Crystalline forms of ketoamide derivatives and their preparation methods

Abstract

The present invention relates to a crystalline form of a ketoamide derivative and a method for preparing the same. A series of crystalline forms of this compound have good drug development potential (stability, flowability, compressibility, solubility, bioavailability, etc.) and provide various raw material options for subsequent pharmaceutical development.

Description

[Technical Field]

[0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to a series of crystalline forms of ketoamide derivatives and methods for preparing the same, as well as drug substances and pharmaceutical compositions containing the crystalline forms. [Background technology]

[0002] SARS-CoV-2 (acute respiratory syndrome coronavirus 2), along with SARS-CoV-1 and MERS-CoV, is a highly pathogenic, widespread zoonotic virus belonging to the Coronaviridae family. These three viruses, unlike several other coronaviruses, such as HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoVHKU1, can cause severe respiratory illness. The etiological agent of COVID-19 is SARS-CoV-2, a member of the Coronaviridae family, which causes respiratory, liver, intestinal, and neurological diseases in mammals. Humans infected with SARS-CoV-2 exhibit a variety of clinical symptoms, primarily including fever, respiratory symptoms, cough, and shortness of breath. Prolonged infection can lead to severe pneumonia and serious complications, including respiratory failure, shock, and organ failure. Some patients with mild symptoms or who have been discharged from the hospital have even experienced relapse after recovery. What's more, this virus is not only highly contagious, but can also be transmitted through asymptomatic, symptomatic, and pre-symptomatic infections.

[0003] During coronavirus infection in the host, the main protease (M PRO, also known as 3CLPRO), an enzyme essential for viral replication, is a type of cysteine ​​hydrolase that can cleave the polyprotein at multiple sites within the virus to generate multiple active functional proteins. The sequence of 3CLPRO is highly conserved among coronaviruses and is crucial for the normal function of coronaviruses. Inhibition of 3CLPRO not only effectively kills coronaviruses but also alleviates immune imbalances within infected host cells. This makes 3CLPRO one of the key targets in the development of broad-spectrum anti-coronavirus drugs, and 3CLPRO inhibitors are attractive targets in the field of antiviral chemotherapy.

[0004] The following compounds are 3CLPRO inhibitors that have been reported to date. S-217622 is an oral treatment for novel coronavirus pneumonia developed by Shionogi Pharmaceuticals that efficiently inhibits the novel coronavirus 3CLPRO and exerts antiviral effects. Preclinical studies have confirmed that S-217622 has a strong effect on 3CLPRO activity in vitro, with an IC50 value of 0.013 μM and an EC50 value of 0.37 μM. Paxlovid, an oral treatment for novel coronavirus pneumonia developed by Pfizer Inc., USA, consists of the 3CL protease inhibitors nirmatrelvir (PF-07321332) and ritonavir. This drug is the most effective oral treatment currently available, and clinical trials have demonstrated an 89% reduction in the risk of COVID-19-related mortality. TIFF2025533244000001.tif48170

[0005] A series of ketoamide derivatives has been reported in patent PCT / CN2022 / 117124, and in vitro activity data shows that some of the compounds exhibit good in vitro anti-coronavirus activity at the cellular level without cytotoxicity, with significantly higher exposure, slower clearance, longer half-life, and excellent pharmacokinetic properties. Among them, compound 1 (Example 1, formula (I)) has relatively good overall performance and is believed to have good potential for drug discovery. TIFF2025533244000002.tif45170

[0006] Crystal form screening is one of the most important aspects in drug development. For a particular compound, the physicochemical properties of its free form, various salt forms, and corresponding crystalline forms are still unknown. Therefore, it is of great significance to drug development to search for an appropriate crystalline form that further considers its drug potential and provides multiple options for intermediate products and / or drug substances for subsequent drug development. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention discloses a series of crystalline forms of the compound of formula (I), which exhibit good drug discoverability (stability, flowability, compressibility, solubility, bioavailability, etc.) and provide various drug substance options for subsequent pharmaceutical development. TIFF2025533244000003.tif51170 [Means for solving the problem]

[0008] The above object of the present invention is achieved by the following technical solutions.

[0009] Regarding the characterization of crystalline forms of a compound, those skilled in the art will understand that for a specific crystalline form of a particular compound, the 2θ angle of each diffraction peak in a powder X-ray diffraction (XRPD) pattern will vary in repeated experiments due to factors such as the instrument, operating method, sample purity, and human factors used in the characterization process, and the range of this variation (error range) is typically within ±0.2°. Furthermore, those skilled in the art will understand that the stability and reproducibility of diffraction peaks can also be affected by a combination of the 2θ angle, absorption intensity (peak height), and other factors of each diffraction peak in a powder X-ray diffraction pattern. Specifically, diffraction peaks with strong absorption intensity, good separation, and small 2θ angles have good stability and reproducibility and can be used to characterize a particular crystalline form. However, diffraction peaks with large 2θ angles and / or poor separation and / or weak relative intensities may vary significantly due to factors such as the instrument, operating method, sample purity, and human factors, and may not be reproducible even after repeated experiments. Therefore, those skilled in the art will not consider such absorption peaks to be diffraction peaks necessary for characterizing a crystalline form. More specifically, the diffraction peaks in the present invention are selected based on common knowledge in the art regarding the characterization of crystalline forms, taking into consideration factors such as 2θ angle and absorption intensity (peak height), and are grouped according to stability and reproducibility.

[0010] As will be understood by those skilled in the art, the test results of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of a sample may vary between samples from the same batch and / or different batches due to the influence of the equipment, detection conditions, inspector, etc. Therefore, in the present invention, based on common knowledge in the field regarding the characterization of crystalline forms, the variation range of the onset of the endothermic peak or exothermic peak in the DSC thermogram is set to ±3°C, and the variation range of the weight loss value in the TGA thermogram is set to ±1%.

[0011] Unless otherwise specified, "room temperature" in the present invention means 25±5°C, and a thermogravimetric analysis curve (TGA) "showing no significant weight loss" in the present invention means that the weight loss before the detection end point temperature is 1% or less.

[0012] As can be understood by those skilled in the art, once the preparation of the compound is completed, the technician cannot further investigate the specific form of the crystalline form of compound (I).Therefore, the compound of formula (I) can exist in the form of an anhydrous, hydrated or solvated form, and the "solvent" in the solvate is an organic solvent commonly used in the art, including, but not limited to, methanol, ethanol, n-propanol, isopropanol, acetone, butanone, acetonitrile, dichloromethane, trichloromethane, ethyl acetate, toluene, etc.

[0013] The first object of the present invention is to provide crystalline form I of the compound of formula (I) and a method for preparing the same, which crystalline form exhibits good drug potential. TIFF2025533244000004.tif45170

[0014] Specifically, the XRPD pattern of crystalline form I of the compound of formula (I) has diffraction peaks that appear stably at 2θ positions of 10.0, 10.6, 11.5, 12.1, 14.1, 16.7, 17.4, 19.0, 19.4, 20.5, 21.9, and 24.9 (±0.2°).

[0015] Furthermore, the XRPD pattern of crystalline Form I of the compound of formula (I) above has diffraction peaks at 2θ of 13.4, 14.5, 17.8, 18.7, 20.0, 21.1, 22.8, 23.8, 26.0, and 26.9 (±0.2°).

[0016] Furthermore, in some embodiments of the present invention, the diffraction peaks in the XRPD pattern of crystalline form I of the compound of formula (I) above are shown in the table below. TIFF2025533244000005.tif88170

[0017] Furthermore, in some embodiments of the present invention, the XRPD pattern of crystalline Form I of the compound of formula (I) above is essentially as shown in FIG.

[0018] The differential scanning calorimetry curve (DSC) of crystalline Form I of the compound of formula (I) above has an endothermic peak onset at 188.1±3°C.

[0019] Furthermore, in some embodiments of the present invention, the DSC thermogram of crystalline Form I of the compound of formula (I) above is essentially as shown in FIG.

[0020] The thermogravimetric analysis curve (TGA) of the crystalline form I of the compound of formula (I) above shows a weight loss of 0.3±1% at 100°C.

[0021] Furthermore, in some embodiments of the present invention, the TGA thermogram of crystalline Form I of the compound of formula (I) above is essentially as shown in FIG.

[0022] A second object of the present invention is to provide crystalline form II of the compound of formula (I) and a method for preparing the same, which crystalline form exhibits good drug potential. TIFF2025533244000006.tif45170

[0023] Specifically, the XRPD pattern of the crystalline form II of the compound of formula (I) has diffraction peaks that appear stably at 2θ positions of 10.9, 12.1, 16.1, 17.0, 17.5, 18.3, and 23.4 (±0.2°).

[0024] Furthermore, in some embodiments of the present invention, the diffraction peaks in the XRPD pattern of crystalline form II of the compound of formula (I) above are shown in the table below. TIFF2025533244000007.tif33170

[0025] Furthermore, in some embodiments of the present invention, the XRPD pattern of crystalline Form II of the compound of formula (I) above is essentially as shown in FIG.

[0026] The differential scanning calorimetry curve (DSC) of the crystalline form II of the compound of formula (I) above has endothermic peak onsets at 72.7, 115.0, 177.3, 262.0±3°C and an exothermic peak onset at 150.8±3°C.

[0027] Furthermore, in some embodiments of the present invention, the DSC thermogram of crystalline Form II of the compound of formula (I) above is essentially as shown in FIG.

[0028] The thermogravimetric analysis curve (TGA) of the crystalline form II of the compound of formula (I) above shows a weight loss of 7.8±1% at 230°C.

[0029] Furthermore, in some embodiments of the present invention, the TGA thermogram of crystalline Form II of the compound of formula (I) above is essentially as shown in FIG.

[0030] The third object of the present invention is to provide crystalline form III of the compound of formula (I) and a process for preparing the same, which crystalline form exhibits good drug potential. TIFF2025533244000008.tif45170

[0031] Specifically, the XRPD pattern of the crystalline form III of the compound of formula (I) has diffraction peaks that appear stably at 2θ positions of 6.1, 10.6, 12.3, 16.6, 17.9, and 18.7 (±0.2°).

[0032] Furthermore, in some embodiments of the present invention, the diffraction peaks in the XRPD pattern of crystalline form III of the compound of formula (I) above are shown in the table below. TIFF2025533244000009.tif28170

[0033] Furthermore, in some embodiments of the present invention, the XRPD pattern of crystalline Form III of the compound of formula (I) above is essentially as shown in FIG.

[0034] The differential scanning calorimetry curve (DSC) of the crystalline form III of the compound of formula (I) above has endothermic peak onsets at 86.0, 130.8, 186.3 (±3° C.).

[0035] Furthermore, in some embodiments of the present invention, the DSC thermogram of crystalline Form III of the compound of Formula (I) above is essentially as shown in FIG.

[0036] The thermogravimetric analysis curve (TGA) of the crystalline form III of the compound of formula (I) above shows a weight loss of 6.3±1% at 100°C and a weight loss of 4.5±1% at 200°C.

[0037] Furthermore, in some embodiments of the present invention, the TGA thermogram of crystalline Form III of the compound of formula (I) above is essentially as shown in FIG.

[0038] A fourth object of the present invention is to provide crystalline form IV of the compound of formula (I) and a process for preparing the same, which crystalline form exhibits good drug potential. TIFF2025533244000010.tif45170

[0039] Specifically, the XRPD pattern of the crystalline form IV of the compound of formula (I) has diffraction peaks that appear stably at 2θ positions of 6.2, 8.1, 10.7, 16.4, 17.1, 18.6, 19.4, and 21.3 (±0.2°).

[0040] Furthermore, the XRPD pattern of crystalline Form IV of the compound of formula (I) above has diffraction peaks at 2θ of 7.1, 11.2, 16.7, 17.7, 18.8, 19.8, 20.4, 22.0, 22.3, 22.5, 23.1, and 24.7 (±0.2°).

[0041] Furthermore, in some embodiments of the present invention, the diffraction peaks in the XRPD pattern of crystalline Form IV of the compound of formula (I) above are shown in the table below. TIFF2025533244000011.tif78170

[0042] Furthermore, in some embodiments of the present invention, the XRPD pattern of crystalline Form IV of the compound of formula (I) above is essentially as shown in FIG.

[0043] The differential scanning calorimetry curve (DSC) of the crystalline form IV of the compound of formula (I) above has an endothermic peak onset at 49.6, 130.5±3°C.

[0044] Furthermore, in some embodiments of the present invention, the DSC thermogram of crystalline Form IV of the compound of formula (I) above is essentially as shown in FIG.

[0045] The thermogravimetric analysis curve (TGA) of the crystalline form IV of the compound of formula (I) above shows a weight loss of 3.8±1% at 110°C and a weight loss of 4.2±1% at 190°C.

[0046] Furthermore, in some embodiments of the present invention, the TGA thermogram of crystalline Form IV of the compound of Formula (I) above is essentially as shown in FIG.

[0047] A fifth object of the present invention is to provide crystalline form V of the compound of formula (I) and a method for preparing the same, which crystalline form exhibits good drug potential. TIFF2025533244000012.tif45170

[0048] Specifically, the XRPD pattern of the crystalline form V of the compound of formula (I) has diffraction peaks that appear stably at 2θ positions of 6.2, 8.1, 10.6, 16.2, 18.5, and 19.1 (±0.2°).

[0049] Furthermore, in some embodiments of the present invention, the diffraction peaks in the XRPD pattern of crystalline form V of the compound of formula (I) above are shown in the table below. TIFF2025533244000013.tif28170

[0050] Furthermore, in some embodiments of the present invention, the XRPD pattern of crystalline Form V of the compound of formula (I) above is essentially as shown in FIG.

[0051] The differential scanning calorimetry curve (DSC) of crystalline form V of the compound of formula (I) above has an endothermic peak onset at 148.4±3°C.

[0052] Furthermore, in some embodiments of the present invention, the DSC thermogram of crystalline Form V of the compound of formula (I) above is essentially as shown in FIG.

[0053] The thermogravimetric analysis curve (TGA) of the crystalline form V of the compound of formula (I) above shows a weight loss of 10.5±1% at 190°C.

[0054] Furthermore, in some embodiments of the present invention, the TGA thermogram of crystalline Form V of the compound of formula (I) above is essentially as shown in FIG.

[0055] A sixth object of the present invention is to provide crystalline form VI of the compound of formula (I) and a process for preparing the same, which crystalline form exhibits good drug potential. TIFF2025533244000014.tif45170

[0056] Specifically, this XRPD pattern has diffraction peaks that appear stably at 2θ positions of 5.5, 5.8, 10.7, 16.9, 17.9, and 18.3 (±0.2°).

[0057] Furthermore, the XRPD pattern of the crystalline form VI of the compound of formula (I) above has diffraction peaks at 2θ of 9.1, 10.4, 15.9, 20.0, 20.9, and 21.6 (±0.2°).

[0058] Furthermore, in some embodiments of the present invention, the diffraction peaks in the XRPD pattern of crystalline form VI of the compound of formula (I) above are shown in the table below. TIFF2025533244000015.tif43170

[0059] Furthermore, in some embodiments of the present invention, the XRPD pattern of crystalline Form VI of the compound of formula (I) above is essentially as shown in FIG.

[0060] The differential scanning calorimetry curve (DSC) of the crystalline form VI of the compound of formula (I) above has an endothermic peak onset at 134.2, 184.3 (±3° C.).

[0061] Furthermore, in some embodiments of the present invention, the DSC thermogram of crystalline Form VI of the compound of Formula (I) above is essentially as shown in FIG.

[0062] The thermogravimetric analysis curve (TGA) of the crystalline form VI of the compound of formula (I) above shows a weight loss of 16.2±1% at 200°C.

[0063] Furthermore, in some embodiments of the present invention, the TGA thermogram of crystalline Form VI of the compound of Formula (I) above is essentially as shown in FIG.

[0064] The seventh object of the present invention is to provide crystalline form VII of the compound of formula (I) and a process for preparing the same, which crystalline form exhibits good drug potential. TIFF2025533244000016.tif45170

[0065] Specifically, this XRPD pattern has diffraction peaks that appear stably at 2θ positions of 6.3 and 10.9 (±0.2°).

[0066] Furthermore, in some embodiments of the present invention, the XRPD pattern of crystalline Form VII of the compound of formula (I) above is essentially as shown in FIG.

[0067] The differential scanning calorimetry curve (DSC) of the crystalline form VII of the compound of formula (I) above has an endothermic peak onset at 130.2±3°C.

[0068] Furthermore, in some embodiments of the present invention, the DSC thermogram of crystalline Form VII of the compound of Formula (I) above is essentially as shown in FIG.

[0069] The thermogravimetric analysis curve (TGA) of the crystalline form VII of the compound of formula (I) above shows a weight loss of 8.6±1% at 190°C.

[0070] Furthermore, in some embodiments of the present invention, the TGA thermogram of crystalline Form VII of the compound of Formula (I) above is essentially as shown in FIG.

[0071] An eighth object of the present invention is to provide crystalline form VIII of the compound of formula (I) and a process for its preparation. TIFF2025533244000017.tif45170

[0072] Specifically, the XRPD pattern of the crystalline form VIII of the compound of formula (I) has diffraction peaks that appear stably at 2θ positions of 5.3, 11.7, 15.8, 16.6, 17.4, 18.8, and 20.3 (±0.2°).

[0073] Furthermore, in some embodiments of the present invention, the diffraction peaks in the XRPD pattern of crystalline Form VIII of the compound of formula (I) above are shown in the table below. TIFF2025533244000018.tif33170

[0074] Furthermore, in some embodiments of the present invention, the XRPD pattern of crystalline Form VIII of the compound of Formula (I) above is essentially as shown in FIG.

[0075] A ninth object of the present invention is to provide crystalline form IX of the compound of formula (I) and a process for its preparation. TIFF2025533244000019.tif45170

[0076] Specifically, the XRPD pattern of the crystalline form IX of the compound of formula (I) has diffraction peaks that appear stably at 2θ of 6.1, 10.6, and 16.6 (±0.2°).

[0077] Furthermore, in some embodiments of the present invention, the diffraction peaks in the XRPD pattern of crystalline form IX of the compound of formula (I) above are shown in the table below. TIFF2025533244000020.tif28170

[0078] Furthermore, in some embodiments of the present invention, the XRPD pattern of crystalline Form IX of the compound of Formula (I) above is essentially as shown in FIG.

[0079] A tenth object of the present invention is to provide a drug substance comprising at least one of crystalline forms I to IX of the compound of formula (I) of the present invention.

[0080] Based on the beneficial effects of the crystalline forms I to IX of the compound of formula (I) of the present invention, the drug substance containing the crystalline forms also has beneficial effects (e.g., stability, water solubility, etc.) substantially consistent with those of the crystalline forms. Specifically, the drug substance may be the compound of formula (I), may be the compound of formula (I) and / or a hydrate of the compound of formula (I), may be the compound of formula (I) and / or an anhydride of the compound of formula (I), or may be the compound of formula (I) and / or a solvate of the compound of formula (I). More specifically, the mass percentage of crystalline Form I of the compound of formula (I) and / or crystalline Form II of the compound of formula (I) and / or crystalline Form III of the compound of formula (I) and / or crystalline Form IV of the compound of formula (I) and / or crystalline Form V of the compound of formula (I) and / or crystalline Form VI of the compound of formula (I) and / or crystalline Form VII of the compound of formula (I) and / or crystalline Form VIII of the compound of formula (I) and / or crystalline Form IX of the compound of formula (I) contained in the above-mentioned drug substance is any value from 0.01 to 99.99%. Furthermore, the mass percentage of crystalline Form I of the compound of formula (I) and / or crystalline Form II of the compound of formula (I) and / or crystalline Form III of the compound of formula (I) and / or crystalline Form IV of the compound of formula (I) and / or crystalline Form V of the compound of formula (I) and / or crystalline Form VI of the compound of formula (I) and / or crystalline Form VII of the compound of formula (I) and / or crystalline Form VIII of the compound of formula (I) and / or crystalline Form IX of the compound of formula (I) contained in the above-mentioned drug substance is any value from 1.00 to 99.00%.

[0081] An eleventh object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned drug substance and a pharmaceutically acceptable adjuvant, which includes, but is not limited to, at least one of a filler, a binder, a disintegrant, a lubricant, etc. Specifically, based on the beneficial effects of crystalline forms I to IX of the compound of formula (I) of the present invention, the beneficial effects are ultimately reflected in the pharmaceutical composition. More specifically, the mass percentage of the above-mentioned drug substance contained in the pharmaceutical composition is any value between 1.00 and 99.00%, further, the mass percentage of the above-mentioned drug substance contained in the pharmaceutical composition is any value between 5.00 and 95.00%, and further, the mass percentage of the above-mentioned drug substance contained in the pharmaceutical composition is any value between 10.00 and 90.00%.

[0082] A twelfth object of the present invention is to provide a pharmaceutical product comprising at least one of the above crystalline form, the above drug substance, or the above pharmaceutical composition. A thirteenth object of the present invention is to provide a use of the pharmaceutical composition in preparing a medicament for treating coronavirus infection, specifically, the coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV or SARS-CoV-2 and its mutants.

[0083] Thus, because crystalline Forms I to IX of the compound of Formula (I) of the present invention have a certain potential for drug discovery, when the presence of crystalline Forms I to IX of the compound of Formula (I) in the above-mentioned drug substance and / or pharmaceutical composition is proven by a detection means, crystalline Forms I to IX of the compound of Formula (I) of the present invention are deemed to have been used. In addition to powder X-ray diffraction, the detection means may further include methods such as differential scanning calorimetry (DSC), infrared spectroscopy (IR), Raman spectroscopy, solid-state nuclear magnetic resonance (SSNMR), and all other detection methods that can be used individually or in combination to verify the use of crystalline Forms I to IX of the compound of Formula (I) of the present invention, and effects due to pharmaceutical adjuvants, etc., are removed using methods commonly used by those skilled in the art, such as subtractive panning.

[0084] The present invention has the following advantages and beneficial effects over the prior art:

[0085] 1. The crystalline form I of the compound of formula (I) and its preparation method are disclosed for the first time, and the crystalline form has characteristics such as high stability and has considerable potential for drug discovery.

[0086] 2. The crystalline form II of the compound of formula (I) and its preparation method are disclosed for the first time, and the crystalline form has characteristics such as high stability and has considerable potential for drug discovery.

[0087] 3. The crystalline form III of the compound of formula (I) and its preparation method are disclosed for the first time, and the crystalline form has characteristics such as high stability and has shown considerable potential for drug discovery.

[0088] 4. The crystalline form IV of the compound of formula (I) and its preparation method are disclosed for the first time, and the crystalline form has characteristics such as high stability and has considerable potential for drug discovery.

[0089] 5. The crystalline form V of the compound of formula (I) and its preparation method are disclosed for the first time, and the crystalline form has characteristics such as high stability and has shown considerable potential for drug discovery.

[0090] 6. Crystalline Form VI of the compound of formula (I) and its preparation method have been disclosed for the first time, providing various intermediate and / or raw material options for large-scale production of drug substance and downstream processing of pharmaceutical products (e.g., formulation process).

[0091] 7. Crystalline Form VII of the compound of formula (I) and its preparation method have been disclosed for the first time, providing various intermediate and / or raw material options for large-scale production of drug substance and downstream processing of pharmaceutical products (e.g., formulation process).

[0092] 8. Crystalline Form VIII of the compound of formula (I) and its preparation method have been disclosed for the first time, providing various intermediate and / or raw material options for large-scale production of drug substance and downstream processing of pharmaceutical products (e.g., formulation process).

[0093] 9. Crystalline Form IX of the compound of formula (I) and its preparation method have been disclosed for the first time, providing various intermediate and / or raw material options for large-scale production of drug substance and downstream processing of pharmaceutical products (e.g., formulation process).

[0094] 10. The present invention provides a drug substance comprising at least one of crystalline forms I to IX of the compound of formula (I) of the present invention, and the drug substance has shown beneficial effects substantially consistent with those of crystalline forms I to IX of the compound of formula (I) of the present invention.

[0095] 11. The present invention provides a pharmaceutical composition comprising the above-mentioned drug substance and a pharmaceutically acceptable adjuvant, and the above-mentioned pharmaceutical composition exhibits beneficial effects substantially consistent with those of Crystalline Form I to Crystalline Form IX of the compound of formula (I) of the present invention. [Brief explanation of the drawings]

[0096] [Figure 1] 1 is an XRPD pattern of crystalline form I of the compound of formula (I). [Figure 2]1 is a DSC thermogram of crystalline Form I of the compound of formula (I). [Figure 3] 1 is a TGA thermogram of crystalline Form I of the compound of formula (I). [Figure 4] 1 is a comparative XRPD diagram of crystalline form I of the compound of formula (I). [Figure 5] 1 is an XRPD pattern of crystalline Form II of the compound of formula (I). [Figure 6] 1 is a DSC thermogram of crystalline Form II of the compound of formula (I). [Figure 7] 1 is a TGA thermogram of crystalline Form II of the compound of formula (I). [Figure 8] 1 is an XRPD pattern of crystalline Form III of the compound of formula (I). [Figure 9] 1 is a DSC thermogram of crystalline Form III of the compound of formula (I). [Figure 10] 1 is a TGA thermogram of crystalline Form III of the compound of formula (I). [Figure 11] 1 is a comparative XRPD diagram of crystalline Form III of the compound of formula (I). [Figure 12] 1 is an XRPD pattern of crystalline Form IV of the compound of formula (I). [Figure 13] 1 is a DSC thermogram of crystalline Form IV of the compound of formula (I). [Figure 14] 1 is a TGA thermogram of crystalline Form IV of the compound of formula (I). [Figure 15] 1 is a comparative XRPD diagram of crystalline Form IV of the compound of formula (I). [Figure 16] 1 is an XRPD pattern of crystalline form V of compound of formula (I). [Figure 17] 1 is a DSC thermogram of crystalline form V of the compound of formula (I). [Figure 18] 1 is a TGA thermogram of crystalline Form V of the compound of formula (I). [Figure 19] 1 is a comparative XRPD diagram of crystalline form V of the compound of formula (I). [Figure 20] 1 is an XRPD pattern of crystalline form VI of the compound of formula (I). [Figure 21]1 is a DSC thermogram of crystalline Form VI of the compound of formula (I). [Figure 22] 1 is a TGA thermogram of crystalline Form VI of the compound of formula (I). [Figure 23] 1 is an XRPD pattern of crystalline Form VII of the compound of formula (I). [Figure 24] 1 is a DSC thermogram of crystalline Form VII of the compound of formula (I). [Figure 25] 1 is a TGA thermogram of crystalline Form VII of the compound of formula (I). [Figure 26] 1 is an XRPD pattern of crystalline Form VIII of the compound of formula (I). [Figure 27] 1 is an XRPD pattern of crystalline Form IX of the compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0097] The present invention will be described in more detail below with reference to examples and the accompanying drawings, but the embodiments of the present invention are not limited thereto.

[0098] Detection Conditions

[0099] Powder X-ray diffraction Powder X-ray diffractometer: Bruker D8 Advance 2θ scan angle: 3° to 45° Scan step length: 0.02° Exposure time: 0.2 seconds Tube voltage and current: 40KV, 40mA.

[0100] Differential scanning calorimetry analysis Differential scanning calorimeter: TA Discovery 2500 (TA, US) Heating rate: 10℃ / min Detection method: A sample was accurately weighed, placed on a DSC Tzero sample plate, and heated to 350°C at a rate of 50 mL / min while purging the furnace with nitrogen.

[0101] thermogravimetric analysis Thermogravimetric analyzer: TA Discovery 55 (TA, US) Detection method: The sample was placed on a balanced open aluminum sample plate and automatically weighed in a heating furnace. The sample was heated to 400°C at a rate of 10°C / min and purged with nitrogen at a rate of 60 mL / min at the sample and 40 mL / min at the balance.

[0102] Example 1 Method for preparing compounds of formula (I) TIFF2025533244000021.tif46170

[0103] Synthetic Route: TIFF2025533244000022.tif144170

[0104] Step 1: Synthesis of the hydrochloride salt of compound 1-2 Compound 1-1 (500 mg, 1.75 mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (10 mL, 4N) was added thereto, followed by reaction with stirring at 20° C. for 2 hours. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of compound 1-2 without further purification. 1 H NMR(400 MHz,CD3OD)δ=4.28-4.20(m,1H),3.91-3.81(m,3H),3.45-3.35(m,2H),2.86-2.74( m, 1H), 2.48-2.36 (m, 1H), 2.29-2.19 (m, 1H), 2.02-1.94 (m, 1H), 1.93-1.80 (m, 1H).

[0105] Step 2: Synthesis of compounds 1-4 Compound Boc-L-cyclohexylglycine (1 g, 3.89 mmol) was added to N,N-dimethylformamide (10 mL), and 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.77 g, 4.66 mmol) was added. The mixture was stirred for 0.5 hours, followed by diisopropylethylamine (1.26 g, 9.72 mmol) and the hydrochloride salt of compound 1-3 (1.02 g, 4.66 mmol). The mixture was stirred for 16 hours at 20 °C. Methyl tert-butyl ether (50 mL) was added to the reaction mixture, which was then washed with water (20 mL), 3% citric acid (20 mL × 2), and saturated aqueous sodium chloride (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) gave compound 1-4. 1 H NMR(400MHz,CDCl3)δ=5.22-5.11(m,1H),4.36(d,J=3.9Hz,1H),4.27(dd,J=6.9,9.3Hz,1H),4.21-4.12(m,2H),3.83(dd,J=7.8,10.4Hz,1H),3.70(br dd,J=3.6,10.4Hz,1H),2.81-2.61(m,2H),1.82-1.70(m,6H),1.68-1.61(m,4H ), 1.56-1.48 (m, 2H), 1.46-1.38 (m, 9H), 1.29-1.22 (m, 4H), 1.21-0.98 (m, 4H).

[0106] Step 3: Synthesis of Compounds 1-5 Compound 1-4 (1.41 g, 3.34 mmol) was added to tetrahydrofuran (14 mL), and a solution of lithium hydroxide monohydrate (LiOH·HO) (280.03 mg, 6.67 mmol) in water (5 mL) was added. The mixture was stirred at 20°C for 16 hours. The crude product was neutralized with 3% citric acid solution (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 1-5 was obtained without further purification. 1H NMR(400MHz,DMSO‐d6)δ=12.58‐12.23(m,1H),6.92‐6.82(m,1H),4.11‐3.94(m,2H),3.82‐3.76(m,1H),3.72‐3.62(m,1 H), 2.73-2.64(m, 1H), 2.62-2.55(m, 1H), 1.92-1.42(m, 12H), 1.40-1.32(m, 9H), 1.18-1.06(m, 3H), 1.00-0.81(m, 2H).

[0107] Step 4: Synthesis of compounds 1-6 Compound 1-5 (650 mg, 1.65 mmol) was added to 2-butanone (7 mL), followed by the addition of 1-hydroxybenzotriazole (222.63 mg, 1.65 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (379.03 mg, 1.98 mmol), and diisopropylethylamine (638.84 mg, 4.94 mmol). The mixture was stirred at 20 °C for 0.5 hours, followed by the addition of compound 1-2 hydrochloride (366.88 mg, 1.65 mmol). The mixture was stirred at 20 °C for 16 hours. Water (20 mL) was added to the reaction mixture, which was then extracted with dichloromethane:methanol (30 mL x 2, 10:1). The combined organic phases were washed with 3% citric acid (20 mL x 2) and saturated aqueous sodium chloride (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain compound 1-6. 1 H NMR(400 MHz, CDCl3)δ=7.49-7.42(m,1H),6.23-6.05(m,1H),5.28-5.17(m,1H),4.64-4.51(m,1H),4.43-4.24(m,2H),3.92-3.81(m,1H),3.78-3.70( m,3H),3.39-3.27(m,2H),2.94-2.75(m,2H),2.57-2.36(m,2H),2.24- 2.07(m, 1H), 1.94-1.50(m, 14H), 1.49-1.41(m, 9H), 1.27-0.95(m, 6H).

[0108] Step 5: Synthesis of Compounds 1-7 Compound 1-6 (3.10 g, 5.51 mmol) was dissolved in tetrahydrofuran (31 mL), lithium borohydride (240.02 mg, 11.02 mmol) was added at 0 °C, and the mixture was allowed to react for 2 h after slowly warming to 20 °C. Water (10 mL) and ethyl acetate (20 mL) were added to the reaction mixture, and the mixture was stirred for 10 min. A white solid precipitated and was filtered to obtain the crude product, i.e., the target product 1-7, as a filter cake. [M+1]+ = 535.4.

[0109] Step 6: Synthesis of Compounds 1-8 Compound 1-7 (0.5 g, 935.13 μmol) was dissolved in dichloromethane (10 mL). Dess-Martin oxidant (594.94 mg, 1.40 mmol) was then added to the reaction mixture and stirred at 25 °C for 16 h. Saturated sodium thiosulfate (15 mL) and saturated sodium bicarbonate solution (15 mL) were added to the reaction mixture and stirred for 10 min. The mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 1-8. [M+1]+ = 533.4.

[0110] Step 7: Synthesis of Compounds 1-9 Compound 1-8 (436 mg, 818.52 μmol) was dissolved in dichloromethane (5 mL), and glacial acetic acid (58.98 mg, 982.22 mmol) and cyclopentyl isocyanate (94.44 mg, 982.22 μmol) were added to the reaction mixture. The mixture was stirred at 25°C for 2 h. Saturated ammonium chloride solution (10 mL) was added to the reaction mixture, and the mixture was stirred for 10 min. The mixture was then extracted with dichloromethane (20 mL). The organic phase was washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 1-9 was obtained by silica gel column chromatography (dichloromethane:methanol = 10:1). [M+1]+ = 688.4.

[0111] Step 8: Synthesis of Compounds 1-10 Compound 1-9 (190 mg, 276.22 μmol) was dissolved in methanol (3 mL), followed by the addition of a solution of potassium carbonate (95.44 mg, 690.54 μmol) in water (2 mL). The mixture was stirred at 20°C for 16 hours. 3% citric acid (20 mL) was added to the reaction mixture, which was then extracted three times with dichloromethane (40 mL). The organic phase was washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 1-10. [M+1] + =646.5.

[0112] Step 9: Synthesis of Compounds 1-11 Compound 1-10 (238.00 mg, 368.52 μmol) was dissolved in dichloromethane (24 mL) and then Dess-Martin oxidant (203.19 mg, 479.08 μmol) was added. The reaction was stirred at 20 °C for 18 h. Sodium thiosulfate (15 mL) and sodium bicarbonate solution (15 mL) were added to the reaction mixture, which was stirred for 10 min. The mixture was then extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The product 1-11 was obtained by silica gel column chromatography (dichloromethane:methanol = 20:1). [M+1] + =644.5.

[0113] Step 10: Synthesis of Compounds 1-12 Compound 1-11 (125 mg, 194.16 μmol) was dissolved in tetrahydrofuran (3 mL), and then ethyl acetate hydrochloride (4 M, 2.91 mL) was added. The reaction was stirred at 20 °C for 1 h. The reaction solution was directly rotary evaporated using an oil pump, and rotary evaporated repeatedly with a small amount of dichloromethane to give compound 1-12. [M+1] + =544.4.

[0114] Step 11: Synthesis of Compound 1 Compound 1-12 (125 mg, 229.91 μmol) was dissolved in tetrahydrofuran (2.5 mL) and added with trifluoroacetic anhydride (193.15 mg, 919.63 μmol) and pyridine (127.30 mg, 1.61 mmol) at 0°C. The mixture was stirred at 20°C for 16 hours. Water (20 mL) was added to the reaction mixture, which was then extracted with dichloromethane (40 mL x 2). The organic phase was washed with 3% citric acid (40 mL) and saturated aqueous sodium chloride (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC to obtain compound 1. [M+1] + =640.0, 1 H NMR(400 MHz,CD3OD)δ ppm 0.94-1.10(m,2H),1.13-1.32(m,3H)1.32-1.46(m,1H),1.47-1.57(m,3H),1.59-1.68(m,4H),1.69-1.8 1(m,6H),1.83-2.00(m,5H),2.01-2.17(m,1H),2.19-2.38(m,1H),2.49-2.57(m,1H),2.58-2.70(m,1H), 2.73-2.89(m,1H),3.20-3.26(m,1H),3.37-3.45(m,1H),3.73-3.86(m,1H),3.88-3.97(m,1H),4.03-4.1 0(m,1H),4.11-4.18(m,1H),4.19-4.29(m,1H),4.29-4.37(m,1H),4.39-4.47(m,1H),4.57-4.60(m,2H).

[0115] Example 2 Method for preparing crystalline form I of compound of formula (I)

[0116] 20.0 mg of the compound of formula (I) prepared in Example 1 was weighed and added to 0.5 mL of acetone / n-heptane (v / v, 1:9) to prepare a suspension, which was stirred at room temperature (∼25°C) for 7 days. The suspension was centrifuged and dried under vacuum at room temperature to obtain a white solid, i.e., crystalline form I, whose XRPD pattern is shown in Figure 1, DSC thermogram is shown in Figure 2, and TGA thermogram is shown in Figure 3.

[0117] Example 3 Method for preparing crystalline form I of compound of formula (I)

[0118] 50.2 mg of the compound of formula (I) prepared in Example 1 was weighed and added to 0.5 mL of acetone / isopropyl ether (v / v, 1:4) to prepare a suspension. The suspension was stirred at 10°C for 24 hours, centrifuged, and dried under vacuum at room temperature to obtain a white solid, i.e., crystalline form I.

[0119] A comparison of the XRPD patterns of the obtained crystalline form I is shown in FIG.

[0120] Example 4 Method for preparing crystalline form II of compound of formula (I)

[0121] 40.1 mg of the compound of Formula (I) prepared in Example 1 was weighed and mixed with 2.0 mL of cyclohexane at 50°C to form a suspension. 4.2 mL of preheated toluene was slowly added dropwise until the solid was completely or nearly dissolved. The mixture was filtered while still hot, and the solution was then cooled to room temperature. After standing at room temperature for 2 hours or more, if sufficient solids were not precipitated, the solution was further cooled at 4°C. If sufficient solids were not precipitated, the solution was further cooled at -15°C. After centrifugation of the system in which sufficient solids had precipitated, the solid was dried under vacuum at room temperature to obtain a white solid, i.e., crystalline Form II, whose XRPD pattern is shown in Figure 5, DSC thermogram in Figure 6, and TGA thermogram in Figure 7.

[0122] Example 5 Method for preparing crystalline form III of compound of formula (I)

[0123] 19.9 mg of the compound of formula (I) prepared in Example 1 was weighed and added to 0.5 mL of methanol / isopropyl ether (v / v, 1:4) to prepare a suspension, which was stirred at 10°C for 24 hours. The suspension was centrifuged and dried under vacuum at room temperature to obtain a white solid, i.e., crystalline form III, whose XRPD pattern is shown in Figure 8, whose DSC thermogram is shown in Figure 9, and whose TGA thermogram is shown in Figure 10.

[0124] Example 6 Method for preparing crystalline form III of compound of formula (I)

[0125] 20.0 mg of the compound of Formula (I) prepared in Example 1 was weighed and mixed with 1.0 mL of isopropyl ether at 50°C to form a suspension. 0.1 mL of preheated methanol was slowly added dropwise until the solid was completely dissolved or nearly dissolved. The mixture was filtered while still hot, and the solution was then cooled to room temperature. After standing at room temperature for 2 hours or more, the system was centrifuged to precipitate a sufficient amount of solid. The solid was then dried under vacuum at room temperature to obtain a white solid, i.e., crystalline Form III.

[0126] A comparison of the XRPD patterns of the resulting crystalline Form III is shown in FIG.

[0127] Example 7 Method for preparing crystalline form IV of compound of formula (I)

[0128] 19.5 mg of the compound of formula (I) prepared in Example 1 was dissolved in 0.1 mL of ethanol, and the resulting clear solution was allowed to stand in the open at room temperature until the solvent was completely evaporated to give a solid, which was then dried under vacuum at room temperature to give a white solid, i.e., crystalline form IV, whose XRPD pattern is shown in Figure 12, whose DSC thermogram is shown in Figure 13, and whose TGA thermogram is shown in Figure 14.

[0129] Example 8 Method for preparing crystalline form IV of compound of formula (I)

[0130] 20.6 mg of the compound of formula (I) prepared in Example 1 was weighed and added to 0.5 mL of ethanol / cyclohexane (v / v, 1:9) to prepare a suspension. The suspension was stirred at room temperature (about 25°C) for 7 days, centrifuged, and dried under vacuum at room temperature to obtain a white solid, i.e., crystalline form IV.

[0131] A comparison of the XRPD patterns of the resulting crystalline Form IV is shown in FIG.

[0132] Example 9 Method for preparing crystalline form V of compound of formula (I)

[0133] 19.5 mg of the compound of formula (I) prepared in Example 1 was dissolved in 0.1 mL of n-propanol, and the resulting clear solution was allowed to stand in the open at room temperature until the solvent was completely evaporated to give a solid, which was then dried under vacuum at room temperature to give a white solid, i.e., crystalline form V, whose XRPD pattern is shown in Figure 16, whose DSC thermogram is shown in Figure 17, and whose TGA thermogram is shown in Figure 18.

[0134] Example 10: Method for preparing crystalline form V of compound of formula (I)

[0135] 19.4 mg of the compound of formula (I) prepared in Example 1 was weighed and added to 0.5 mL of n-propanol / water (v / v, 1:9) to prepare a suspension. The suspension was stirred at room temperature (~25°C) for 7 days, centrifuged, and dried under vacuum at room temperature to obtain a white solid, i.e., crystalline form V.

[0136] A comparison of the XRPD patterns of the resulting crystalline form V is shown in FIG.

[0137] Example 11 Method for preparing crystalline form VI of compound of formula (I)

[0138] 20.2 mg of the compound of Formula (I) prepared in Example 1 was weighed out, and an appropriate amount (0.1 mL) of ethylene glycol methyl ether was added dropwise at room temperature to completely dissolve the sample. Then, 1.0 mL of isopropyl ether was added dropwise until a solid precipitated. After stirring at room temperature for 1 hour, the system from which the solid precipitated was centrifuged and dried under vacuum at room temperature to obtain a white solid, i.e., crystalline Form VI. The XRPD pattern of the resulting crystalline Form VI is shown in Figure 20, its DSC thermogram in Figure 21, and its TGA thermogram in Figure 22.

[0139] Example 12: Method for preparing crystalline form VII of compound of formula (I)

[0140] 20.0 mg of the compound of Formula (I) prepared in Example 1 was weighed and mixed with 1.0 mL of cyclohexane at 50°C to form a suspension. 0.4 mL of preheated chloroform was slowly added dropwise until the solid was completely or nearly dissolved. The mixture was filtered while still hot, and the solution was then cooled to room temperature. After standing at room temperature for 2 hours or more, if sufficient solids were not precipitated, the solution was further cooled at 4°C. If sufficient solids were not precipitated, the solution was further cooled at -15°C. After centrifugation of the system in which sufficient solids had precipitated, the solid was dried under vacuum at room temperature to obtain a white solid, i.e., crystalline Form VII, whose XRPD pattern is shown in Figure 23, DSC thermogram in Figure 24, and TGA thermogram in Figure 25.

[0141] Example 13: Method for preparing crystalline form VIII of compound of formula (I)

[0142] 20.5 mg of the compound of Formula (I) prepared in Example 1 was weighed and mixed with 1.0 mL of cyclohexane at 50°C to form a suspension. 0.05 mL of preheated n-propanol was slowly added dropwise until the solid was completely or nearly dissolved. The mixture was filtered while still hot, and the solution was then transferred to room temperature and cooled. After standing at room temperature for 2 hours or more, a solid precipitated. After centrifuging the system with sufficient solid precipitated, the solid was vacuum dried at room temperature to obtain a white solid, i.e., crystalline Form VIII, whose XRPD pattern is shown in Figure 26. By comparison, crystalline Form VIII was substantially identical to the crystalline form of the compound of Formula (I) prepared in Example 1. The obtained crystalline Form VIII had some hygroscopicity, poor powder shape, and was difficult to mold.

[0143] Example 14 Method for preparing crystalline form IX of compound of formula (I)

[0144] 19.8 mg of the compound of Formula (I) prepared in Example 1 was weighed and mixed with 1.0 mL of n-heptane at 50°C to form a suspension. 0.9 mL of preheated butyl formate was slowly added dropwise until the solid was completely dissolved or nearly dissolved. The solution was filtered while still hot, and then transferred to room temperature and cooled. After standing at room temperature for 2 hours or more, if sufficient solids were not precipitated, the solution was further cooled at 4°C. If sufficient solids were not precipitated, the solution was further cooled at -15°C. After centrifugation of the system in which sufficient solids had precipitated, the solid was dried under vacuum at room temperature to obtain a white solid, i.e., crystalline Form IX, the XRPD pattern of which is shown in Figure 27.

[0145] Example 15 Solid-state stability test of crystalline form I, crystalline form IV and crystalline form V of the compound of formula (I) under high temperature and humidity conditions

[0146] Approximately 100 mg of each of two samples of crystalline Form I, Form IV, and Form V of the compound of formula (I) were weighed in parallel and placed in the bottom of a glass sample vial. The vial was then spread into a thin layer. The mouth of the sample vial was sealed with aluminum foil, and several small holes were poked in the aluminum foil to allow sufficient contact with the outside air. The vial was then placed in a temperature- and humidity-controlled box at 40°C and 75% humidity. The samples were sampled and tested on days 0, 12, and 30 under the above conditions. The results were compared with the initial results on day 0. The test results are shown in Tables 1 to 3 below.

[0147] TIFF2025533244000023.tif120170*N / A is not detected

[0148] TIFF2025533244000024.tif120170*N / A is not detected

[0149] TIFF2025533244000025.tif120170*N / A means not detected

[0150] The detected items of this product were compared with those on day 0.

[0151] When the crystalline form I of the compound of formula I was kept at a high temperature of 60°C for 30 days, there was no change in the crystalline form, no change in properties, a slight increase in total impurities, and no increase in water.

[0152] When the sample was kept under high humidity conditions of 92.5%RH for 30 days, there was no difference in the crystal form, no difference in the properties, a slight increase in total impurities, and a slight increase in moisture. When the sample was kept under high humidity conditions in an open environment for 30 days, the weight after moisture absorption increased by 0.56%, and there was no significant hygroscopicity.

[0153] When kept at high temperature and humidity conditions of 40°C and 75%RH for 30 days, there was no difference in the crystal form, no difference in properties, a slight increase in total impurities, and a slight increase in moisture.

[0154] Crystalline Form I of the compound of formula (I) was relatively stable under high temperature, high temperature and high humidity conditions, and high humidity conditions, compared with the compound of formula (I) prepared in Example 1.

[0155] When the crystalline form IV of the compound of formula I was kept at a high temperature of 60°C for 30 days, there was no change in the crystalline form, no change in properties, no increase in total impurities, and no increase in water.

[0156] When the sample was kept under high humidity conditions of 92.5%RH for 30 days, there was no difference in the crystal form, no difference in the properties, but there was a slight increase in the total impurities and a slight increase in the moisture content. When the sample was kept under high humidity conditions in an open environment for 30 days, the weight after absorbing moisture increased by 2.0%, indicating significant hygroscopicity.

[0157] When kept at high temperature and humidity of 40°C and 75%RH for 30 days, there was no difference in the crystal form, no difference in properties, no increase in total impurities, and a slight increase in moisture.

[0158] Crystalline Form IV of the compound of formula (I) was relatively stable under high temperature conditions compared to the compound of formula (I) prepared in Example 1.

[0159] When crystalline form V of the compound of formula I was kept at a high temperature of 60°C for 30 days, there was no change in the crystalline form, no change in properties, a slight increase in total impurities, and no increase in water.

[0160] When the sample was kept under high humidity conditions of 92.5%RH for 30 days, there was no difference in the crystal form, no difference in the properties, a slight increase in total impurities, and an increase in moisture. When the sample was kept under high humidity conditions in an open environment for 30 days, the weight after moisture absorption increased by 1.1%, and there was no significant hygroscopicity.

[0161] When kept at high temperature and humidity conditions of 40°C and 75%RH for 30 days, there was no difference in the crystal form, no difference in properties, a slight increase in total impurities, and a slight increase in moisture.

[0162] Crystalline Form V of the compound of formula (I) was relatively stable under high temperature conditions compared to the compound of formula (I) prepared in Example 1.

[0163] As described above, when stored in an open environment, crystalline form I of the compound of formula (I) was relatively stable under high temperature, high temperature and high humidity conditions, and crystalline forms IV and V were relatively stable under high temperature conditions.

[0164] Furthermore, the inventors discovered the following during the course of their experiments and further research.

[0165] Crystalline Form II was obtained by cooling in a solvent system of cyclohexane and toluene and then evaporating. After the evaporated crystallized form II was dried under vacuum at room temperature, the sample remained as crystallized form II, which is considered to have high stability. Crystalline Form III was obtained by crystallizing in a methanol / isopropyl ether system with prolonged stirring at 10°C. Those skilled in the art will recognize that crystallographic form III has high stability.

[0166] Crystalline form VIII is an unstable crystal form, and undergoes a crystal transformation during the post-treatment process (vacuum drying at room temperature) to transform into crystal form V. Crystalline form V is finally obtained by transitioning from an intermediate metastable crystal form (crystal form VIII), and it has been found to be highly stable.

[0167] Example 16 Crystallographic thermal transition experiment

[0168] Starting with different crystalline forms, the samples were placed on the BTS500 heating stage and XRPD tests were performed at room temperature, then heated to the selected temperature at 10 °C / min, held for 10 min, and XRPD tests were performed at this temperature, then cooled to room temperature and XRPD tests were performed again. The results are shown in Table 4.

[0169] TIFF2025533244000026.tif41170

[0170] From the above experimental results, it was revealed that crystalline forms V and VI have high stability under heating conditions, and crystalline form II transforms into crystalline form I under heating conditions, and thus crystalline form I has high stability under high temperature conditions.

[0171] Furthermore, the role of crystalline Form II has been demonstrated, which can be used as an intermediate crystalline form to prepare some of the other stable crystalline forms of the present invention. Thus, the crystalline forms of the compound of formula (I) of the present invention have at least one effect such as stability, and can therefore provide various intermediate and / or raw material options for large-scale production of drug substances and downstream processes of pharmaceuticals (e.g., formulation processes).

[0172] The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principles of the present invention are equivalent exchanges and shall fall within the protection scope of the present invention.

Claims

1. Crystalline Form I of the compound of formula (I), The XRPD pattern of crystalline Form I of the compound of formula (I) has diffraction peaks at 2θ of 10.0, 10.6, 11.5, 12.1, 14.1, 16.7, 17.4, 19.0, 19.4, 20.5, 21.9, and 24.9 (±0.2°), and the XRPD pattern of crystalline Form I of the compound of formula (I) has diffraction peaks at 2θ of 13.4, 14.5, 17.8, 18.7, 20.0, 21.1, 22.8, 23.8, 26.0, and 26.9 (±0.2°). The diffraction peaks in the XRPD pattern of crystalline Form I of the compound of formula (I) are set forth in the following table: Still further, crystalline Form I of the compound of formula (I), characterized in that the XRPD pattern of said crystalline Form I of the compound of formula (I) is essentially as shown in Figure 1.

2. The crystalline form I of the compound of formula (I) according to claim 1, characterized in that the DSC thermogram of the compound of formula (I) has an endothermic peak onset at 188.1±3°C, and the DSC thermogram of the compound of formula (I) is shown in Figure 2.

3. 2. The crystalline form I of the compound of formula (I) according to claim 1, wherein the TGA thermogram of the crystalline form I of the compound of formula (I) shows a weight loss of 0.3±1% at 100°C, and the TGA thermogram of the crystalline form I of the compound of formula (I) is shown in Figure 3.

4. Crystalline Form II of the compound of formula (I), The XRPD pattern of the crystalline form II of the compound of formula (I) has diffraction peaks at 2θ angles of 10.9, 12.1, 16.1, 17.0, 17.5, 18.3, and 23.4 (±0.2°). Further, the diffraction peaks in the XRPD pattern of the crystalline form II of the compound of formula (I) are shown in the following table: Still further, crystalline Form II of the compound of formula (I), characterized in that the XRPD pattern of said crystalline Form II of the compound of formula (I) is essentially as shown in Figure 5.

5. 5. The crystalline form II of the compound of formula (I) according to claim 4, wherein the DSC thermogram of the crystalline form II of the compound of formula (I) has endothermic peak onsets at 72.7, 115.0, 177.3, and 262.0 (±3°C) and an exothermic peak onset at 150.8±3°C, and the DSC thermogram of the crystalline form II of the compound of formula (I) is shown in Figure 6.

6. 5. The crystalline form II of compound of formula (I) according to claim 4, wherein the TGA thermogram of the crystalline form II of compound of formula (I) shows a weight loss of 7.8±1% at 230°C, and the TGA thermogram of the crystalline form II of compound of formula (I) is shown in Figure 7.

7. Crystalline Form III of the compound of formula (I), The XRPD pattern of the crystalline form III of the compound of formula (I) has diffraction peaks at 2θ of 6.1, 10.6, 12.3, 16.6, 17.9, and 18.7 (±0.2°). Further, the diffraction peaks in the XRPD pattern of the crystalline form III of the compound of formula (I) are shown in the following table: Still further, crystalline Form III of the compound of formula (I), characterized in that the XRPD pattern of said crystalline Form III of the compound of formula (I) is essentially as shown in Figure 8.

8. The crystalline form III of the compound of formula (I) according to claim 7, characterized in that the DSC thermogram of the crystalline form III of the compound of formula (I) has endothermic peak onsets at 86.0, 130.8, and 186.3 (±3°C), and the DSC thermogram of the crystalline form III of the compound of formula (I) is shown in Figure 9.

9. 8. The crystalline form III of compound of formula (I) according to claim 7, wherein the TGA thermogram of the crystalline form III of compound of formula (I) shows a weight loss of 6.3±1% at 100°C and a weight loss of 4.5±1% at 200°C, and the TGA thermogram of the crystalline form III of compound of formula (I) is shown in Figure 10.

10. Crystalline Form IV of the compound of formula (I), The XRPD pattern of crystalline Form IV of the compound of formula (I) has diffraction peaks at 2θ of 6.2, 8.1, 10.7, 16.4, 17.1, 18.6, 19.4, and 21.3 (±0.2°), and the XRPD pattern of crystalline Form IV of the compound of formula (I) has diffraction peaks at 2θ of 7.1, 11.2, 16.7, 17.7, 18.8, 19.8, 20.4, 22.0, 22.3, 22.5, 23.1, and 24.7 (±0.2°). The diffraction peaks in the XRPD pattern of crystalline Form IV of the compound of formula (I) are set forth in the following table: Still further, crystalline Form IV of the compound of formula (I), characterized in that the XRPD pattern of said crystalline Form IV of the compound of formula (I) is essentially as shown in Figure 12.

11. The crystalline form IV of the compound of formula (I) according to claim 10, characterized in that the DSC thermogram of the crystalline form IV of the compound of formula (I) has endothermic peak onsets at 49.6 and 130.5 (±3°C), and the DSC thermogram of the crystalline form IV of the compound of formula (I) is shown in Figure 13.

12. 11. The crystalline form IV of compound of formula (I) according to claim 10, wherein the TGA thermogram of the crystalline form IV of compound of formula (I) is 3.8±1% weight loss at 110°C and 4.2±1% weight loss at 190°C, and the TGA thermogram of the crystalline form IV of compound of formula (I) is shown in Figure 14.

13. Crystalline form V of the compound of formula (I), The XRPD pattern of the crystalline form V of the compound of formula (I) has diffraction peaks at 2θ of 6.2, 8.1, 10.6, 16.2, 18.5, and 19.1 (±0.2°). Further, the diffraction peaks in the XRPD pattern of the crystalline form V of the compound of formula (I) are shown in the following table: Still further, crystalline form V of the compound of formula (I), characterized in that the XRPD pattern of said crystalline form V of the compound of formula (I) is essentially as shown in Figure 16.

14. 14. The crystalline form V of the compound of formula (I) according to claim 13, wherein the DSC thermogram of the crystalline form V of the compound of formula (I) has an endothermic peak onset at 148.4±3°C, and the DSC thermogram of the crystalline form V of the compound of formula (I) is shown in Figure 17.

15. 14. The crystalline form V of compound of formula (I) according to claim 13, wherein the TGA thermogram of the crystalline form V of compound of formula (I) shows a weight loss of 10.5±1% at 190°C, and the TGA thermogram of the crystalline form V of compound of formula (I) is shown in Figure 18.

16. Crystalline Form VI of the compound of formula (I), The XRPD pattern of crystalline Form VI of the compound of formula (I) has diffraction peaks at 2θ of 5.5, 5.8, 10.7, 16.9, 17.9, and 18.3 (±0.2°), and the XRPD pattern of crystalline Form VI of the compound of formula (I) has diffraction peaks at 2θ of 9.1, 10.4, 15.9, 20.0, 20.9, and 21.6 (±0.2°). The diffraction peaks in the XRPD pattern of crystalline Form VI of the compound of formula (I) are set forth in the following table: Still further, crystalline Form VI of the compound of formula (I), characterized in that the XRPD pattern of said crystalline Form VI of the compound of formula (I) is essentially as shown in Figure 20.

17. 17. The crystalline form VI of the compound of formula (I) according to claim 16, wherein the DSC thermogram of the crystalline form VI of the compound of formula (I) has endothermic peak onsets at 134.2 and 184.3 (±3°C), and the DSC thermogram of the crystalline form VI of the compound of formula (I) is shown in Figure 21.

18. 17. The crystalline form VI of compound of formula (I) according to claim 16, wherein the TGA thermogram of the crystalline form VI of compound of formula (I) shows a weight loss of 16.2±1% at 200°C, and the TGA thermogram of the crystalline form VI of compound of formula (I) is shown in Figure 22.

19. Crystalline Form VII of the compound of formula (I), Form VII of compound of formula (I), wherein the XRPD pattern of Form VII has diffraction peaks at 2θ of 6.3 and 10.9 (±0.2°); and further wherein the XRPD pattern of Form VII of compound of formula (I) is essentially as shown in Figure 23.

20. 20. The crystalline form VII of the compound of formula (I) according to claim 19, wherein the DSC thermogram of the crystalline form VII of the compound of formula (I) has an endothermic peak onset at 130.2±3°C, and the DSC thermogram of the crystalline form VII of the compound of formula (I) is shown in Figure 24.

21. 20. The crystalline form VII of compound of formula (I) according to claim 19, wherein the TGA thermogram of the crystalline form VII of compound of formula (I) shows a weight loss of 8.6±1% at 190°C, and the TGA thermogram of the crystalline form VII of compound of formula (I) is shown in Figure 25.

22. A drug substance comprising a compound of formula (I) and / or a hydrate or solvate thereof, characterized in that the drug substance comprises at least one crystalline form of the compound of formula (I) according to any one of claims 1 to 21.

23. 23. A pharmaceutical composition comprising a pharmaceutically acceptable adjuvant and the drug substance of claim 22.

24. 24. The pharmaceutical composition of claim 23, wherein the pharmaceutically acceptable adjuvant comprises at least one of a filler, a binder, a disintegrant, and a lubricant.

25. A pharmaceutical product comprising at least one of the crystalline form according to any one of claims 1 to 21, the drug substance according to claim 22, or the pharmaceutical composition according to any one of claims 23 to 24.

26. Use of the crystalline form of any one of claims 1 to 21, the drug substance of claim 22 or the pharmaceutical composition of any one of claims 23 to 24 in the preparation of a medicament for treating coronavirus infection.

27. 27. The method of claim 26, wherein the coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV or SARS-CoV-2 and variants thereof.

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