Crystal form of ketone amide derivative and preparation method thereof

Abstract

The invention relates to a crystal form of a ketoamide derivative and a preparation method thereof, and the series of crystal forms of the compound have good druggability (stability, fluidity, compressibility, solubility, bioavailability and the like), and provide choices of various bulk drugs for subsequent drug development.

Description

A crystal form of a ketoamide derivative and a preparation method thereof Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a series of crystal forms of ketoamide derivatives and preparation methods thereof, as well as raw materials and pharmaceutical compositions containing the crystal forms. Background Art

[0002] SARS-CoV-2 (acute respiratory syndrome coronavirus 2) is a highly pathogenic, pandemic zoonotic virus belonging to the same family as SARS-CoV-1 and MERS-CoV. These three viruses, unlike several other coronaviruses (HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoVHKU1), can cause severe respiratory illness. The causative agent of COVID-19, SARS-CoV-2, a member of the Coronaviridae family, causes respiratory, hepatic, intestinal, and neurological diseases in mammals. Human infection with SARS-CoV-2 presents with a variety of clinical manifestations, with fever, respiratory symptoms, cough, and shortness of breath being the most common. Prolonged infection can progress to severe pneumonia, leading to serious complications such as respiratory failure, shock, and organ failure. Some patients who have experienced mild symptoms or have been discharged from the hospital may experience relapses of their illness after recovery. Furthermore, this virus is not only highly contagious but can be transmitted by asymptomatic individuals and those in the symptomatic and pre-symptomatic stages.

[0003] During coronavirus infection, the main protease (MPRO, also known as 3CLPRO), an enzyme essential for viral replication, is a type of cysteine ​​hydrolase that cleaves the polyprotein complex at multiple sites within the virus, generating multiple active, functional proteins. The 3CLPRO sequence is highly conserved among coronaviruses and is crucial for their normal function. Inhibiting 3CLPRO can not only effectively kill coronaviruses but also reduce immune imbalances within infected host cells. Therefore, 3CLPRO is a key target in the development of broad-spectrum anti-coronavirus drugs, and 3CLPRO inhibitors have become a highly sought-after target in the field of antiviral chemotherapy.

[0004] The following compounds are reported 3CLPRO inhibitor compounds. S-217622 is an oral drug for the treatment of COVID-19 developed by Shionogi Co., Ltd. of Japan. It has high efficiency in inhibiting the novel coronavirus 3CLPRO and exerting an antiviral effect. Preclinical studies have shown that S-217622 has a strong activity against 3CLPRO in vitro, with an IC50 value of 0.013μM and an EC50 value of 0.37μM. The new crown oral drug Paxlovid is an oral drug for the treatment of COVID-19 developed by Pfizer of the United States. It consists of the 3CL protease inhibitor Nirmatrelvir (PF-07321332) and Ritonavir. As the most effective oral drug currently on the market, this drug has been verified by clinical trials to reduce the risk of death related to COVID-19 by 89%.

[0005] Patent PCT / CN2022 / 117124 reports on a series of ketoamide derivatives. In vitro activity data show that some compounds have good in vitro anti-coronavirus activity at the cellular level, are non-cytotoxic, and exhibit significantly increased exposure, slower clearance rates, longer half-lives, and better pharmacokinetic properties. Among them, Compound 1 (Example 1, Formula (I)) has relatively outstanding overall performance and is considered to have good drug development prospects.

[0006] Crystal form screening is an important step in drug development. For a specific compound, the physical and chemical properties of its free form, various salt forms, and corresponding crystal forms are unknown. Based on further consideration of its drugability, finding a suitable crystal form to provide a variety of intermediates and / or APIs for subsequent drug development is of great significance to drug development.

[0007] Summary of the Invention

[0008] The present invention discloses a series of crystalline forms of compounds of formula (I), which exhibit good drugability (stability, fluidity, compressibility, solubility, bioavailability, etc.), providing a variety of raw material drug options for subsequent drug development.

[0009] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0010] Regarding the characterization of the crystal form of a compound, those skilled in the art will understand that for a specific crystal form of a specific compound, due to the influence of instruments, operating methods, sample purity, human factors, etc. during the characterization process, the 2θ angle of each diffraction peak in its X-ray powder diffraction pattern (XRPD) will fluctuate to a certain extent in repeated experiments, and the fluctuation range (error range) is generally within ±0.2°; In addition, those skilled in the art will also understand that the stability and repeatability of the diffraction peak will be affected by factors such as the 2θ angle of each diffraction peak in the X-ray powder diffraction pattern and the absorption intensity (peak height); specifically, the stronger the absorption intensity, the better the separation, and the better the 2θ angle. The smaller the diffraction peak, the better its stability and repeatability, and the more it can be used to characterize the specific crystal form; however, for diffraction peaks with larger 2θ angles and / or poorer separation and / or weaker relative intensity, they may fluctuate greatly due to the influence of instrumentation, operating methods, sample purity, human factors, etc., and may not reappear in repeated experiments. Therefore, for those skilled in the art, such absorption peaks are not necessary diffraction peaks for characterizing the current crystal form; more specifically, the present invention follows the consensus in the field for crystal form characterization, and the selection of diffraction peaks comprehensively considers factors such as 2θ angle and absorption intensity (peak height), and is grouped according to stability and repeatability.

[0011] Those skilled in the art will also understand that for the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of the samples, the samples in the same batch and / or between batches will also be affected by the instruments, testing conditions, testing personnel, etc., resulting in fluctuations in the test results. Therefore, in accordance with the consensus in the art on crystal form characterization, the present invention sets the fluctuation range of the starting points of the endothermic peak and the exothermic peak in the DSC spectrum to ±3°C, and the fluctuation range of the weight loss value in the TGA spectrum to ±1%.

[0012] Unless otherwise specified, "room temperature" in the present invention refers to 25±5° C., and "no obvious weight loss" in the thermogravimetric analysis (TGA) curve in the present invention refers to a weight loss of ≤1% before the detection endpoint temperature.

[0013] Those skilled in the art will understand that at this point in time when the compound is prepared, the technician cannot further study the specific crystalline form of compound (I). Therefore, the compound of formula (I) may exist as anhydrate, hydrate, or solvate. The "solvent" in the solvate is an organic solvent, including but not limited to methanol, ethanol, n-propanol, isopropanol, acetone, butanone, acetonitrile, dichloromethane, chloroform, ethyl acetate, toluene, and the like, which are commonly used in the art.

[0014] The first object of the present invention is to provide a crystalline form I of the compound of formula (I) and a preparation method thereof, wherein the crystalline form exhibits good drugability.

[0015] Specifically, the XRPD spectrum of the crystalline form I of the compound of formula (I) has stable 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°).

[0016] Furthermore, the XRPD spectrum of the crystalline form I of the compound of formula (I) above also 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°).

[0017] Furthermore, in some embodiments of the present invention, the diffraction peaks of the XRPD pattern of the crystalline form I of the compound of formula (I) are shown in the following table:

[0018] Furthermore, in some embodiments of the present invention, the XRPD pattern of the crystalline form I of the compound of formula (I) is substantially as shown in FIG1 .

[0019] The differential scanning calorimetry (DSC) curve of the crystalline form I of the compound of formula (I) has an endothermic peak starting point at 188.1±3°C.

[0020] Furthermore, in some embodiments of the present invention, the DSC spectrum of the crystalline form I of the compound of formula (I) is substantially as shown in FIG2 .

[0021] The thermogravimetric analysis (TGA) curve of the crystalline form I of the compound of formula (I) shows a weight loss of 0.3±1% at 100°C.

[0022] Furthermore, in some embodiments of the present invention, the TGA spectrum of the crystalline form I of the compound of formula (I) is substantially as shown in FIG3 .

[0023] The second object of the present invention is to provide a crystalline form II of the compound of formula (I) and a preparation method thereof, wherein the crystalline form exhibits good drugability.

[0024] Specifically, the crystalline form II of the compound of formula (I) has an XRPD spectrum with stable diffraction peaks at 2θ of 10.9, 12.1, 16.1, 17.0, 17.5, 18.3, and 23.4 (±0.2°).

[0025] Furthermore, in some embodiments of the present invention, the diffraction peaks of the XRPD pattern of the crystalline form II of the compound of formula (I) are shown in the following table:

[0026] Furthermore, in some embodiments of the present invention, the XRPD pattern of the crystalline form II of the compound of formula (I) is substantially as shown in FIG5 .

[0027] The differential scanning calorimetry (DSC) curve 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.

[0028] Furthermore, in some embodiments of the present invention, the DSC spectrum of the crystalline form II of the compound of formula (I) is substantially as shown in FIG6 .

[0029] The thermogravimetric analysis (TGA) curve of the crystalline form II of the compound of formula (I) shows a weight loss of 7.8±1% at 230°C.

[0030] Furthermore, in some embodiments of the present invention, the TGA spectrum of the crystalline form II of the compound of formula (I) is substantially as shown in FIG7 .

[0031] The third object of the present invention is to provide a crystalline form III of the compound of formula (I) and a preparation method thereof, wherein the crystalline form exhibits good drugability.

[0032] Specifically, the crystalline form III of the compound of formula (I) has an XRPD spectrum with stable diffraction peaks at 2θ of 6.1, 10.6, 12.3, 16.6, 17.9, and 18.7 (±0.2°).

[0033] Furthermore, in some embodiments of the present invention, the diffraction peaks of the XRPD spectrum of the crystalline form III of the compound of formula (I) are shown in the following table:

[0034] Furthermore, in some embodiments of the present invention, the XRPD pattern of Form III of the compound of formula (I) is substantially as shown in FIG8 .

[0035] The differential scanning calorimetry (DSC) curve of the crystalline form III of the compound of formula (I) has endothermic peak starting points at 86.0, 130.8, and 186.3 (±3° C.).

[0036] Furthermore, in some embodiments of the present invention, the DSC spectrum of the crystalline form III of the compound of formula (I) is substantially as shown in FIG9 .

[0037] The thermogravimetric analysis (TGA) curve of the crystalline form III of the 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.

[0038] Furthermore, in some embodiments of the present invention, the TGA spectrum of the crystalline form III of the compound of formula (I) is substantially as shown in FIG10 .

[0039] The fourth object of the present invention is to provide a crystalline form IV of the compound of formula (I) and a preparation method thereof, wherein the crystalline form exhibits good drugability.

[0040] Specifically, the crystalline form IV of the compound of formula (I) has an XRPD spectrum with stable diffraction peaks at 2θ of 6.2, 8.1, 10.7, 16.4, 17.1, 18.6, 19.4, and 21.3 (±0.2°).

[0041] Furthermore, the crystalline form IV of the compound of formula (I) above also has diffraction peaks in its XRPD spectrum 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°).

[0042] Furthermore, in some embodiments of the present invention, the diffraction peaks of the XRPD pattern of the crystalline form IV of the compound of formula (I) are shown in the following table:

[0043] Furthermore, in some embodiments of the present invention, the XRPD pattern of Form IV of the compound of formula (I) is substantially as shown in FIG12 .

[0044] The differential scanning calorimetry (DSC) curve of the crystalline form IV of the compound of formula (I) has an endothermic peak starting point at 49.6,130.5±3°C.

[0045] Furthermore, in some embodiments of the present invention, the DSC spectrum of the crystalline form IV of the compound of formula (I) is substantially as shown in FIG13 .

[0046] The thermogravimetric analysis (TGA) curve of the crystalline form IV of the compound of formula (I) shows a weight loss of 3.8±1% at 110°C and a weight loss of 4.2±1% at 190°C.

[0047] Furthermore, in some embodiments of the present invention, the TGA spectrum of the crystalline form IV of the compound of formula (I) is substantially as shown in FIG14 .

[0048] The fifth object of the present invention is to provide a crystalline form V of the compound of formula (I) and a preparation method thereof, wherein the crystalline form exhibits good drugability.

[0049] Specifically, the crystalline form V of the compound of formula (I) has an XRPD spectrum with stable diffraction peaks at 2θ of 6.2, 8.1, 10.6, 16.2, 18.5, and 19.1 (±0.2°).

[0050] Furthermore, in some embodiments of the present invention, the diffraction peaks of the XRPD pattern of the crystalline form V of the compound of formula (I) are shown in the following table:

[0051] Furthermore, in some embodiments of the present invention, the XRPD pattern of the crystalline form V of the compound of formula (I) is substantially as shown in FIG16 .

[0052] The differential scanning calorimetry (DSC) curve of the crystalline form V of the compound of formula (I) has an endothermic peak starting point at 148.4±3°C.

[0053] Furthermore, in some embodiments of the present invention, the DSC spectrum of the crystalline form V of the compound of formula (I) is substantially as shown in FIG17 .

[0054] The thermogravimetric analysis (TGA) curve of the crystalline form V of the compound of formula (I) above shows a weight loss of 10.5±1% at 190°C.

[0055] Furthermore, in some embodiments of the present invention, the TGA spectrum of the crystalline form V of the compound of formula (I) is substantially as shown in FIG18 .

[0056] The sixth object of the present invention is to provide a crystalline form VI of the compound of formula (I) and a preparation method thereof, wherein the crystalline form exhibits good drugability.

[0057] Specifically, its XRPD spectrum has stable diffraction peaks at 2θ of 5.5, 5.8, 10.7, 16.9, 17.9, and 18.3 (±0.2°).

[0058] Furthermore, the XRPD spectrum of the crystalline form VI of the compound of formula (I) also has diffraction peaks at 2θ of 9.1, 10.4, 15.9, 20.0, 20.9, and 21.6 (±0.2°).

[0059] Furthermore, in some embodiments of the present invention, the diffraction peaks of the XRPD spectrum of the crystalline form VI of the compound of formula (I) are shown in the following table:

[0060] Furthermore, in some embodiments of the present invention, the XRPD pattern of the crystalline form VI of the compound of formula (I) is substantially as shown in FIG20 .

[0061] The differential scanning calorimetry (DSC) curve of the crystalline form VI of the compound of formula (I) has an endothermic peak starting point at 134.2, 184.3 (±3° C.).

[0062] Furthermore, in some embodiments of the present invention, the DSC spectrum of the crystalline form VI of the compound of formula (I) is substantially as shown in FIG21 .

[0063] The thermogravimetric analysis (TGA) curve of the crystalline form VI of the compound of formula (I) above shows a weight loss of 16.2±1% at 200°C.

[0064] Furthermore, in some embodiments of the present invention, the TGA spectrum of the crystalline form VI of the compound of formula (I) is substantially as shown in FIG22 .

[0065] The seventh object of the present invention is to provide a crystalline form VII of the compound of formula (I) and a preparation method thereof, wherein the crystalline form exhibits good drugability.

[0066] Specifically, its XRPD spectrum has stable diffraction peaks at 2θ of 6.3, 10.9 (±0.2°).

[0067] Furthermore, in some embodiments of the present invention, the XRPD pattern of the crystalline form VII of the compound of formula (I) is substantially as shown in FIG23 .

[0068] The differential scanning calorimetry (DSC) curve of the crystalline form VII of the compound of formula (I) has an endothermic peak starting point at 130.2±3°C.

[0069] Furthermore, in some embodiments of the present invention, the DSC spectrum of the crystalline form VII of the compound of formula (I) is substantially as shown in FIG24 .

[0070] The thermogravimetric analysis (TGA) curve of the crystalline form VII of the compound of formula (I) above at 190° C. shows a weight loss of 8.6±1%;

[0071] Furthermore, in some embodiments of the present invention, the TGA spectrum of the crystalline form VII of the compound of formula (I) is substantially as shown in FIG25 .

[0072] The eighth object of the present invention is to provide a crystalline form VIII of the compound of formula (I) and a preparation method thereof.

[0073] Specifically, the crystalline form VIII of the compound of formula (I) has an XRPD pattern with stable diffraction peaks at 2θ of 5.3, 11.7, 15.8, 16.6, 17.4, 18.8, and 20.3 (±0.2°).

[0074] Furthermore, in some embodiments of the present invention, the diffraction peaks of the XRPD pattern of the crystalline form VIII of the compound of formula (I) are shown in the following table:

[0075] Furthermore, in some embodiments of the present invention, the XRPD pattern of the crystalline form VIII of the compound of formula (I) is substantially as shown in FIG26 .

[0076] The ninth object of the present invention is to provide a crystalline form IX of the compound of formula (I) and a preparation method thereof.

[0077] Specifically, the crystalline form IX of the compound of formula (I) has an XRPD spectrum with stable diffraction peaks at 2θ of 6.1, 10.6, and 16.6 (±0.2°).

[0078] Furthermore, in some embodiments of the present invention, the diffraction peaks of the XRPD pattern of the crystalline form IX of the compound of formula (I) are shown in the following table:

[0079] Furthermore, in some embodiments of the present invention, the XRPD pattern of the crystalline form IX of the compound of formula (I) is substantially as shown in FIG. 27 .

[0080] The tenth object of the present invention is to provide a bulk drug containing at least one of the crystal forms I to IX of the compound of formula (I) of the present invention.

[0081] Based on the beneficial effects of the aforementioned crystal forms I to IX of the compound of formula (I) of the present invention, the API containing the crystal forms also exhibits the same beneficial effects (such as stability, water solubility, etc.) as the crystal forms. Specifically, the API can be the compound of formula (I), or it can be a hydrate of the compound of formula (I) and / or a hydrate of the compound of formula (I), or it can be an anhydrate of the compound of formula (I) and / or a solvate of the compound of formula (I) and / or a solvate of the compound of formula (I); More specifically, the mass percentage of the compound of formula (I) crystal form I and / or the compound of formula (I) crystal form II and / or the compound of formula (I) crystal form III and / or the compound of formula (I) crystal form IV and / or the compound of formula (I) crystal form V and / or the compound of formula (I) crystal form VI and / or the compound of formula (I) crystal form VII and / or the compound of formula (I) crystal form VIII and / or the compound of formula (I) crystal form IX in the raw material medicine is any value of 0.01 to 99.99%. Furthermore, the mass percentage of the compound of formula (I) crystal form I and / or the compound of formula (I) crystal form II and / or the compound of formula (I) crystal form III and / or the compound of formula (I) crystal form IV and / or the compound of formula (I) crystal form V and / or the compound of formula (I) crystal form VI and / or the compound of formula (I) crystal form VII and / or the compound of formula (I) crystal form VIII and / or the compound of formula (I) crystal form IX in the raw material medicine is any value of 1.00 to 99.00%.

[0082] An eleventh object of the present invention is to provide a pharmaceutical composition, comprising the aforementioned API and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients include, but are not limited to, at least one of a filler, a binder, a disintegrant, a lubricant, and the like. Specifically, based on the beneficial effects of the aforementioned crystalline forms I to IX of the compound of formula (I) of the present invention, the beneficial effects are ultimately embodied in the pharmaceutical composition; more specifically, the pharmaceutical composition contains the aforementioned API in an amount of any value ranging from 1.00 to 99.00% by mass, further, the pharmaceutical composition contains the aforementioned API in an amount of any value ranging from 5.00 to 95.00% by mass, and further, the pharmaceutical composition contains the aforementioned API in an amount of any value ranging from 10.00 to 90.00% by mass.

[0083] The twelfth object of the present invention is to provide a drug comprising at least one of the above-mentioned crystal form, the above-mentioned raw material drug, or the above-mentioned pharmaceutical composition.

[0084] The thirteenth object of the present invention is to provide an application of a pharmaceutical composition in the preparation of a drug 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 variants.

[0085] In summary, the crystal forms I to IX of the compound of formula (I) of the present invention have certain drug development prospects. Therefore, if the presence of crystal forms I to IX of the compound of formula (I) in the aforementioned bulk drug and / or pharmaceutical composition is confirmed by detection means, it should be deemed that the crystal forms I to IX of the compound of formula (I) provided by the present invention have been used. In addition to the aforementioned X-ray powder diffraction, the detection means may further include differential scanning calorimetry (DSC), infrared spectroscopy (IR), Raman spectroscopy (Raman), solid-state nuclear magnetic resonance (SSNMR) and other methods that can be used alone or in combination to confirm the use of the crystal forms I to IX of the compound of formula (I) of the present invention, and methods commonly used by those skilled in the art, such as subtraction spectroscopy, can be used to eliminate the effects of pharmaceutical excipients.

[0086] The present invention has the following advantages and beneficial effects compared to the prior art:

[0087] 1. Disclosed for the first time is a crystalline form I of a compound of formula (I) and a method for its preparation. This crystalline form has the characteristics of high stability and has considerable drug development prospects;

[0088] 2. A crystalline form II of the compound of formula (I) and its preparation method are disclosed for the first time. This crystalline form has the characteristics of high stability and has considerable drug development prospects;

[0089] 3. A crystalline form III of the compound of formula (I) and its preparation method are disclosed for the first time. This crystalline form has the characteristics of high stability and has considerable drug development prospects;

[0090] 4. A crystalline form IV of the compound of formula (I) and its preparation method are disclosed for the first time. This crystalline form has the characteristics of high stability and has considerable drug development prospects;

[0091] 5. A crystalline form V of the compound of formula (I) and its preparation method are disclosed for the first time. This crystalline form has the characteristics of high stability and has considerable drug development prospects;

[0092] 6. Disclosed for the first time is a crystalline form VI of the compound of formula (I) and a method for its preparation, providing a variety of intermediates and / or APIs for the large-scale production of APIs and downstream processes of pharmaceutical products (such as formulation processes);

[0093] 7. Disclosed for the first time is a crystalline form VII of the compound of formula (I) and a method for its preparation, providing a variety of intermediates and / or APIs for the large-scale production of APIs and downstream processes of pharmaceutical products (such as formulation processes);

[0094] 8. Disclosed for the first time is a crystalline form VIII of the compound of formula (I) and a method for its preparation, providing a variety of intermediates and / or APIs for the large-scale production of APIs and downstream processes of pharmaceutical products (such as formulation processes);

[0095] 9. A 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 intermediates and / or APIs for the large-scale production of APIs and downstream processes of pharmaceutical products (such as formulation processes);

[0096] 10. Provided is a bulk drug comprising at least one of the crystalline forms I to IX of the compound of formula (I) of the present invention, wherein the bulk drug exhibits substantially the same beneficial effects as the crystalline forms I to IX of the compound of formula (I) of the present invention;

[0097] 11. Provided is a pharmaceutical composition, which is composed of the raw material of the present invention and pharmaceutically acceptable excipients, and has the same beneficial effects as the crystal forms I to IX of the compound of formula (I) of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] Figure 1: XRPD spectrum of Form I of the compound of formula (I);

[0099] Figure 2: DSC spectrum of Form I of the compound of formula (I);

[0100] Figure 3: TGA spectrum of Form I of the compound of formula (I);

[0101] Figure 4: XRPD comparison diagram of Form I of the compound of formula (I);

[0102] Figure 5: XRPD spectrum of Form II of the compound of formula (I);

[0103] Figure 6: DSC spectrum of Form II of the compound of formula (I);

[0104] Figure 7: TGA spectrum of Form II of the compound of formula (I);

[0105] Figure 8: XRPD spectrum of Form III of the compound of formula (I);

[0106] Figure 9: DSC spectrum of Form III of the compound of formula (I);

[0107] Figure 10: TGA spectrum of Form III of the compound of formula (I);

[0108] Figure 11: XRPD comparison diagram of Form III of the compound of formula (I);

[0109] Figure 12: XRPD spectrum of Form IV of the compound of formula (I);

[0110] Figure 13: DSC spectrum of Form IV of the compound of formula (I);

[0111] Figure 14: TGA spectrum of Form IV of the compound of formula (I);

[0112] Figure 15: XRPD comparison diagram of Form IV of the compound of formula (I);

[0113] Figure 16: XRPD spectrum of Form V of the compound of formula (I);

[0114] Figure 17: DSC spectrum of Form V of the compound of formula (I);

[0115] Figure 18: TGA spectrum of Form V of the compound of formula (I);

[0116] Figure 19: XRPD comparison diagram of Form V of the compound of formula (I);

[0117] Figure 20: XRPD spectrum of Form VI of the compound of formula (I);

[0118] Figure 21: DSC spectrum of Form VI of the compound of formula (I);

[0119] Figure 22: TGA spectrum of Form VI of the compound of formula (I);

[0120] Figure 23: XRPD spectrum of Form VII of the compound of formula (I);

[0121] Figure 24: DSC spectrum of Form VII of the compound of formula (I);

[0122] Figure 25: TGA spectrum of Form VII of the compound of formula (I);

[0123] Figure 26: XRPD spectrum of Form VIII of the compound of formula (I);

[0124] Figure 27: XRPD spectrum of Form IX of the compound of formula (I). DETAILED DESCRIPTION

[0125] The present invention will be further described in detail below with reference to the examples and drawings, but the embodiments of the invention are not limited thereto.

[0126] X-ray powder diffraction

[0127] X-ray powder diffractometer: Bruker D8 Advance;

[0128] 2θ scanning angle: from 3° to 45°;

[0129] Scanning step: 0.02°;

[0130] Exposure time: 0.2 seconds;

[0131] Light tube voltage and current: 40KV, 40mA.

[0132] Differential scanning calorimetry

[0133] Differential scanning calorimetry analyzer: TA Discovery 2500 (TA, US);

[0134] Heating rate: 10°C / min;

[0135] Test method: The sample is accurately weighed and placed in a DSCTzero sample tray, heated to 350°C, and the nitrogen purge rate in the furnace is 50 mL / min.

[0136] Thermogravimetric analysis

[0137] Thermogravimetric analyzer: TA Discovery 55 (TA, US);

[0138] Test method: Place the sample in a balanced open aluminum sample pan and automatically weigh it in a heating furnace. Heat the sample to 400°C at a rate of 10°C / min. Purge nitrogen at a rate of 60 mL / min at the sample and 40 mL / min at the balance.

[0139] Example 1 Preparation method of compound of formula (I)

[0140] Synthesis route:

[0141] Step 1: Synthesis of the hydrochloride salt of compound 1-2

[0142] 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 reaction was stirred at 20° C. for 2 hours and concentrated under reduced pressure without purification to obtain the hydrochloride salt of compound 1-2. 1 H NMR (400MHz, 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).

[0143] Step 2: Synthesis of Compounds 1-4

[0144] Compound Boc-L-cyclohexylglycine (1 g, 3.89 mmol) was added to N,N-dimethylformamide (10 mL), followed by 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.77 g, 4.66 mmol). The reaction was stirred for 0.5 hr. Diisopropylethylamine (1.26 g, 9.72 mmol) and the hydrochloride salt of compound 1-3 (1.02 g, 4.66 mmol) were then added. The reaction was stirred at 20°C for 16 hr. Methyl tert-butyl ether (50 mL) was added to the reaction solution, which was then washed with water (20 mL), 3% citric acid (20 mL x 2), and saturated sodium chloride solution (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 (petroleum ether:ethyl acetate = 3:1) to obtain 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(brdd, 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).

[0145] Step 3: Synthesis of Compounds 1-5

[0146] Compound 1-4 (1.41 g, 3.34 mmol) was added to tetrahydrofuran (14 mL), followed by a solution of lithium hydroxide monohydrate (LiOH·H2O) (280.03 mg, 6.67 mmol) in water (5 mL). The reaction 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 sodium chloride solution (30 mL), 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).

[0147] Step 4: Synthesis of Compounds 1-6

[0148] Compound 1-5 (650 mg, 1.65 mmol) was added to 2-butanone (7 mL), followed by 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 reaction was stirred at 20°C for 0.5 hr. Compound 1-2 hydrochloride (366.88 mg, 1.65 mmol) was then added, and the reaction was stirred at 20°C for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane:methanol (30 mL × 2, 10:1). The organic phases were combined, washed with 3% citric acid (20 mL × 2) and saturated sodium chloride solution (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol=20:1) gave compound 1-6. 1 H NMR(400MHz, 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).

[0149] Step 5: Synthesis of Compounds 1-7

[0150] 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 temperature was slowly raised to 20°C for 2 h. Water (10 mL) and ethyl acetate (20 mL) were added to the reaction solution and stirred for 10 min. A white solid precipitated and was filtered to obtain a filter cake, which was the crude target product 1-7. [M+1]+ = 535.4.

[0151] Step 6: Synthesis of Compounds 1-8

[0152] Compound 1-7 (0.5 g, 935.13 μmol) was dissolved in dichloromethane (10 mL), and Dess-Martin periodinane (594.94 mg, 1.40 mmol) was added to the reaction system. The reaction was stirred at 25°C for 16 h. Saturated sodium thiosulfate (15 mL) and saturated sodium bicarbonate solution (15 mL) were added to the reaction system and 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 to afford crude compound 1-8. [M+1] = 533.4.

[0153] Step 7: Synthesis of Compound 1-9

[0154] 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 isocyanide (94.44 mg, 982.22 μmol) were added to the reaction system. The reaction was stirred at 25°C for 2 h. Saturated ammonium chloride solution (10 mL) was added to the reaction system and stirred for 10 min. Dichloromethane (20 mL) was then added for extraction. The organic phase was washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 10:1) afforded compound 1-9. [M+1]+ = 688.4.

[0155] Step 8: Synthesis of Compounds 1-10

[0156] Compound 1-9 (190 mg, 276.22 μmol) was dissolved in methanol (3 mL), followed by a solution of potassium carbonate (95.44 mg, 690.54 μmol) in water (2 mL). The reaction was stirred at 20°C for 16 h. 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 solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound 1-10. [M+1] + =646.5.

[0157] Step 9: Synthesis of Compound 1-11

[0158] Compound 1-10 (238.00 mg, 368.52 μmol) was dissolved in dichloromethane (24 mL), and Dess-Martin periodinane (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 system 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. Purification by silica gel column chromatography (dichloromethane:methanol = 20:1) gave product 1-11. [M+1] + =644.5.

[0159] Step 10: Synthesis of Compounds 1-12

[0160] 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 the rotary evaporation was repeated with a small amount of dichloromethane to obtain compound 1-12. [M+1] + =544.4.

[0161] Step 11: Synthesis of Compound 1

[0162] Compound 1-12 (125 mg, 229.91 μmol) was dissolved in tetrahydrofuran (2.5 mL) at 0°C. Trifluoroacetic anhydride (193.15 mg, 919.63 μmol) and pyridine (127.30 mg, 1.61 mmol) were added. The reaction was stirred at 20°C for 16 h. Water (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (40 mL x 2). The organic phase was washed sequentially with 3% citric acid (40 mL) and saturated sodium chloride solution (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC to yield compound 1. [M+1] + =640.0, 1H NMR (400MHz, CD3OD) δppm0.94-1.10(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),4.0 3-4.10(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).

[0163] Example 2 Preparation Method of Crystalline Form I of Compound of Formula (I)

[0164] 20.0 mg of the compound of formula (I) prepared by the method of Example 1 was weighed and added to 0.5 mL of acetone / n-heptane (v / v, 1:9) to prepare a suspension. The resulting suspension was suspended and stirred at room temperature (~25°C) for 7 days. The suspension was centrifuged and dried in vacuo at room temperature to obtain a white solid, which is Form I. The XRPD spectrum of the obtained Form I is shown in Figure 1, the DSC spectrum is shown in Figure 2, and the TGA spectrum is shown in Figure 3.

[0165] Example 3 Preparation Method of Crystalline Form I of Compound of Formula (I)

[0166] 50.2 mg of the compound of formula (I) prepared by the method of Example 1 was weighed and added to 0.5 mL of acetone / isopropyl ether (v / v, 1:4) to prepare a suspension. The resulting suspension was suspended and stirred at 10° C. for 24 h. The suspension was centrifuged and dried in vacuo at room temperature to obtain a white solid, which is Form I.

[0167] The comparison of the XRPD spectra of the obtained Form I is shown in FIG4 .

[0168] Example 4 Preparation of Crystalline Form II of Compound of Formula (I)

[0169] 40.1 mg of the compound of formula (I) prepared by the method of 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 dissolved or mostly dissolved. The mixture was filtered while hot and the solution was transferred to room temperature for cooling. After standing at room temperature for more than 2 hours, if no sufficient solid precipitated, the solution was further cooled at 4°C. If no sufficient solid precipitated, the solution was further cooled at -15°C. After centrifugation, the system with sufficient solid precipitation was vacuum dried at room temperature to obtain a white solid, which is Form II. The XRPD spectrum of the obtained Form II is shown in Figure 5, the DSC spectrum is shown in Figure 6, and the TGA spectrum is shown in Figure 7.

[0170] Example 5 Preparation Method of Crystalline Form III of Compound of Formula (I)

[0171] 19.9 mg of the compound of formula (I) prepared by the method of Example 1 was weighed and added to 0.5 mL of methanol / isopropyl ether (v / v, 1:4) to prepare a suspension. The resulting suspension was suspended and stirred at 10° C. for 24 h. The suspension was centrifuged and dried in vacuo at room temperature to obtain a white solid, which is Form III. The XRPD spectrum of the obtained Form III is shown in Figure 8, the DSC spectrum is shown in Figure 9, and the TGA spectrum is shown in Figure 10.

[0172] Example 6 Preparation of Form III of the Compound of Formula (I)

[0173] 20.0 mg of the compound of formula (I) prepared by the method of 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 mostly dissolved. The mixture was filtered while hot and cooled to room temperature. The mixture was allowed to stand at room temperature for at least 2 hours. After sufficient solid precipitated, the system was centrifuged and dried under vacuum at room temperature to obtain a white solid, Form III.

[0174] The comparison of the XRPD spectra of the obtained Form III is shown in FIG11 .

[0175] Example 7 Preparation of Form IV of the Compound of Formula (I)

[0176] 19.5 mg of the compound of formula (I) prepared by the method of Example 1 was dissolved in 0.1 mL of ethanol, and the resulting clear solution was allowed to stand at room temperature in an open state until the solvent was completely evaporated to obtain a solid, which was then dried in vacuo at room temperature to obtain a white solid, which is Form IV. The XRPD spectrum of the obtained Form IV is shown in Figure 12, the DSC spectrum is shown in Figure 13, and the TGA spectrum is shown in Figure 14.

[0177] Example 8 Preparation of Form IV of the Compound of Formula (I)

[0178] 20.6 mg of the compound of formula (I) prepared by the method of Example 1 was weighed and added to 0.5 mL of ethanol / cyclohexane (v / v, 1:9) to prepare a suspension. The resulting suspension was stirred at room temperature (~25°C) for 7 days. The suspension was centrifuged and dried in vacuo at room temperature to obtain a white solid, which is Form IV.

[0179] The comparison of the XRPD spectra of the obtained Form IV is shown in FIG15 .

[0180] Example 9 Preparation of Form V of the Compound of Formula (I)

[0181] 19.5 mg of the compound of formula (I) prepared by the method of Example 1 was dissolved in 0.1 mL of n-propanol, and the resulting clear solution was allowed to stand at room temperature in an open state until the solvent was completely evaporated to obtain a solid, which was then dried in vacuo at room temperature to obtain a white solid, which is Form V. The XRPD spectrum of the obtained Form V is shown in Figure 16, the DSC spectrum is shown in Figure 17, and the TGA spectrum is shown in Figure 18.

[0182] Example 10 Preparation of Form V of the Compound of Formula (I)

[0183] 19.4 mg of the compound of formula (I) prepared by the method of Example 1 was weighed and added to 0.5 mL of n-propanol / water (v / v, 1:9) to prepare a suspension. The resulting suspension was suspended and stirred at room temperature (~25°C) for 7 days. The suspension was centrifuged and dried in vacuo at room temperature to obtain a white solid, which is Form V.

[0184] The comparison of the XRPD spectra of the obtained Form V is shown in FIG19 .

[0185] Example 11 Preparation of Crystalline Form VI of the Compound of Formula (I)

[0186] 20.2 mg of the compound of formula (I) prepared by the method of Example 1 was weighed, and a certain amount of 0.1 mL of ethylene glycol methyl ether was added dropwise at room temperature to completely dissolve the sample, followed by 1.0 mL of isopropyl ether until solid precipitated. After stirring at room temperature for 1 hour, the system with solid precipitation was centrifuged and the solid was vacuum dried at room temperature to obtain a white solid, which is Form VI. The XRPD spectrum of the obtained Form VI is shown in Figure 20, the DSC spectrum is shown in Figure 21, and the TGA spectrum is shown in Figure 22.

[0187] Example 12 Preparation of Form VII of the Compound of Formula (I)

[0188] Weigh 20.0 mg of the compound of formula (I) prepared by the method of Example 1, mix it with 1.0 mL of cyclohexane at 50°C to form a suspension, gradually add 0.4 mL of preheated chloroform dropwise until the solid is just completely dissolved or mostly dissolved, filter it while hot, and transfer the solution to room temperature for cooling. Let it stand at room temperature for more than 2 hours. If no sufficient solid precipitates, place the solution at 4°C for further cooling. If no sufficient solid precipitates, place the solution at -15°C for further cooling. After the system with sufficient solid precipitation is centrifuged, the solid is vacuum dried at room temperature to obtain a white solid, which is Form VII. The XRPD spectrum of the obtained Form VII is shown in Figure 23, the DSC spectrum is shown in Figure 24, and the TGA spectrum is shown in Figure 25.

[0189] Example 13 Preparation of Crystalline Form VIII of the Compound of Formula (I)

[0190] 20.5 mg of the compound of formula (I) prepared by the method of 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 dissolved or mostly dissolved. The mixture was filtered while hot and the solution was transferred to room temperature for cooling. After standing at room temperature for more than 2 hours, solid precipitated. After centrifugation of the system with sufficient solid precipitation, the solid was vacuum dried at room temperature to obtain a white solid, which is Form VIII. The XRPD spectrum of the obtained Form VIII is shown in Figure 26. By comparison, Form VIII is basically the same as the crystal form of the compound of formula (I) prepared by the method of Example 1. The obtained Form VIII has a certain hygroscopicity, and the powder shape is poor and difficult to shape.

[0191] Example 14 Preparation of Crystalline Form IX of the Compound of Formula (I)

[0192] 19.8 mg of the compound of formula (I) prepared by the method of 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 dissolved or mostly dissolved. The mixture was filtered while hot and the solution was transferred to room temperature for cooling. After standing at room temperature for at least 2 hours, if sufficient solid precipitated, the solution was further cooled to 4°C. If sufficient solid precipitated, the solution was further cooled to -15°C. The system with sufficient solid precipitation was centrifuged and the solid was vacuum dried at room temperature to obtain a white solid, Form IX. The XRPD spectrum of the obtained Form IX is shown in Figure 27.

[0193] Example 15 Solid Stability Test of Form I, Form IV and Form V of Compound of Formula (I) under High Temperature and High Humidity Conditions

[0194] Two samples of Form I, Form IV, and Form V of the compound of Formula (I) were weighed in parallel, approximately 100 mg each, and placed at the bottom of a glass sample bottle, spreading it into a thin layer. The bottles were sealed with aluminum foil, and small holes were pricked in the foil to ensure sufficient contact with ambient air. The samples were then placed in a constant temperature and humidity chamber at 40°C and 75% humidity. The samples were tested under these conditions on days 0, 12, and 30. The test results were compared with the initial test results on day 0. The test results are shown in Tables 1 to 3 below:

[0195] Table 1 Solid Stability Test of Crystal Form I of Compound of Formula (I) *N / A means not tested

[0196] Table 2 Solid stability test of the crystal form IV of the compound of formula (I) *N / A means not tested

[0197] Table 3 Solid Stability Test of Form V of Compound of Formula (I) *N / A means not tested

[0198] The test items of this product are compared with those on day 0.

[0199] When the crystal form I of the compound of formula I was placed at a high temperature of 60°C for 30 days, there was no difference in the crystal form or properties, only a slight increase in total impurities and no increase in moisture.

[0200] When placed under high humidity conditions of 92.5% RH for 30 days, there is no difference in crystal form, no difference in properties, a slight increase in total impurities, and a slight increase in moisture. When the sample is left open under high humidity conditions for 30 days, it absorbs moisture and gains weight by 0.56%, and the hygroscopicity is not obvious.

[0201] After being placed under high temperature and high humidity conditions of 40°C and 75% RH for 30 days, there was no difference in crystal form or properties, but the total impurities and moisture content increased slightly.

[0202] Compared with the compound of formula (I) prepared in Example 1, the crystalline form I of the compound of formula (I) is relatively stable under high temperature, high temperature and high humidity, and high humidity conditions.

[0203] When the crystal form IV of the compound of formula I was placed at a high temperature of 60° C. for 30 days, there was no difference in the crystal form, no difference in properties, no increase in total impurities, and no increase in moisture.

[0204] When placed under high humidity conditions of 92.5% RH for 30 days, there is no difference in crystal form and properties, but the total impurities increase slightly and the moisture content increases. When the sample is placed open under high humidity conditions for 30 days, it absorbs moisture and increases in weight by 2.0%, and is obviously hygroscopic.

[0205] When placed under high temperature and high humidity conditions of 40°C and 75% RH for 30 days, there was no difference in crystal form, no difference in properties, no increase in total impurities, and a slight increase in moisture.

[0206] Compared with the compound of formula (I) prepared in Example 1, the crystalline form IV of the compound of formula (I) is relatively stable under high temperature conditions.

[0207] When the crystal form V of the compound of formula I was placed at a high temperature of 60°C for 30 days, there was no difference in the crystal form or properties, only a slight increase in total impurities and no increase in moisture.

[0208] When placed under high humidity conditions of 92.5% RH for 30 days, there is no difference in crystal form and properties, but the total impurities increase slightly and the moisture content increases. When the sample is placed open under high humidity conditions for 30 days, it absorbs moisture and increases in weight by 1.1%, and the hygroscopicity is not obvious.

[0209] After being placed under high temperature and high humidity conditions of 40°C and 75% RH for 30 days, there was no difference in crystal form or properties, but the total impurities and moisture content increased slightly.

[0210] Compared with the compound of formula (I) prepared in Example 1, the crystalline form V of the compound of formula (I) is relatively stable under high temperature conditions.

[0211] In summary, the crystalline form I of the compound of formula (I) is relatively stable under high temperature, high temperature and high humidity, and high humidity conditions when placed in the open air, and the crystalline forms IV and V are relatively stable under high temperature conditions.

[0212] In addition, the inventors found during the experiment and further research that:

[0213] Form II can be obtained by cooling and then volatilizing in a cyclohexane and toluene solvent system. After vacuum drying the volatilized Form II at room temperature, the sample crystal form remains Form II, indicating that Form II has high stability. Form III can be obtained by prolonged stirring and crystallization in a methanol / isopropyl ether system at 10°C. Those skilled in the art will understand that Form III has high stability.

[0214] Crystal form VIII is an unstable crystal form. It undergoes crystal transformation during the post-treatment process (vacuum drying at room temperature) to become crystal form V. It can be seen that crystal form V is finally obtained from the intermediate metastable crystal form (crystal form VIII) and has high stability. Example 16 Thermal Transformation Experiment

[0215] Using different crystalline forms as raw materials, samples were placed on a BTS500 hot plate and subjected to XRPD analysis at room temperature. The samples were then heated at a rate of 10°C / min to the selected temperature. After stabilization for 10 minutes, XRPD analysis was performed at the same temperature. The samples were then cooled to room temperature and then subjected to XRPD analysis again. The results are shown in Table 4.

[0216] Table 4 Thermal Transformation Results

[0217] Comprehensive experimental results show that Form V and Form VI have higher stability under heating conditions, and Form II will be converted into Form I under heating conditions. It can be seen that Form I has higher stability under high temperature conditions.

[0218] It is further demonstrated that Form II can also serve as an intermediate crystal form for further preparation of some of the other stable crystal forms described in the present invention. In summary, the crystal form of the compound of formula (I) described in the present invention has at least one of the following effects, such as stability, and provides a variety of intermediate products and / or APIs for the large-scale production of APIs and downstream processes of pharmaceutical products (such as formulation processes).

[0219] The above embodiments are preferred implementations of the present invention, but the implementations of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A crystalline form I of a compound of formula (I), It is characterized by: The XRPD pattern of the 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°); further, the XRPD pattern of the crystalline form I of the compound of formula (I) also 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°); further, the diffraction peaks of the XRPD pattern of the crystalline form I of the compound of formula (I) are shown in the following table: Furthermore, the XRPD pattern of Form I of the compound of formula (I) is substantially as shown in FIG1 .

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

3. The crystalline form I of the compound of formula (I) according to claim 1, characterized in that: The TGA spectrum of the crystalline form I of the compound of formula (I) shows a weight loss of 0.3±1% at 100° C.; further, the TGA spectrum of the crystalline form I of the compound of formula (I) is shown in FIG3 .

4. A crystalline form II of a compound of formula (I), It is characterized by: The XRPD pattern of the 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°); further, the diffraction peaks of the XRPD pattern of the crystalline form II of the compound of formula (I) are shown in the following table: Furthermore, the XRPD pattern of Form II of the compound of formula (I) is substantially as shown in FIG5 .

5. The crystalline form II of the compound of formula (I) according to claim 4, characterized in that The DSC spectrum of the crystalline form II of the compound of formula (I) has the starting points of the endothermic peak at 72.7, 115.0, 177.3, and 262.0 (±3°C), and the starting point of the exothermic peak at 150.8±3°C; further, the DSC spectrum of the crystalline form II of the compound of formula (I) is shown in Figure 6.

6. The crystalline form II of the compound of formula (I) according to claim 4, characterized in that The TGA spectrum of the crystalline form II of the compound of formula (I) shows a weight loss of 7.8±1% at 230° C.; further, the TGA spectrum of the crystalline form II of the compound of formula (I) is shown in FIG7 .

7. A crystalline form III of a compound of formula (I), It is characterized by: The XRPD spectrum 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 of the XRPD spectrum of the crystalline form III of the compound of formula (I) are shown in the following table: Furthermore, the XRPD pattern of Form III of the compound of formula (I) is substantially as shown in FIG8 .

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

9. The crystalline form III of the compound of formula (I) according to claim 7, characterized in that The TGA spectrum of the crystalline form III of the 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; further, the TGA spectrum of the crystalline form III of the compound of formula (I) is shown in Figure 10.

10. A crystalline form IV of a compound of formula (I), It is characterized by: The XRPD pattern of the 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°); further, the XRPD pattern of the crystalline form I of the compound of formula (I) The spectrum also 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°). Furthermore, the diffraction peaks of the XRPD spectrum of the crystalline form IV of the compound of formula (I) are shown in the following table: Furthermore, the XRPD pattern of Form IV of the compound of formula (I) is substantially as shown in FIG12 .

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

12. The crystalline form IV of the compound of formula (I) according to claim 10, characterized in that The TGA spectrum of the crystalline form IV of the compound of formula (I) shows a weight loss of 3.8±1% at 110°C and a weight loss of 4.2±1% at 190°C; further, the TGA spectrum of the crystalline form IV of the compound of formula (I) is shown in Figure 14.

13. A crystalline form V of a compound of formula (I), It is characterized by: 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 of the XRPD pattern of the crystalline form V of the compound of formula (I) are shown in the following table: Furthermore, the XRPD pattern of Form V of the compound of formula (I) is substantially as shown in FIG16 .

14. The crystalline form V of the compound of formula (I) according to claim 13, characterized in that The DSC spectrum of the crystalline form V of the compound of formula (I) has an onset point of an endothermic peak at 148.4±3°C; further, the DSC spectrum of the crystalline form V of the compound of formula (I) is shown in Figure 17.

15. The crystalline form V of the compound of formula (I) according to claim 13, characterized in that The TGA spectrum of the crystalline form V of the compound of formula (I) shows a weight loss of 10.5±1% at 190° C.; further, the TGA spectrum of the crystalline form V of the compound of formula (I) is shown in FIG18 .

16. A crystalline form VI of a compound of formula (I), It is characterized by: The XRPD pattern of the 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°); further, the XRPD pattern of the crystalline form VI of the compound of formula (I) also has diffraction peaks at 2θ of 9.1, 10.4, 15.9, 20.0, 20.9, and 21.6 (±0.2°); further, the diffraction peaks of the XRPD pattern of the crystalline form VI of the compound of formula (I) are shown in the following table: Furthermore, the XRPD pattern of Form VI of the compound of formula (I) is basically as shown in Figure 20.

17. The crystalline form VI of the compound of formula (I) according to claim 16, characterized in that The DSC spectrum of the crystalline form VI of the compound of formula (I) has the starting points of the endothermic peak at 134.2, 184.3 (±3°C); further, the DSC spectrum of the crystalline form VI of the compound of formula (I) is shown in Figure 21.

18. The crystalline form VI of the compound of formula (I) according to claim 16, characterized in that The TGA spectrum of the crystalline form VI of the compound of formula (I) shows a weight loss of 16.2±1% at 200° C.; further, the TGA spectrum of the crystalline form VI of the compound of formula (I) is shown in FIG22 .

19. A crystalline form VII of a compound of formula (I), It is characterized by: The XRPD spectrum of the crystalline form VII of the compound of formula (I) has diffraction peaks at 2θ of 6.3, 10.9 (±0.2°); further, the XRPD spectrum of the crystalline form VII of the compound of formula (I) is basically as shown in Figure 23.

20. The crystalline form VII of the compound of formula (I) according to claim 19, characterized in that The DSC spectrum of the crystalline form VII of the compound of formula (I) has an endothermic peak starting point at 130.2±3°C; further, the DSC spectrum of the crystalline form VII of the compound of formula (I) is shown in Figure 24.

21. The crystalline form VII of the compound of formula (I) according to claim 19, characterized in that The TGA spectrum of the crystalline form VII of the compound of formula (I) shows a weight loss of 8.6±1% at 190° C.; further, the TGA spectrum of the crystalline form VII of the compound of formula (I) is shown in FIG25 .

22. A bulk drug comprising a compound of formula (I) and / or a hydrate or solvate thereof, characterized in that: The drug substance comprises at least one of the crystalline forms of the compound of formula (I) according to any one of claims 1 to 21; 23. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises pharmaceutically acceptable excipients and the raw material drug according to claim 22.

24. A pharmaceutical composition according to claim 23, characterized in that The pharmaceutically acceptable excipients include at least one of a filler, a binder, a disintegrant, and a lubricant.

25. A drug, characterized in that The drug comprises at least one of the crystalline form according to any one of claims 1 to 21, the bulk drug according to claim 22, or the pharmaceutical composition according to any one of claims 23 to 24.

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

27. The method according to claim 26, characterized in that The coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV or SARS-CoV-2 and its variants.

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