present application provides a method for preparing a compound of formula (102D-4), which comprises:

[0201] (a) condensing a compound of formula (VI) with a compound of formula (102M2-D1) to obtain a compound of formula (V);

[0202] wherein Y in formula (VI) and formula (V) is C1-C10alkyl, optionally selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, heptyl, octyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 3-methyl-1-pentyl and 4-methyl-1-pentyl;

[0203] (b) reacting the compound of formula (V) with an oxidizing agent to obtain a compound of formula (IV);

[0204] wherein Y in formula (IV) is defined the same as Y in formula (V);

[0205] (c) dehydroxylating the compound of formula (IV) to obtain a compound of formula (102D-4);

[0206] Y in formula (IV) is C1-C10alkyl, optionally selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, heptyl, octyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 3-methyl-1-pentyl and 4-methyl-1-pentyl. 10 Y in formula (IV) is C1-C10alkyl, optionally selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, heptyl, octyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 3-methyl-1-pentyl and 4-methyl-1-pentyl.

[0207] In some embodiments, the reaction conditions of steps (a), (b) and (c) are as described above.

[0208] In some embodiments, the compound of formula (VI) in step (a) can be prepared by:

[0209] reacting a compound of formula (102D-0) with a compound of formula (VII) to obtain a compound of formula (VI);

[0210] wherein Bn in formula (102D-0) is benzyl; Y in formula (VII) is defined the same as in formula (VI).

[0211] In some embodiments, the reaction conditions of the method for preparing the compound of formula (VI) in step (a) are as described above.

[0212] According to a twenty-fourth aspect of the present application, the present application provides an intermediate compound as shown in formula (IV):

[0213] wherein Y in formula (IV) is C1-C 10 alkyl, optionally selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, heptyl, octyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 3-methyl-1-pentyl and 4-methyl-1-pentyl.

[0214] In some embodiments, the present application provides a compound of formula (102D-3):

[0215] In the present application, the structure of compound 102D-5 is:

[0216] In the present application, the structure of compound 102D-6D is: BRIEF DESCRIPTION OF DRAWINGS

[0217] Figure 1 is an XRPD pattern of compound 102D-6 in crystalline Form I provided by the present application;

[0218] Figure 2 is a DSC pattern of compound 102D-6 in crystalline Form I provided by the present application;

[0219] Figure 3 is a TGA pattern of compound 102D-6 in crystalline Form I provided by the present application;

[0220] Figure 4 is an XRPD pattern of compound 102D-6 in crystalline Form II provided by the present application;

[0221] Figure 5 is a DSC pattern of compound 102D-6 in crystalline Form II provided by the present application;

[0222] Figure 6 is a TGA pattern of compound 102D-6 in crystalline Form II provided by the present application;

[0223] Figure 7 is an XRPD pattern of compound 102D-6 in crystalline Form III provided by the present application;

[0224] Figure 8 is a DSC pattern of compound 102D-6 in crystalline Form III provided by the present application;

[0225] Figure 9 is a TGA pattern of crystalline Form III compound 102D-6 provided herein;

[0226] Figure 10 is an XRPD pattern of crystalline Form IV compound 102D-6 provided herein;

[0227] Figure 11 is a DSC pattern of crystalline Form IV compound 102D-6 provided herein;

[0228] Figure 12 is a TGA pattern of crystalline Form IV compound 102D-6 provided herein;

[0229] Figure 13 is an XRPD pattern of crystalline Form V compound 102D-6 provided herein;

[0230] Figure 14 is a DSC pattern of crystalline Form V compound 102D-6 provided herein;

[0231] Figure 15 is a TGA pattern of crystalline Form V compound 102D-6 provided herein;

[0232] Figure 16 is an XRPD pattern of crystalline Form VI compound 102D-6 provided herein;

[0233] Figure 17 is a DSC pattern of crystalline Form VI compound 102D-6 provided herein;

[0234] Figure 18 is a TGA pattern of crystalline Form VI compound 102D-6 provided herein;

[0235] Figure 19 is an XRPD pattern of existing amorphous compound 102D-6;

[0236] Figure 20 is a DSC pattern of existing amorphous compound 102D-6;

[0237] Figure 21 is a TGA pattern of existing amorphous compound 102D-6;

[0238] Figure 22 is a liquid chromatogram of amorphous 102D-6 stability test 0 days;

[0239] Figure 23 is a liquid chromatogram of amorphous 102D-6 stability test high temperature condition 30 days;

[0240] Figure 24 is a liquid chromatogram of amorphous 102D-6 stability test high humidity condition 30 days;

[0241] Figure 25 is a liquid chromatogram of amorphous 102D-6 stability test accelerated condition 30 days;

[0242] Figure 26 is a liquid chromatogram of crystalline Form II 102D-6 stability test 0 days;

[0243] Figure 27 is a liquid chromatogram of 102D-6 stability test of Form II at high temperature for 30 days;

[0244] Figure 28 is a liquid chromatogram of 102D-6 stability test of Form II at high humidity for 30 days;

[0245] Figure 29 is a liquid chromatogram of 102D-6 stability test of Form II at accelerated condition for 30 days;

[0246] Figure 30 is a plot of the plasma concentration-time curve of 102D-6 in SD rats after a single oral administration of different forms of 102D-6;

[0247] Figure 31 is a plot of the plasma concentration-time curve of 102D-6 in cynomolgus monkeys after a single oral administration of different forms of 102D-6;

[0248] Figure 32 is a plot of the body weight change of mice in Groups 1-5 in the influenza virus mouse pharmacodynamics study;

[0249] Figure 33 is a plot of the body weight change of mice in Groups 6-10 in the influenza virus mouse pharmacodynamics study;

[0250] Figure 34 is a plot of the body weight change of mice in Groups 11-15 in the influenza virus mouse pharmacodynamics study;

[0251] Figure 35 is a plot of the survival rate of mice in each group in the influenza virus mouse pharmacodynamics study;

[0252] Figure 36 is a plot of the body temperature change of ferrets in each group in the influenza virus ferret pharmacodynamics study;

[0253] Figure 37 is a plot of the clinical symptom score of ferrets in each group in the influenza virus ferret pharmacodynamics study;

[0254] Figure 38 is a plot of the virus titer of nasal lavage fluid of ferrets in each group in the influenza virus ferret pharmacodynamics study;

[0255] Figure 39 is a mass spectrum of 102D-1;

[0256] Figure 40 is a mass spectrum of 102D-2;

[0257] Figure 41 is a mass spectrum of 102D-3;

[0258] Figure 42 is a mass spectrum of 102D-4;

[0259] Figure 43 is a mass spectrum of 102D-5;

[0260] Figure 44 is a mass spectrum of 102D-5A. DETAILED DESCRIPTION

[0261] The embodiments of the present application will be described in detail below with specific examples, which do not constitute limitation on the scope of protection claimed by the present application. Any obvious substitutions made under the teaching of the present application, using the techniques known in the art, shall still fall within the scope of protection of the present application.

[0262] The technical solutions of the present application will be further described in detail below with specific examples; however, the present application is not limited to these examples.

[0263] Abbreviations DSC differential scanning calorimetry TGA thermogravimetric analysis T max Peak time C max Maximum plasma concentration AUC 0-t Area under the plasma concentration-time (0-t) curve AUC 0-∞ Area under the plasma concentration-time (0-∞) curve t 1 / 2 Half-life CL / F apparent clearance

[0264] Instrument

[0265] In the examples of the present application, the high-performance liquid chromatography instrument is agilent 1200 type liquid chromatograph

[0266] Chromatographic column: Inertsil TM ODS-3V 5um 4.6mm*250mm

[0267] Mobile phase A: 0.1% phosphoric acid water

[0268] Mobile phase B: acetonitrile-methanol (50:50)

[0269] Ultraviolet detection wavelength: 210nm

[0270] Flow rate: 1.0ml / min

[0271] Powder X-ray diffractometer:

[0272] D8 ADVANCE X-ray diffractometer, Bruker Company

[0273] Cu target, continuous scanning

[0274] Tube pressure: 40kV

[0275] Tube flow: 25mA

[0276] Scanning range: 5-60° (2θ)

[0277] Differential scanning calorimeter: PE Diamond DSC differential scanning calorimeter

[0278] Thermogravimetric analyzer: PE Pyrisl TGA thermogravimetric analyzer

[0279] Test conditions: Nitrogen atmosphere

[0280] TGA Nitrogen atmosphere

[0281] Preparation method of compound 102D-6 of crystalline form I in Example 1

[0282] Compound 102D-6, 0.9 g, was weighed into a single-neck flask, 4 ml of methanol was added, and the solution was warmed to reflux and dissolved, and then cooled to 20-30°C. After crystallization, 2 ml of methanol was added, and the mixture was stirred at 20-30°C for 1 hour. The mixture was filtered, and the filter cake was dried at 40°C under vacuum to obtain 0.78 g of a white solid. The crystal was confirmed to be crystalline form I by analysis. The X-ray powder diffraction pattern thereof was substantially the same as that of FIG. 1, the DSC pattern thereof was substantially the same as that of FIG. 2, and the TGA pattern thereof was substantially the same as that of FIG. 3.

[0283] The X-ray powder diffraction pattern of crystalline form I is shown below:

[0284] Preparation method of compound 102D-6 of crystalline form I in Example 2

[0285] Compound 102D-6, 1 g, was weighed into a single-neck flask, 6 ml of ethanol was added, and the solution was warmed to reflux and dissolved, and then cooled to 20-30°C. The mixture was stirred overnight to crystallize, and then filtered. The filter cake was dried at 40°C under vacuum to obtain 0.85 g of a white solid. The crystal was confirmed to be crystalline form I by analysis. The X-ray powder diffraction pattern thereof was substantially the same as that of FIG. 1, the DSC pattern thereof was substantially the same as that of FIG. 2, and the TGA pattern thereof was substantially the same as that of FIG. 3.

[0286] Preparation method of compound 102D-6 of crystalline form I in Example 3

[0287] Compound 102D-6, 1 g, was weighed into a single-neck flask, 5 ml of methanol was added, and the solution was warmed to reflux and dissolved. Then, 4 ml of water was added, and a solid was precipitated. 4 ml of methanol was added to dissolve the solid, and then the solution was cooled to 0-5°C. The mixture was stirred for 6 hours to crystallize, and then filtered. The filter cake was dried at 50°C under vacuum to obtain 0.89 g of a white solid. The crystal was confirmed to be crystalline form I by analysis. The X-ray powder diffraction pattern thereof was substantially the same as that of FIG. 1, the DSC pattern thereof was substantially the same as that of FIG. 2, and the TGA pattern thereof was substantially the same as that of FIG. 3.

[0288] Preparation method of compound 102D-6 of crystalline form I in Example 4

[0289] Take 1 g of compound 102D-6 in a single-mouth flask, add 4 ml of ethanol, heat to reflux to dissolve, add 7 ml of water, precipitate the solid, add 1 ml of ethanol, dissolve after cooling to 0-5°C, stir for 1 hour, filter, and the filter cake is dried at 40°C under vacuum to obtain 0.92 g of a white solid. Analysis confirms that the crystal is Form I, and its X-ray powder diffraction pattern is substantially the same as that of Figure 1, its DSC pattern is substantially the same as that of Figure 2, and its TGA pattern is substantially the same as that of Figure 3.

[0290] Preparation method of compound 102D-6 of Form I in Example 5

[0291] Take 1 g of compound 102D-6 in a single-mouth flask, add 4 ml of ethanol, heat to reflux to dissolve, add 7 ml of water, precipitate the solid, add 1 ml of ethanol, dissolve after cooling to 0-5°C, stir for 1 hour, filter, and the filter cake is dried at 40°C under vacuum to obtain 0.92 g of a white solid. Analysis confirms that the crystal is Form I, and its X-ray powder diffraction pattern is substantially the same as that of Figure 1, its DSC pattern is substantially the same as that of Figure 2, and its TGA pattern is substantially the same as that of Figure 3.

[0292] Preparation method of compound 102D-6 of Form I in Example 5

[0293] Take 1 g of compound 102D-6 in a single-mouth flask, add 4 ml of ethanol, heat to reflux to dissolve, add 7 ml of water, precipitate the solid, add 1 ml of ethanol, dissolve after cooling to 0-5°C, stir for 1 hour, filter, and the filter cake is dried at 40°C under vacuum to obtain 0.92 g of a white solid. Analysis confirms that the crystal is Form I, and its X-ray powder diffraction pattern is substantially the same as that of Figure 1, its DSC pattern is substantially the same as that of Figure 2, and its TGA pattern is substantially the same as that of Figure 3.

[0294] Preparation method of compound 102D-6 of Form II in Example 7

[0295] Take 1 g of compound 102D-6 in a single-mouth flask, add 4 ml of ethanol, heat to reflux to dissolve, add 7 ml of water, precipitate the solid, add 1 ml of ethanol, dissolve after cooling to 0-5°C, stir for 1 hour, filter, and the filter cake is dried at 40°C under vacuum to obtain 0.92 g of a white solid. Analysis confirms that the crystal is Form I, and its X-ray powder diffraction pattern is substantially the same as that of Figure 1, its DSC pattern is substantially the same as that of Figure 2, and its TGA pattern is substantially the same as that of Figure 3.

[0296] Characteristic diffraction data table of Form II

[0297] Preparation method of compound 102D-6 of Form II in Example 8

[0298] Example 1 Preparation of Compound 102D-6 in crystalline form II

[0299] Example 9 Preparation of Compound 102D-6 in crystalline form II

[0300] Example 9 Preparation of Compound 102D-6 in crystalline form II

[0301] Example 10 Preparation of Compound 102D-6 in crystalline form II

[0302] Example 10 Preparation of Compound 102D-6 in crystalline form II

[0303] Example 11 Preparation of Compound 102D-6 in crystalline form II

[0304] Take 1 g of compound 102D-6 of crystal form I (prepared according to the method of Example 1 to Example 6) in a single-mouth bottle, add 5 ml of ethyl acetate, dissolve at 20-30°C, add 5 ml of n-heptane, no solid precipitates, add crystal form II seed crystal (prepared according to the method of Example 7 to Example 10), stir at 20-30°C for 0.5 hours, precipitate a large amount of solid, add 5 ml of n-heptane, stir at 20-30°C for 0.5 hours, add 5 ml of n-heptane, stir at 20-30°C for 1.5 hours, filter, and the filter cake is dried at 50°C with air blowing to obtain 0.93 g of white solid, which is confirmed to be crystal form II by analysis, its X-ray powder diffraction pattern is basically consistent with Figure 4, its DSC pattern is basically consistent with Figure 5, and its TGA pattern is basically consistent with Figure 6.

[0305] Preparation method of compound 102D-6 of crystal form II in Example 12

[0306] Take 5 g of compound 102D-6 of crystal form VI (prepared according to the method of Example 34 to Example 38) in a single-mouth bottle, add 20 ml of ethyl acetate and 0.25 g of water, dissolve at 20-30°C, add 5 ml of n-heptane, add 0.01 g of crystal form II seed crystal (prepared according to the method of Example 7 to Example 11), stir at 20-30°C for 0.5 hours, add 25 ml of n-heptane, stir at 20-30°C for 0.5 hours, add 30 ml of n-heptane, stir at 20-30°C for 1 hour, filter, and the filter cake is dried at 50°C with air blowing to obtain 4.8 g of white solid, the yield is 96%, which is confirmed to be crystal form II by analysis, its X-ray powder diffraction pattern is basically consistent with Figure 4, its DSC pattern is basically consistent with Figure 5, and its TGA pattern is basically consistent with Figure 6.

[0307] Preparation method of compound 102D-6 of crystal form II in Example 13

[0308] Take 5 g of compound 102D-6 of crystal form VI (prepared according to the method of Example 34 to Example 38) in a single-mouth bottle, add 20 ml of ethyl acetate and 0.25 g of water, heat to 60-65°C, add 10 ml of n-heptane, add 0.005 g of crystal form II seed crystal (prepared according to the method of Example 7 to Example 12), stir at 60-65°C for 0.5 hours, add 25 ml of n-heptane, stir at 60-65°C for 0.5 hours, add 25 ml of n-heptane, stir at 60-65°C for 0.5 hours, cool to 0-10°C, stir at 0-10°C for 1 hour, filter, and the filter cake is dried at 50°C with air blowing to obtain 4.64 g of white solid, the yield is 92.8%, which is confirmed to be crystal form II by analysis, its X-ray powder diffraction pattern is basically consistent with Figure 4, its DSC pattern is basically consistent with Figure 5, and its TGA pattern is basically consistent with Figure 6.

[0309] Preparation method of compound 102D-6 of crystalline form II in example 14

[0310] Take 10 g of compound 102D-6 of crystalline form I (prepared according to the method of example 1 to example 6) in a single-mouth bottle, add 100 ml of n-heptane, warm to 40-45 °C, keep 40-45 °C for 21 hours, filter, and the filter cake is dried by blowing air at 50 °C to obtain 9.6 g of white solid, which is confirmed to be crystalline form II by analysis, and its X-ray powder diffraction pattern is basically consistent with that of figure 4, its DSC pattern is basically consistent with that of figure 5, and its TGA pattern is basically consistent with that of figure 6.

[0311] Preparation method of compound 102D-6 of crystalline form II in example 15

[0312] Take 10 g of compound 102D-6 of crystalline form I (prepared according to the method of example 1 to example 6) in a single-mouth bottle, add 150 ml of n-heptane, warm to 60-65 °C, keep 60-65 °C for 8 hours, filter, and the filter cake is dried by blowing air at 50 °C to obtain 9.5 g of white solid, which is confirmed to be crystalline form II by analysis, and its X-ray powder diffraction pattern is basically consistent with that of figure 4, its DSC pattern is basically consistent with that of figure 5, and its TGA pattern is basically consistent with that of figure 6.

[0313] Preparation method of compound 102D-6 of crystalline form II in example 16

[0314] Take 10 g of compound 102D-6 of crystalline form I (prepared according to the method of example 1 to example 6) in a single-mouth bottle, add 100 ml of n-heptane, warm to 80-85 °C, keep 80-85 °C for 8 hours, filter, and the filter cake is dried by blowing air at 50 °C to obtain 9.4 g of white solid, which is confirmed to be crystalline form II by analysis, and its X-ray powder diffraction pattern is basically consistent with that of figure 4, its DSC pattern is basically consistent with that of figure 5, and its TGA pattern is basically consistent with that of figure 6.

[0315] Preparation method of compound 102D-6 of crystalline form III in example 17

[0316] Take 2 g of amorphous compound 102D-6 (prepared according to the method of comparative example 1 to comparative example 2) in a single-mouth bottle, add 8 ml of ethyl acetate, warm to 60-65 °C, dissolve, add 10 ml of n-hexane, precipitate the solid, cool to 0-10 °C, stir at 0-10 °C for 1 hour, filter, and the filter cake is dried by vacuum drying at 45 °C to obtain 1.4 g of white solid, which is confirmed to be crystalline form III by analysis, and its X-ray powder diffraction pattern is basically consistent with that of figure 7, its DSC pattern is basically consistent with that of figure 8, and its TGA pattern is basically consistent with that of figure 9.

[0317] Characteristic diffraction data table of crystalline form III

[0318] Preparation method of compound 102D-6 of crystalline form III in Example 18

[0319] Take 12 g of amorphous compound 102D-6 (prepared by the method of Comparative Example 1-Comparative Example 2) in a single-mouth bottle, add 60 ml of ethyl acetate, and dissolve at 65-70°C. Add 60 ml of n-hexane to precipitate the solid. Cool to 0-10°C, and stir for 1 hour at 0-10°C. Filter, and dry the filter cake at 45°C under vacuum to obtain 7.43 g of a white solid, with a yield of 61.9%. Analysis confirms that the crystal is crystalline form III, with an X-ray powder diffraction pattern substantially the same as that of FIG. 7, a DSC pattern substantially the same as that of FIG. 8, and a TGA pattern substantially the same as that of FIG. 9.

[0320] Preparation method of compound 102D-6 of crystalline form III in Example 19

[0321] Take 10 g of amorphous compound 102D-6 (prepared by the method of Comparative Example 1-Comparative Example 2) in a single-mouth bottle, add 50 ml of ethyl acetate, and dissolve at 65-70°C. Add 30 ml of n-hexane to precipitate the solid. Cool to 0-10°C, and stir for 1 hour at 0-10°C. Filter, and dry the filter cake at 45°C under vacuum to obtain 4.5 g of a white solid, with a yield of 45%. Analysis confirms that the crystal is crystalline form III, with an X-ray powder diffraction pattern substantially the same as that of FIG. 7, a DSC pattern substantially the same as that of FIG. 8, and a TGA pattern substantially the same as that of FIG. 9.

[0322] Preparation method of compound 102D-6 of crystalline form III in Example 20

[0323] Take 1 g of amorphous compound 102D-6 (prepared by the method of Comparative Example 1-Comparative Example 2) in a single-mouth bottle, add 5 ml of ethyl acetate, and dissolve at 60-70°C. Add 5 ml of n-hexane, and stir for 0.5 hours at 60-70°C. Add 5 ml of n-hexane, and stir for 0.5 hours at 60-70°C. Add 5 ml of n-hexane, and cool to 0-10°C. Stir for 1 hour at 0-10°C. Filter, and dry the filter cake at 45°C under vacuum to obtain 0.8 g of a white solid. Analysis confirms that the crystal is crystalline form III, with an X-ray powder diffraction pattern substantially the same as that of FIG. 7, a DSC pattern substantially the same as that of FIG. 8, and a TGA pattern substantially the same as that of FIG. 9.

[0324] Preparation method of compound 102D-6 of crystalline form III in Example 21

[0325] Take 1 g of amorphous compound 102D-6 (prepared by the method of Comparative Example 1-Comparative Example 2) in a single-mouth flask, add 5 ml of ethyl acetate, warm to 70-80°C, dissolve, add 5 ml of n-heptane, keep at 70-80°C and stir for 0.5 hour, add 5 ml of n-heptane, keep at 70-80°C and stir for 0.5 hour, add 5 ml of n-heptane, cool to 0-10°C, stir at 0-10°C for 1 hour, filter, and dry the filter cake at 50°C under vacuum to obtain 0.82 g of a white solid. Analysis confirms that the crystal is Form III, and its X-ray powder diffraction pattern is substantially the same as that of Figure 7, its DSC pattern is substantially the same as that of Figure 8, and its TGA pattern is substantially the same as that of Figure 9.

[0326] Method for preparing compound 102D-6 of Form III

[0327] Take 5 g of compound 102D-6 of Form VI (prepared by the method of Comparative Example 1-Comparative Example 2) in a single-mouth flask, add 10 ml of ethyl acetate, warm to 70-80°C, dissolve, cool to 20-30°C, and crystallize. Filter, and dry the filter cake at 50°C under a blast of air to obtain 1.9 g of a white solid. Analysis confirms that the crystal is Form III, and its X-ray powder diffraction pattern is substantially the same as that of Figure 7, its DSC pattern is substantially the same as that of Figure 8, and its TGA pattern is substantially the same as that of Figure 9.

[0328] Method for preparing compound 102D-6 of Form III

[0329] Take 1 g of amorphous compound 102D-6 (prepared by the method of Comparative Example 1-Comparative Example 2) in a single-mouth flask, add 10 ml of n-heptane, warm to 60-70°C, keep at 60-70°C and stir for 20 hours, filter, and dry the filter cake at 50°C under a blast of air to obtain a white solid. Analysis confirms that the crystal is Form III, and its X-ray powder diffraction pattern is substantially the same as that of Figure 7, its DSC pattern is substantially the same as that of Figure 8, and its TGA pattern is substantially the same as that of Figure 9.

[0330] Method for preparing compound 102D-6 of Form III

[0331] Take 1 g of amorphous compound 102D-6 (prepared by the method of Comparative Example 1-Comparative Example 2) in a single-mouth flask, add 20 ml of isopropyl ether, warm to 60-70°C, keep at 60-70°C and stir for 15 hours, filter, and dry the filter cake at 50°C under a blast of air to obtain 0.6 g of a white solid. Analysis confirms that the crystal is Form III, and its X-ray powder diffraction pattern is substantially the same as that of Figure 7, its DSC pattern is substantially the same as that of Figure 8, and its TGA pattern is substantially the same as that of Figure 9.

[0332] Method for preparing compound 102D-6 of Form IV

[0333] Example 26 Preparation method of compound 102D-6 in crystal form IV

[0334] Characteristic diffraction data table of crystal form IV

[0335] Example 26 Preparation method of compound 102D-6 in crystal form IV

[0336] Example 26 Preparation method of compound 102D-6 in crystal form IV

[0337] Example 26 Preparation method of compound 102D-6 in crystal form IV

[0338] Example 26 Preparation method of compound 102D-6 in crystal form IV

[0339] Example 26 Preparation method of compound 102D-6 in crystal form IV

[0340] Example 26 Preparation method of compound 102D-6 in crystal form IV

[0341] Preparation method of compound 102D-6 of crystalline form IV in example 29

[0342] Take 5g of compound 102D-6 of crystalline form VI (prepared according to the method of example 34 to example 38) in a single mouth bottle, add 20ml of ethyl acetate, control the temperature at 20-30℃, stir to dissolve, add 20ml of n-heptane, control the temperature at 20-30℃, stir for 0.5 hours, add 40ml of n-heptane, control the temperature at 20-30℃, stir for 1 hour, filter, and the filter cake is dried by blowing air at 55℃ to obtain 3.7g of white solid, which is confirmed to be crystalline form IV by analysis, and its X-ray powder diffraction pattern is basically consistent with that of Figure 10, its DSC pattern is basically consistent with that of Figure 11, and its TGA pattern is basically consistent with that of Figure 12.

[0343] Preparation method of compound 102D-6 of crystalline form IV in example 30

[0344] Take 5g of compound 102D-6 of crystalline form VI (prepared according to the method of example 34 to example 38) in a single mouth bottle, add 20ml of ethyl acetate, control the temperature at 20-30℃, stir to dissolve, add 20ml of n-heptane, control the temperature at 20-30℃, stir for 0.5 hours, add 40ml of n-heptane, control the temperature at 20-30℃, stir for 1 hour, filter, and the filter cake is dried by blowing air at 55℃ to obtain 3.7g of white solid, which is confirmed to be crystalline form IV by analysis, and its X-ray powder diffraction pattern is basically consistent with that of Figure 10, its DSC pattern is basically consistent with that of Figure 11, and its TGA pattern is basically consistent with that of Figure 12.

[0345] Preparation method of compound 102D-6 of crystalline form V in example 31

[0346] Take 5g of compound 102D-6 of crystalline form VI (prepared according to the method of example 34 to example 38) in a single mouth bottle, add 20ml of ethyl acetate, control the temperature at 20-30℃, stir to dissolve, add 20ml of n-heptane, control the temperature at 20-30℃, stir for 0.5 hours, add 40ml of n-heptane, control the temperature at 20-30℃, stir for 1 hour, filter, and the filter cake is dried by blowing air at 55℃ to obtain 3.7g of white solid, which is confirmed to be crystalline form IV by analysis, and its X-ray powder diffraction pattern is basically consistent with that of Figure 10, its DSC pattern is basically consistent with that of Figure 11, and its TGA pattern is basically consistent with that of Figure 12.

[0347] Characteristic diffraction data table of crystalline form V

[0348] Preparation method of compound 102D-6 of crystalline form V in example 32

[0349] Take 10 g of compound 102D-6 of Form VI (prepared according to the method of Example 34 to Example 38) in a single-mouth bottle, add 150 ml of n-heptane, warm to 50-60 °C, keep at 50-60 °C for 8 hours, cool to 20-30 °C, keep at 20-30 °C for 1 hour, filter, and dry the filter cake at 50 °C under blast to obtain 9.4 g of a white solid, which is confirmed to be Form V by analysis, and its X-ray powder diffraction pattern is basically consistent with that of Figure 13, its DSC pattern is basically consistent with that of Figure 14, and its TGA pattern is basically consistent with that of Figure 15.

[0350] Preparation method of compound 102D-6 of Form V

[0351] Take 10 g of compound 102D-6 of Form VI (prepared according to the method of Example 34 to Example 38) in a single-mouth bottle, add 200 ml of n-heptane, warm to 95-100 °C, keep at 95-100 °C for 4 hours, cool to 0-10 °C, keep at 0-10 °C for 1 hour, filter, and dry the filter cake at 60 °C under blast to obtain 9.5 g of a white solid, which is confirmed to be Form V by analysis, and its X-ray powder diffraction pattern is basically consistent with that of Figure 13, its DSC pattern is basically consistent with that of Figure 14, and its TGA pattern is basically consistent with that of Figure 15.

[0352] Preparation method of compound 102D-6 of Form VI

[0353] Take 206 g of amorphous 102D-6 (prepared according to the method of Comparative Example 1 to Comparative Example 2) in a single-mouth bottle, add 1030 ml of methanol, warm to 60-70 °C to dissolve, control the temperature at 50-70 °C, add 1060 ml of water, cool to 20-30 °C, and stir to crystallize for 0.5 hours, filter, and dry the filter cake at 50 °C under blast for 19 hours to obtain 196.27 g of a white solid, with a yield of 95.3%, which is confirmed to be Form VI by analysis, and its X-ray powder diffraction pattern is basically consistent with that of Figure 16, its DSC pattern is basically consistent with that of Figure 17, and its TGA pattern is basically consistent with that of Figure 18.

[0354] Table of characteristic diffraction data of Form VI

[0355] Preparation method of compound 102D-6 of Form VI

[0356] Example 1 Preparation of compound 102D-6 of crystalline form VI

[0357] Example 36 Preparation of compound 102D-6 of crystalline form VI

[0358] Example 36 Preparation of compound 102D-6 of crystalline form VI

[0359] Example 36 Preparation of compound 102D-6 of crystalline form VI

[0360] Example 36 Preparation of compound 102D-6 of crystalline form VI

[0361] Example 36 Preparation of compound 102D-6 of crystalline form VI

[0362] Example 36 Preparation of compound 102D-6 of crystalline form VI

[0363] Example 39

[0364] Into a reaction flask, 200 g of isopentyl alcohol, 130 g of tetrahydrofuran were sequentially added, and the nitrogen was replaced. 22 g of sodium tert-butyl alcohol was added at room temperature, and 50 g of the compound of formula 102D-0 was added. The reaction was controlled at room temperature for 3 hours, 300 g of 8% citric acid aqueous solution was added, and the water phase was discarded after extraction and phase separation. 32 g of p-toluenesulfonic acid monohydrate was added to the organic phase, 100 g of anhydrous sodium sulfate was added, stirred for 1 hour, filtered, and the filtrate was concentrated under reduced pressure until no liquid drops flowed out. The filtrate was heated to 50-60°C, 850 g of n-heptane was added, and the temperature was lowered to 0-10°C for 2 hours. The crystal was filtered and dried to constant weight to obtain 67.1 g of a white solid compound of formula 102D-1, with a yield of 91.5%.

[0365] 1 H NMR (400 MHz, DMSO-d6) δ: 9.27 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 12.4 Hz, 1H), 7.47 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 7.08 (d, J = 7.2 Hz, 1H), 4.94-5.00 (m, 1H), 4.19-4.03 (m, 5H), 3.47 (td, J = 11.9, 3.1 Hz, 1H), 3.25 (dd, J = 11.5, 9.9 Hz, 1H), 3.01 (ddd, J = 13.7, 12.1, 4.4 Hz, 1H), 2.29 (s, 3H), 1.76-1.86 (m, 1H), 1.69-1.64 (m, 2H), 0.93 (dd, J = 6.7, 1.6 Hz, 6H).

[0366] ESI: [M+H] + 308.3 (see Figure 39).

[0367] Example 40

[0368] Into a reaction flask, 200 g of isopentyl alcohol, 130 g of tetrahydrofuran were sequentially added, and the nitrogen was replaced. 22 g of sodium tert-butyl alcohol was added at room temperature, and 50 g of the compound of formula 102D-0 was added. The reaction was controlled at room temperature for 3 hours, 300 g of 8% citric acid aqueous solution was added, and the water phase was discarded after extraction and phase separation. 32 g of p-toluenesulfonic acid monohydrate was added to the organic phase, 100 g of anhydrous sodium sulfate was added, stirred for 1 hour, filtered, and the filtrate was concentrated under reduced pressure until no liquid drops flowed out. The filtrate was heated to 50-60°C, 850 g of n-heptane was added, and the temperature was lowered to 0-10°C for 2 hours. The crystal was filtered and dried to constant weight to obtain 67.1 g of a white solid compound of formula 102D-1, with a yield of 91.5%.

[0369] Example 41

[0370] To the reaction flask was added 210 g of ethyl acetate, 70 g of cyclohexane, 60 g of the compound of formula 102D-1, 50 g of the compound of formula 102M1-D1, 160 g of T3P (propyl phosphonic anhydride) ethyl acetate solution, and 20 g of methanesulfonic acid, warmed to 60-70 °C for 15 hours, cooled to room temperature, added 160 g of tetrahydrofuran and 120 g of water, added 150 g of 20% aqueous sodium hydroxide solution, extracted, separated the phases, discarded the aqueous phase, added 36 g of methanesulfonic acid to the organic phase, controlled the temperature to 0-10 °C for 2 hours to crystallize, filtered, and dried the wet product to constant weight to obtain 69 g of the white solid compound of formula 102D-2, with a yield of 84.8%.

[0371] 1 H NMR (400 MHz, DMSO-d6) δ: 7.42 (dd, J = 10.2, 6.4 Hz, 2H), 7.33 (d, J = 7.7 Hz, 1H), 7.19-7.06 (m, 3H), 6.97 (dd, J = 7.9, 1.5 Hz, 1H), 6.82 (td, J = 7.4, 1.4 Hz, 1H), 5.86-5.77 (m, 2H), 5.44 (dd, J = 14.3, 2.4 Hz, 1H), 4.51-4.42 (m, 2H), 4.25 (dt, J = 9.1, 6.7 Hz, 1H), 4.07 (d, J = 14.3 Hz, 1H), 4.03-3.93 (m, 2H), 3.66 (dd, J = 11.6, 3.2 Hz, 1H), 3.52 (t, J = 10.4 Hz, 1H), 3.30 (td, J = 11.7, 2.7 Hz, 1H), 2.94 (ddd, J = 14.8, 11.9, 3.4 Hz, 1H), 2.37 (s, 3H), 1.84 (dt, J = 13.4, 6.7 Hz, 1H), 1.67-1.60 (m, 2H), 0.95 (dd, J = 6.7, 5.2 Hz, 6H).

[0372] ESI: [M+H] + 554.2 (see Figure 40).

[0373] Example 42

[0374] Into a reaction flask, 270 g of ethyl acetate, 85 g of cyclohexane, 60 g of the compound of formula 102D-1, 50 g of the compound of formula 102M1-D1, 180 g of T4P (n-butylphosphoric anhydride) ethyl acetate solution and 24 g of methanesulfonic acid were sequentially added, warmed to 70-80°C for 10 hours, cooled to room temperature, 180 g of tetrahydrofuran and 150 g of water were added, 150 g of 20% sodium hydroxide aqueous solution was added, extracted, separated into two phases, the aqueous phase was discarded, 36 g of methanesulfonic acid was added to the organic phase, controlled to 0-10°C for crystallization for 2 hours, filtered, and the wet product was dried to constant weight to obtain 66 g of the compound of formula 102D-2 in white solid form, with a yield of 81.2%.

[0375] Example 43

[0376] Into a reaction flask, 60 g of the compound of formula 102D-2 and 400 g of dichloromethane were added, stirring was started, 200 g of 10% sodium bicarbonate aqueous solution was added dropwise, separated into two phases, the aqueous phase was discarded, the organic phase was cooled to 0-10°C, 20.6 g of meta-chloroperoxybenzoic acid was added, reacted at 0-10°C for 1 hour, 6 g of sodium sulfite was added to quench the reaction, 300 g of water was added, separated into two phases, the aqueous phase was discarded, 300 g of saturated sodium bicarbonate aqueous solution was added to the organic phase for extraction, separated into two phases, the aqueous phase was discarded, 30 g of anhydrous sodium sulfate was added to the organic phase for drying for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 49.3 g of the compound of formula 102D-3 in yellow solid form, with a yield of 93.7%.

[0377] 1 H NMR (400 MHz, DMSO-d6) δ: 7.83 (dd, J = 7.9, 1.3 Hz, 1H), 7.62-7.41 (m, 4H), 7.31 (td, J = 7.5, 1.4 Hz, 1H), 7.21 (dd, J = 7.9, 1.4 Hz, 1H), 6.01 (s, 1H), 5.75 (dd, J = 13.3, 2.4 Hz, 1H), 5.56 (d, J = 7.7 Hz, 1H), 5.04 (d, J = 13.2 Hz, 1H), 4.48 (ddd, J = 11.7, 7.1, 2.7 Hz, 2H), 4.24 (dt, J = 9.0, 6.7 Hz, 1H), 4.06-3.94 (m, 2H), 3.67 (dd, J = 11.6, 3.2 Hz, 1H), 3.51 (t, J = 10.3 Hz, 1H), 3.35-3.24 (m, 2H), 2.92 (ddd, J = 13.4, 11.6, 3.4 Hz, 1H), 1.92-1.74 (m, 1H), 1.64 (m, 2H), 0.95 (dd, J = 6.6, 4.5 Hz, 6H).

[0378] ESI: [M+H] +570.2 (see Figure 41).

[0379] Example 44

[0380] Into a reaction flask was added 30 g of the compound of Formula 102D-2 and 200 g of dichloromethane, stirring was started, 100 g of 5% sodium hydroxide aqueous solution was added dropwise, the aqueous phase was discarded, the organic phase was cooled to 0-10 °C, 5.8 g of hydrogen peroxide was added, and the reaction was carried out at 0-10 °C for 1 hour. The reaction was quenched by adding 3 g of sodium sulfite, 150 g of water was added, the aqueous phase was discarded, 150 g of saturated sodium bicarbonate aqueous solution was added to the organic phase for extraction, the aqueous phase was discarded, 15 g of anhydrous sodium sulfate was added to the organic phase for drying for 1 hour, filtration was performed, and the filtrate was concentrated under reduced pressure to dryness to obtain 24.8 g of the compound of Formula 102D-3 as a yellow solid with a yield of 94.3%.

[0381] Example 45

[0382] Into a reaction flask was added 150 g of N-methylpyrrolidone, 47 g of the compound of Formula 102D-3, 24.5 g of lithium chloride, and 3.8 g of methylsulfonic acid, and the reaction was carried out at 80-90 °C for 15 hours. The reaction was cooled to 40-50 °C, 56 g of acetonitrile and 700 g of water were added, the reaction was cooled to 0-10 °C, and stirring was performed for 1 hour. Filtration was performed, and the wet product was dried to constant weight to obtain 31.7 g of the compound of Formula 102D-4 as a white solid with a yield of 76.9%.

[0383] 1 H NMR (400 MHz, DMSO-d6) δ: 11.83 (s, 1H), 7.83 (dd, J = 7.8, 1.3 Hz, 1H), 7.58 (td, J = 7.6, 1.4 Hz, 1H), 7.53-7.40 (m, 3H), 7.34 (td, J = 7.5, 1.3 Hz, 1H), 7.22 (dd, J = 7.8, 1.4 Hz, 1H), 5.99 (s, 1H), 5.79-5.67 (m, 1H), 5.48 (d, J = 7.7 Hz, 1H), 5.07 (d, J = 13.2 Hz, 1H), 4.57 (dd, J = 9.9, 3.0 Hz, 1H), 4.45 (dd, J = 13.4, 2.4 Hz, 1H), 4.03 (dd, J = 10.7, 3.1 Hz, 1H), 3.73-3.61 (m, 2H), 3.48-3.38 (m, 1H), 3.03 (t, J = 12.1 Hz, 1H).

[0384] ESI: [M+H] + 500.2 (see Figure 42).

[0385] Example 46

[0386] Into a reaction flask was added 48 g of the compound of formula 102D-4, 26.4 g of potassium carbonate, 8.16 g of potassium iodide, 636 g of dichloromethane, and the temperature was lowered to 10-20°C. Then, 32.1 g of ethyl 1-bromoacetate was added, and the temperature was controlled at 10-20°C for 15 hours. Then, 240 g of water was added to extract, and the water phase was discarded. Then, 24 g of anhydrous sodium sulfate was added to the organic phase for drying for 1 hour. Then, the filtrate was concentrated under reduced pressure, and 112 g of acetonitrile was added to the concentrate for crystallization at room temperature for 1 hour. Then, the filter cake was dried to constant weight to obtain 24.8 g of the compound of formula 102D-5A as a yellow solid, with a yield of 44%.

[0387] Example 47

[0388] Into a reaction flask was added 48 g of the compound of formula 102D-4, 26.4 g of potassium carbonate, 8.16 g of potassium iodide, 636 g of dichloromethane, and the temperature was lowered to 10-20°C. Then, 32.1 g of ethyl 1-bromoacetate was added, and the temperature was controlled at 10-20°C for 15 hours. Then, 240 g of water was added to extract, and the water phase was discarded. Then, 24 g of anhydrous sodium sulfate was added to the organic phase for drying for 1 hour. Then, the filtrate was concentrated under reduced pressure, and 112 g of acetonitrile was added to the concentrate for crystallization at room temperature for 1 hour. Then, the filter cake was dried to constant weight to obtain 24.8 g of the compound of formula 102D-5A as a yellow solid, with a yield of 44%.

[0389] The filtrate of 102D-5A was concentrated under reduced pressure, and 211 g of toluene was added to the concentrate for crystallization at room temperature for 1 hour. Then, the filter cake was dried to constant weight to obtain 22.4 g of the compound of formula 102D-5 as a yellow solid, with a yield of 39.8%.

[0390] 102D-5 of 1 H 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).

[0391] 102D-5A1 H 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).

[0392] 102D-5 ESI: [M+H] + 586.2 (see Figure 43).

[0393] 102D-5A ESI: [M+H] + 586.2 (see Figure 44).

[0394] Example 48

[0395] Into a reaction flask was added 20 g of the compound of formula 102D-4, 23.3 g of cesium carbonate, 1.7 g of potassium iodide, 90 g of ethyl acetate, and the temperature was lowered to 0-10 °C. Then, 20.1 g of ethyl 1-bromoacetate was added, and the temperature was controlled at 0-10 °C for 20 hours. Then, 100 g of water was added for extraction, and the aqueous phase was discarded after phase separation. Then, 10 g of anhydrous sodium sulfate was added to the organic phase for drying for 1 hour, and the filtrate was concentrated under reduced pressure to dryness. Then, 31.2 g of acetonitrile was added to the concentrate, and the temperature was controlled at 0-10 °C for crystallization for 1 hour. Then, the product was filtered, and the filter cake was dried to constant weight to obtain 9.1 g of a white solid of the compound of formula 102D-5A at a yield of 38.9%.

[0396] The filtrate of 102D-5A was concentrated under reduced pressure to dryness, and 88 g of toluene was added to the concentrate. The temperature was controlled at 0-10 °C for crystallization for 1 hour, and the product was filtered and dried to constant weight to obtain 8.3 g of a yellow solid of the compound of formula 102D-5 at a yield of 35.4%.

[0397] Example 49

[0398] Into a reaction flask was added 20 g of the compound of formula 102D-4, 12.1 g of triethylamine, 3.4 g of potassium iodide, 265 g of dichloromethane, and the temperature was lowered to 10-20 °C. Then, 20.1 g of ethyl 1-bromoacetate was added, and the temperature was controlled at 10-20 °C for 20 hours. Then, 100 g of water was added for extraction, and the phases were separated. The water phase was discarded, and 10 g of anhydrous sodium sulfate was added to the organic phase for drying for 1 hour. Then, the filtrate was concentrated under reduced pressure to dryness. Then, 24 g of acetonitrile was added to the concentrate, and the temperature was controlled at room temperature for 1 hour for crystallization. Then, the product was filtered, and the filter cake was dried to constant weight to obtain 9.6 g of the compound of formula 102D-5A in the form of a yellow solid, with a yield of 41%.

[0399] The filtrate of 102D-5A was concentrated under reduced pressure to dryness. Then, 45 g of toluene was added to the concentrate, and the temperature was controlled at room temperature for 1 hour for crystallization. Then, the product was filtered, and the wet product was dried to constant weight to obtain 8.7 g of the compound of formula 102D-5 in the form of a yellow solid, with a yield of 37.1%.

[0400] Example 50

[0401] Into a reaction flask was added 19 g of the compound of formula 102D-5, 16.9 g of sodium bisulfite, 4.2 g of iodine, and 281 g of chloroform, and the temperature was controlled at 10-20 °C for 15 hours. Then, the product was filtered, and 100 g of water was added to the filtrate for extraction. The phases were separated, and the water phase was discarded. Then, 10 g of anhydrous sodium sulfate was added to the organic phase for drying for 1 hour. Then, the filtrate was concentrated under reduced pressure to dryness. Then, 150 g of methanol was added to the concentrate, and the temperature was raised for dissolution. Then, the temperature was lowered to 0-10 °C for 1 hour for crystallization. Then, the product was filtered, and the wet product was dried to constant weight to obtain 16.1 g of the compound of formula 102D-6 in the form of a white solid, with a yield of 87.1%. Analysis confirmed that the crystal was in the form of Form I, with an X-ray powder diffraction pattern substantially the same as that in FIG. 1, a DSC pattern substantially the same as that in FIG. 2, and a TGA pattern substantially the same as that in FIG. 3.

[0402] ESI: [M+H] + 570.2.

[0403] Example 51

[0404] Into a reaction flask was added 20 g of the compound of formula 102D-5, 10.7 g of sodium bisulfite, 2.6 g of iodine, and 265 g of dichloromethane, and the temperature was controlled at 0-10 °C for 20 hours. Then, the product was filtered, and 100 g of water was added to the filtrate for extraction. The phases were separated, and the water phase was discarded. Then, 10 g of anhydrous sodium sulfate was added to the organic phase for drying for 1 hour. Then, the filtrate was concentrated under reduced pressure to dryness. Then, 125 g of ethanol was added to the concentrate, and the temperature was raised for dissolution. Then, the temperature was lowered to 0-10 °C for 1 hour for crystallization. Then, the product was filtered, and the wet product was dried to constant weight to obtain 16.4 g of the compound of formula 102D-6 in the form of a white solid, with a yield of 84.3%. Analysis confirmed that the crystal was in the form of Form I, with an X-ray powder diffraction pattern substantially the same as that in FIG. 1, a DSC pattern substantially the same as that in FIG. 2, and a TGA pattern substantially the same as that in FIG. 3.

[0405] Example 52

[0406] Into a reaction flask was added 10 g of the compound of Formula 102D-5, 8.9 g of sodium bisulfite, 2.2 g of iodine, 74 g of chloroform, and the temperature was controlled at 10-20 °C for 12 hours. The mixture was filtered, 50 g of water was added to the filtrate, and the mixture was separated into two phases. 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. The mixture was filtered, and the filtrate was concentrated under reduced pressure. To the concentrate was added 39 g of ethyl acetate, the mixture was dissolved by heating to 60-70 °C, 97 g of n-hexane was added, and the mixture was precipitated at 0-10 °C for 1 hour. The mixture was filtered, and the wet product was dried to constant weight to obtain 7.8 g of a white solid of the compound of Formula 102D-6, in a yield of 80.2%. The crystal was confirmed to be Form II by analysis, and the X-ray powder diffraction pattern thereof was substantially the same as that of FIG. 4, the DSC pattern thereof was substantially the same as that of FIG. 5, and the TGA pattern thereof was substantially the same as that of FIG. 6.

[0407] Example 53

[0408] Into a reaction flask was added 10 g of the compound of Formula 102D-5, 8.9 g of sodium bisulfite, 2.2 g of iodine, 74 g of chloroform, and the temperature was controlled at 10-20 °C for 12 hours. The mixture was filtered, 50 g of water was added to the filtrate, and the mixture was separated into two phases. 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. The mixture was filtered, and the filtrate was concentrated under reduced pressure. To the concentrate was added 39 g of ethyl acetate, the mixture was dissolved by heating to 60-70 °C, 97 g of n-hexane was added, and the mixture was precipitated at 0-10 °C for 1 hour. The mixture was filtered, and the wet product was dried to constant weight to obtain 7.8 g of a white solid of the compound of Formula 102D-6, in a yield of 80.2%. The crystal was confirmed to be Form II by analysis, and the X-ray powder diffraction pattern thereof was substantially the same as that of FIG. 4, the DSC pattern thereof was substantially the same as that of FIG. 5, and the TGA pattern thereof was substantially the same as that of FIG. 6.

[0409] Example 54

[0410] Into a reaction flask was added 10 g of the compound of Formula 102D-5, 8.9 g of sodium bisulfite, 2.2 g of iodine, 74 g of chloroform, and the temperature was controlled at 10-20 °C for 12 hours. The mixture was filtered, 50 g of water was added to the filtrate, and the mixture was separated into two phases. 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. The mixture was filtered, and the filtrate was concentrated under reduced pressure. To the concentrate was added 39 g of ethyl acetate, the mixture was dissolved by heating to 60-70 °C, 97 g of n-hexane was added, and the mixture was precipitated at 0-10 °C for 1 hour. The mixture was filtered, and the wet product was dried to constant weight to obtain 7.8 g of a white solid of the compound of Formula 102D-6, in a yield of 80.2%. The crystal was confirmed to be Form II by analysis, and the X-ray powder diffraction pattern thereof was substantially the same as that of FIG. 4, the DSC pattern thereof was substantially the same as that of FIG. 5, and the TGA pattern thereof was substantially the same as that of FIG. 6.

[0411] ESI: [M+H] + 570.2.

[0412] Example 55

[0413] Into a reaction flask was added 5 g of the compound of formula 102D-5A, 4 g of sodium bisulfite, 0.5 g of iodine, 66 g of dichloromethane, and the temperature was controlled at 20-30°C for 10 hours. Filtration was performed, 25 g of water was added to the filtrate for extraction, and the aqueous phase was discarded. 2 g of anhydrous sodium sulfate was added to the organic phase for drying for 1 hour, filtration was performed, and the filtrate was concentrated under reduced pressure to dryness. 20 g of acetonitrile was added to the concentrate for dissolution, and the temperature was lowered to 10-20°C for crystallization for 1 hour. Filtration was performed, and the wet product was dried to constant weight to obtain 3.8 g of white solid of the compound of formula 102D-6A, with a yield of 78.1%.

[0414] Preparation method of amorphous 102D-6 of Comparative Example 1

[0415] Amorphous 102D-6 was prepared according to the method disclosed in Chinese Invention Patent CN 118496239, which was determined to be amorphous by XRPD, and the spectrum is shown in FIG. 19. The DSC spectrum thereof is basically consistent with FIG. 20, and the TGA spectrum thereof is basically consistent with FIG. 21.

[0416] Preparation method of amorphous 102D-6 of Comparative Example 2

[0417] The 102D-6 mixed with one or more of crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, and crystal form VI was dissolved in 10 times the volume of dichloromethane, and the temperature was controlled at 40-50°C for concentration under reduced pressure to dryness to obtain a foamy solid, which was determined to be amorphous by XRPD, and the spectrum is shown in FIG. 19.

[0418] Stability investigation of 102D-6 of amorphous, crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, and crystal form VI

[0419] 1. Purpose of the study

[0420] According to the ICH “Q1A Stability Testing of New Drug Substances and Products” and the guidelines for drug substances in the Chinese Pharmacopoeia, the influence factor test (high temperature test and high humidity test) and the accelerated test of 102D-6 of amorphous, crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, and crystal form VI were performed to investigate the stability of different crystal forms.

[0421] 2. Stability investigation scheme

[0422] 2.1 High temperature condition: an appropriate amount of 102D-6 of each crystal form was placed in a constant temperature oven at 60°C, and after 30 days, the sample was taken out for related substance detection.

[0423] 2.2 High humidity condition: an appropriate amount of 102D-6 of each crystal form was placed in a constant temperature and humidity oven at 25°C / RH 92.5%, and after 30 days, the sample was taken out for related substance detection.

[0424] 2.3 Accelerated condition: 102D-6 of each crystal form was placed in a constant temperature and humidity chamber at 40°C / RH 75%, after 30 days the sample was taken out for related substance detection.

[0425] 3. Results of stability investigation

[0426] The results of related substance detection of stability investigation of different crystal forms are shown in Table 1.

[0427] Table 1 Stability related substance results of 102D-6 of each crystal form

[0428] The 0 day HPLC chromatogram of amorphous 102D-6 is shown in Figure 22.

[0429] The 0 day HPLC chromatogram of 102D-6 of Form II is shown in Figure 26.

[0430] The results of related substance detection in Table 1 show that amorphous 102D-6 is the least stable under high temperature condition, the HPLC chromatogram of 102D-6 of amorphous after 30 days of high temperature storage is shown in Figure 23; 102D-6 of Form II is the most stable under high temperature condition, the HPLC chromatogram of 102D-6 of Form II after 30 days of high temperature storage is shown in Figure 27; the stability of 102D-6 of each crystal form under high temperature condition from high to low is Form II > Form III > Form I > Form V > Form VI > Form IV > amorphous.

[0431] The results of related substance detection in Table 1 show that amorphous 102D-6 is the least stable under high humidity condition, the HPLC chromatogram of 102D-6 of amorphous after 30 days of high humidity storage is shown in Figure 24; 102D-6 of Form II is the most stable under high humidity condition, the HPLC chromatogram of 102D-6 of Form II after 30 days of high humidity storage is shown in Figure 28; the stability of 102D-6 of each crystal form under high humidity condition from high to low is Form II > Form I > Form VI > Form III > Form V > Form IV > amorphous.

[0432] The results of related substance detection in Table 1 show that amorphous 102D-6 is the least stable under accelerated condition, the HPLC chromatogram of 102D-6 of amorphous after 30 days is shown in Figure 25; 102D-6 of Form II is the most stable under accelerated condition, the HPLC chromatogram of 102D-6 of Form II after 30 days is shown in Figure 29; the stability of 102D-6 of each crystal form under accelerated condition from high to low is Form II > Form I > Form III > Form VI > Form V > Form IV > amorphous.

[0433] Equilibrium solubility test of 102D-6 of Form I, Form II, Form III, Form IV, Form V and Form VI

[0434] 1. Purpose of the study

[0435] Determine the equilibrium solubility of different crystalline forms of the drug substance in pH 1.0 hydrochloric acid, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and pure water according to ICH M9: Guidance on Bioequivalence Waivers Based on the Biopharmaceutics Classification System.

[0436] 2. Test article, reference article and other solvent, medium information

[0437] 2.1 Test article

[0438] 2.1.1 Name: Form I 102D-6 Lot No: 20240423-1

[0439] 2.1.2 Name: Form II 102D-6 Lot No: 20240425-1

[0440] 2.1.3 Name: Form III 102D-6 Lot No: 20240423-3

[0441] 2.1.4 Name: Form IV 102D-6 Lot No: 20241113-1

[0442] 2.1.5 Name: Form V 102D-6 Lot No: 20241127-1

[0443] 2.1.6 Name: Form VI 102D-6 Lot No: 20241126-1

[0444] 2.2 Solvent, medium information

[0445] 2.2.1 Name: Hydrochloric acid Lot No: 20240723

[0446] 2.2.2 Name: Sodium acetate anhydrous Lot No: 20240507

[0447] 2.2.3 Name: Glacial acetic acid Lot No: 20240111

[0448] 2.2.4 Name: Sodium hydroxide Lot No: 20240408

[0449] 2.2.5 Name: Sodium phosphate monobasic Lot No: 20240221

[0450] 3. Test method

[0451] 3.1 Preparation of aqueous medium

[0452] pH 1.0 hydrochloric acid: measure 991 ml of purified water, add 9 ml of hydrochloric acid, and stir until uniform.

[0453] pH 4.5 acetate buffer: take 1000 ml purified water, add 1.8 g anhydrous sodium acetate, stir until completely dissolved, add 1.6 ml glacial acetic acid, stir uniformly, adjust the pH to 4.5 ± 0.05 with sodium hydroxide solution or glacial acetic acid, and obtain.

[0454] pH 6.8 buffer: take 1000 ml purified water, add 7.8 g sodium dihydrogen phosphate dihydrate, 0.9 g sodium hydroxide, stir until completely dissolved, adjust the pH to 6.8 ± 0.05 with sodium hydroxide solution or phosphoric acid, and obtain.

[0455] 3.2 Test process

[0456] Take the tool plug centrifuge tube, add an appropriate amount of medium to each tube, then add an excess of different crystal form of raw materials, and measure the initial pH value. Place the centrifuge tube in a 37℃ ± 0.5℃ constant temperature water bath shaker, set the rotation speed to 100 rpm, and shake for 24 h. Measure the pH value of the sample. Take an appropriate amount of sample, filter through a 0.45 μm filter membrane, and determine the content by sample injection. Prepare three samples in parallel for each medium.

[0457] 4 Test results

[0458] The equilibrium solubility of different crystal forms is shown in Table 2. The equilibrium solubility from high to low is in the order of crystal form II > crystal form III ≈ crystal form V > crystal form IV > crystal form I ≈ crystal form VI.

[0459] Table 2 Equilibrium solubility of different crystal forms of raw materials Note: pH 1.2 is the sum of the prodrug and the hydrolysis product

[0460] Biological test 1-rat PK study of 102D-6 of crystal form II, crystal form III and crystal form V

[0461] 1. Purpose of the study

[0462] SD rats were orally administered with different crystal forms of drugs. The drug content in the plasma at different time points after administration was detected, and the pharmacokinetic parameters of different crystal forms of drugs in SD rats were calculated and compared.

[0463] 2. Test sample, control sample and other solvents and media information

[0464] 2.1 Test sample

[0465] 2.1.1 Name: crystal form II 102D-6 Batch number: 20240425-1

[0466] 2.1.2 Name: crystal form III 102D-6 Batch number: 20240423-3

[0467] 2.1.3 Name: Form V 102D-6 Batch: 20241127-1

[0468] 2.2 Solvent, medium information

[0469] 2.2.1 Name: Sodium Dodecyl Sulfate Batch: E2406220

[0470] 2.2.2 Name: Ethanol Batch: 161112194B

[0471] 3. Experimental system

[0472] 3.1 Animal grouping

[0473] 56 SD rats weighing 180-220 g were selected, half male and half female, and randomly divided into 3 groups according to weight, 8 rats in each group. The animal grouping information is as follows:

[0474] Table 3 Grouping and identification of SD rats

[0475] 3.2 Dosing and sample collection

[0476] After the SD rats were randomly grouped, they were fasted for more than 12 h before dosing and allowed to drink water freely. Water was prohibited from 1 h before dosing to 1 h after dosing. The animals were fed 4 h after dosing. Each group was dosed orally at a single dose of 3.0 mg / kg (based on active ingredient). Blood samples of about 0.2 mL were collected from the jugular vein at 0 h before dosing and 5 min, 10 min, 15 min, 30 min, 1, 2, 4, 6, 10, 24 h after dosing, and placed in EDTA-K2 anticoagulant tubes.

[0477] 3.3 Analysis of biological samples

[0478] The whole blood was collected at 4°C and centrifuged at 4000 rpm for 10 min to obtain plasma, which was stored at -80°C for testing. The plasma drug concentrations of each group were determined by LC-MS / MS method.

[0479] Phoenix winnonlin 8.0 was used to calculate the PK parameters using a non-compartment model. The data analysis included pharmacokinetic parameters such as C max , T max , AUC 0-t , AUC 0-∞ , t 1 / 2 , and CL / F.

[0480] 4. Test results

[0481] 4.1 Cage-side observation

[0482] No obvious abnormalities were observed in all animals after dosing.

[0483] 4.2 Test Results

[0484] The main pharmacokinetic parameters of SD rats after single oral gavage administration of the same dose (calculated as active ingredient) of each group of compounds are shown in Table 4, and the drug-time curve is shown in Figure 30.

[0485] Table 4 Pharmacokinetic parameters of SD rats after single oral gavage administration of different drugs

[0486] Note: (1) Compared with the crystal form III group, ＊＊ P<0.005. (2) Compared with the crystal form V group, ##P<0.005.

[0487] Research Results

[0488] (1) After single oral gavage administration of the same dose (calculated as active ingredient) of each group of compounds to SD rats, the bioavailability (C max and AUC 0-t ) of each group of rats was ranked in descending order as follows: crystal form II > crystal form III > crystal form V.

[0489] (2) Compared with the crystal form III group and the crystal form V group, the bioavailability (C max and AUC 0-t ) of the compound in the crystal form II group was significantly improved, with a statistically significant difference (P<0.005).

[0490] Biological test 2 - cynomolgus monkey PK study of 102D-6 of crystal form II, crystal form III and crystal form V

[0491] 1. Purpose of the study

[0492] Cynomolgus monkeys were administered different crystal form drugs by single oral gavage. Blood plasma was collected at different time points after administration to detect drug content, and the pharmacokinetic parameters of different groups of drugs in cynomolgus monkeys were calculated and compared.

[0493] 2. Test sample, control sample and other solvent, medium information

[0494] 2.1 Test sample

[0495] 2.1.1 Name: Crystal Form II 102D-6 Batch No.: 20240425-1

[0496] 2.1.2 Name: Crystal Form III 102D-6 Batch No.: 20240423-3

[0497] 2.1.3 Name: Crystal Form V 102D-6 Batch No.: 20241127-1

[0498] 2.2 Solvent, medium information

[0499] 2.2.1 Name: Sodium dodecyl sulfate Batch number: E2406220

[0500] 2.2.2 Name: Anhydrous ethanol Batch number: 161112194B

[0501] 3. Experimental system

[0502] 3.1 Animal grouping

[0503] 24 cynomolgus monkeys, aged 3-5 years, weighing 3-7 kg, half male and half female, were randomly divided into 3 groups according to body weight, 8 in each group. The animal grouping information is as follows:

[0504] Table 5 Grouping and identification of cynomolgus monkeys

[0505] 3.2 Drug administration and sample collection

[0506] After the cynomolgus monkeys were randomly grouped, they were fasted for more than 12 hours before administration and allowed to drink water freely. Water was prohibited from 1 hour before administration to 1 hour after administration. Food was given 4 hours after administration. Each group was administered a single oral gavage of 5.0 mg / kg (based on active ingredient) dose. Blood samples of about 1.0 mL were collected from the jugular vein of each animal at 0 h before administration and 5 min, 10 min, 15 min, 30 min, 1, 2, 3, 4, 6, 8, 12, 24, 48 h (D2) after administration and placed in EDTA-K2 anticoagulant tubes.

[0507] 3.3 Analysis of biological samples

[0508] The whole blood was collected at 4℃, centrifuged at 4000 rpm for 10 min to obtain plasma, and stored at -80℃ for testing. The plasma drug concentrations of each group were determined by LC-MS / MS method.

[0509] Phoenix winnonlin 8.0 was used to calculate the PK parameters using a non-compartment model. The data analysis included C max , T max , AUC 0-t , AUC 0-∞ , t 1 / 2 , C L / F and other pharmacokinetic parameters.

[0510] 4. Test results

[0511] 4.1 Cage-side observation

[0512] No obvious abnormalities were observed in all animals after administration.

[0513] 4.2 Test results

[0514] The main pharmacokinetic parameters of each group of compounds after single oral gavage administration of the same dose (calculated as active ingredient) to cynomolgus monkeys are shown in Table 6, and the pharmacokinetic curves are shown in Figure 31.

[0515] Table 6 Pharmacokinetic parameters of different groups of drugs after single oral gavage administration to cynomolgus monkeys

[0516] Note: (1) Compared with the crystal form III group, ＊＊ P < 0.005; *** P < 0.001. (2) Compared with the crystal form V group, ## P < 0.005; ###P < 0.001.

[0517] Research results:

[0518] (1) After single oral gavage administration of the same dose (calculated as active ingredient) of the compounds to cynomolgus monkeys, the bioavailability (C max and AUC 0-t ) of each group of cynomolgus monkeys was ranked in descending order as follows: crystal form II > crystal form III > crystal form V.

[0519] (2) Compared with the crystal form III group and the crystal form V group, the bioavailability (C max and AUC 0-t ) of the crystal form II group of compounds was significantly improved, with statistical difference.

[0520] In summary, the 102D-6 of crystal form II can maintain stability under high temperature, high humidity and accelerated conditions; the equilibrium solubility of 102D-6 of crystal form II is better than that of other crystal forms; compared with the crystal form III group and the crystal form V group, the bioavailability (C max and AUC 0-t ) of the crystal form II group of compounds is significantly improved.

[0521] Pharmacodynamic study of crystal form II: influenza-infected mouse model

[0522] 1. Research purpose

[0523] This study used an influenza virus-infected mouse model to evaluate the survival protection of the crystal form II compound on influenza-infected mice.

[0524] Female BALB / c mice were infected with a lethal dose of influenza A virus by intranasal instillation, and the mice were treated with vehicle (0.5% (w / v) methyl cellulose + 0.5% polysorbate 80 + ultrapure water), Compound of Form II, positive control (Marbocizumab) at 24 hours, 48 hours and 72 hours post-infection, respectively. During the experiment, the body weight, health status and survival of the mice were monitored daily to evaluate the in vivo anti-influenza virus efficacy of the test substances.

[0525] 2. Test article, control article and other vehicle, medium information

[0526] 2.1 Test article

[0527] 2.1.1 Name: Compound of Form II 102D-6 Lot No: 20240425-1

[0528] 2.1.2 Name: Marbocizumab Lot No: BLX-705-240403

[0529] 2.2 Vehicle, medium information

[0530] 2.2.1 Name: Methyl cellulose Lot No: 230226-19

[0531] 2.2.2 Name: Polysorbate 80 Lot No: F104C240501

[0532] 2.3 Virus strain

[0533] Influenza A virus, A / PR / 8 / 34 (H1N1), wild type, purchased from ATCC, Cat No: VR1469. Titer: 7.15 E+07 PFU / mL.

[0534] 2.4 Animal information

[0535] 6-8 weeks old, 18-20 g, specific pathogen free level female BALB / c mice, purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0536] 3. Experimental system

[0537] 3.1 Animal grouping

[0538] According to the experimental design, the animals were randomly divided into 15 groups, with 10 mice in each group.

[0539] 3.2 Virus inoculation

[0540] On day 0, after the mice were anesthetized by intraperitoneal injection of anesthetic (the injection volume was 5 mL / kg), the mice were inoculated with the virus by intranasal instillation, and the inoculation amount of each mouse was 830 PFU, and the inoculation volume was 50 microliters.

[0541] 3.3 Administration

[0542] Mice were treated with solvent, Compound of Form II, positive control (Marbocizumab) by gavage, twice a day for 7 consecutive days, with 8 / 16 hours interval between the two doses. The first dose of Groups 1-5 was given at 24 hours post-virus inoculation, the first dose of Groups 6-10 was given at 48 hours post-virus inoculation, and the first dose of Groups 10-15 was given at 72 hours post-virus inoculation. Details are shown in Table 7.

[0543] Table 7. In vivo experimental design

[0544] 3.4 Evaluation index

[0545] (1) Body weight change: The state of mice was observed daily during the experiment, and the body weight of mice was recorded.

[0546] (2) Median survival time: The survival time corresponding to the cumulative survival rate of 50%.

[0547] Note: According to the IACUC protocol, any mouse with a body weight loss of more than 35% (including) of the initial body weight, or / and showing signs of impending death, will be euthanized during the experiment.

[0548] 3.5 Data analysis

[0549] The data were statistically analyzed by Prism 7, the body weight change of mice was analyzed by Two-way ANOVA, and the survival status of mice was analyzed by Log-rank (Mantel-cox) test.

[0550] 4. Test results

[0551] The in vivo efficacy of the test compound in the mouse model of influenza A virus infection was evaluated by the body weight change and survival rate of mice.

[0552] 4.1 Protection of the test substance on the body weight of mice in the model

[0553] The body weight change of mice in Groups 1-15 after virus inoculation is shown in Figures 32-34.

[0554] Solvent group: The body weight of mice in Groups 1 (+24h), 6 (+48h) and 11 (+72h) started to decrease from the 3rd day, and then continued to decrease until death or euthanasia.

[0555] Marbocizumab group:

[0556] Group 2 (+24h): Group 2 mice showed a significant decrease in body weight from day 6, with a maximum average decrease of -13.6%, and recovered until normal levels from day 8. Compared to the vehicle group, marboclimia was able to significantly attenuate the decrease in body weight of mice due to viral infection from days 2 to 9, with a statistically significant difference (P<0.05); Group 7 (+48h): Group 7 mice showed a significant decrease in body weight from day 3, with a maximum average decrease of -24.7%, and recovered until normal levels from day 8. Compared to the vehicle group, marboclimia was able to significantly attenuate the decrease in body weight of mice due to viral infection from days 5 to 8, with a statistically significant difference (P<0.05); Group 12 (+72h): Group 12 mice showed a significant decrease in body weight from day 3, with a maximum average decrease of -32.6%, and the surviving animals recovered until normal levels from day 9. Compared to the vehicle group, marboclimia was able to significantly attenuate the decrease in body weight of mice due to viral infection from days 8 to 9, with a statistically significant difference (P<0.05).

[0557] Group of compound of Form II (0.5 mpk):

[0558] Groups 3 (+24h) and 13 (+72h) showed a decrease in body weight from day 3, and the surviving animals recovered from day 10; Group 8 (+48h) showed a decrease in body weight from day 3, and the surviving animals recovered from day 9. Compared to the vehicle group, the compound of Form II (0.5 mpk, group 3) was able to significantly attenuate the decrease in body weight of mice due to viral infection at day 6, with a statistically significant difference (P<0.05).

[0559] Group of compound of Form II (5 mpk):

[0560] Group 4 (+24h): Group 4 mice showed a decrease in body weight from day 6, with a maximum average decrease of -9.5%, and recovered until normal levels from day 8. Compared to the vehicle group, the compound of Form II was able to significantly attenuate the decrease in body weight of mice due to viral infection from days 2 to 9, with a statistically significant difference (P<0.05). Compared to marboclimia, the compound of Form II was able to further attenuate the decrease in body weight of mice at days 6-8 and 10, with a statistically significant difference (P<0.05); Group 9 (+48h): Group 9 mice showed a decrease in body weight from day 3, with a maximum average decrease of -23.0%, and recovered until normal levels from day 8. Compared to the vehicle group, the compound of Form II was able to significantly attenuate the decrease in body weight of mice due to viral infection from days 5 to 8, with a statistically significant difference (P<0.05); Group 14 (+72h): Group 14 mice showed a decrease in body weight from day 3, and the surviving animals recovered until normal levels from day 9.

[0561] Group 5 (+24h): The body weight of mice in Group 5 started to decrease from Day 6, with an average maximum decrease of -8.7%, and recovered to normal level from Day 8. Compared with the vehicle group, the Compound of Form II significantly alleviated the body weight loss of mice caused by viral infection from Day 3 to Day 9, with a statistically significant difference (P<0.05); compared with marboclimia, the Compound of Form II further alleviated the body weight loss of mice from Day 6 to Day 7, with a statistically significant difference (P<0.05).

[0562] Group 10 (+72h): The body weight of mice in Group 10 started to decrease from Day 3, with an average maximum decrease of -20.1%, and recovered to normal level from Day 8. Compared with the vehicle group, the Compound of Form II significantly alleviated the body weight loss of mice caused by viral infection from Day 4 to Day 8, with a statistically significant difference (P<0.05); compared with marboclimia, the Compound of Form II further alleviated the body weight loss of mice from Day 4 to Day 10, with a statistically significant difference (P<0.05). Group 15 (+72h): The body weight of mice in Group 15 started to decrease from Day 3, and the body weight of surviving animals recovered to normal level from Day 9. Compared with the vehicle group, the Compound of Form II significantly alleviated the body weight loss of mice caused by viral infection from Day 7 to Day 9, with a statistically significant difference (P<0.05); compared with marboclimia, the Compound of Form II further alleviated the body weight loss of mice from Day 9 to Day 10 and from Day 13 to Day 14, with a statistically significant difference (P<0.05).

[0563] 4.2 Protection of test compounds on mouse survival in the model

[0564] The survival status of mice in each group after viral inoculation is summarized in Figure 35.

[0565] Vehicle group: Group 1 (+24h) mice died on day 6, all died on day 9, the median survival was 7 days, and the final animal survival rate was 0%; Group 6 (+48h) mice died on day 6, all died on day 8, the median survival was 7 days, and the final animal survival rate was 0%; Group 11 (+72h) mice died on day 6, all died on day 9, the median survival was 8 days, and the final animal survival rate was 0%; Mavrilimumab group: Groups 2 (+24h), 7 (+48h) mice did not die, and the final survival rate was 100%; Group 12 (+72h) mice reached the set humane euthanasia alert line for weight loss from day 7, and all dead animals were artificially killed, and the final survival rate was 70%; Compound of Form II (0.5 mpk) group: Groups 3 (+24h), 8 (+48h) and 13 (+72h) mice died on day 7, the median survival was 9, 8 and 7.5 days, respectively, and the final survival rate was 10%; Compound of Form II (5 mpk) group: Groups 4 (+24h), 9 (+48h) mice did not die, and the final survival rate was 100%; Group 14 (+72h) mice reached the set humane euthanasia alert line for weight loss from day 7, and all dead animals were artificially killed, the median survival was 8 days, and the final survival rate was 10%; Compound of Form II (15 mpk) group: Groups 5 (+24h), 10 (+48h) mice did not die, and the final survival rate was 100%; Group 15 (+72h) mice died on day 7 (the animal weight reached the humane endpoint, all were euthanized), and the final survival rate was 80%.

[0566] Pharmacodynamics study of Form II - influenza infection ferret model

[0567] 1. Purpose of the study

[0568] This study used an influenza virus ferret infection model to evaluate the survival protection of the compound of Form II on influenza-infected mice.

[0569] Female M. putorius ferrets were infected with influenza A virus by nasal drop, and were treated with vehicle, test compound, and control compound. During the experiment, the body weight, body temperature, and clinical symptoms of the ferrets were monitored daily to evaluate the protective effect of the test compound on the ferrets; and the nasal lavage fluid of the experimental ferrets was collected at 72 hours after infection to detect the virus titer and evaluate the inhibitory effect of the test compound on virus replication.

[0570] 2. Test article, control article, and other solvents, media information

[0571] 2.1 Test article

[0572] 2.1.1 Name: Form II 102D-6 Batch: 20240425-1

[0573] 2.1.2 Name: Maraviroc Batch: BLX-705-240403

[0574] 2.2 Solvent, medium information

[0575] 2.2.1 Name: Methylcellulose Batch: 230226-19

[0576] 2.2.2 Name: Polysorbate 80 Batch: F104C240501

[0577] 2.3 Virus strain

[0578] Influenza A virus, A / PR / 8 / 34 (H1N1), wild type, purchased from ATCC, Cat. No: VR1469. Titer: 7.20 E+07 PFU / mL.

[0579] 2.4 Animal information

[0580] 16-18 weeks old, 1-1.5 kg, female, common level, influenza negative ferrets, purchased from Wuxi Coral Reef Biotechnology Co., Ltd.

[0581] 3. Experimental system

[0582] 3.1 Animal grouping

[0583] According to the experimental design, the animals were randomly divided into 5 groups, 6 ferrets in each group.

[0584] 3.2 Virus inoculation

[0585] On day 0, after the experimental animals were deeply anesthetized by intramuscular injection of anesthetic (injection dose was 2 mg / kg), the virus was inoculated by nasal drops, the inoculation amount was 2.88 E+07 pFU per animal, and the inoculation volume was 0.4 mL / ferret (0.2 mL / naris).

[0586] 3.3 Drug administration

[0587] The ferrets were treated with solvent, maraviroc or Form II compound, and the administration method was gavage, twice a day for 7 days, the interval between the two administrations was 8 / 16 hours, and the first administration time was 2 hours after virus inoculation. See Table 8 for details.

[0588] Table 8. In vivo experimental design

[0589] 3.4 Evaluation index

[0590] (1) Health monitoring

[0591] During the experiment, the ferrets were observed daily, and the body weight, body temperature and clinical symptom score were recorded.

[0592] Clinical symptom score: activity: normal activity 0 points, reduced activity 1 point, inactive or lethargy 2 points; nasal discharge: no nasal discharge 0 points, nasal discharge 1 point; sneezing: no sneezing 0 points, sneezing 1 point. After infection, clinical symptoms were observed 4 times a day (09:00-21:00), once every 4 hours, and each observation lasted 20 minutes.

[0593] (2) Virus titer

[0594] At 72 hours after virus inoculation, the ferrets were deeply anesthetized, 2 mL of PBS was injected into the nasal cavity in small volumes (1 mL per nostril), the nasal cavity was lavaged, the ferrets were stimulated to sneeze with a gun head, and the secretions and sputum were collected in 2 mL sterile EP tubes and stored in a -80°C refrigerator until influenza virus titer detection.

[0595] 3.5 Data analysis

[0596] The data were statistically analyzed by Prism 7, and the changes in body weight, body temperature and clinical symptoms of ferrets were analyzed by Two-way ANOVA; the virus titer in the nasal lavage fluid was analyzed by One-way ANOVA.

[0597] 4. Experimental results

[0598] The protective effect of the test compound on ferrets in the influenza A virus ferret infection model was evaluated by changes in body weight, body temperature and clinical symptom score of ferrets, and the inhibition of virus replication was evaluated by virus titer in the nasal lavage fluid.

[0599] 4.1 Protection of test compound on body temperature of ferrets in the model

[0600] After virus inoculation, the body temperature of ferrets in each group is summarized in Figure 36.

[0601] Vehicle group: The body temperature of ferrets began to rise at 24 hours after virus infection, and reached the highest at 36 hours, which was 40.2°C, and began to recover after 60 hours.

[0602] Marbocizavir: The body temperature of ferrets remained stable during the experiment, and marbocizavir at the set dose could protect ferrets from body temperature rise caused by virus infection. At 24 hours after virus inoculation, the body temperature of the vehicle group animals began to be significantly higher than that of the group.

[0603] Form II compound group (0.5 mpk): The temperature of ferrets started to increase at 24 hours post-virus infection, and reached the highest at 36 hours, 40.4 °C, and started to recover at 48 hours.

[0604] Form II compound group (5 mpk): The temperature of ferrets remained stable during the experiment, and 102D-6 at the set dose could protect ferrets from the temperature increase caused by virus infection. The temperature of the solvent group animals started to be significantly higher than this group at 24 hours post-virus inoculation.

[0605] Form II compound group (15 mpk): The temperature of ferrets remained stable during the experiment, and 102D-6 at the set dose could protect ferrets from the temperature increase caused by virus infection. The temperature of the solvent group animals started to be significantly higher than this group at 24 hours post-virus inoculation.

[0606] 4.2 Protection of the tested compounds on clinical symptoms of ferrets in the model

[0607] The clinical symptom scores of ferrets in each group after virus inoculation are summarized in Figure 37.

[0608] Solvent group: The ferrets in the solvent group were affected by the virus infection, and the frequency of lethargy, nasal discharge, sneezing was significantly increased.

[0609] Marboclimia (5 mpk): Compared with the solvent group, the clinical symptoms of ferrets were alleviated, and the frequency of lethargy, nasal discharge, sneezing was significantly reduced.

[0610] Form II compound group (0.5, 5 and 15 mpk): The clinical symptom scores of ferrets were lower than those of the solvent group, and the symptoms of lethargy, nasal discharge, sneezing were significantly improved, and with the increase of the dose, the clinical symptoms were milder.

[0611] 4.3 Effect of the tested compounds on the titer of influenza virus in the model

[0612] The nasal lavage samples were collected at 72 hours post-virus inoculation, and the titer of IFV in the nasal lavage of ferrets in each group is summarized in Figure 38.

[0613] The average IFV virus titer in the nasal lavage of ferrets in the solvent group at day 3 of the experiment was 3.292 Log (plaque # / mL nasal wash), and the average IFV virus titer in the nasal lavage of ferrets in the Marboclimia group at day 3 of the experiment was 2.120 Log (plaque # / mL nasal wash), which was significantly lower than that of the solvent group, consistent with the expected of the model.

[0614] Test group: compared with the solvent group, the compound of crystal form II at a set dose (0.5 mpk) failed to significantly reduce the IFV virus titer in the nasal lavage fluid of the infected animals after 2 hours of administration; compared with the solvent group, the compound of crystal form II at a set dose (5 mpk and 15 mpk) both significantly reduced the IFV virus titer in the nasal lavage fluid of the infected animals after 2 hours of administration, with an average reduction of 1.615 Log (P<0.001) and 1.702 Log (P<0.001), respectively, indicating that both showed good in vivo anti-IFV virus 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 to 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, then 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. 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, for use in the prevention and / or treatment of viral infectious diseases, which can be infectious diseases caused by influenza viruses, such as infectious diseases caused by influenza A viruses or influenza B viruses.

32. Use of at least one of the crystalline Form I of any one of claims 1 to 5, the crystalline Form II of any one of claims 6 to 10, the crystalline Form III of any one of claims 11 to 15, the crystalline Form IV of any one of claims 16 to 18, the crystalline Form V of claim 19, and the crystalline Form VI of any one of claims 20 to 22, or the pharmaceutical composition of claim 29 or 30, in the preparation of a medicament for the prevention and / or treatment of a viral infectious disease, optionally, the viral infectious disease is an infectious disease caused by an influenza virus, for example, an infectious disease caused by an influenza A virus or an influenza B virus.

33. A method for the prevention and / or treatment of a viral infectious disease, comprising administering to a subject in need thereof at least one of the crystalline Form I of any one of claims 1 to 5, the crystalline Form II of any one of claims 6 to 10, the crystalline Form III of any one of claims 11 to 15, the crystalline Form IV of any one of claims 16 to 18, the crystalline Form V of claim 19, and the crystalline Form VI of any one of claims 20 to 22, or the pharmaceutical composition of claim 29 or 30; optionally, the viral infectious disease is an infectious disease caused by an influenza virus, for example, an infectious disease caused by an influenza A virus or an influenza B virus.

34. An industrialized preparation method of acyl ethyl ester polycyclic compounds, comprising the following steps: The compound of formula (102D-4) is subjected to etherification reaction with the compound of formula (III) to obtain a mixture of the compound of formula (II-1) and the compound of formula (II-2); and the compound of formula (II-1) or the compound of formula (II-2) is obtained by recrystallization; The compound of formula (II-1) or formula (II-2) is subjected to a reduction reaction with a reducing agent to obtain the compound of formula (I-1) or formula (I-2): wherein R1, R2, R3, R4, R5, R6and R7in formula (III), formula (II-1), formula (II-2), formula (I-1) or formula (I-2) are each independently selected from hydrogen and deuterium; X in formula (III) is iodine, bromine, chlorine or sulfonate, preferably, X is bromine; Preferably, R1, R2, R3, R4, R5, R6and R7in formula (I-1), formula (I-2), formula (II-1), formula (II-2) and formula (III) are all hydrogen; or, R1, R2and R3in formula (I-1), formula (I-2), formula (II-1), formula (II-2) and formula (III) are all deuterium, and R4, R5, R6and R7are all hydrogen.

35. The method of manufacturing according to claim 34, wherein, The etherification reaction is carried out in the presence of a base, which can be an inorganic base or an organic base, the inorganic base can be selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, and the organic base can be selected from triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, preferably potassium carbonate or triethylamine; Optionally, the reaction is carried out in a reaction solvent, which can be selected from dichloromethane, ethyl acetate, chloroform, etc., preferably dichloromethane; Optionally, the etherification reaction temperature is selected from -10℃ to 30℃, preferably 10℃ to 20℃.

36. The method of manufacturing according to claim 34 or 35, wherein, The reducing agent is one or more of sodium bisulfite / iodine, sodium iodide / boron trifluoride etherate and potassium iodide / trichloroisocyanuric acid; and / or The recrystallization solvent after the etherification reaction is acetonitrile or a mixed solvent of acetonitrile and methyl tert-butyl ether; and / or The recrystallization solvent after the etherification reaction is toluene or a mixed solvent of toluene and methyl tert-butyl ether.

37. The method of manufacturing according to any one of claims 34 to 36, wherein, The preparation method further comprises the following step: the compound of formula (IV) is subjected to a dehydroxyl substituent reaction to obtain a compound of formula (102D-4); Y in formula (IV) is C1-C 10 alkyl, optionally selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, heptyl, octyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 3-methyl-1-pentyl and 4-methyl-1-pentyl; Optionally, the method further comprises the step of reacting the compound of formula (V) with an oxidizing agent to obtain the compound of formula (IV); wherein Y in formula (V) is defined the same as in formula (IV); Optionally, the preparation method further comprises the following step: condensation reaction of the compound of formula (VI) with the compound of formula (102M2-D1) to obtain the compound of formula (V); wherein Y in formula (VI) is defined the same as in formula (V); Optionally, the process further comprises the step of reacting a compound of formula (102D-0) with a compound of formula (VII) to obtain a compound of formula (VI); wherein Bnin formula (102D-0) is benzyl; and Y in formula (VII) is defined the same as in formula (VI).

38. A compound of formula (II): ###00019### (II) ​ wherein R1, R2, R3, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen and deuterium; Optionally, the compound of formula (II) is a compound of formula (II-1): Alternatively, the compound of formula (II) is a compound of formula (II-2): Alternatively, the compound of formula (II) is a mixture of a compound of formula (II-1) and a compound of formula (II-2): Optionally, R1, R2, R3, R4, R5, R6, and R7in the compound of formula (II), (II-1), or (II-2) are all hydrogen; or, the compound of formula (II-2) is a compound of formula (102D-5); or, the compound of formula (II-1) is a compound of formula (102D-5A); or, the compound of formula (II) is a compound of formula (102D-5), (102D-5A), or a mixture of a compound of formula (102D-5) and a compound of formula (102D-5A). or, R1, R2, and R3in the compound of formula (II), (II-1), or (II-2) are all deuterium, and R4, R5, R6, and R7are all hydrogen.

39. Use of a compound of claim 38 as an intermediate compound.

40. A method of preparing a compound of formula (102D-4), the method comprising: (a) condensation of a compound of formula (VI) with a compound of formula (102M2-D1) to give a compound of formula (V); wherein Y in formula (VI) and formula (V) is C1-C 10 alkyl, optionally selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, heptyl, octyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 3-methyl-1-pentyl and 4-methyl-1-pentyl; (b) reacting the compound of formula (V) with an oxidizing agent to obtain a compound of formula (IV); wherein Y in formula (IV) is defined the same as in formula (V); (c) dehydroxylating the substituent of the compound of formula (IV) to obtain a compound of formula (102D-4); Y in formula (IV) is C1-C 10 alkyl, optionally selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, heptyl, octyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 3-methyl-1-pentyl and 4-methyl-1-pentyl; Optionally, the compound of formula (VI) in step (a) can be prepared by: (VII) to give a compound of formula (VI); wherein Bnin formula (102D-0) is benzyl; and Y in formula (VII) is defined the same as in formula (VI).

41. An intermediate compound as shown in formula (IV): wherein Y in formula (IV) is C1-C 10 alkyl, optionally selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, heptyl, octyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 3-methyl-1-pentyl and 4-methyl-1-pentyl; Optionally, the compound of formula (102D-3) is:

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