Crystalline form of a viral protease inhibitor

Abstract

The application relates to a crystal form of a viral protease inhibitor, a crystal form of a pharmaceutically acceptable salt and use; the application also relates to a preparation method of the crystal form, a composition containing the crystal and a pharmaceutical composition; the crystal form of the application is stable, has a high yield, a mild crystallization condition, is suitable for industrial production, has good pharmacokinetic properties, and can well meet the needs of the pharmaceutical industry.

Description

Technical Field

[0001] This application relates to a crystal form of a protease inhibitor compound and a method for preparing the same, pharmaceutical compositions comprising the crystal form or a combination thereof, and their uses. This application also relates to phosphates, succinates, hippurates, glycolates, and maleates of the protease inhibitor compound, as well as the crystal forms of said salts, methods for preparing said salts, pharmaceutical compositions comprising said salts, and their uses. Technical Background

[0002] Over 70% of the coronavirus genome sequence encodes 16 non-structural proteins (NSPs), named Nsp1 to Nsp16. These 16 NSPs are translated into two long peptide chains, pp1a and pp1ab, which are then proteases that produce individual NSPs. This hydrolysis is catalyzed by two proteases among the 16 NSPs—Nsp3 and Nsp5. Nsp5, or 3CLpro, catalyzes the hydrolysis of the peptide bonds linking Nsp4 to Nsp16. At the catalytic center of 3CLpro, there exists a catalytic duodenome consisting of His41 and Cys145. The working mechanism and protein sequence of the catalytic domain of 3CLpro are conserved among different coronaviruses. The sequence identity between SARS-CoV-2 and SARS-CoV 3CLpro reaches 96%. Inhibiting the protease activity of 3CLpro will block the release of Nsp4 to Nsp16, which are essential for coronavirus replication. Therefore, 3CLpro is an important target for developing anti-coronavirus drugs.

[0003] WO2024212101A1 discloses compounds as inhibitors of coronavirus 3CLpro, including compound 1 described in this invention, the entire contents of which are incorporated herein by reference. The disclosed compound non-covalently binds to the 3CLpro catalytic pocket, competitively inhibiting the binding of 3CLpro substrates to it, thereby reducing or inhibiting the activity of 3CLpro. Furthermore, this compound can reduce or inhibit coronavirus replication.

[0004] The catalytic pocket-related sequence of coronavirus 3CLpro is highly conserved, and the substrates it recognizes are also highly conserved. Therefore, this compound can serve as a broad-spectrum inhibitor of coronavirus 3CLpro and play a therapeutic role in infections caused by coronaviruses, including SARS-CoV-2, SARS-CoV, and MERS-CoV.

[0005] Those skilled in the art will understand that the crystal form or salt form of a drug, and the crystal form of its salt, has a significant impact on various drug properties, including solubility, hygroscopicity, solid-state stability, and bioavailability. Therefore, there is a need for pharmaceutical compounds with crystal forms and / or salt forms suitable for drug development, preparation, storage, and use. Summary of the Invention

[0006] During the research and development experiments, the inventors unexpectedly discovered that certain crystal forms of compound 1 and certain pharmaceutically acceptable salts thereof exhibit properties particularly suitable for drug development. Therefore, the object of the present invention is to provide crystal forms of compound 1 or pharmaceutically acceptable salts thereof suitable for drug development, pharmaceutical compositions comprising such crystal forms, and pharmaceutical uses of such crystal forms.

[0007] Compound 1 of this application is named (S)-5-chloro-2-((4,4-difluoro-1-(1,6-naphthidium-8-carbonyl)piperidin-3-yl)amino)-N-methyl-3-nitrobenzamide, and its structure is as follows:

[0008]

[0009] The invention can be described in various ways, and the invention described in these aspects and any of their embodiments is independent of each other but related to each other, and together constitutes the content of the invention.

[0010] In a first aspect, the present invention provides a crystal form of compound 1 or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the present invention provides a free crystal form of compound 1.

[0012] In some embodiments, the present invention provides a pharmaceutically acceptable crystal form of a salt of compound 1, the salt being selected from phosphates, succinates, hippurates, glycolates, and maleates of compound 1.

[0013] In a second aspect, the present invention provides a composition comprising the crystal form described in any embodiment of the first aspect of the present invention, wherein the crystal form accounts for more than 50% by mass of the composition, preferably more than 75%, more preferably more than 90%, and most preferably more than 95%.

[0014] Thirdly, the present invention provides a pharmaceutical composition comprising the crystal form described in any embodiment of the first aspect of the invention and at least one pharmaceutically acceptable carrier.

[0015] Fourthly, the present invention provides the use of the crystal form described in any embodiment of the first aspect of the present invention in the preparation of a medicament for treating diseases or symptoms caused by coronaviruses.

[0016] Fifthly, the present invention provides a crystal form according to any embodiment of the first aspect of the present invention, a composition according to the second aspect of the present invention, or a pharmaceutical composition according to the third aspect of the present invention, which are used as pharmaceuticals.

[0017] In a sixth aspect, the present invention provides a crystal form according to any embodiment of the first aspect of the present invention, a composition according to the second aspect of the present invention, or a pharmaceutical composition according to the third aspect of the present invention for treating diseases or symptoms caused by coronaviruses.

[0018] In a seventh aspect, the present invention provides a method for treating a disease or symptoms of a coronavirus in a subject, comprising the step of applying a therapeutically effective amount of the crystal form described in any embodiment of the first aspect of the present invention to the patient.

[0019] Experiments have shown that the crystal form of compound 1 or its pharmaceutically acceptable salt provided by this invention exhibits excellent performance in one or more aspects such as solubility, hygroscopicity, and stability, demonstrating good pharmaceutical properties and excellent drug development prospects.

[0020] The crystallization yield of compound 1 or its pharmaceutically acceptable salt provided by this invention is high, the crystallization conditions are mild, it is suitable for industrial production, and it can well meet the needs of the pharmaceutical industry. Attached Figure Description

[0021] Figure 1A XRPD diagram of the free state A crystal form of compound 1

[0022] Figure 1B TGA image of the free A crystal form of compound 1

[0023] Figure 1C DSC diagram of the free A crystal form of compound 1

[0024] Figure 2A XRPD diagram of the free B crystal form of compound 1

[0025] Figure 2B TGA image of the free B crystal form of compound 1

[0026] Figure 2C DSC diagram of the free B crystal form of compound 1

[0027] Figure 3A XRPD diagram of the free C crystal form of compound 1

[0028] Figure 3B TGA image of the free C crystal form of compound 1

[0029] Figure 3C DSC diagram of the free C crystal form of compound 1

[0030] Figure 4A XRPD diagram of phosphate A crystal form of compound 1

[0031] Figure 4BTGA image of phosphate A crystal form of compound 1

[0032] Figure 4C DSC diagram of phosphate A crystal form of compound 1

[0033] Figure 5A XRPD diagram of the B-crystal form of the phosphate of compound 1

[0034] Figure 5B TGA image of the B-crystal form of the phosphate of compound 1

[0035] Figure 5C DSC diagram of the B-crystal form of the phosphate of compound 1

[0036] Figure 6A XRPD diagram of the A crystal form of succinate of compound 1

[0037] Figure 6B TGA image of the A crystal form of succinate of compound 1

[0038] Figure 6C DSC diagram of crystal form A of succinate of compound 1

[0039] Figure 7A XRPD diagram of the B crystal form of succinate of compound 1

[0040] Figure 7B TGA image of the B crystal form of succinate of compound 1

[0041] Figure 7C DSC diagram of the B crystal form of succinate of compound 1

[0042] Figure 8A XRPD diagram of the A crystal form of hippurate of compound 1

[0043] Figure 8B TGA image of the A crystal form of hippurate of compound 1

[0044] Figure 8C DSC diagram of the A crystal form of hippurate of compound 1

[0045] Figure 9A XRPD diagram of the A crystal form of the glycolate of compound 1

[0046] Figure 9B TGA image of the A crystal form of the glycolate of compound 1

[0047] Figure 9C DSC diagram of the A crystal form of the glycolate of compound 1

[0048] Figure 10AXRPD diagram of maleate A crystal form of compound 1

[0049] Figure 10B TGA image of maleate A crystal form of compound 1

[0050] Figure 10C DSC diagram of maleate A crystal form of compound 1

[0051] Figure 11A XRPD diagram of maleate B crystal form of compound 1

[0052] Figure 11B TGA image of maleate B crystal form of compound 1

[0053] Figure 11C DSC diagram of maleate B crystal form of compound 1

[0054] Figure 12A XRPD image of an amorphous sample of compound 1

[0055] Figure 12B TGA / mDSC image of an amorphous sample of compound 1 Detailed Implementation

[0056] 1. Definitions and Explanations

[0057] Unless otherwise stated, the following terms and phrases used in this invention have the following meanings.

[0058] The term "coronavirus" as used in this invention refers to a related group of RNA viruses that cause diseases in mammals and birds, such as respiratory infectious diseases commonly seen in humans and birds, ranging from mild to fatal diarrhea in cattle and pigs, and hepatitis and encephalomyelitis in mice. Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome and a helical nucleocapsid. They have characteristic rod-shaped spikes protruding from their surface, which, in electron micrographs, evoke the shape of a solar corona, hence the name coronavirus. Fatal coronaviruses encompass those that can cause diseases such as SARS (Severe Acute Respiratory Syndrome), MERS (Middle East Respiratory Syndrome), and COVID-19 (a contact-transmitted infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2).

[0059] In this invention, the terms "pharmaceutical acceptable" and "medicinally usable" mean, within reasonable medical judgment, suitable for contact with tissues of humans and other mammals without excessive toxicity, irritation, allergic reactions, etc., and commensurate with a reasonable benefit / risk ratio. "Medicinally usable salt" refers to any salt that is non-toxic to the recipient and, upon administration to the recipient, can directly or indirectly provide the compounds of this invention. Suitable medicinally usable salts are, for example, those disclosed by SMBerge et al. in J. Pharmaceutical Sciences, 1977, 66, pp. 1-19. For example, pharmaceutically acceptable salts of Compound 1 include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, decanoates, heptanoates, propargylates, oxalates, malonates, succinates, caprylates, sebacic acid, fumarates, maleates, etc. Alkyne-1,4-diacidate, hexyne-1,6-diacidate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts.

[0060] In this invention, the terms “subject,” “patient,” or “recipient” refer to animals susceptible to coronavirus infection, preferably mammals, and in particular humans.

[0061] The term "therapeuticly effective amount" in this invention refers to the amount of compound 1 or a pharmaceutically acceptable salt thereof required to produce the desired therapeutic effect (e.g., improvement of disease and / or symptoms caused by coronavirus, reduction of the severity of disease and / or symptoms caused by coronavirus, and / or slowing of the progression of disease and / or symptoms caused by coronavirus). The precise amount of the therapeutically effective amount will depend on the therapeutic purpose and can be determined by those skilled in the art using known techniques.

[0062] The term "treatment" as used in this invention includes, but is not limited to, the following: complete or partial relief, cure of disease caused by coronavirus, and reduction of the risk of symptoms of disease caused by coronavirus. Improvement or reduction in the severity of any of these symptoms can be evaluated according to methods and techniques known in the art.

[0063] In this invention, the term "room temperature" means ambient temperature, for example, 10 to 40°C, preferably 15 to 35°C, and more preferably 20 to 30°C, for example, around 25°C.

[0064] In this invention, the terms “about” and “approximately” when used in conjunction with figures such as percentages include the specified figures, as well as ranges of figures recognized by those skilled in the art (e.g., ±10%; preferably, ±5%; further preferably, ±2%; most preferably, ±1%).

[0065] In this invention, "having characteristic diffraction peaks at approximately the following 2θ angles" and "XRPD pattern having diffraction peaks at approximately ... 2θ angles" means that the X-ray powder diffraction pattern has diffraction peaks within the range of ±0.5° of the indicated 2θ angle; preferably, within ±0.2°; and more preferably, within ±0.1°.

[0066] In this invention, "at ... °C" means near that temperature. For example, "at 98.2 °C" means that there is a heat absorption signal within the range of 98.2 °C ± 1 °C; preferably, within the range of ± 0.5 °C; and more preferably, within the range of ± 0.2 °C.

[0067] 2. The crystal form of the present invention

[0068] In some embodiments, the present invention provides a free A-state crystal form of compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at approximately the following 2θ angles: 6.74, 9.71, 14.54, 20.19, 20.92, 23.02.

[0069] In some embodiments, the X-ray powder diffraction pattern of the free A-state crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 6.74, 8.09, 9.71, 13.44, 13.83, 14.54, 16.68, 19.42, 20.19, 20.92, 21.92, 23.02, 25.19, 26.59, 26.89, 27.79, and 29.66.

[0070] In some embodiments, the X-ray powder diffraction pattern of the free A-phase crystal form of compound 1 exhibits characteristic diffraction peaks at approximately the following 2θ angles: 6.74, 8.09, 9.71, 10.74, 11.48, 13.24, 13.44, 13.83, 14.54, 15.49, 16.15, 16.68, 17.13, 17.95, 19.42. 20.19, 20.92, 21.54, 21.92, 23.02, 23.58, 24.27, 24.74, 25.19, 25.94, 26.59, 26.89, 27.25, 27.79, 29.29, 29.66, 30.40, 32.09, 32.51, 32.81, 33.59, 35.01, 35.89.

[0071] In some embodiments, the XRPD of the free A-crystal form of compound 1 is substantially as follows: Figure 1A As shown.

[0072] In some embodiments, the TGA results of the free A-phase crystal form of compound 1 are essentially as follows: Figure 1B As shown, the sample lost approximately 11.37% of its weight when heated to approximately 150°C.

[0073] In some embodiments, the DSC results of the free A-phase of compound 1 are substantially as follows: Figure 1C As shown, there is an endothermic peak at approximately 98.2℃.

[0074] In some embodiments, the present invention provides a free B-type crystal of compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at approximately the following 2θ angles: 6.89, 9.74, 14.72, 19.49, 22.50, 25.83.

[0075] In some embodiments, the X-ray powder diffraction pattern of the free B crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 6.89, 7.97, 9.74, 11.90, 14.72, 15.76, 17.20, 19.49, 20.56, 20.96, 22.50, 22.88, 25.83, 27.34, 27.62.

[0076] In some embodiments, the X-ray powder diffraction pattern of the free B crystal form of compound 1 exhibits characteristic diffraction peaks at approximately the following 2θ angles: 6.89, 7.97, 9.74, 11.21, 11.90, 13.59, 14.16, 14.72, 15.76, 16.70, 17.20, 18.09, 18.53, 19.49, 20.56, 20.9. 6, 21.31, 22.50, 22.88, 23.22, 23.89, 24.16, 24.87, 25.51, 25.83, 26.73, 27.34, 27.62, 28.22, 28.51, 29.32, 29.90, 30.17, 31.21, 31.97, 33.04, 34.14, 35.17, 38.36.

[0077] In some embodiments, the XRPD results of the free B-crystal form of compound 1 are essentially as follows: Figure 2A As shown.

[0078] In some embodiments, the TGA results of the free B-crystal form of compound 1 are essentially as follows: Figure 2B As shown, the sample lost approximately 9.16% of its weight when heated to approximately 120°C.

[0079] In some embodiments, the DSC results of the free B-phase crystal form of compound 1 are essentially as follows: Figure 2C As shown, there are three endothermic signals at approximately 73.9°C, approximately 116.7°C, and approximately 144.2°C.

[0080] In some embodiments, the present invention provides a free C crystal form of compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at approximately the following 2θ angles: 10.64, 15.12, 21.32, 27.75.

[0081] In some embodiments, its X-ray powder diffraction pattern has characteristic diffraction peaks at approximately the following 2θ angles: 8.52, 10.64, 15.12, 16.89, 17.05, 20.81, 21.32, 23.52, 27.42, 27.75, 30.64.

[0082] In some embodiments, the X-ray powder diffraction pattern of the free C crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 8.52, 10.64, 13.17, 13.64, 14.06, 15.12, 16.89, 17.05, 20.19, 20.81, 21.32, 21.51, 22.20, 23.52, 24.97, 25.59, 27.42, 27.75, 28.29, 29.30, 29.72, 30.64, 31.35, 33.49, 33.91, 34.42, 35.60.

[0083] In some embodiments, the XRPD results of the free C crystal form of compound 1 are essentially as follows: Figure 3A As shown.

[0084] In some embodiments, the TGA results of the free C crystal form of compound 1 are essentially as follows: Figure 3B As shown, the sample lost approximately 8.32% of its weight when heated to approximately 130°C.

[0085] In some embodiments, the DSC results of the free C crystal form of compound 1 are essentially as follows: Figure 3C As shown, there is an endothermic peak at approximately 110.5℃.

[0086] In some embodiments, the present invention provides phosphate A crystal form of compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at approximately the following 2θ angles: 5.57, 8.40, 12.67, 18.25, 21.08.

[0087] In some embodiments, the X-ray powder diffraction pattern of phosphate A form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 5.57, 6.89, 8.40, 12.67, 13.72, 15.23, 16.93, 18.25, 21.08, 21.68, 24.82, 25.30.

[0088] In some embodiments, the X-ray powder diffraction pattern of phosphate A form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 3.33, 5.57, 6.89, 8.40, 9.99, 10.91, 12.67, 13.72, 15.23, 16.93, 18.25, 21.08, 21.68, 23.54, 24.82, 25.30, 26.12, 26.72, 27.58, 29.54, 32.37, and 33.29.

[0089] In some embodiments, the XRPD results of phosphate A crystal form of compound 1 are essentially as follows: Figure 4A As shown.

[0090] In some embodiments, the TGA results for the phosphate A crystal form of compound 1 are essentially as follows: Figure 4B As shown, the sample lost approximately 3.79% of its weight when heated to approximately 120°C, and approximately 3.23% of its weight when heated further to approximately 180°C.

[0091] In some embodiments, the DSC results of phosphate A crystal form of compound 1 are essentially as follows: Figure 4C As shown, there are two endothermic signals at approximately 77.2°C and approximately 142.0°C.

[0092] In some embodiments, the acid-base molar ratio of the phosphate A crystal form of compound 1 is 0.5 to 1.5:1, preferably about 0.8:1.

[0093] In some embodiments, the present invention provides a phosphate B crystal form of compound 1, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at approximately the following 2θ angles: 8.48, 13.06, 17.26, 18.76, 21.50.

[0094] In some embodiments, the X-ray powder diffraction pattern of phosphate B crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 5.67, 6.98, 8.48, 13.06, 13.46, 16.97, 17.26, 18.76, 21.50, 21.92, 22.37, 25.20.

[0095] In some embodiments, the X-ray powder diffraction pattern of phosphate B crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 3.70, 4.69, 5.67, 6.98, 8.48, 8.83, 10.18, 10.96, 11.76, 13.06, 13.46, 14.05, 15.41, 16.97, 17.26, 18.16, 18.76, 19.62, 20.19, 20.90, 21.50, 21.92, 22.37, 23.91, 25.20, 25.54, 26.28, 27.11, 27.94, 30.49, 31.90, 33.07, 33.75, 35.69, 36.83.

[0096] In some embodiments, the XRPD results of the phosphate B crystal form of compound 1 are essentially as follows: Figure 5A As shown.

[0097] In some embodiments, the TGA results for the phosphate B crystal form of compound 1 are essentially as follows: Figure 5B As shown, the phosphate B crystal form of compound 1 loses approximately 4.95% of its weight at approximately 150°C.

[0098] In some embodiments, the DSC results of the phosphate B crystal form of compound 1 are essentially as follows: Figure 5C As shown, there are two endothermic signals at approximately 65.4°C and approximately 158.3°C.

[0099] In some embodiments, the acid-base molar ratio of the phosphate B crystal form of compound 1 is 0.2 to 0.8:1, preferably about 0.5:1.

[0100] In some embodiments, the present invention provides succinate A crystal form of compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at approximately the following 2θ angles: 4.70, 6.97, 8.17, 11.03, 19.84.

[0101] In some embodiments, the X-ray powder diffraction pattern of succinate A of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 4.70, 6.97, 8.17, 10.66, 11.03, 12.01, 16.61, 19.84, 20.46, 21.62.

[0102] In some embodiments, the X-ray powder diffraction pattern of succinate A of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 4.70, 6.97, 7.42, 8.17, 9.90, 10.27, 10.66, 11.03, 11.68, 12.01, 14.88, 16.61, 17.37, 19.84, 20.46, 20.92, 21.62, 22.11, 24.10, 24.59, 24.92, 25.72, 27.06.

[0103] In some embodiments, the XRPD results of succinate A crystal form of compound 1 are essentially as follows: Figure 6A As shown.

[0104] In some embodiments, the TGA results for the succinate A crystal form of compound 1 are essentially as follows: Figure 6B As shown, the sample lost approximately 4.75% of its weight when heated to approximately 150°C.

[0105] In some embodiments, the DSC results of the succinate A crystal form of compound 1 are essentially as follows: Figure 6C As shown, there are two endothermic signals at approximately 53.0°C and approximately 123.6°C.

[0106] In some embodiments, the acid-base molar ratio of the succinate A crystal form of compound 1 is 0.9 to 1.1:1, preferably about 1:1.

[0107] In some embodiments, the present invention provides a succinate B crystal form of compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at approximately the following 2θ angles: 12.29, 13.61, 24.67, 27.39.

[0108] In some embodiments, the X-ray powder diffraction pattern of the succinate B crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 7.44, 11.28, 12.29, 13.61, 15.04, 19.60, 21.00, 21.98, 24.67, 25.50, 27.39.

[0109] In some embodiments, the X-ray powder diffraction pattern of the succinate B crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 7.44, 9.78, 11.28, 12.29, 13.61, 15.04, 15.93, 18.64, 19.60, 21.00, 21.98, 24.67, 25.50, 27.39, 32.28.

[0110] In some embodiments, the XRPD results of the succinate B crystal form of compound 1 are essentially as follows: Figure 7A As shown.

[0111] In some embodiments, the TGA results for the succinate B crystal form of compound 1 are essentially as follows: Figure 7B As shown, heating to approximately 150°C results in a weight loss of approximately 3.95%.

[0112] In some embodiments, the DSC results of the succinate B crystal form of compound 1 are essentially as follows: Figure 7C As shown, there are three endothermic signals at approximately 131.8°C, approximately 160.9°C, and approximately 229.3°C.

[0113] In some embodiments, the acid-base molar ratio of the succinate B crystal form of compound 1 is 0.2 to 0.8:1, preferably about 0.5:1.

[0114] In some embodiments, the present invention provides hippurate A crystal form of compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at approximately the following 2θ angles: 4.97, 8.31, 10.43, 12.39, 16.93, 21.75.

[0115] In some embodiments, the X-ray powder diffraction pattern of the hippurate A crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 4.97, 8.31, 9.90, 10.43, 11.53, 12.39, 13.07, 16.93, 20.48, 21.75, 23.64, 24.90.

[0116] In some embodiments, the X-ray powder diffraction pattern of the hippurate A crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 4.97, 5.76, 6.83, 8.31, 9.90, 10.43, 11.53, 12.39, 13.07, 13.37, 14.85, 16.58, 16.93, 17.42, 18.14, 18.86, 19.56, 19.84, 20.48, 21.75, 22.31, 22.62, 23.64, 24.46, 24.90, 27.38, 28.05, 28.94, 29.88, 31.59, 32.95, 33.49, 34.33, and 36.00.

[0117] In some embodiments, the XRPD results of the hippurate A crystal form of compound 1 are essentially as follows: Figure 8A As shown.

[0118] In some embodiments, the TGA results for the hippurate A crystal form of compound 1 are essentially as follows: Figure 8B As shown, the sample lost approximately 3.36% of its weight when heated to approximately 150°C.

[0119] In some embodiments, the DSC results of the hippurate A crystal form of compound 1 are essentially as follows: Figure 8C As shown, there is an endothermic signal at approximately 132.4°C.

[0120] In some embodiments, the acid-base molar ratio of the hippurate A crystal form of compound 1 is 1 to 2:1, preferably about 1.5:1.

[0121] In some embodiments, the present invention provides an glycolate A crystal form of compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at approximately the following 2θ angles: 6.76, 9.68, 20.78, and 23.27.

[0122] In some embodiments, the X-ray powder diffraction pattern of the glycolate A crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 6.76, 8.01, 9.68, 13.51, 14.46, 20.30, 20.78, 22.85, 23.27, 25.11.

[0123] In some embodiments, the X-ray powder diffraction pattern of the glycolate A crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 6.76, 8.01, 9.68, 11.60, 13.19, 13.51, 13.80, 14.46, 15.46, 16.72, 17.88, 19.39, 20.30, 20.78, 21.85, 22.20, 22.85, 23.27, 23.65, 24.13, 25.11, 25.95, 26.55, 26.85, 27.76, 29.20, 29.97, 31.20, 31.73, 34.97, 35.90.

[0124] In some embodiments, the XRPD results of the glycolate A crystal form of compound 1 are essentially as follows: Figure 9A As shown.

[0125] In some embodiments, the TGA of the glycolate A crystal form of compound 1 is substantially as follows: Figure 9B As shown, the sample lost approximately 9.07% of its weight when heated to approximately 140°C.

[0126] In some embodiments, the DSC results of the glycolate A crystal form of compound 1 are essentially as follows: Figure 9C As shown, there is an endothermic peak at approximately 95.7℃.

[0127] In some embodiments, the acid-base molar ratio of the glycolate A crystal form of compound 1 is 0.5 to 1:1, preferably about 0.7:1.

[0128] In some embodiments, the present invention provides maleate A crystal form of compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at approximately the following 2θ angles: 4.70, 5.01, 6.97, 8.10, 11.12.

[0129] In some embodiments, the X-ray powder diffraction pattern of maleate A crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 4.70, 5.01, 6.97, 8.10, 11.12, 19.88, 20.66, 22.93, 28.82.

[0130] In some embodiments, the X-ray powder diffraction pattern of maleate A crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 4.70, 5.01, 6.97, 8.10, 9.95, 10.78, 11.12, 11.73, 14.97, 16.71, 17.50, 19.88, 20.66, 21.04, 21.65, 22.93, 24.16, 24.75, 28.82, 29.44.

[0131] In some embodiments, the XRPD results of maleate A crystal form of compound 1 are essentially as follows: Figure 10A As shown.

[0132] In some embodiments, the TGA results for maleate A crystal form of compound 1 are essentially as follows: Figure 10B As shown, the sample lost approximately 3.85% of its weight when heated to approximately 100°C.

[0133] In some embodiments, the DSC results of maleate A crystal form of compound 1 are essentially as follows: Figure 10C As shown, there are two endothermic signals at approximately 53.7°C and approximately 130.5°C (peak temperature).

[0134] In some embodiments, the acid-base molar ratio of maleate A crystal form of compound 1 is 0.5 to 1.5:1, preferably about 1:1.

[0135] In some embodiments, the present invention provides maleate B crystal form of compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at approximately the following 2θ angles: 10.96, 15.05, 22.63, 23.03, 25.78.

[0136] In some embodiments, the X-ray powder diffraction pattern of maleate B crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 7.47, 10.96, 15.05, 17.75, 22.63, 23.03, 25.78.

[0137] In some embodiments, the X-ray powder diffraction pattern of maleate B crystal form of compound 1 has characteristic diffraction peaks at approximately the following 2θ angles: 7.47, 10.96, 12.69, 15.05, 17.75, 18.16, 18.95, 19.66, 20.07, 20.75, 21.07, 22.02, 22.63, 23.03, 23.81, 25.48, 25.78, 27.30, 30.21, 31.10, 32.24, 34.52.

[0138] In some implementations, the XRPD results for maleate crystal form B are essentially as follows: Figure 11A As shown.

[0139] In some implementations, the TGA results for maleate crystal form B are essentially as follows: Figure 11B As shown, the sample lost approximately 1.89% of its weight when heated to approximately 100°C.

[0140] In some implementations, the DSC results for maleate crystal form B are essentially as follows: Figure 11CAs shown, there are three endothermic signals at approximately 52.3°C, approximately 74.3°C, and approximately 134.5°C (peak temperature).

[0141] In some embodiments, the acid-base molar ratio of the maleate B crystal form of compound 1 is 1 to 2:1, preferably about 1.4:1.

[0142] 3. Preparation of the crystal form of the present invention

[0143] The crystal form described in any embodiment of the first aspect of the present invention can be prepared by means of the methods disclosed in this application or obvious alternatives thereof, combined with common technical knowledge and conventional experimental techniques in the art.

[0144] In some embodiments, the free A crystal form of compound 1 is obtained by drying the crystal form of compound 1 in an aqueous solution of IPA at room temperature.

[0145] Preferably, the free state A crystal form of compound 1 is obtained by stirring an amorphous sample of compound 1 in IPA / H2O (19:1, v / v) at room temperature for about 2 days, followed by solid vacuum drying at room temperature overnight.

[0146] In some embodiments, the free B-crystal form of compound 1 is obtained by stirring compound 1 in acetone at room temperature, adding an antisolvent to form an oil, suspending and stirring at temperature to precipitate a solid, and then drying it.

[0147] Preferably, the free B crystal form of compound 1 is obtained by stirring an amorphous sample of compound 1 in acetone at room temperature for about 1 day, then adding the antisolvent n-heptane to form an oil, stirring at room temperature for another day, then cycling and stirring at 5-50°C for about 1 day to precipitate a solid, and then vacuum drying at room temperature overnight.

[0148] In some embodiments, the free C crystal form of compound 1 is obtained by stirring compound 1 in ethyl acetate at room temperature and then at low temperature, adding an antisolvent to form a gel, then precipitating a solid by temperature cycling and stirring, and finally drying it under vacuum at room temperature.

[0149] Preferably, the free C crystal form of compound 1 is obtained by stirring an amorphous sample of compound 1 in ethyl acetate at room temperature for about 2 days, then stirring at about 5°C for about 3 days to obtain a clear solution, then adding the antisolvent n-heptane dropwise to form a gel, then circulating and stirring at 5-50°C to precipitate a solid, and then drying under vacuum at room temperature for about 3 days.

[0150] In some embodiments, the phosphate A crystal form of compound 1 is obtained by stirring an amorphous sample of compound 1 and phosphoric acid in acetone at room temperature, followed by vacuum drying at room temperature.

[0151] Preferably, the mixture is stirred at room temperature for about 2 days and then vacuum dried at room temperature overnight.

[0152] In some embodiments, the phosphate B crystal form of compound 1 is obtained by dissolving the amorphous sample of compound 1 in acetone, adding phosphoric acid, stirring magnetically at low temperature to precipitate a solid, centrifuging to separate the solid, and vacuum drying at room temperature.

[0153] Preferably, the mixture is magnetically stirred at 5°C and vacuum dried at room temperature for about 2 days.

[0154] In some embodiments, the succinate A crystal form of compound 1 is obtained by magnetically stirring an amorphous sample of compound 1 and succinic acid in ethyl acetate at room temperature, centrifuging to separate the solid, and then vacuum drying at room temperature.

[0155] Preferably, the mixture is magnetically stirred at room temperature for about 2 days and then vacuum dried at room temperature overnight.

[0156] In some embodiments, the succinate B crystal form of compound 1 is obtained by suspending and stirring the succinate A crystal form in n-BuOH / MTBE (1:1, v / v) at temperature cycling (5-50°C) and then drying the solid at room temperature under vacuum.

[0157] In some embodiments, the hippurate A crystal form of compound 1 is obtained by dissolving an amorphous sample of compound 1 and hippuric acid in acetone, stirring at room temperature, adding an antisolvent, stirring at room temperature, precipitating a solid, centrifuging the solid, and vacuum drying at room temperature.

[0158] Preferably, the amorphous sample of compound 1 and hippuric acid are added to acetone and stirred at room temperature for about 3 hours. The antisolvent n-Heptane is added dropwise over about 1 hour. After stirring at room temperature for about 6 hours, a solid is precipitated. The solid is then separated by centrifugation and dried under vacuum at room temperature overnight.

[0159] In some embodiments, the glycolate A crystal form of compound 1 is obtained by stirring an amorphous sample of compound 1 and glycolic acid in an aqueous solution of IPA at room temperature, followed by vacuum drying of the solid at room temperature.

[0160] Preferably, the glycolate A crystal form of compound 1 is obtained by stirring the amorphous sample of compound 1 and glycolic acid in IPA / H2O (19:1, v / v) at room temperature for about 2 days, followed by vacuum drying of the solid at room temperature overnight.

[0161] In some embodiments, the maleate A crystal form of compound 1 is obtained by adding an amorphous sample of compound 1 and maleic acid to acetone, stirring magnetically at room temperature for about 3 days, separating the solid, and then vacuum drying at room temperature.

[0162] In some embodiments, the maleate B crystal form of compound 1 is obtained by adding an amorphous sample of compound 1 to an ethyl acetate solution, then adding maleic acid, stirring magnetically at room temperature for about 3 days until it becomes clear, transferring it to 5°C and stirring until it remains clear, adding the antisolvent n-Heptane to form an oil or gel, transferring it to 50-5°C and stirring cyclically until a solid precipitates, and drying and crystallizing.

[0163] 4. Application of the crystal form of the present invention

[0164] Compound 1 described in this invention can reduce or inhibit the activity of 3CLpro, and can reduce or inhibit the replication of coronaviruses. Therefore, the crystal form of this invention can be used as a broad-spectrum inhibitor of coronavirus 3CLpro for the treatment of infections caused by coronaviruses, including SARS-CoV-2, SARS-CoV, and MERS-CoV.

[0165] For pharmaceutical applications, the crystal forms of the present invention can be administered to patients in need in any standard pharmaceutical composition form. The pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable carrier, which may be selected from excipients and mediators. The pharmaceutically acceptable carriers used in the present invention may be selected from any and all suitable solvents, diluents, mediators, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants. Those skilled in the art can select suitable carriers from known pharmaceutically acceptable carriers for use in the present invention according to the desired specific dosage form. For example, Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York, disclose various carriers for formulating pharmaceutical compositions and known techniques for preparing them. Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), mixtures of metaglycerides of saturated vegetable fatty acids, water, salts, and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxylic acid). Sodium methylcellulose, ethylcellulose, and cellulose acetate), tragacanth powder, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer, non-toxic and compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavoring agents, aroma agents, preservatives, and antioxidants.

[0166] The pharmaceutical compositions of the present invention can be administered to patients in need via any convenient route. For example, the crystal form of compound 1 of the present invention, its pharmaceutically usable salt, or the crystal form of the salt can be formulated into a corresponding pharmaceutical preparation such that the preparation can be administered, for example, via oral, parenteral, sublingual, topical, rectal, nasal, sublingual, vaginal, transdermal, patch, pump, or via an implanted reservoir.

[0167] For oral administration, any suitable pharmaceutical carrier commonly used in the preparation of solid dosage forms can be used, employing formulation techniques known in the art, to formulate the crystal form of the present invention into solid dosage forms, such as syrups, suspensions, emulsions, tablets, capsules, and lozenges. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, cellulose, etc. Alternatively, any suitable pharmaceutical carrier commonly used in the preparation of liquid dosage forms can be used, employing formulation techniques known in the art, to formulate the crystal form of the present invention into a liquid dosage form. The liquid dosage form of the present invention may also contain one or more suspending agents, preservatives, flavoring agents, or coloring agents.

[0168] For parenteral administration, any suitable drug carrier commonly used in the preparation of parenteral formulations can be used. Using formulation techniques known in the art, the crystal form of the present invention can be formulated into a formulation suitable for parenteral administration, such as sterile injections, lyophilized powders, transdermal patches, aerosols, oral and nasal inhalers, and suppositories. Parenteral administration routes include intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and local routes. Parenteral administration can be continuous infusion over a selected time period.

[0169] To better understand the content of this invention, further explanation will be provided below with reference to specific embodiments. However, the specific implementation methods are not intended to limit the content of this invention.

[0170] All solvents used in the following examples are commercially available and can be used without further processing, unless otherwise stated.

[0171] The following abbreviations are used in this invention:

[0172] v / v represents the volume ratio;

[0173] ACN stands for acetonitrile;

[0174] Acetone stands for acetone;

[0175] MeOH represents methanol;

[0176] EtOAc represents ethyl acetate;

[0177] IPA stands for isopropanol;

[0178] n-Heptane represents n-heptane;

[0179] n-BuOH represents n-butanol;

[0180] MTBE stands for methyl tert-butyl ether;

[0181] XRPD stands for X-ray powder diffraction.

[0182] TGA stands for thermogravimetric analysis;

[0183] DSC stands for Differential Scan Calorimetry;

[0184] DVS stands for Dynamic Moisture Adsorption;

[0185] UPLC stands for Ultra-High Performance Liquid Chromatography;

[0186] SGF represents simulated gastric juice;

[0187] FaSSIF represents simulated intestinal fluid during a fasting state;

[0188] FeSSIF represents the intestinal fluid simulation during the feeding state.

[0189] Example 1: Preparation of Compound 1

[0190]

[0191] Intermediate I-1: (S)-3-((4-chloro-2-(methoxycarbonyl)-6-nitrophenyl)amino)-4,4-difluoropiperidine-1-carboxylic acid tert-butyl ester

[0192] To a solution of methyl 5-chloro-2-fluoro-3-nitrobenzene (3.00 g, 12.82 mmol) in N,N-dimethylformamide (30 mL), tert-butyl (S)-3-amino-4,4-difluoropiperidine-1-carboxylate (3.55 g, 15.04 mmol) and N,N-diisopropylethylamine (8.27 g, 64.10 mmol) were added, and the reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with saturated brine (80 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in petroleum ether as eluent (ethyl acetate: petroleum ether = 1:3) to give (S)-3-((4-chloro-2-(methoxycarbonyl)-6-nitrophenyl)amino)-4,4-difluoropiperidin-1-carboxylic acid tert-butyl ester (2.00 g, 4.44 mmol, yield 33%) as a yellow solid. LC-MS (ESI) (M+H) + =450.1

[0193] Intermediate I-2: (S)-2-((1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)amino)-5-chloro-3-nitrobenzoic acid

[0194] Sodium hydroxide (0.13 g, 3.33 mmol) was added to a methanol / water (v / v 5:1) solution of (S)-3-((4-chloro-2-(methoxycarbonyl)-6-nitrophenyl)amino)-4,4-difluoropiperidin-1-carboxylic acid tert-butyl ester (1.00 g, 2.22 mmol) at 25 °C and reacted for 2 h. The reaction mixture was evaporated to dryness, water was added, and the pH was adjusted to 4. The solvent was removed under vacuum, and water (10 mL) was added, followed by extraction with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give (S)-2-((1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)amino)-5-chloro-3-nitrobenzoic acid (400 mg, 0.92 mmol, yield 41%) as a yellow solid. LC-MS(ESI)(M+H) + =436.1

[0195] Intermediate I-3: (S)-3-((4-chloro-2-(methylcarbamoyl)-6-nitrophenyl)amino)-4,4-difluoropiperidine-1-carboxylic acid tert-butyl ester

[0196] At 25 °C, methylamine hydrochloride (52 mg, 0.92 mmol), triethylamine (202 mg, 0.92 mmol), and propylphosphonic anhydride (T3P, 292 mg, 0.92 mmol, 50% ethyl acetate solution) were added to a solution of (S)-2-((1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)amino)-5-chloro-3-nitrobenzoic acid (400 mg, 0.92 mmol) in dichloromethane (5 mL), and the reaction was carried out for 18 hours. Water (10.0 mL) was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in dichloromethane as eluent (methanol:dichloromethane = 1:50) to give (S)-3-((4-chloro-2-(methylcarbamoyl)-6-nitrophenyl)amino)-4,4-difluoropiperidin-1-carboxylic acid tert-butyl ester (170 mg, 0.37 mmol, yield 39%) as a yellow solid. LC-MS (ESI) (M+H) + =449.1

[0197] Intermediate I-4: (S)-5-chloro-2-((4,4-difluoropiperidin-3-yl)amino)-N-methyl-3-nitrobenzamide

[0198] At 25 °C, a solution of dioxane in hydrochloric acid (2 mL, 23.47 mmol) was added to a solution of (S)-3-((4-chloro-2-(methylcarbamoyl)-6-nitrophenyl)amino)-4,4-difluoropiperidin-1-carboxylic acid tert-butyl ester (170 mg, 0.37 mmol) in dichloromethane (1 mL), and the reaction was allowed to proceed for 2 h. The reaction solution was concentrated by rotary evaporation to give (S)-5-chloro-2-((4,4-difluoropiperidin-3-yl)amino)-N-methyl-3-nitrobenzamide (120 mg, 0.34 mmol, yield 89%) as a yellow solid. LC-MS (ESI) (M+H) + =349.1

[0199] Compound 1: (S)-5-chloro-2-((4,4-difluoro-1-(1,6-naphthidium-8-carbonyl)piperidin-3-yl)amino)-N-methyl-3-nitrobenzamide

[0200] At 25°C, N,N-diisopropylethylamine (184 mg, 1.43 mmol), 1,6-naphthyl-8-carboxylic acid (50 mg, 0.29 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 11 mg, 0.03 mmol) were added to a solution of (S)-5-chloro-2-((4,4-difluoropiperidin-3-yl)amino)-N-methyl-3-nitrobenzamide (100 mg, 0.28 mmol) in N,N-dimethylformamide (2 mL), and reacted for 2 h. The reaction mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 3), dried over sodium sulfate, and concentrated to obtain a crude product. This crude product was purified by preparative high-performance liquid chromatography (HPLC) to give (S)-5-chloro-2-((4,4-difluoro-1-(1,6-naphthidium-8-carbonyl)piperidin-3-yl)amino)-N-methyl-3-nitrobenzamide (12 mg, 0.03 mmol, yield 9%) as a yellow solid. LC-MS (ESI) (M+H) + =505.12; 1 H NMR(400MHz,DMSO-d6)δ9.54(d,J=19.9Hz,1H),9.17(s,1H),9.03-8.51(m, 3H),8.22-7.51(m,4H),4.55-3.05(m,5H),2.95-2.61(m,3H),2.26(s,2H).

[0201] Example 2: Preparation and characterization of the free state A crystal form of compound 1

[0202] The preparation steps for the free state A crystal form of compound 1 are as follows:

[0203] (1) Weigh about 400 mg of the free amorphous sample of compound 1 into a glass bottle, add IPA / H2O (19:1, v / v) solvent, and prepare a solution of 40 mg / mL.

[0204] (2) Stir magnetically at room temperature for about 3 days, then centrifuge to separate the solid.

[0205] (3) The obtained solid was dried under vacuum at room temperature overnight.

[0206] The diffraction peak data of the free A crystal form of compound 1 are shown in Table 1.

[0207] The XRPD results of the free A-state crystal form of compound 1 are shown in [reference needed]. Figure 1A .

[0208] In some embodiments, the TGA results of the free A-phase crystal form of compound 1 are shown in [the figure]. Figure 1B The sample lost approximately 11.37% of its weight when heated to approximately 150°C.

[0209] In some embodiments, the DSC results of the free state A crystal form of compound 1 are shown in [the figure]. Figure 1C There is an endothermic peak at approximately 98.2℃.

[0210] Table 1: XRPD diffraction peak data of the free A-state crystal form of compound 1

[0211]

[0212]

[0213] Example 3: Preparation and characterization of the free B-phase crystal form of compound 1

[0214] The preparation steps for the free B crystal form of compound 1 are as follows:

[0215] (1) Weigh 299.8 mg of free amorphous sample of compound 1 into a 20 mL glass bottle, add 3 mL of Lacetone, stir at room temperature for 1 day and then clarify.

[0216] (2) Add 4 mL of n-heptane dropwise while stirring to form an oil. Stir at room temperature for 1 day, then switch to temperature-controlled circulating suspension stirring for 1 day to precipitate solid.

[0217] (3) The solid was separated by centrifugation and vacuum dried overnight at room temperature. (87.5%)

[0218] The diffraction peak data of the free B crystal form of compound 1 are shown in Table 2.

[0219] The XRPD pattern of the free B crystal form of compound 1 is shown below. Figure 2A .

[0220] The TGA results for the free B-crystal form of compound 1 are shown in [reference needed]. Figure 2B When the sample was heated to approximately 150°C, it lost about 11.87% of its weight.

[0221] The DSC results for the free B-phase crystal form of compound 1 are shown in the figure. Figure 2C There are three endothermic signals at approximately 73.9°C, approximately 116.7°C, and approximately 144.2°C.

[0222] Table 2: XRPD diffraction peak data of the free B-type crystal form of compound 1

[0223]

[0224]

[0225] Example 4: Preparation and characterization of the free C crystal form of compound 1

[0226] The steps for preparing the free C crystal form of compound 1 are as follows:

[0227] (1) Approximately 400 mg of the free amorphous sample of compound 1 was stirred in EtOAc at room temperature for 2 days.

[0228] (2) A clear solution was obtained after stirring at 5℃ for 3 days.

[0229] (3) The gel is formed after adding the antisolvent n-Heptane.

[0230] (4) After being transferred to a temperature of 5-50℃ and stirred, solids are precipitated.

[0231] (5) Vacuum dry at room temperature for 3 days.

[0232] The diffraction peak data of the free C crystal form of compound 1 are shown in Table 3.

[0233] The XRPD results for the free C crystal form of compound 1 are shown in [reference needed]. Figure 3A .

[0234] The TGA results for the free C crystal form of compound 1 are shown in [reference needed]. Figure 3B The sample lost approximately 8.32% of its weight when heated to approximately 130°C.

[0235] The DSC results for the free C crystal form of compound 1 are shown in [reference needed]. Figure 3C There is an endothermic peak at approximately 110.5℃.

[0236] Table 3: XRPD diffraction peak data of the free C crystal form of compound 1

[0237]

[0238]

[0239] Example 5: Preparation and characterization of phosphate A crystal form of compound 1

[0240] The steps for preparing the phosphate A crystal form of compound 1 are as follows:

[0241] (1) Approximately 400 mg of the free amorphous sample of compound 1 and an equimolar amount of phosphoric acid were stirred in acetone at room temperature for 2 days.

[0242] (2) Dry the solid under vacuum at room temperature overnight.

[0243] The diffraction peak data of phosphate A crystal form of compound 1 are shown in Table 4.

[0244] XRPD results for phosphate A crystal form of compound 1 are shown in [Figure number missing]. Figure 4A .

[0245] The TGA results for the phosphate A crystal form of compound 1 are shown in [Figure number missing]. Figure 4B The sample lost approximately 3.79% of its weight when heated to approximately 120°C, and approximately 3.23% of its weight when heated further to approximately 180°C.

[0246] DSC results for phosphate A crystal form of compound 1 are shown in [Figure number missing]. Figure 4C There are two endothermic signals at approximately 77.2°C and approximately 142.0°C.

[0247] Table 4: XRPD diffraction peak data of phosphate A crystal form of compound 1

[0248]

[0249]

[0250] Example 6: Preparation and characterization of the B phosphate crystal form of compound 1

[0251] Preparation of the B phosphate crystal form of compound 1

[0252] (1) Weigh 100.0 mg of free amorphous sample of compound 1 into a 3 mL glass bottle and add 2 mL of Acetone to dissolve it.

[0253] (2) Transfer 7.9 μL of phosphoric acid to the above solution and stir magnetically at 5°C to precipitate solid.

[0254] (3) The solid was separated by centrifugation and dried under vacuum at room temperature for 2 days. (71.1%)

[0255] The diffraction peak data of phosphate B crystal form of compound 1 are shown in Table 5.

[0256] XRPD results for the phosphate B crystal form of compound 1 are shown in [Figure number missing]. Figure 5A .

[0257] The TGA results for the phosphate B crystal form of compound 1 are shown in [Figure number missing]. Figure 5B The phosphate B crystal form of compound 1 loses approximately 4.95% of its weight at approximately 150°C.

[0258] DSC results for the B phosphate crystal form of compound 1 are shown in [Figure number missing]. Figure 5C There are two endothermic signals at approximately 65.4°C and approximately 158.3°C.

[0259] Table 5: XRPD diffraction peak data of phosphate B crystal form of compound 1

[0260]

[0261]

[0262] Example 7: Preparation and characterization of succinate A crystal form of compound 1

[0263] The preparation steps for the succinate A crystal form of compound 1 are as follows:

[0264] (1) Weigh 299.7 mg of free amorphous sample of compound 1 and 70.5 mg of succinic acid, and add 6 mL of ethyl acetate.

[0265] (2) Stir magnetically at room temperature for about 2 days.

[0266] (3) The solid was separated by centrifugation and dried under vacuum at room temperature to obtain crystals. (Yield 46.5%)

[0267] The diffraction peak data of the succinate A crystal form of compound 1 are shown in Table 6.

[0268] XRPD results for succinate A of compound 1 are shown in the figure. Figure 6A .

[0269] TGA results for succinate A crystal form of compound 1 are shown in [Figure number missing]. Figure 6B The sample lost approximately 4.75% of its weight when heated to approximately 150°C.

[0270] DSC results for succinate A crystal form of compound 1 are shown in [Figure number missing]. Figure 6C There are two endothermic signals at approximately 53.0°C and approximately 123.6°C.

[0271] Table 6: XRPD diffraction peak data of succinate A crystal form of compound 1

[0272]

[0273] Example 8: Preparation and characterization of the succinate B crystal form of compound 1

[0274] The preparation steps for the succinate B crystal form of compound 1 are as follows:

[0275] (1) Weigh about 400 mg of succinate A crystal form of compound 1 and suspend and stir it in n-BuOH / MTBE (1:1, v / v) at temperature cycling (5-50℃).

[0276] (2) Solid crystallization by vacuum drying at room temperature.

[0277] The diffraction peak data of the succinate B crystal form of compound 1 are shown in Table 7.

[0278] The XRPD results for the succinate B crystal form of compound 1 are shown in [reference needed]. Figure 7A .

[0279] The TGA results for the succinate B crystal form of compound 1 are shown in [reference needed]. Figure 7B When heated to approximately 120°C, the weight loss is approximately 7.06%, and when heated further to 240°C, the weight loss is approximately 10.32%.

[0280] The DSC results for the succinate B crystal form of compound 1 are shown in [reference needed]. Figure 7C There are three endothermic signals at approximately 131.8°C, approximately 160.9°C, and approximately 229.3°C.

[0281] Table 7: XRPD diffraction peak data of succinate B crystal form of compound 1

[0282]

[0283] Example 9: Preparation and characterization of the hippurate A crystal form of compound 1

[0284] The preparation steps for the hippurate A crystal form of compound 1 are as follows:

[0285] (1) Weigh about 300 mg of free amorphous sample of compound 1 and about 106.8 mg of hippuric acid into a 20 mL glass bottle, add about 7.5 mL of Lacetone to dissolve, and stir at room temperature for about 3 hours.

[0286] (2) Add 12 mL of antisolvent n-Heptane within 1 hour, and continue stirring at room temperature for about 6 hours to precipitate solid.

[0287] (3) The solid was separated by centrifugation and vacuum dried overnight at room temperature. (Yield approximately 60.2%)

[0288] The diffraction peak data of the hippurate A crystal form of compound 1 are shown in Table 8.

[0289] The XRPD results for the hippurate A crystal form of compound 1 are shown in [reference needed]. Figure 8A .

[0290] The TGA results for the hippurate A crystal form of compound 1 are shown in [the table below]. Figure 8B The sample lost approximately 3.36% of its weight when heated to approximately 150°C.

[0291] The DSC results for the hippurate A crystal form of compound 1 are shown below. Figure 8C There is an endothermic signal at approximately 132.4°C.

[0292] Table 8: XRPD diffraction peak data of hippurate A crystal form of compound 1

[0293]

[0294]

[0295] Example 10: Preparation and characterization of the glycolate A crystal form of compound 1

[0296] The steps for preparing the glycolate A crystal form of compound 1 are as follows:

[0297] (1) Approximately 400 mg of free amorphous sample of compound 1 and an equimolar amount of glycolic acid were stirred in IPA / H2O (19:1, v / v) at room temperature for about 2 days.

[0298] (2) The solid was obtained by vacuum drying at room temperature overnight.

[0299] The diffraction peak data of the glycolate A crystal form of compound 1 are shown in Table 9.

[0300] The XRPD results for the glycolate A crystal form of compound 1 are shown in the figure. Figure 9A .

[0301] The TGA of the glycolate A crystal form of compound 1 is shown in [reference needed]. Figure 9B The sample lost approximately 9.07% of its weight when heated to approximately 140°C.

[0302] The DSC results for the glycolate A crystal form of compound 1 are shown below. Figure 9C There is an endothermic peak at approximately 95.7℃.

[0303] Table 9: XRPD diffraction peak data of the glycolate A crystal form of compound 1

[0304]

[0305]

[0306] Example 11: Preparation and characterization of maleate A crystal form of compound 1

[0307] The preparation steps for the maleate A crystal form of compound 1 are as follows:

[0308] (1) Prepare an acetone solution of approximately 40 mg / mL of the free amorphous sample of compound 1.

[0309] (2) Add 0.5 mL of the above solution and an equimolar amount of maleic acid ligand to the HPLC vial.

[0310] (3) After stirring magnetically at room temperature (about 1000 rpm) for about 3 days, the solids were separated.

[0311] (4) Vacuum drying and crystallization.

[0312] The diffraction peak data of maleate A crystal form of compound 1 are shown in Table 10.

[0313] The XRPD results for the maleate A crystal form of compound 1 are shown in [reference needed]. Figure 10A .

[0314] The TGA results for the maleate A crystal form of compound 1 are shown below. Figure 10B The sample lost approximately 3.85% of its weight when heated to approximately 100°C.

[0315] The DSC results for the maleate A crystal form of compound 1 are shown in [reference needed]. Figure 10C There are two endothermic signals at approximately 53.7°C and approximately 130.5°C.

[0316] Table 10: XRPD diffraction peak data of maleate A crystal form of compound 1

[0317]

[0318] Example 12: Preparation and characterization of maleate B crystal form of compound 1

[0319] The preparation steps for the maleate B crystal form of compound 1 are as follows:

[0320] (1) Prepare an ethyl acetate solution of approximately 40 mg / mL of the free amorphous sample of compound 1.

[0321] (2) Add 0.5 mL of the above solution and an equimolar amount of maleic acid ligand to the HPLC vial, and stir magnetically at room temperature for about 3 days until the solution is clear.

[0322] (3) After being transferred to 5°C and stirred, it remains clear. After adding the antisolvent n-Heptane, it becomes an oil or a gel.

[0323] (4) After transferring to a temperature of 50-50℃ and stirring continuously, solids precipitate out and are dried to crystallize.

[0324] The diffraction peak data of maleate B crystal form of compound 1 are shown in Table 11.

[0325] The XRPD results for maleate crystal form B are shown below. Figure 11A .

[0326] The TGA results for maleate crystal form B are shown below. Figure 11B The sample lost approximately 1.89% of its weight when heated to approximately 100°C.

[0327] The DSC results for maleate crystal form B are shown below. Figure 11C There are three endothermic signals at approximately 52.3°C, approximately 74.3°C, and approximately 134.5°C (peak temperature).

[0328] Table 11: XRPD diffraction peak data of maleate B crystal form of compound 1

[0329]

[0330] Example 13: Dynamic Solubility Test

[0331] The solubility of the free B crystal form, phosphate B crystal form, hippurate A crystal form, and succinate A crystal form of compound 1 obtained in Examples 3, 6, 7, and 9 was tested in H2O and biological solvents (simulated gastric juice (SGF), fasting state simulated intestinal juice (FaSSIF), and feeding state simulated intestinal juice (FeSSIF)) for 1, 2, 4, and 24 hours.

[0332] The specific steps of the test are as follows:

[0333] 1) Weigh approximately 40 mg of the corresponding crystal form into 5 mL glass vials, and add 4 mL of the corresponding medium (H2O, SGF, FaSSIF, and FeSSIF).

[0334] 2) Mix at 25 rpm in a rotary incubator at 37°C. Sampling points were taken at 1, 2, 4, and 24 hours.

[0335] 3) Take about 0.8 mL of the suspension at each sampling point into a centrifuge tube and centrifuge (12000 rpm, 5 min, 37℃).

[0336] 4) The supernatant was filtered through a PTFE membrane (0.45 μm pore size). The filtrate was used to test solubility and pH, and the solid was used to measure XRPD.

[0337] Test results:

[0338] Table 12: Results of Dynamic Solubility Assessment

[0339]

[0340] S: Solubility (mg / mL), in free state.

[0341] FC: Crystal form transformation.

[0342] The results show that:

[0343] 1) In H2O, the solubility of all three salts was highest after 1 hour, and decreased after 2, 4, and 24 hours. Among them, the solubility of succinate crystal form A (1.3 mg / mL) was higher than that of the other salt forms and the free crystal form B at 1 / 2 hour.

[0344] 2) In SGF, the solubility of the three salts was high at 1 / 2 / 4 hours and decreased at 24 hours. Among them, the solubility of succinate crystal form A (3.0 mg / mL) at 1 / 2 / 4 hours was higher than that of the other salt forms and the free crystal form B.

[0345] 3) In FaSSIF and FeSSIF, hippurate crystal form A and succinate crystal form A have the highest solubility at 1 / 2 hour, and the solubility decreases at 4 / 24 hours. The phosphate crystal form B has a slightly higher 24-hour solubility than other salt forms and free crystal form B.

[0346] 4) XRPD results showed that hippurate crystal form A and succinate crystal form A underwent disproportionation in all four media; phosphate crystal form B underwent disproportionation in H2O and SGF, and showed no significant change in crystal form in FaSSIF and FeSSIF (the crystal density increased, and an additional diffraction peak was observed); free crystal form B did not undergo crystal transformation in any media.

[0347] Example 14: Hygroscopicity Test

[0348] In accordance with the guidelines for drug hygroscopicity testing in the 2020 edition of the Chinese Pharmacopoeia, the crystal forms in Examples 2-12 were subjected to DVS testing to determine their hygroscopicity.

[0349] Table 13: Results of Hygroscopicity Test

[0350]

[0351] DVS results showed that all tested crystal forms were almost hygroscopic, which was a significant advantage over the free amorphous samples, and no crystal form transformation occurred after DVS testing.

[0352] Example 15: Solid-state stability test

[0353] Appropriate amounts of the crystal form samples from Examples 3, 6, 7, and 9 were weighed and placed in an open environment for 7–10 days under conditions of 25°C / 60%RH and 40°C / 75%RH, respectively, for stability experiments. The solid samples separated under different conditions were evaluated for physical stability by XRPD testing of crystal form and for chemical stability by UPLC testing of purity.

[0354] Table 14: Solid-state stability test results

[0355]

[0356] Solid-state stability results show:

[0357] XRPD results showed that no crystal form transformation occurred in phosphate crystal form B, succinate crystal form A, and free crystal form B under both evaluation conditions.

[0358] UPLC results showed that neither succinate crystal form A nor free crystal form B showed a significant decrease in purity under either evaluation condition, while phosphate crystal form B and hippurate crystal form A showed a slight decrease in purity under both evaluation conditions.

[0359] Considering hygroscopicity, solid stability, and dynamic solubility, phosphate crystal form B, succinate crystal form A, hippurate crystal form A, and free crystal form B are the dominant crystal forms and salt crystals, showing significant potential for medicinal use.

[0360] Instruments and methods

[0361] 1. X-ray powder diffraction (or "powder X-ray diffraction", XRPD method)

[0362] XRPD results were acquired using an X'Pert3 and an Empyrean X-ray powder diffractometer, and the scanning parameters are shown in Table 15.

[0363] Table 15: XRPD Test Parameters

[0364]

[0365] 2. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0366] TGA results were acquired on a TA Discovery 5500 thermogravimetric analyzer, while DSC and mDSC results were acquired on a TA Discovery 2500 differential scanning calorimeter. The test parameters are listed in Tables 16 and 17.

[0367] Table 16: TGA and DSC Test Parameters

[0368]

[0369] Table 17: mDSC Test Parameters

[0370]

[0371] 3. Dynamic Moisture Adsorption (DVS)

[0372] Dynamic vapor sorption (DVS) curves were acquired using a DVS Intrinsic from SMS (Surface Measurement Systems). Relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg(NO3)2, and KCl. DVS test parameters are listed in Table 18.

[0373] Table 18: DVS Test Parameters

[0374]

[0375]

[0376] 4. Ultra-high performance liquid chromatography (HPLC)

[0377] Purity, solubility, and molar ratio were measured using a Waters H-Class UPLC ultra-high performance liquid chromatograph, and the analytical conditions are shown in Tables 19 and 20.

[0378] Table 19: Ultra-high performance liquid chromatography (UHPLC) test conditions for purity testing

[0379]

[0380] Table 20: Ultra-high performance liquid chromatography test conditions for solubility and molar ratio testing

[0381]

[0382]

[0383] Example 16: In vivo pharmacokinetic experiment in CD1 mice

[0384] Using male CD1 mice as test animals, the pharmacokinetic behavior of the compound of this invention in male CD1 mice was studied.

[0385] Test samples: amorphous sample of reference compound 1, free crystal form B of compound 1, succinate crystal form A of compound 1, and phosphate crystal form B of compound 1.

[0386] experimental animals

[0387] Species: Male CD1 mice (3 mice / group)

[0388] Grade: SPF, Weight: Approx. 20-30g, Age: 6-9 weeks

[0389] Male CD1 mice were administered the test solution by gavage at a dose of 50 mg / kg and a volume of 10 mL / kg.

[0390] Preparation of test solution: The test sample is dissolved in solvent (5% E-TPGS purified water).

[0391] Control group: The amorphous XRPD and TGA / mDSC chromatograms of compound 1 are shown below. Figure 12A and Figure 12B .

[0392] Experimental group: Free crystal form B of compound 1, succinate crystal form A of compound 1, phosphate crystal form B of compound 1

[0393] At the set blood collection time points of 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after drug administration, approximately 0.025–0.03 mL of whole blood (anticoagulated with EDTA-K2) was collected from the dorsal vein of the mouse paw. The blood was placed under wet ice conditions and centrifuged at 4000g, 4℃, and for 5 min within 30 min after collection to separate the plasma and transfer it to the test tube.

[0394] The main pharmacokinetic parameters were calculated using WinNonlin (Phoenix WinNonlin, version 6.3). The pharmacokinetic parameters and results are shown in Table 21.

[0395] Table 21 Pharmacokinetic Experiment Results

[0396]

[0397] The results showed that, compared with the amorphous sample in the control group, the free crystal form B, succinate crystal form A, and phosphate crystal form B of compound 1 had significantly higher exposure levels in mice and also had longer half-lives, exhibiting good pharmacokinetic properties.

Claims

1. The crystal form of a compound of formula I, or the crystal form of its pharmaceutically acceptable salt.

2. The crystal form of claim 1, wherein the salt is a salt formed by the compound and an acid, wherein the acid is selected from phosphoric acid, succinic acid, hippuric acid, glycolic acid, and maleic acid.

3. The crystal form of the salt of the compound according to claim 1, characterized in that... The compound forms a salt with an acid in a molar ratio of 1:0.5 to 2.

4. The crystal form of the compound according to claim 1, characterized in that: The XRPD pattern of the crystal form of the compound has diffraction peaks at 2θ angles of approximately 6.74, 9.71, 14.54, 20.19, 20.92, and 23.

02.

5. The crystal form of the compound according to claim 1, wherein the XRPD pattern of the crystal form of the compound has diffraction peaks at 2θ angles of approximately 6.89, 9.74, 14.72, 19.49, 22.5, and 25.

83.

6. The crystal form of the compound according to claim 1, wherein the XRPD pattern of the crystal form of the compound has diffraction peaks at 2θ angles of approximately 10.64, 15.12, 21.32, and 27.

75.

7. The crystal form of the phosphate of the compound of claim 1, wherein the XRPD pattern of the crystal form of the phosphate of the compound has diffraction peaks at 2θ angles of approximately 5.57, 8.40, 12.67, 18.25, and 21.

08.

8. The crystal form of the phosphate of the compound of claim 1, wherein the XRPD pattern of the crystal form of the phosphate of the compound has diffraction peaks at 2θ angles of approximately 8.48, 13.06, 17.26, 18.76, and 21.

50.

9. The crystal form of the succinate of the compound of claim 1, wherein the XRPD pattern of the crystal form of the succinate of the compound has diffraction peaks at 2θ angles of approximately 4.70, 6.97, 8.17, 11.03, and 19.

84.

10. The crystal form of the succinate of the compound of claim 1, wherein the XRPD pattern of the crystal form of the succinate of the compound has diffraction peaks at 2θ angles of approximately 12.29, 13.61, 24.67, and 27.

39.

11. The crystalline form of the hippurate of the compound of claim 1, wherein the XRPD pattern of the crystalline form of the hippurate of the compound has diffraction peaks at 2θ angles of approximately 4.97, 8.31, 10.43, 12.39, 16.93, and 21.

75.

12. The crystal form of the glycolate of the compound of claim 1, wherein the XRPD pattern of the crystal form of the glycolate of the compound has diffraction peaks at 2θ angles of approximately 6.76, 9.68, 20.78, and 23.

27.

13. The maleate crystal form of the compound of claim 1, wherein the XRPD pattern of the maleate crystal form of the compound has diffraction peaks at 2θ angles of approximately 4.70, 5.01, 6.97, 8.10, and 11.

12.

14. The maleate crystal form of the compound of claim 1, wherein the XRPD pattern of the maleate crystal form of the compound has diffraction peaks at 2θ angles of approximately 10.96, 15.05, 22.63, 23.03, and 25.

78.

15. A composition wherein the crystal form according to any one of claims 1-14 accounts for more than 50% by mass of the composition, preferably more than 75%, more preferably more than 90%, and most preferably more than 95%.

16. A pharmaceutical composition comprising the crystal form according to any one of claims 1-14 and at least one pharmaceutically acceptable carrier.

17. The use of the crystal form according to any one of claims 1-14, the crystal form composition according to claim 15, or the pharmaceutical composition according to claim 16 in the preparation of a medicament for treating diseases or symptoms caused by coronaviruses; preferably, the disease or symptoms are selected from COVID-19, SARS, and MERS.

18. The use of the crystal form according to any one of claims 1-14, the crystal form composition according to claim 15, or the pharmaceutical composition according to claim 16 in treating diseases or symptoms caused by coronaviruses; preferably, the disease or symptoms are selected from COVID-19, SARS, and MERS.

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