Crystalline form of ketoamide derivatives and method for preparing them

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] This invention belongs to the field of medicinal chemistry, and more particularly to a series of crystalline forms of ketoamide derivatives and methods for preparing them, as well as active pharmaceutical ingredients and pharmaceutical compositions containing these 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, large-scale zoonotic virus belonging to the Coronaviridae family. Unlike some other coronaviruses such as HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1, these three viruses can cause severe respiratory illness. The pathogen of COVID-19 is the SARS-CoV-2 virus, which belongs to the Coronaviridae family and causes respiratory, hepatic, intestinal, and neurological disorders in mammals. Humans infected with SARS-CoV-2 exhibit a variety of clinical symptoms, with fever, respiratory symptoms, cough, and shortness of breath being the main common symptoms. If the infection persists, it can develop into severe pneumonia and cause serious complications such as respiratory failure, shock, and organ failure. Some patients with mild symptoms or those who have been discharged from the hospital may experience relapses after recovery. Even more serious is that this virus is not only highly infectious but can also be transmitted through asymptomatic carriers or those with symptoms or pre-symptomatic infections.

[0003] During coronavirus infection in a host, the main protease (M PRO, also known as 3CLPRO), an enzyme essential for viral replication, is a type of cysteine ​​hydrolase capable of cleaving polyproteins at multiple sites within the virus to produce multiple active functional proteins. The 3CLPRO sequence is highly conserved among coronaviruses and is crucial for the normal function of coronaviruses. Because inhibition of 3CLPRO can not only effectively kill coronaviruses but also alleviate immune imbalances in infected host cells, 3CLPRO has become a key target in the current development of broad-spectrum anticoronavirus 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 COVID-19 developed by Shionogi & Co., Ltd., which efficiently inhibits 3CLPRO in the novel coronavirus and exerts an antiviral effect. In preclinical trials, S-217622 was confirmed to strongly affect 3CLPRO activity in vitro, with an IC50 value of 0.013 μM and an EC50 value of 0.37 μM. Paxlovid is an oral treatment for COVID-19 developed by Pfizer in the United States, and consists of the 3CL protease inhibitors nirmatrelvir (PF-07321332) and ritonavir. This drug is currently the most effective oral medication on the market, and clinical trials have shown that it reduces the risk of death related to COVID-19 by 89%. TIFF0007875383000001.tif48170

[0005] A series of ketoamide derivatives have been reported in patent PCT / CN2022 / 117124. In vitro activity data shows that some of the compounds exhibit good in vitro anticoronavirus activity at the cellular level without cytotoxicity, with significantly higher exposure levels, slower clearance rates, longer half-lives, and superior pharmacokinetic properties. Among these, compound 1 (Example 1, formula (I)) shows relatively good overall performance and is considered to have good drug discovery potential. TIFF0007875383000002.tif45170

[0006] Crystalline form screening is one of the most important aspects of drug development. For a given compound, the physicochemical properties of its free form, various salt forms, and corresponding crystal forms are still unknown. Therefore, finding a suitable crystal form, while further considering its drug potential, and providing multiple intermediate products and / or active pharmaceutical ingredient options for subsequent drug development is of great significance to drug development. [Overview of the project] [Problems that the invention aims to solve]

[0007] This invention discloses a series of crystalline forms of compounds of formula (I), which exhibit good drug discovery potential (stability, flowability, compressibility, solubility, bioavailability, etc.) and provide a variety of active pharmaceutical ingredient (API) options for subsequent drug development. TIFF0007875383000003.tif51170 [Means for solving the problem]

[0008] The above-mentioned objectives of the present invention are achieved by the following technical solutions.

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

[0010] As those skilled in the art will understand, the differential scanning calorimetry (DSC) curve and thermogravimetric analysis (TGA) curve of a sample may vary in test results for samples from the same batch and / or different batches due to the influence of the equipment, detection conditions, inspector, etc. Therefore, based on common knowledge in the art regarding the characterization of crystal forms, the present invention sets the variation range of the starting point of the endothermic and exothermic peaks in the DSC thermogram to ±3°C, and the variation range of the weight loss value in the TGA thermogram to ±1%.

[0011] Unless otherwise specified, "room temperature" in this invention means 25±5℃, and "the thermogravimetric analysis curve (TGA) does not show a significant weight loss" in this invention means that the weight loss before the detection endpoint temperature is 1% or less.

[0012] As those skilled in the art will understand, once the preparation of the compound is complete, it is not possible for the technician to further investigate the specific crystalline form of compound (I). Therefore, the compound of formula (I) may exist in the form of anhydrous, hydrate, or solvate, where the “solvent” in the solvate is an organic solvent, including but not limited to methanol, ethanol, n-propanol, isopropanol, acetone, butanone, acetonitrile, dichloromethane, trichloromethane, ethyl acetate, toluene, and others commonly used in the art.

[0013] The first object of the present invention is to provide crystalline form I of a compound of formula (I) and a method for preparing the same, the crystalline form of which shows good drug discovery potential. TIFF0007875383000004.tif45170

[0014] Specifically, the XRPD pattern of crystalline form I of the compound of formula (I) above has diffraction peaks that appear stably at 2θ values ​​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 values ​​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) are shown in the table below. TIFF0007875383000005.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 shown in Figure 1.

[0018] The differential scanning calorimetry curve (DSC) of crystalline form I of the compound of formula (I) has an endothermic peak starting point 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) is essentially as shown in FIG. 2.

[0020] The thermogravimetric analysis curve (TGA) of crystalline form I of the compound of formula (I) has 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) is essentially as shown in FIG. 3.

[0022] A second object of the present invention is to provide crystalline form II of the compound of formula (I) and a method for its preparation, and this crystalline form exhibits good drug discovery potential. TIFF0007875383000006.tif45170

[0023] Specifically, the XRPD pattern of crystalline form II of the compound of formula (I) has diffraction peaks that stably appear at positions where 2θ is 10.9, 12.1, 16.1, 17.0, 17.5, 18.3, 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) are shown in the following table. TIFF0007875383000007.tif33170

[0025] Furthermore, in some embodiments of the present invention, the XRPD pattern of crystalline form II of the compound of formula (I) is essentially as shown in FIG. 5.

[0026] The differential scanning calorimetry (DSC) curve of crystalline form II of the compound of formula (I) above has endothermic peaks at 72.7, 115.0, 177.3, and 262.0 ± 3°C, and an exothermic peak 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 shown in Figure 6.

[0028] The thermogravimetric analysis curve (TGA) of crystalline form II of the compound in equation (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 shown in Figure 7.

[0030] A third object of the present invention is to provide crystalline form III of the compound of formula (I) and a method for preparing the same, the crystalline form of which shows good drug discovery potential. TIFF0007875383000008.tif45170

[0031] Specifically, the XRPD pattern of crystalline form III of the compound of formula (I) above has diffraction peaks that appear stably at 2θ values ​​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. TIFF0007875383000009.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 shown in Figure 8.

[0034] The differential scanning calorimetry (DSC) curve of crystalline form III of the compound of formula (I) above has an endothermic peak starting at 86.0, 130.8, and 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 shown in Figure 9.

[0036] The thermogravimetric analysis (TGA) curve of the compound of formula (I) above in crystalline form III 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 shown in Figure 10.

[0038] A fourth object of the present invention is to provide a crystalline form IV of the compound of formula (I) and a method for preparing the same, the crystalline form of which shows good drug discovery potential. TIFF0007875383000010.tif45170

[0039] Specifically, the XRPD pattern of the compound of formula (I) above, crystal form IV, has diffraction peaks that appear stably at 2θ values ​​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 values ​​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. TIFF0007875383000011.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 shown in Figure 12.

[0043] The differential scanning calorimetry (DSC) curve of the compound of formula (I) above in crystalline form IV has an endothermic peak starting at 49.6 and 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 shown in Figure 13.

[0045] The thermogravimetric analysis (TGA) curve (TGA) of the compound of formula (I) above in crystalline form IV 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 shown in Figure 14.

[0047] A fifth object of the present invention is to provide a crystalline form V of the compound of formula (I) and a method for preparing the same, the crystalline form of which shows good drug discovery potential. TIFF0007875383000012.tif45170

[0048] Specifically, the XRPD pattern of the crystalline form V of the compound of formula (I) above has diffraction peaks that appear stably at 2θ values ​​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. TIFF0007875383000013.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 shown in Figure 16.

[0051] The differential scanning calorimetry (DSC) curve of the crystalline form V of the compound of formula (I) above has an endothermic peak starting 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 shown in Figure 17.

[0053] The thermogravimetric analysis curve (TGA) of the crystalline form V of the compound in 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 shown in Figure 18.

[0055] A sixth object of the present invention is to provide a crystalline form VI of a compound of formula (I) and a method for preparing the same, the crystalline form of which shows good drug discovery potential. TIFF0007875383000014.tif45170

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

[0057] Furthermore, the XRPD pattern of crystalline form VI of the compound of formula (I) above has diffraction peaks at 2θ values ​​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. TIFF0007875383000015.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 shown in Figure 20.

[0060] The differential scanning calorimetry (DSC) curve of crystalline form VI of the compound of formula (I) above has an endothermic peak starting at 134.2 and 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 shown in Figure 21.

[0062] The thermogravimetric analysis curve (TGA) of the crystalline form VI of the compound in 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 shown in Figure 22.

[0064] A seventh object of the present invention is to provide a crystalline form VII of the compound of formula (I) and a method for preparing the same, the crystalline form of which shows good drug discovery potential. TIFF0007875383000016.tif45170

[0065] Specifically, this XRPD pattern has diffraction peaks that appear stably at 2θ values ​​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 shown in Figure 23.

[0067] The differential scanning calorimetry (DSC) curve of the compound of formula (I) above in crystalline form VII has an endothermic peak starting 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 shown in Figure 24.

[0069] The thermogravimetric analysis curve (TGA) of the compound of formula (I) above in crystalline form VII 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 shown in Figure 25.

[0071] The eighth object of the present invention is to provide a crystalline form VIII of the compound of formula (I) and a method for preparing the same. TIFF0007875383000017.tif45170

[0072] Specifically, the XRPD pattern of the compound of formula (I) above, crystal form VIII, has diffraction peaks that appear stably at 2θ values ​​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. TIFF0007875383000018.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 shown in Figure 26.

[0075] The ninth object of the present invention is to provide the crystalline form IX of the compound of formula (I) and a method for preparing the same. TIFF0007875383000019.tif45170

[0076] Specifically, the XRPD pattern of the crystalline form IX of the compound of formula (I) above has diffraction peaks that appear stably at 2θ values ​​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. TIFF0007875383000020.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 shown in Figure 27.

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

[0080] Based on the beneficial effects of crystalline forms I to IX of the compound of formula (I) described above in the present invention, the active pharmaceutical ingredient (API) containing the above crystalline forms also has beneficial effects (e.g., stability, water solubility, etc.) that are substantially consistent with those of the crystalline forms. Specifically, the API may be the compound of formula (I), the compound of formula (I) and / or a hydrate of the compound of formula (I), the compound of formula (I) and / or an anhydrous of the compound of formula (I), or 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 compound (I) and / or crystalline form II of compound (I) and / or crystalline form III of compound (I) and / or crystalline form IV of compound (I) and / or crystalline form V of compound (I) and / or crystalline form VI of compound (I) and / or crystalline form VII of compound (I) and / or crystalline form VIII of compound (I) and / or crystalline form IX of compound (I) contained in the above-mentioned active pharmaceutical ingredient is any value between 0.01 and 99.99%. Furthermore, the mass percentage of crystalline form I of compound (I) and / or crystalline form II of compound (I) and / or crystalline form III of compound (I) and / or crystalline form IV of compound (I) and / or crystalline form V of compound (I) and / or crystalline form VI of compound (I) and / or crystalline form VII of compound (I) and / or crystalline form VIII of compound (I) and / or crystalline form IX of compound (I) contained in the above-mentioned active pharmaceutical ingredient is any value between 1.00 and 99.00%.

[0081] An eleventh object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned active pharmaceutical ingredient and a pharmaceutically acceptable adjuvant, wherein the pharmaceutically acceptable adjuvant includes, but is not limited to, at least one of fillers, binders, disintegrants, lubricants, etc. Specifically, based on the beneficial effects of crystalline forms I to IX of the compound of formula (I) above, the beneficial effects are ultimately reflected in the pharmaceutical composition. More specifically, the mass percentage of the above-mentioned active pharmaceutical ingredient contained in the pharmaceutical composition is any value between 1.00 and 99.00%, furthermore, the mass percentage of the above-mentioned active pharmaceutical ingredient contained in the pharmaceutical composition is any value between 5.00 and 95.00%, and furthermore, the mass percentage of the above-mentioned active pharmaceutical ingredient 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-described crystalline form, the above-described active pharmaceutical ingredient, or the above-described pharmaceutical composition. A thirteenth object of the present invention is to provide the use of a pharmaceutical composition in the preparation of a drug for treating coronavirus infection, specifically, the coronavirus being HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2 and its variants.

[0083] Thus, since the crystalline forms I to IX of the compound of formula (I) of the present invention have a certain drug discovery potential, if the presence of crystalline forms I to IX of the compound of formula (I) of the present invention is proven by detection means, it is considered that crystalline forms I to IX of the compound of formula (I) provided in the present invention have been used. The above detection means may further include, in addition to powder X-ray diffraction as described above, methods such as differential scanning calorimetry (DSC), infrared spectroscopy (IR), Raman spectroscopy (Raman), solid-state nuclear magnetic resonance (SSNMR), and all other detection methods that can be used individually or in combination to demonstrate the use of crystalline forms I to IX of the compound of formula (I) of the present invention, and influences 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 compared to 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. The above crystalline form possesses characteristics such as high stability and demonstrates 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. The above crystalline form possesses characteristics such as high stability and demonstrates 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. This crystalline form possesses characteristics such as high stability and demonstrates 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. The above crystalline form possesses characteristics such as high stability and demonstrates considerable drug discovery potential.

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

[0090] 6. The crystalline form VI of the compound of formula (I) and a method for preparing it are disclosed for the first time, providing a variety of intermediate products and / or raw material options for large-scale production of active pharmaceutical ingredients and downstream processes of pharmaceuticals (e.g., formulation processes).

[0091] 7. The crystalline form VII of the compound of formula (I) and a method for its preparation are disclosed for the first time, providing a variety of intermediate products and / or raw material options for large-scale production of active pharmaceutical ingredients and downstream processes of pharmaceuticals (e.g., formulation processes).

[0092] 8. The crystalline form VIII of the compound of formula (I) and a method for its preparation are disclosed for the first time, providing a variety of intermediate products and / or raw material options for large-scale production of active pharmaceutical ingredients and downstream processes of pharmaceuticals (e.g., formulation processes).

[0093] 9. The crystalline form IX of the compound of formula (I) and a method for its preparation are disclosed for the first time, providing a variety of intermediate products and / or raw material options for large-scale production of active pharmaceutical ingredients and downstream processes of pharmaceuticals (e.g., formulation processes).

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

[0095] 11. The present invention provides a pharmaceutical composition comprising the above-mentioned active pharmaceutical ingredient and a pharmaceutically acceptable adjuvant, wherein the pharmaceutical composition exhibits beneficial effects substantially consistent with crystalline forms I to IX of the compound of formula (I) above. [Brief explanation of the drawing]

[0096] [Figure 1] This is the XRPD pattern of crystalline form I of the compound of formula (I). [Figure 2]This is a DSC thermogram of crystalline form I of the compound of formula (I). [Figure 3] This is a TGA thermogram of crystalline form I of the compound of formula (I). [Figure 4] XRPD comparison diagram of crystalline form I of compound (I). [Figure 5] This is the XRPD pattern of crystalline form II of the compound of formula (I). [Figure 6] This is a DSC thermogram of crystalline form II of the compound of formula (I). [Figure 7] This is a TGA thermogram of crystalline form II of the compound of formula (I). [Figure 8] This is the XRPD pattern of crystalline form III of the compound of formula (I). [Figure 9] This is a DSC thermogram of crystalline form III of the compound of formula (I). [Figure 10] This is a TGA thermogram of the crystalline form III of the compound of formula (I). [Figure 11] XRPD comparison diagram of crystalline form III of the compound of formula (I). [Figure 12] This is the XRPD pattern of crystalline form IV of the compound of formula (I). [Figure 13] This is a DSC thermogram of crystalline form IV of the compound of formula (I). [Figure 14] This is a TGA thermogram of crystalline form IV of the compound of formula (I). [Figure 15] XRPD comparison diagram of crystalline form IV of the compound of formula (I). [Figure 16] This is the XRPD pattern of crystalline form V of the compound of formula (I). [Figure 17] This is a DSC thermogram of crystalline form V of the compound of formula (I). [Figure 18] This is a TGA thermogram of the crystalline form V of the compound of formula (I). [Figure 19] XRPD comparison diagram of crystalline form V of compound (I). [Figure 20] This is the XRPD pattern of crystalline form VI of the compound of formula (I). [Figure 21]This is a DSC thermogram of crystalline form VI of the compound of formula (I). [Figure 22] This is a TGA thermogram of crystalline form VI of the compound of formula (I). [Figure 23] This is the XRPD pattern of crystalline form VII of the compound of formula (I). [Figure 24] This is a DSC thermogram of crystalline form VII of the compound of formula (I). [Figure 25] This is a TGA thermogram of crystalline form VII of the compound of formula (I). [Figure 26] This is the XRPD pattern of crystalline form VIII of the compound of formula (I). [Figure 27] This is the XRPD pattern of crystalline form IX of the compound of formula (I). [Modes for carrying out the invention]

[0097] The present invention will be described in more detail below with reference to examples and 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 scanning angle: 3° to 45° Scanning 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: The sample was accurately weighed, placed on a DSC Tzero sample plate, and heated to 350°C while purging the furnace with nitrogen at a rate of 50 mL / min.

[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 the compound of formula (I) TIFF0007875383000021.tif46170

[0103] Synthesis pathway: TIFF0007875383000022.tif144170

[0104] Step 1: Synthesis of hydrochloride salts of compounds 1 and 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, 4 N) was added. The mixture was reacted at 20°C for 2 hours with stirring. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of compound 1-2 without 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 reacted with stirring for 0.5 hours, then diisopropylethylamine (1.26 g, 9.72 mmol) and the hydrochloride salt of compound 1-3 (1.02 g, 4.66 mmol) were added, and the mixture was reacted with stirring at 20°C for 16 hours. Methyl tert-butyl ether (50 mL) was added to the reaction mixture, washed with water (20 mL), washed with 3% citric acid (20 mL x 2), washed with saturated sodium chloride aqueous solution (20 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compounds 1-4 were obtained by purification using silica gel column chromatography (petroleum ether:ethyl acetate = 3:1). 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 Compounds 1-4 (1.41 g, 3.34 mmol) were added to tetrahydrofuran (14 mL), and a solution of lithium hydroxide monohydrate LiOH·H2O (280.03 mg, 6.67 mmol) in water (5 mL) was added. The mixture was reacted at 20°C for 16 hours with stirring. The crude product was neutralized with 3% citric acid solution (50 mL), extracted with ethyl acetate (50 mL), the organic phase was washed with saturated sodium chloride aqueous solution (30 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compounds 1-5 were obtained without 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), to which 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) were added. The mixture was reacted at 20°C for 0.5 hours with stirring, then the hydrochloride of compound 1-2 (366.88 mg, 1.65 mmol) was added, and the mixture was reacted at 20°C for 16 hours with stirring. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane:methanol (30 mL x 2, 10:1). The organic phases were combined, washed with 3% citric acid (20 mL x 2), washed with saturated sodium chloride aqueous solution (20 mL), and the organic layer was dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated under reduced pressure. The compounds were purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compounds 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 Compounds 1-6 (3.10 g, 5.51 mmol) were dissolved in tetrahydrofuran (31 mL), lithium borohydride (240.02 mg, 11.02 mmol) was added at 0°C, and the mixture was slowly heated to 20°C and reacted for 2 hours. Water (10 mL) and ethyl acetate (20 mL) were added to the reaction mixture and stirred for 10 minutes to precipitate a white solid. The mixture was filtered to obtain the filtration cake, i.e., the crude product of the target products 1-7. [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), then Dess-Martin oxidizing agent (594.94 mg, 1.40 mmol) was added to the reaction system and the reaction was carried out at 25°C for 16 hours with stirring. Saturated sodium thiosulfate (15 mL) and saturated sodium bicarbonate solution (15 mL) were added to the reaction system and stirred for 10 minutes. 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 obtain the crude product of 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 system and the mixture was reacted at 25°C for 2 hours with stirring. Saturated ammonium chloride solution (10 mL) was added to the reaction system and stirred for 10 minutes. The mixture was 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. The mixture was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 1-9. [M+1]+ = 688.4.

[0111] Step 8: Synthesis of Compounds 1-10 Compounds 1-9 (190 mg, 276.22 μmol) were dissolved in methanol (3 mL), and then a solution of potassium carbonate (95.44 mg, 690.54 μmol) in water (2 mL) was added. The reaction was carried out at 20°C for 16 hours with stirring. 3% citric acid (20 mL) was added to the reaction system, and the mixture was extracted three times with dichloromethane (40 mL). The organic phase was washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude products 1-10 were obtained. [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 oxidizing agent (203.19 mg, 479.08 μmol) was added. The reaction was carried out at 20°C for 18 hours with stirring. Sodium thiosulfate (15 mL) and sodium bicarbonate solution (15 mL) were added to the reaction system, and the mixture was stirred for 10 minutes. 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. The solution was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain product 1-11. [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 carried out at 20°C for 1 hour with stirring. The reaction mixture was directly evaporated by rotation using an oil pump, and rotation evaporation was repeated with a small amount of dichloromethane to obtain 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 trifluoroacetic anhydride (193.15 mg, 919.63 μmol) and pyridine (127.30 mg, 1.61 mmol) were added at 0 °C. The reaction was carried out with stirring at 20 °C for 16 h. Water (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phase was successively washed with 3% citric acid (40 mL) and saturated aqueous sodium chloride solution (40 mL × 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 - 1.81 (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 - 4.10 (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 Preparation method of crystalline form I of the compound of formula (I)

[0116] Weighed 20.0 mg of the compound of formula (I) prepared in Example 1, added it to 0.5 mL of acetone / n-heptane (v / v, 1:9) to prepare a suspension, suspended it with stirring at room temperature (~25 °C) for 7 days, centrifuged the suspension, and dried it under vacuum at room temperature to obtain a white solid, that is, crystalline form I. Its XRPD pattern is shown in Figure 1, its DSC thermogram is shown in Figure 2, and its TGA thermogram is shown in Figure 3.

[0117] Example 3: Method for preparing crystalline form I of compound (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, the suspension was centrifuged, and the suspension was vacuum-dried at room temperature to obtain a white solid, i.e., crystalline form I.

[0119] A comparison of the XRPD patterns of the obtained crystal form I is shown in Figure 4.

[0120] Example 4: Method for preparing crystalline form II of the 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 gradually added dropwise until the solid was completely or nearly dissolved. The suspension was filtered while still hot, and the solution was allowed to cool to room temperature. The solution was left to stand at room temperature for at least 2 hours. If sufficient solid precipitation did not occur, the solution was further cooled to 4°C. If sufficient solid precipitation still did not occur, the solution was further cooled to -15°C. After centrifugation of the system in which sufficient solid precipitation occurred, the solid was vacuum-dried at room temperature to obtain a white solid, i.e., crystalline form II, the XRPD pattern of which is shown in Figure 5, the DSC thermogram in Figure 6, and the TGA thermogram in Figure 7.

[0122] Example 5: Method for preparing crystalline form III of the 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 methanol / isopropyl ether (v / v, 1:4) to prepare a suspension. The suspension was stirred at 10°C for 24 hours, the suspension was centrifuged, and the mixture was vacuum-dried at room temperature to obtain a white solid, i.e., crystalline form III. Its XRPD pattern is shown in Figure 8, its DSC thermogram is shown in Figure 9, and its TGA thermogram is shown in Figure 10.

[0124] Example 6: Method for preparing crystalline form III of the 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 gradually added dropwise until the solid was completely or nearly dissolved. The suspension was filtered while still hot, and the solution was allowed to cool to room temperature. After standing at room temperature for at least 2 hours and centrifugation of the system where sufficient solid had precipitated, the solid was vacuum-dried at room temperature to obtain a white solid, i.e., crystalline form III.

[0126] A comparison of the XRPD patterns of the obtained crystal form III is shown in Figure 11.

[0127] Example 7: Method for preparing crystalline form IV of the 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 left to stand open at room temperature until the solvent completely evaporated and a solid was obtained. The solution was then vacuum-dried at room temperature to obtain a white solid, i.e., crystal form IV. Its XRPD pattern is shown in Figure 12, its DSC thermogram is shown in Figure 13, and its TGA thermogram is shown in Figure 14.

[0129] Example 8: Method for preparing crystalline form IV of the 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 left to stand with stirring at room temperature (~25°C) for 7 days, the suspension was centrifuged, and the suspension was vacuum-dried at room temperature to obtain a white solid, i.e., crystalline form IV.

[0131] A comparison of the XRPD patterns of the obtained crystal form IV is shown in Figure 15.

[0132] Example 9: Method for preparing crystalline form V of the 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. The resulting clear solution was left to stand open at room temperature until the solvent completely evaporated and a solid was obtained. The solution was then vacuum-dried at room temperature to obtain a white solid, i.e., crystalline form V. Its XRPD pattern is shown in Figure 16, its DSC thermogram in Figure 17, and its TGA thermogram in Figure 18.

[0134] Example 10: Method for preparing crystalline form V of the 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 allowed to stand with stirring at room temperature (~25°C) for 7 days, the suspension was centrifuged, and the suspension was vacuum-dried at room temperature to obtain a white solid, i.e., crystalline form V.

[0136] A comparison of the XRPD patterns of the obtained crystal form V is shown in Figure 19.

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

[0138] 20.2 mg of the compound of formula (I) prepared in Example 1 was weighed, 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 in which the solid had precipitated was centrifuged, and the solid was vacuum-dried at room temperature to obtain a white solid, i.e., crystalline form VI. The XRPD pattern of the obtained crystalline form VI is shown in Figure 20, the DSC thermogram is shown in Figure 21, and the TGA thermogram is shown in Figure 22.

[0139] Example 12: Method for preparing crystalline form VII of the 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 gradually added dropwise until the solid was completely or nearly dissolved. The suspension was filtered while still hot, and the solution was allowed to cool to room temperature. After standing at room temperature for at least 2 hours, if sufficient solid precipitation did not occur, the solution was further cooled to 4°C. If sufficient solid precipitation still did not occur, the solution was further cooled to -15°C. After centrifugation of the system in which sufficient solid precipitation occurred, the solid was vacuum-dried at room temperature to obtain a white solid, i.e., crystal form VII, the XRPD pattern is shown in Figure 23, the DSC thermogram is shown in Figure 24, and the TGA thermogram is shown in Figure 25.

[0141] Example 13: Method for preparing crystalline form VIII of the 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 gradually added dropwise until the solid was completely or nearly dissolved. The suspension was filtered while still hot, and the solution was allowed to cool to room temperature. After standing at room temperature for at least 2 hours to allow the solid to precipitate, the system with sufficient solid precipitate was centrifuged, and the solid was vacuum-dried at room temperature to obtain a white solid, i.e., crystalline form VIII, the XRPD pattern of which 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 the 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 gradually added dropwise until the solid was completely or nearly dissolved. The solution was filtered while still hot, and then allowed to cool to room temperature. After standing at room temperature for at least 2 hours, if sufficient solid precipitation did not occur, the solution was further cooled to 4°C. If sufficient solid precipitation still did not occur, the solution was further cooled to -15°C. After centrifugation of the system in which sufficient solid precipitation occurred, the solid was vacuum-dried at room temperature to obtain a white solid, i.e., crystal form IX, the XRPD pattern of which is shown in Figure 27.

[0145] Example 15 Solid Stability Test of Crystal Forms I, IV, and V of Compound (I) under High Temperature and High Humidity Conditions

[0146] Approximately 100 mg each of two samples of the compound of formula (I) in crystalline forms I, IV, and V were weighed in parallel and placed in the bottom of a glass sample vial, spreading them into a thin layer. The mouth of the sample vial was sealed with aluminum foil, and several small holes were made in the aluminum foil to allow sufficient contact between the sample and the outside air. The vial was then placed in a constant temperature and humidity chamber at 40°C / 75% humidity. Samples were taken and detected on day 0, day 12, and day 30 under the above conditions, and the detection results were compared with the initial detection results on day 0. The test results are shown in Tables 1 to 3 below.

[0147] TIFF0007875383000023.tif120170*N / A indicates no detection.

[0148] TIFF0007875383000024.tif120170*N / A indicates no detection.

[0149] TIFF0007875383000025.tif120170*N / A indicates no detection.

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

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

[0152] When held for 30 days under high humidity conditions of 92.5% RH, there was no difference in crystal form or properties. Total impurities increased slightly, and moisture content increased slightly. When the sample was held in an open environment under high humidity conditions for 30 days, the weight after moisture absorption increased by 0.56%, indicating that the hygroscopicity was not significant.

[0153] When held for 30 days under high temperature and high humidity conditions of 40°C and 75% RH, there was no difference in crystal form or properties, but the total impurities and moisture content increased slightly.

[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 to the compound of formula (I) prepared in Example 1.

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

[0156] When held for 30 days under high humidity conditions of 92.5%RH, there was no difference in crystal form or properties, only a slight increase in total impurities and moisture content. The sample, when held in an open environment under high humidity conditions for 30 days, showed a significant increase in weight after moisture absorption, indicating remarkable hygroscopicity.

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

[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 the crystalline form V of compound I was maintained at a high temperature of 60°C for 30 days, there was no difference in crystalline form or properties, only a slight increase in total impurities and no increase in moisture content.

[0160] When held for 30 days under high humidity conditions of 92.5%RH, there was no difference in crystal form or properties. Total impurities increased slightly, and moisture content increased. When the sample was held in an open environment under high humidity conditions for 30 days, the weight after moisture absorption increased by 1.1%, indicating that the hygroscopicity was not significant.

[0161] When held for 30 days under high temperature and high humidity conditions of 40°C and 75% RH, there was no difference in crystal form or properties, but the total impurities and moisture content increased slightly.

[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 held 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 high humidity conditions, while crystalline forms IV and V were relatively stable under high temperature conditions.

[0164] Furthermore, the inventor discovered the following during the experimental process and further research:

[0165] Crystal form II is obtained by cooling in a cyclohexane-toluene solvent system and then evaporating it. After vacuum drying the evaporated crystal form II at room temperature, the sample remains in crystal form II, suggesting that crystal form II has high stability. Crystal form III is obtained by crystallization by prolonged stirring in a methanol / isopropyl ether system at 10°C, and those skilled in the art will understand that crystal form III has high stability.

[0166] Crystal form VIII is an unstable crystal form, and during the post-processing process (vacuum drying at room temperature), a crystal transition occurs, transforming into crystal form V. Crystal form V is ultimately obtained by transitioning from the intermediate metastable crystal form (crystal form VIII), and it was found to be highly stable.

[0167] Example 16: Crystallographic thermal transition experiment

[0168] Using different crystal forms as starting materials, samples were placed on a BTS500 heating stage, and XRPD testing was performed at room temperature. Subsequently, the samples were heated to a selected temperature at 10°C / min, held for 10 minutes, and then XRPD testing was performed again at this temperature. After cooling to room temperature, XRPD testing was performed again. The results are shown in Table 4.

[0169] TIFF0007875383000026.tif41170

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

[0171] Furthermore, the role of crystal form II has been demonstrated to be that it can be used as an intermediate crystal form to further prepare some of the other stable crystal forms of the present invention. Thus, the crystal forms of the compound of formula (I) described above of the present invention have at least one of the following effects, such as stability, making it possible to provide a variety of intermediate products and / or raw material options for large-scale production of active pharmaceutical ingredients and downstream processes of pharmaceuticals (e.g., formulation processes).

[0172] While the above embodiments represent preferred embodiments of the present invention, the embodiments of the present invention are not limited thereto. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principles of the present invention are equivalent exchanges and are within the scope of protection of the present invention.

Claims

1. A crystalline form of the compound of formula (I), wherein the crystalline form is selected from at least one of crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V, crystalline form VI, and crystalline form VII. Equation (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 furthermore, 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°), and furthermore, the diffraction peaks in the XRPD pattern of crystalline form I of the compound of formula (I) are shown in the table below. The XRPD pattern of crystalline form II of the compound of formula (I) has diffraction peaks at 2θ of 10.9, 12.1, 16.1, 17.0, 17.5, 18.3, and 23.4 (±0.2°). Furthermore, the diffraction peaks in the XRPD pattern of crystalline form II of the compound of formula (I) are shown in the table below. 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°). Furthermore, the diffraction peaks in the XRPD pattern of the crystalline form III of the compound of formula (I) are shown in the table below. 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 furthermore, 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°), and furthermore, the diffraction peaks in the XRPD pattern of crystalline form IV of the compound of formula (I) are shown in the table below. The XRPD pattern of 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°). Furthermore, the diffraction peaks in the XRPD pattern of crystalline form V of the compound of formula (I) are shown in the table below. 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 furthermore, 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°), and furthermore, the diffraction peaks in the XRPD pattern of crystalline form VI of the compound of formula (I) are shown in the table below. The XRPD pattern of the crystalline form VII of the compound of formula (I) is characterized by having diffraction peaks at 2θ of 6.3 and 10.9 (±0.2°). The crystalline form of the compound of formula (I).

2. The DSC thermogram of crystalline form I of the compound of formula (I) above has an endothermic peak starting at 188.1 ± 3°C. Furthermore, the TGA thermogram of crystalline form I of the compound of formula (I) is characterized by a weight loss of 0.3 ± 1% at 100°C. The crystalline form of the compound of formula (I) described in claim 1.

3. The DSC thermogram of crystalline form II of the compound of formula (I) above has endothermic peaks at 72.7, 115.0, 177.3, and 262.0 (±3°C), and exothermic peaks at 150.8±3°C. Furthermore, the TGA thermogram of crystalline form II of the compound of formula (I) shows a weight loss of 7.8 ± 1% at 230°C. Furthermore, the DSC thermogram of the crystalline form III of the compound of formula (I) has endothermic peaks starting at 86.0, 130.8, and 186.3 (±3°C). Furthermore, the TGA thermogram of the crystalline form III of the compound of formula (I) is characterized by a weight loss of 6.3 ± 1% at 100°C and a weight loss of 4.5 ± 1% at 200°C. The crystalline form of the compound of formula (I) described in claim 1.

4. The DSC thermogram of crystalline form IV of the compound of formula (I) above has an endothermic peak starting at 49.6, 130.5 (±3°C). Furthermore, the TGA thermogram of the crystalline form IV of the compound of formula (I) is characterized by a weight loss of 3.8 ± 1% at 110°C and a weight loss of 4.2 ± 1% at 190°C. The crystalline form of the compound of formula (I) described in claim 1.

5. The DSC thermogram of the crystalline form V of the compound of formula (I) above has an endothermic peak starting point at 148.4 ± 3°C. Furthermore, the TGA thermogram of the crystalline form V of the compound of formula (I) is characterized by a weight loss of 10.5 ± 1% at 190°C. The crystalline form of the compound of formula (I) described in claim 1.

6. The DSC thermogram of the crystalline form VI of the compound of formula (I) above has an endothermic peak starting point at 134.2, 184.3 (±3°C). Furthermore, the TGA thermogram of the crystalline form VI of the compound of formula (I) shows a weight loss of 16.2 ± 1% at 200°C. Furthermore, the DSC thermogram of crystalline form VII of the compound of formula (I) has an endothermic peak starting point at 130.2 ± 3°C. Furthermore, the TGA thermogram of the crystalline form VII of the compound of formula (I) is characterized by a weight loss of 8.6 ± 1% at 190°C. The crystalline form of the compound of formula (I) described in claim 1.

7. A drug substance comprising a compound of formula (I) and / or its hydrate or solvate, characterized in that it comprises a crystalline form of the compound of formula (I) as described in any one of claims 1 to 6.

8. A pharmaceutically acceptable adjuvant comprising the active pharmaceutical ingredient described in claim 7, Furthermore, the pharmaceutical composition is characterized in that the pharmaceutically acceptable adjuvant comprises at least one of a filler, a binder, a disintegrant, and a lubricant.

9. A pharmaceutical product characterized by containing a crystalline form of the compound of formula (I) described in any one of claims 1 to 6.

10. A pharmaceutical product for treating coronavirus infection, comprising as an active ingredient the crystalline form of the compound of formula (I) described in any one of claims 1 to 6, A pharmaceutical product characterized in that the coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2 or its variants.

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