Crystal form of heterocyclic derivative as well as preparation method and application of crystal form

Abstract

The present invention relates to a crystal form of a heterocyclic derivative and a crystal form of a pharmaceutically acceptable salt thereof, and a preparation method and pharmaceutical use thereof. Specifically, the invention discloses a heterocyclic derivative, such as two solid forms (an amorphous form A and a crystal form B) of a chemical formula (I), two solid forms (an amorphous form A and a crystal form B) of a sodium salt formula (II), and three solid forms (an amorphous form A and two crystal forms B and C) of a potassium salt formula (III). The solid can be used for preparing medicines for treating and / or preventing diseases, especially resisting viruses, especially resisting HCMV virus infection. The solid form not only retains good antiviral activity of the compound, but also provides a complete optimal scheme for subsequent drug development in bioavailability, and also ensures medicinal requirements in hygroscopicity and stability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a crystal form of a heterocyclic derivative, its preparation method, and its application. Background Technology

[0002] Human cytomegalovirus (HCMV) possesses double-stranded DNA and belongs to the β subfamily of the herpesvirus family. After infection, HCMV can remain latent in the host for a long period. When the immune system is weakened or compromised, the latent HCMV virus can be reactivated, leading to repeated active infections. HCMV often presents as an asymptomatic infection in immunocompetent individuals, but it has a high morbidity and mortality rate in HIV patients, organ transplant recipients, or other immunocompromised individuals. HCMV is also a major viral cause of congenital developmental delays and intellectual disability in newborns. The standard treatment for HCMV infection is intravenous ganciclovir, foscarnet, cidofovir, or oral valganciclovir. Although these nucleoside analogues have significant clinical efficacy, these traditional drugs have adverse reactions such as bone marrow suppression or nephrotoxicity. Furthermore, drug resistance has frequently occurred over decades of use, making their use in allogeneic hematopoietic cell transplant recipients more challenging.

[0003] Letemmovir is a potent viral terminal enzyme inhibitor with good safety and clinical efficacy. However, its bioavailability is only about 37%, so the oral dose for monotherapy is 480 mg once daily. Even when co-administered with cyclosporine to achieve 85% bioavailability, the dose still needs to be 240 mg once daily. Its activity and dosage require further improvement. Therefore, clinical practice needs drugs with appropriate administration methods, high activity, and low clinical doses to better serve clinical needs, providing safe, potent, low-toxicity anti-HCMV drugs that do not require boosters for organ transplant patients.

[0004] Patent WO2023236752A1 discloses a class of heterocyclic derivatives that can serve as anti-HCMV compounds. Compared to letemovir, the new compounds in this patent exhibit 8-40 times greater HCMV inhibitory activity, potentially offering patients more effective treatment. For example, compound (I). It is a typical example of injectable compounds, possessing good antiviral activity. This compound has good lipid solubility, but relatively weak water solubility, which limits the formulations available for its clinical use.

[0005] Different crystal forms of the same drug may have different physicochemical properties, such as appearance, density, hardness, melting point, solubility, stability, dissolution rate, and bioavailability, which may significantly affect its drugability. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a class of heterocyclic derivative crystal forms that have excellent physicochemical properties, good drug-likeness, and high bioavailability, in order to address the shortcomings and deficiencies of the prior art.

[0007] To solve the above technical problems, the present invention adopts the following technical solution:

[0008] A solid form of a compound of formula (I), wherein the solid form is an amorphous structure or crystalline:

[0009]

[0010] The compound of formula (I) is in the form of a free acid.

[0011] In this invention, the solid form includes any existing form such as amorphous, crystalline, solvate, and hydrate.

[0012] In some embodiments, the amorphous structure is a type A amorphous structure, whose X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-45° at a 2θ angle.

[0013] In some embodiments, the type A amorphous structure shows a weight loss of 7.5 ± 0.2% when heated to 150 ± 2 °C in a thermogravimetric analysis.

[0014] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the type A amorphous structure is as follows: Figure 2 As shown.

[0015] In some embodiments, the A-type amorphous structure shows endothermic peaks at 66±2℃ and 114±2℃ in the spectrum determined by differential scanning calorimetry.

[0016] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the type A amorphous structure is as follows: Figure 3 As shown.

[0017] Combination Figure 2 , Figure 3 The results show that the type A amorphous structure contains adsorbed water and / or solvent.

[0018] In some embodiments, the crystal is of type B, and its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 9.63°±0.2°, 10.89°±0.2°, 13.48°±0.2°, 13.75°±0.2°, 15.32°±0.2°, 16.33°±0.2°, 16.84°±0.2°, 17.85°±0.2°, 18.63°±0.2°, 19.29°±0.2°, 19.50°±0.2°, 20.63°±0.2°, 23.25°±0.2°, 23.87°±0.2°, 24.90°±0.2°, and 26.32°±0.2°.

[0019] In some embodiments, the X-ray powder diffraction patterns of the type B crystal form also show 2θ angles of 15.91°±0.2°, 18.18°±0.2°, 21.13°±0.2°, 21.50°±0.2°, 21.87°±0.2°, 22.49°±0.2°, 22.88°±0.2°, 24.50°±0.2°, 26.01°±0.2°, 26.73°±0.2°, and 27°±0.2°. One or more of the following values ​​are characteristic peaks: 0.14°±0.2°, 27.39°±0.2°, 27.72°±0.2°, 27.92°±0.2°, 28.66°±0.2°, 29.06°±0.2°, 29.90°±0.2°, 31.88°±0.2°, 32.74°±0.2°, 34.00°±0.2°, 35.85°±0.2°, and 37.01°±0.2°.

[0020] In some embodiments, the X-ray powder diffraction pattern of the B-type crystal is as follows: Figure 5 As shown.

[0021] In some embodiments, the B-type crystal form shows a weight loss of 0.3 ± 0.2% when heated to 150 ± 2 °C in a thermogravimetric analysis.

[0022] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the B-type crystal form is as follows: Figure 6 As shown.

[0023] In some embodiments, the B-type crystal form shows an endothermic peak in the spectrum determined by differential scanning calorimetry, indicating that the melting point onset temperature of the B-type crystal form is 246±2℃.

[0024] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the B-type crystal form is as follows: Figure 6 As shown.

[0025] The present invention also provides a method for preparing the solid form of the aforementioned compound of formula (I) or its solvate, the method comprising:

[0026] 1) Dissolve compound (I) in a solvent, remove the solvent by evaporation or lyophilization to obtain an amorphous structure; or

[0027] 2) Dissolve compound (I) in a solvent, add an antisolvent or water to the solvent to precipitate the solid, filter or centrifuge to obtain the amorphous structure; or

[0028] 3) Dissolve compound (I) in a solvent, cool and crystallize while stirring, and then filter or centrifuge to obtain the crystal form;

[0029] The solvent is selected from one or more combinations of ether solvents, ester solvents, alcohol solvents, ketone solvents, nitrile solvents, halogenated hydrocarbons, and aromatic hydrocarbons; the antisolvent is selected from one or more combinations of ether solvents, alkanes, and water; preferably, the solvent is selected from one or more combinations of ethyl acetate, methyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, acetone, methyl ethyl ketone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol, acetonitrile, methyl tert-butyl ether, and dioxane; the antisolvent is selected from one or more combinations of petroleum ether, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, isopropyl ether, diethyl ether, and water.

[0030] In some embodiments, the free acid form B crystal is prepared by dissolving the compound of chemical formula (I) in a solvent at a set first temperature, cooling to a set second temperature and stirring until crystallization to obtain a solid, and then separating the solid by filtration or centrifugation.

[0031] Furthermore, the first temperature is 10-60℃;

[0032] Furthermore, the second temperature is -15 to -10°C.

[0033] The present invention also provides a solid form of the compound of formula (II), wherein the solid form is an amorphous structure or crystalline, and in formula (II), X is 0-10, and X is an integer multiple of 0.5:

[0034]

[0035] Compound (II) is in sodium salt form.

[0036] In some embodiments, the amorphous structure is a type A amorphous structure, whose X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-45° at a 2θ angle.

[0037] In some embodiments, the X-ray powder diffraction pattern of the type A amorphous structure is as follows: Figure 8 As shown.

[0038] In some embodiments, the type A amorphous structure shows a weight loss of 22.8 ± 0.2% when heated to 160 ± 2 °C in a thermogravimetric analysis.

[0039] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the type A amorphous structure is as follows: Figure 9 As shown.

[0040] In some embodiments, the A-type amorphous structure shows endothermic peaks at 77±2℃ and 120±2℃ in the spectrum determined by differential scanning calorimetry.

[0041] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the type A amorphous structure is as follows: Figure 10 As shown.

[0042] In some embodiments, in the type A amorphous structure, X is a multiple of 0.5 within the range of 0-10.

[0043] In some embodiments, the crystal is of type B, and its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.15°±0.2°, 10.66°±0.2°, 12.31°±0.2°, 13.75°±0.2°, 15.09°±0.2°, 16.29°±0.2°, 18.49°±0.2°, 20.45°±0.2°, 21.37°±0.2°, 22.26°±0.2°, 23.10°±0.2°, 23.93°±0.2°, 26.98°±0.2°, 28.40°±0.2°, and 29.74°±0.2°.

[0044] In some embodiments, the X-ray powder diffraction pattern of the B-type crystal also has characteristic peaks at one or more of the following 2θ angles: 24.71°±0.2°, 25.51°±0.2°, 26.23°±0.2°, 30.37°±0.2°, 31.05°±0.2°, 32.29°±0.2°, 33.51°±0.2°, 34.14°±0.2°, 34.64°±0.2°, 35.85°±0.2°, 37.54°±0.2°, 38.02°±0.2°, 39.01°±0.2°, 41.07°±0.2°, and 42.03°±0.2°.

[0045] In some embodiments, the X-ray powder diffraction pattern of the B-type crystal is as follows: Figure 12 As shown.

[0046] In some embodiments, the B-type crystal form shows a weight loss of 3.7±0.2% when heated to 100±2℃ and 3.3±0.2% when heated to 160±2℃.

[0047] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the B-type crystal form is as follows: Figure 13 As shown.

[0048] In some embodiments, the B-type crystal form shows two endothermic peaks at 71±2℃ and 136±2℃ in the spectrum determined by differential scanning calorimetry.

[0049] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the B-type crystal form is as follows: Figure 14 As shown.

[0050] In some embodiments, X is 1-3 in the B-type crystal form; more preferably, X is 1. That is, the B-type crystal form is a hydrate.

[0051] The present invention also provides a method for preparing a solid form of a compound of formula (II), the method comprising:

[0052] 1) Dissolve compound (I) in a solvent, add ligands to react, and remove the solvent by evaporation or lyophilization after the reaction to obtain an amorphous structure; or

[0053] 2) Dissolve compound (I) in a solvent, add the ligand to react, and after the reaction is complete, add an antisolvent to the solvent to precipitate the solid. Filter or centrifuge to obtain the amorphous structure; or

[0054] 3) Dissolve compound (I) in a solvent, add ligands to react, and after the reaction is complete, cool and crystallize under stirring, then filter or centrifuge to obtain the crystals;

[0055] 4) The B-type crystal form is placed under conditions of humidity greater than or equal to 90% to undergo crystal transformation, thereby obtaining the A-type amorphous structure;

[0056] Among them, compound (I) is

[0057] The solvent is selected from one or more combinations of ether solvents, ester solvents, alcohol solvents, ketone solvents, nitrile solvents, halogenated hydrocarbons, aromatic hydrocarbons, or water; the antisolvent is selected from one or more combinations of ether solvents or alkanes; the ligand is selected from one or more combinations of sodium hydroxide, sodium methoxide, sodium ethoxide, and sodium tert-butoxide.

[0058] Preferably, the solvent is selected from one or more combinations of ethyl acetate, methyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, acetone, methyl ethyl ketone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol, acetonitrile, methyl tert-butyl ether, dioxane, and water; the antisolvent is selected from one or more combinations of petroleum ether, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, isopropyl ether, and diethyl ether.

[0059] More preferably, the solvent is methyl tert-butyl ether, a mixture of ethanol and n-heptane, or a mixture of ethyl acetate and cyclohexane, and the antisolvent is preferably cyclohexane or n-heptane.

[0060] In some embodiments, the amorphous structure of sodium salt form A can be prepared by placing the sodium salt form B crystal form in a high humidity environment for 15 to 20 days to obtain the desired solid product.

[0061] Furthermore, a high-humidity environment is defined as an environment with a humidity level of 90% or higher.

[0062] Furthermore, the reaction temperature for adding ligands is 10-60℃;

[0063] Furthermore, the temperature at which the solid precipitates is -15 to -10℃.

[0064] The present invention also provides a solid form of a compound of formula (III), wherein the solid form is an amorphous structure or crystalline, and in formula (III), X is 0-10, and X is an integer multiple of 0.5:

[0065]

[0066] Compound (III) is in the form of potassium salt.

[0067] In some embodiments, the amorphous structure is a type A amorphous structure, whose X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-45° at a 2θ angle.

[0068] In some embodiments, the X-ray powder diffraction pattern of the type A amorphous structure is as follows: Figure 16 As shown.

[0069] In some embodiments, the type A amorphous structure shows a weight loss of 8.4 ± 0.2% when heated to 150 ± 2 °C in a thermogravimetric analysis (TGA) spectrum.

[0070] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the type A amorphous structure is as follows: Figure 17 As shown.

[0071] In some embodiments, the type A amorphous structure shows an endothermic peak at 78±2℃ in the spectrum determined by differential scanning calorimetry.

[0072] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the type A amorphous structure is as follows: Figure 18 As shown.

[0073] In some embodiments, in the type A amorphous structure, X is 0, 1, 2 or 3; preferably, X is 0.

[0074] In some embodiments, the crystal is of type B crystal form, with X-ray powder diffraction patterns at 2θ angles of 6.15°±0.2°, 10.62°±0.2°, 12.31°±0.2°, 13.73°±0.2°, 15.05°±0.2°, 15.48°±0.2°, 16.29°±0.2°, 16.66°±0.2°, and 17.77°±0.2°. Characteristic peaks are observed at 18.47°±0.2°, 19.81°±0.2°, 20.43°±0.2°, 20.74°±0.2°, 21.37°±0.2°, 21.66°±0.2°, 22.26°±0.2°, 23.10°±0.2°, 23.37°±0.2°, 23.91°±0.2°, and 26.96°±0.2°.

[0075] In some embodiments, the X-ray powder diffraction patterns of the type B crystal form also show 2θ angles of 9.37°±0.2°, 12.76°±0.2°, 18.78°±0.2°, 24.73°±0.2°, 24.98°±0.2°, 25.72°±0.2°, 26.26°±0.2°, 26.52°±0.2°, 27.24°±0.2°, 27.86°±0.2°, 28.40°±0.2°, and 29. One or more of the following values ​​are characteristic peaks: 30°±0.2°, 29.74°±0.2°, 30.64°±0.2°, 31.90°±0.2°, 32.46°±0.2°, 33.11°±0.2°, 34.29°±0.2°, 34.70°±0.2°, 35.44°±0.2°, 35.85°±0.2°, 36.53°±0.2°, 38.65°±0.2°, and 39.03°±0.2°.

[0076] In some embodiments, the X-ray powder diffraction pattern of the B-type crystal is as follows: Figure 20 As shown.

[0077] In some embodiments, the B-type crystal form shows a weight loss of 3.8±0.2% when heated to 60±2℃ and a weight loss of 2.9±0.2% when heated to 160±2℃.

[0078] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the B-type crystal form is as follows: Figure 21 As shown.

[0079] In some embodiments, the B-type crystal form shows endothermic peaks at 42±2℃, 61±2℃, and 141±2℃ in the spectrum determined by differential scanning calorimetry.

[0080] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the B-type crystal form is as follows: Figure 22 As shown.

[0081] In some embodiments, X in the B-type crystal form is 1, 2, or 3; preferably, X is 1. That is, the B-type crystal form is a hydrate.

[0082] In some embodiments, the crystal is of the C-type crystal form, and its X-ray powder diffraction pattern is observed at 2θ angles of 6.07°±0.2°, 9.39°±0.2°, 10.52°±0.2°, 11.18°±0.2°, 12.15°±0.2°, 12.74°±0.2°, 15.38°±0.2°, 16.10°±0.2°, 16.55°±0.2°, and 17.6°. Characteristic peaks are observed at 5°±0.2°, 18.86°±0.2°, 19.81°±0.2°, 20.59°±0.2°, 21.13°±0.2°, 21.48°±0.2°, 22.01°±0.2°, 26.25°±0.2°, 26.69°±0.2°, 26.98°±0.2°, 27.80°±0.2°, and 29.02°±0.2°.

[0083] In some embodiments, the X-ray powder diffraction patterns of the C-type crystal form also show 2θ angles of 10.85°±0.2°, 13.44°±0.2°, 13.71°±0.2°, 17.83°±0.2°, 18.59°±0.2°, 19.27°±0.2°, 23.21°±0.2°, 23.84°±0.2°, 24.44°±0.2°, 24.77°±0.2°, 25.66°±0.2°, 28.09°±0.2°, 28.50°±0.2°, 29.69°±0.2°, and 30°. One or more of the following values ​​are characteristic peaks: 40°±0.2°, 30.70°±0.2°, 31.07°±0.2°, 31.57°±0.2°, 32.17°±0.2°, 32.54°±0.2°, 32.85°±0.2°, 34.04°±0.2°, 34.29°±0.2°, 34.62°±0.2°, 35.09°±0.2°, 35.67°±0.2°, 36.20°±0.2°, 40.28°±0.2°, 42.30°±0.2°, and 43.52°±0.2°.

[0084] In some embodiments, the X-ray powder diffraction pattern of the C-type crystal is as follows: Figure 24 As shown.

[0085] In some embodiments, the C-type crystal form shows a weight loss of 5.0±0.2% when heated to 100±2℃ and a weight loss of 2.7±0.2% when heated to 100±2℃-160±2℃.

[0086] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the C-type crystal form is as follows: Figure 25 As shown.

[0087] In some embodiments, the C-type crystal form shows endothermic peaks at 100±2℃ and 145±2℃ in the spectrum determined by differential scanning calorimetry.

[0088] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the C-type crystal form is as follows: Figure 26 As shown.

[0089] In some embodiments, X in the C-type crystal form is a multiple of 0.5 between 1 and 3; preferably, X is 2. That is, the C-type crystal form is a hydrate.

[0090] The present invention also provides a method for preparing a solid form of a compound of formula (III), the method comprising:

[0091] 1) Dissolve compound (I) in a solvent, add ligands to react, and remove the solvent by evaporation or lyophilization after the reaction to obtain an amorphous structure; or

[0092] 2) Dissolve compound (I) in a solvent, add the ligand to react, and after the reaction is complete, add an antisolvent to the solvent to precipitate the solid. Filter or centrifuge to obtain the amorphous structure; or

[0093] 3) Dissolve compound (I) in a solvent, add ligands to react, and after the reaction is complete, cool and crystallize under stirring, then filter or centrifuge to obtain the crystals;

[0094] Among them, compound (I) is

[0095] The solvent is selected from one or more combinations of ether solvents, ester solvents, alcohol solvents, ketone solvents, nitrile solvents, halogenated hydrocarbons, aromatic hydrocarbons, or water; the antisolvent is selected from one or more combinations of ether solvents or alkanes; the ligand is selected from one or more combinations of potassium hydroxide, potassium methoxide, potassium ethoxide, and potassium tert-butoxide.

[0096] Preferably, the solvent is selected from one or more combinations of ethyl acetate, methyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, acetone, methyl ethyl ketone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol, acetonitrile, methyl tert-butyl ether, dioxane, and water; the antisolvent is selected from one or more combinations of petroleum ether, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, isopropyl ether, and diethyl ether.

[0097] The preferred solvent is a mixture of ethanol and n-heptane, and the preferred antisolvent is n-heptane.

[0098] Furthermore, the reaction temperature for adding ligands is 10-60℃;

[0099] Furthermore, the temperature at which the solid precipitates is -15 to -10℃.

[0100] The present invention also provides a pharmaceutical composition comprising the solid form of the aforementioned compound of formula (I), formula (II) or formula (III) and a pharmaceutically acceptable carrier.

[0101] In some embodiments, the pharmaceutically acceptable carrier is selected from diluents, excipients, fillers, binders, disintegrants, absorption enhancers, surfactants, lubricants, flavorings, sweeteners, etc.

[0102] In some embodiments, the pharmaceutical composition may be in various forms, such as tablets, powders, capsules, granules, oral solutions, and injectable formulations. The preferred dosage form of the pharmaceutical composition is tablets, capsules, or injections.

[0103] Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0104] The heterocyclic derivatives of the present invention (including free acid, sodium salt form and potassium salt form) are in solid form, have excellent physicochemical properties, good drug-likeness, and high bioavailability. Attached Figure Description

[0105] Figure 1 The XRPD spectrum of free acid form A (amorphous);

[0106] Figure 2 The TGA spectrum shows the amorphous form of free acid A.

[0107] Figure 3 The DSC spectrum of the free acid form A (amorphous);

[0108] Figure 4 The NMR spectrum of the free acid form A (amorphous);

[0109] Figure 5 XRPD spectrum of free acid B crystal form;

[0110] Figure 6 TGA and DSC spectra of free acid form B crystal;

[0111] Figure 7 The NMR spectrum of the free acid form, B crystal;

[0112] Figure 8 The XRPD spectrum of sodium salt form A (amorphous);

[0113] Figure 9 The TGA spectrum of sodium salt form A (amorphous);

[0114] Figure 10 The DSC spectrum of sodium salt form A (amorphous);

[0115] Figure 11 The NMR spectrum is for sodium salt form A, amorphous.

[0116] Figure 12 XRPD spectrum of sodium salt in crystal form B;

[0117] Figure 13 The TGA spectrum is for sodium salt form B.

[0118] Figure 14 The DSC spectrum of sodium salt in crystal form B;

[0119] Figure 15 The NMR spectrum is for sodium salt form B.

[0120] Figure 16 The XRPD spectrum of potassium salt form A (amorphous).

[0121] Figure 17 The TGA spectrum of potassium salt form A (amorphous);

[0122] Figure 18 The DSC spectrum of potassium salt form A (amorphous).

[0123] Figure 19 The NMR spectrum is for potassium salt form A, amorphous.

[0124] Figure 20 The XRPD spectrum of potassium salt B crystal form;

[0125] Figure 21 The TGA spectrum is for potassium salt form B crystal.

[0126] Figure 22 The DSC spectrum of potassium salt in crystal form B;

[0127] Figure 23 The NMR spectrum is for potassium salt form B.

[0128] Figure 24 XRPD spectrum of potassium salt in C crystal form;

[0129] Figure 25 The TGA spectrum is for the C-type potassium salt.

[0130] Figure 26 The DSC spectrum of the C-type potassium salt is shown.

[0131] Figure 27 The NMR spectrum is for the C-type potassium salt.

[0132] Figure 28 The DVS spectrum is for sodium salt form B.

[0133] Figure 29 The DVS spectrum is for potassium salt B crystal form;

[0134] Figure 30 PLM image of sodium salt B crystal form;

[0135] Figure 31 PLM image of potassium salt B crystal form. Detailed Implementation

[0136] Terminology Definition

[0137] Unless otherwise specified, the term "solvent" as used herein refers to a molecular complex comprising a drug substance and stoichiometric or non-stoichiometric amounts of solvent molecules, wherein the drug substance may be a free base, or a pharmaceutically acceptable salt, eutectic, salt eutectic, or other molecular complex thereof. When the solvent is water, the solvate is referred to as a "hydrate".

[0138] Hydrates can be stoichiometric hydrates, where water exists in a defined molar equivalent in the crystal lattice, independent of humidity, such as hemihydrates, monohydrates, dihydrates, etc. Hydrates can also be non-stoichiometric hydrates, also known as variable hydrates, where the water content is variable and depends on external conditions such as humidity, temperature, and drying conditions. Therefore, other hydrate forms, such as channel hydrates, are also included in the meaning of this term.

[0139] XRPD, or X-ray powder diffraction, is characteristic of specific crystal forms. X-ray powder diffraction patterns are characteristic of specific crystal forms. When determining whether a crystal form is identical to a known crystal form, attention should be paid to the relative positions of the peaks (i.e., 2θ) rather than their relative intensities. This is because the relative intensities of the spectra can vary due to the preferential orientation effects caused by differences in crystal conditions, particle size, and other measurement conditions. In particular, low-intensity peaks (intensity less than 20%) may not be present in some cases. The relative intensity of diffraction peaks is not characteristic for determining the crystal form. In fact, the relative intensity of diffraction peaks in an XRPD pattern is related to the preferred orientation of the crystal. The peak intensities shown in this article are illustrative rather than for absolute comparison. Furthermore, it is known in the art that when determining the crystallization of compounds using X-ray diffraction, the 2θ value for the same crystal form can have a certain measurement error, approximately ±0.2°, due to the influence of the measuring instrument or measurement conditions. Therefore, this error should be taken into account when determining each crystal structure. In XRPD patterns, peak positions are typically represented by the 2θ angle or the interplanar spacing d, with a simple conversion relationship: d = λ / 2sinθ, where d represents the interplanar spacing d, λ represents the wavelength of the incident X-rays, and θ is the diffraction angle. It should be noted that in the identification of mixtures, factors such as decreased content can cause some diffraction lines to be missing. Additionally, experimental factors such as sample height can cause an overall shift in peak angles, which is generally permissible. Therefore, those skilled in the art will understand that the X-ray diffraction patterns of the crystal forms referred to in this application need not be completely identical to those in the examples cited herein. The phrase "same XRPD pattern" does not mean absolutely identical; identical peak positions can differ by ±0.2° (or greater), and peak intensities are allowed to vary to some extent. Any crystal form with a pattern having the same or similar characteristic peaks as those in these patterns falls within the scope of this application. Those skilled in the art can compare the patterns listed in this application with a pattern of an unknown crystal form to verify whether the two sets of patterns reflect the same or different crystal forms.

[0140] Based on a specific X-ray crystal diffraction pattern, those skilled in the art are typically allowed to select several characteristic peaks to define the crystal form. The selection of these characteristic peaks is based on a specific purpose and can be comprehensively considered; there are no strict limitations. For example, those skilled in the art tend to select peaks with relatively high intensity, relatively low angles, and relatively complete peak shapes, as well as peaks that are sufficiently distinguishable from other crystals, so that the characteristic peaks have distinguishable, identifiable, and evaluable significance. Therefore, one cannot conclude that a different crystal form or that the originally requested crystal form range has been formed simply because the combination of selected characteristic peaks has changed.

[0141] DSC determines the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting. For the same crystal form of the same compound, the error in thermal transition temperature and melting point is typically within about 5 °C in consecutive analyses. When we say that a compound has a given DSC peak or melting point, we mean that DSC peak or melting point ±5 °C. It should be noted that for mixtures, the DSC peak or melting point may vary over a wider range. Furthermore, since decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0142] The present invention will be further described below with reference to embodiments, but these embodiments are not intended to limit the scope of protection of the present invention.

[0143] The following embodiments are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of this invention should be determined by the appended claims.

[0144] In this embodiment, the instruments and methods used for detection are as follows:

[0145] 1. Nuclear magnetic resonance analysis (¹H NMR)

[0146] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and analyzed by nuclear magnetic resonance on a Bruker AVANCE NEO 400 (Bruker, GER).

[0147] 2. X-ray powder diffraction (XRPD)

[0148] The solid samples obtained in the experiment were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, GER). The 2θ scanning angle ranged from 3° to 45°, the scanning step size was 0.02°, and the exposure time was 0.08 seconds. The testing method was Cu target Kα1 radiation, voltage 40 kV, current 40 mA, and a zero-background sample disk.

[0149] Online variable-temperature XRPD testing was performed using a Malvern Panalytical Aeris (UK) X-ray powder diffractometer. The 2θ scanning angle ranged from 3° to 40°, the scanning step size was 0.02°, and the testing time was 13 min. The phototube voltage and current of the test sample were 40 kV and 7.5 mA, respectively, and the sample disk was a zero-background sample disk. The sample was placed on a BTS500 hot stage (Anton Paar, AT) and XRPD testing was performed at room temperature. Subsequently, it was heated to the selected temperature at a rate of 20 °C / min, held at that temperature for 10 min, and then XRPD testing was performed at that temperature. Finally, it was cooled to room temperature and XRPD testing was performed again.

[0150] 3. Thermogravimetric analysis (TGA)

[0151] The thermogravimetric analyzer was a TA Discovery 550 (TA, US). 2-5 mg of sample was placed in a pre-equilibrated open aluminum sample pan and automatically weighed inside the TGA furnace. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at the sample location at 60 mL / min and at the balance at 40 mL / min.

[0152] 4. Differential Scanning Calorimetry (DSC)

[0153] The differential scanning calorimeter was a TA Discovery 250 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at a rate of 50 mL / min.

[0154] 5. Dynamic moisture adsorption-desorption analysis (DVS)

[0155] Dynamic moisture adsorption-desorption analysis for preliminary assessment of hygroscopicity was performed using DVS Intrinsic Plus (SMS, UK). The test employed a gradient mode with humidity variations of 50%-95%-50%, each gradient representing a 15% change in humidity. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the endpoint, or a maximum duration of 60 minutes for each gradient. After testing, XRPD analysis was performed on the samples to confirm whether the solid form had changed.

[0156] Dynamic moisture adsorption-desorption analysis of the system was performed using DVS Intrinsic Plus (SMS, UK). The test employed a gradient mode with humidity variations of 50%-95%-0%-50%. Within the 0% to 90% range, each gradient represented a 10% change in humidity. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the endpoint, or each gradient lasting a maximum of 180 minutes. After the test, XRPD analysis was performed on the samples to confirm whether the solid speciation had changed.

[0157] 6. Polarizing Microscopy (PLM) Analysis

[0158] The polarizing microscope used was a Nikon Ci-POL (Nikon, JP). A small amount of sample was placed on a glass slide, and a suitable lens was selected to observe the sample morphology.

[0159] 7. High Performance Liquid Chromatography (HPLC)

[0160] The high-performance liquid chromatograph was a SHIMADZU LC-20A (Shimadzu, JP), and the test conditions are shown in Table 1.

[0161] Table 1 HPLC test conditions

[0162]

[0163] 8. Ion chromatography: The ion chromatograph model is 925ECO IC (Metrohm, Swiss), and the instrument parameters are shown in Table 2 below.

[0164] Table 2 IC Test Parameters

[0165]

[0166]

[0167] 9. Stability Study

[0168] Approximately 15 mg of sodium salt Type A and potassium salt Type A samples were weighed and placed in weighing bottles. The bottles were then placed under high temperature (60℃), high humidity (25℃ / 92.5% RH), light (25℃ / 4500 Lux), and accelerated conditions (40℃ / 75% RH), respectively. Samples were taken at 7 and 15 days for XRPD characterization and HPLC testing.

[0169] 10. Thermal crystal transfer

[0170] Thermal crystallization was performed using an Instec HCS424GXY hot stage (Instec Inc., US). 6-8 mg of sample was placed on a glass slide on the hot stage and heated to the target temperature at a rate of 10 °C / min. The temperature was held for 5 min and then allowed to cool naturally to room temperature to obtain a solid.

[0171] Thermal conversion to crystallization was performed using an online variable-temperature X-ray powder diffractometer, Malvern PANalytical Aeris (Malvern Panalytical, UK). The sample was placed on a BTS500 hot stage (Anton Paar, AT) and XRPD was performed at room temperature. Then, it was heated to the selected temperature at 20 °C / min, held at that temperature for 10 min, and then XRPD was performed at that temperature. Finally, it was cooled to room temperature and XRPD was performed again.

[0172] 11. Biological media and water solubility test

[0173] The preparation process of the biological medium is as follows: The sample was added to the biological medium and water and incubated at 37°C with shaking for 24 hours. Samples were taken at 0.5 hours, 2 hours, and 24 hours. The sampled solutions were filtered through a 0.22 μm aqueous filter membrane. Some samples with higher concentrations were appropriately diluted with diluent. The signal peak area of ​​the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. In addition, the pH value of the supernatant after 24 hours was tested, and the remaining solids were subjected to XRPD analysis.

[0174] Table 3. Preparation process of biological media

[0175]

[0176] The abbreviations of the compound names used in the examples are as follows:

[0177] X-phos: 2-Dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl

[0178] Pd2(dba)3: Tris(dibenzylacetone dipalladium)

[0179] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0180] DCM: Dichloromethane

[0181] MeOH: Methanol

[0182] PE: Petroleum ether

[0183] EA: Ethyl acetate

[0184] THF: Tetrahydrofuran

[0185] MTBE: Methyl tert-butyl ether

[0186] 1,4-Dioxane: 1,4-Dioxane

[0187] DMF: N,N-dimethylformamide

[0188] DMAc: dimethylacetamide

[0189] DMSO: Dimethyl sulfoxide

[0190] TFA: Trifluoroacetic acid

[0191] Synthesis of starting compound (I)

[0192] Example 1: Preparation of compound (I)

[0193] The route is as follows:

[0194]

[0195] Synthesis of IM1: SM1 (1.00 g, 5.00 mmol), SM2 (1.12 g, 6.00 mmol), X-phos (95 mg, 0.20 mmol), Pd2(dba)3 (183 mg, 0.20 mmol), and cesium carbonate (3.16 g, 10.00 mmol) were added to 1,4-dioxane (10 mL), and the mixture was heated to 100 °C and stirred for 3 h under nitrogen protection. The reaction solution was cooled and poured into water (10 mL), extracted with ethyl acetate (10 mL), washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 8:1) to obtain a yellow oil (1.3 g).

[0196] Synthesis of IM2: Compound IM1 (1.3 g, 4.24 mmol) was weighed and dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was diluted with ethyl acetate (200 mL), and saturated sodium bicarbonate aqueous solution (200 mL) was added to adjust the pH to 7-8. The aqueous phase separated into layers. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by slurry mixing (PE:EA = 5:1, 20 mL) to obtain a pink solid (1.04 g).

[0197] Synthesis of compound IM3: SM3 (500 mg, 1.16 mmol) was dissolved in 1,4-dioxane (5 mL), and compound IM2 (239 mg, 1.16 mmol) and DBU (457 mg, 3.48 mmol) were added. The mixture was heated to 100 °C and stirred for 1 h. The reaction solution was cooled and poured into water (200 mL). Extraction was performed with ethyl acetate (200 mL). The organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain a white solid (137 mg).

[0198] Synthesis of compound IM4: IM3 (19.0 g, 31.65 mmol) was chirally resolved (CHIRALPAK IG (IG00CD-BU015), Hexane / EtOH = 80 / 20) to give a white solid (13.5 g, RT = 4.26 min, ee = 98.8%).

[0199] Synthesis of compound (I): A solution of IM4 (3.00 g, 4.99 mmol) in tetrahydrofuran (20 mL) was added to a solution of sodium hydroxide (0.82 g, 19.98 mmol) in 20 mL. The mixture was heated to 60-65 °C and stirred for 5.5 h. After cooling to room temperature, MTBE (15 mL) and water (6 mL) were added. The pH was adjusted to 7 with solid citric acid. The mixture was extracted with EA (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in acetone, added dropwise to water, and stirred to induce crystallization for 1 hour. The crystals were filtered, washed with water, and dried under reduced pressure to obtain 2.30 g of solid powder. LCMS ESI m / z: 585.4 (MH) -

[0200] Synthesis of the target solid

[0201] Example 2: Preparation of amorphous form of free acid A

[0202] At room temperature, compound (I) (100 mg) was dissolved in acetone (2 mL). Water (4 mL) was added to a 20 mL vial, and the acetone solution of compound (I) was slowly added dropwise while stirring. A solid precipitated. After stirring for 1 hour, the mixture was filtered. The solid was dried at 40°C for 4 hours to obtain 91 mg, a yield of 92%. Using Cu-Kα radiation, its XRPD diffraction angle 2θ showed no obvious characteristic peaks in the range of 2-45°. Figure 1 As shown. The chromatogram determined by thermogravimetric analysis is as follows. Figure 2 As shown, the spectrum determined by differential scanning calorimetry is as follows: Figure 3 As shown.

[0203] Example 3: Preparation of free acid form B crystal

[0204] At room temperature, compound (I) (60 mg) was added to methyl tert-butyl ether (3 mL), heated to 60 °C and stirred to dissolve, then cooled to 5 °C and stirred to precipitate crystals. The reaction solution was filtered, and the solid was dried in a forced-air oven at 50 °C to obtain 45 mg, with a yield of 75%. Its X-ray powder diffraction pattern is shown below. Figure 5 As shown. The chromatogram determined by thermogravimetric analysis is as follows. Figure 6 As shown.

[0205] Table 4. XRPD spectra details of free acid form B

[0206]

[0207] Example 4: Preparation of sodium salt form B

[0208] The reaction route is shown below:

[0209]

[0210] Compound (I) (527.3 mg) was weighed and added to MTBE (18.0 mL) at room temperature to form a suspension. Then, 990 μL of 1 M sodium hydroxide ethanol solution was added. After magnetic stirring at room temperature for 2 days, the solid was centrifuged, dried under vacuum at 40 °C for 18 h, then at 60 °C for 2 h, and finally at 70 °C for 2 h to obtain a white powder (488.2 mg), with a yield of 89%. Samples were taken for XRPD characterization and NMR analysis. Its X-ray powder diffraction pattern is shown below. Figure 12 As shown. The chromatogram determined by thermogravimetric analysis is as follows. Figure 13 As shown; the spectrum determined by differential scanning calorimetry is as follows. Figure 14 As shown.

[0211] Table 5. XRPD spectra details of sodium salt B crystal form.

[0212]

[0213]

[0214] Example 5: Preparation of amorphous sodium salt form A

[0215] 15 mg of sodium salt form B obtained in Example 4 was weighed and placed in a weighing bottle. The bottle was then placed in a high-humidity environment (25°C / 92.5% RH) for 7 days. Samples were then taken for XRPD characterization and NMR testing. NMR showed that, relative to the free raw material, some peak positions of this solid were significantly shifted, similar to sodium salt form B, indicating that the solid was still a sodium salt. XRPD showed that the solid was in an amorphous state. Its XRPD diffraction angle 2θ showed no obvious characteristic peaks in the range of 2-45°. Figure 8 As shown. The spectra determined by thermogravimetric analysis and differential scanning calorimetry are respectively as follows. Figure 9 , 10 As shown.

[0216] Example 6: Preparation of potassium salt form A (amorphous)

[0217] The reaction route is shown below:

[0218]

[0219] Compound (I) (205.5 mg) was weighed and added to MTBE (7.0 mL) at room temperature to form a suspension. Then, 21.4 mg of potassium hydroxide solid was added. After magnetic stirring at room temperature for 2 days, the solution dissolved completely. 7.0 mL of n-heptane was added, precipitating a large amount of solid. The suspension was further suspended for 17 hours, and then the suspension was centrifuged. The solid was dried under vacuum at room temperature for 17 hours to obtain a white powder (167 mg), with a yield of 77%. Samples were taken for XRPD characterization and NMR analysis. NMR showed that, relative to the free sample, some peak positions in this solid were significantly shifted, indicating that the solid had formed a salt. XRPD… Figure 16 This indicates that the solid is in an amorphous state. Its thermogravimetric analysis spectrum is shown below. Figure 17 As shown, the spectrum determined by differential scanning calorimetry is as follows: Figure 18 As shown.

[0220] Example 7: Preparation of potassium salt form B

[0221] The reaction route is shown below:

[0222]

[0223] Compound (I) (527.5 mg) was weighed and suspended in methyl tert-butyl ether (18 mL) at room temperature. Then, an ethanol solution of potassium hydroxide (1 M, 0.99 mL) was added. The mixture was magnetically stirred at room temperature for 48 h, and the solid was centrifuged and dried under vacuum at 40 °C for 18 h to obtain 415 mg of white powder, with a yield of 73%. Samples were taken for XRPD characterization and NMR analysis. NMR showed that, relative to the free sample, some peak positions in this solid were significantly shifted, indicating salt formation. XRPD… Figure 20 This indicates that the solid is crystalline. Its thermogravimetric analysis spectrum is shown below. Figure 21 As shown, the spectrum determined by differential scanning calorimetry is as follows: Figure 22 As shown.

[0224] Table 6. XRPD patterns of potassium salt B crystal form.

[0225]

[0226] Example 8: Preparation of potassium salt C-type crystals

[0227] The reaction route is shown below:

[0228]

[0229] Compound (I) (29.4 mg) was weighed and added to 0.5 mL of ethanol / n-heptane (v / v, 1 / 4) to form a suspension. Then, 55 μL of 1 M potassium hydroxide solution in ethanol was added. After stirring at room temperature for 1 h, the solution became slightly turbid. Upon addition of 2.0 mL of n-heptane, a large amount of solid precipitated. The suspension was further suspended at room temperature for 2 h, then centrifuged and vacuum dried at room temperature for 17 h to obtain a white solid. Samples were taken for XRPD characterization and NMR analysis. NMR showed that, relative to the free sample, some peak positions of this solid were significantly shifted, indicating salt formation. XRPD… Figure 24 This indicates that the solid is crystalline. Its thermogravimetric analysis spectrum is shown below. Figure 25 As shown, the spectrum determined by differential scanning calorimetry is as follows: Figure 26 As shown.

[0230] Table 7. XRPD patterns of potassium salt C-type crystals.

[0231]

[0232] Example 9: Solid-state stability assessment

[0233] The stability of sodium salt form B and potassium salt form B was studied under high temperature (60℃), high humidity (25℃ / 92.5% RH), light (25℃ / 4500Lux), and accelerated (40℃ / 75% RH) conditions. Samples were taken at 7 days and 15 days for XRPD characterization and HPLC testing, respectively. The results are shown in Table 8.

[0234] It is evident that sodium salt form B remained stable under high temperature, light, and accelerated conditions for 15 days without undergoing a crystal form transformation; however, it transformed into an amorphous form after 15 days under high humidity conditions. HPLC results showed that the purity of sodium salt form B did not change significantly after 15 days under high humidity and accelerated conditions; similarly, the purity did not change significantly after 15 days under high temperature and light conditions.

[0235] Potassium salt form B remained stable under high temperature and light conditions for 15 days without any crystal transformation. Under high humidity conditions for 15 days, it transformed into an amorphous form. Under accelerated conditions for 15 days, it transformed into potassium salt form C. HPLC results showed that the purity of potassium salt form B did not change significantly under high humidity and accelerated conditions for 15 days; the purity also did not change significantly under high temperature and light conditions for 15 days.

[0236] Table 8 Results of the stability study

[0237]

[0238] Example 10: Biological Media and Water Solubility Test

[0239] The dynamic solubility of sodium salt form B and potassium salt form B was determined in three biological media (FaSSIF, FeSSIF, and FaSSGF) and water. The results are shown in Table 9.

[0240] Table 9. Solubility Tests in Biological Media and Water

[0241]

[0242] *The solubility value is the solubility corresponding to the free state, calculated based on the standard curve of the free state.

[0243] The results showed that the 24-hour solubility of sodium salt B and potassium salt B in biological media and water was similar, with the order of solubility being: water > FaSSGF > FaSSIF ≈ FeSSIF. In FaSSGF and FaSSIF media, some samples showed solid dissolution followed by re-precipitation. Sodium salt B and potassium salt B dissolved completely in water after 24 hours of shaking, leaving no solid residue. In FaSSGF, FeSSIF, and FaSSIF media, the remaining solid after 24 hours of shaking dissociated into free form B.

[0244] Example 11: Evaluation of the hygroscopicity of solids

[0245] Hygroscopicity was assessed for sodium salt form B, potassium salt form B, and potassium salt form C. The results are shown in Table 10.

[0246] Table 10 Hygroscopicity Assessment Table

[0247]

[0248]

[0249] Rapid DVS results showed that sodium salt form B had an adsorption weight gain of approximately 8.18% at 95% RH and an adsorption weight gain of approximately 1.58% at 80% RH, with a desorption weight gain of approximately 4.95%. XRPD results showed no change in crystal structure after DVS testing. Rapid DVS results showed that potassium salt form B had an adsorption weight gain of approximately 13.38% at 95% RH and an adsorption weight gain of approximately 1.09% at 80% RH, with a desorption weight gain of approximately 9.34%. XRPD results showed a decrease in crystallinity after DVS testing, but no change in crystal structure. Rapid DVS results showed that potassium salt form C had an adsorption weight gain of approximately 5.43% at 95% RH and an adsorption weight gain of approximately 0.64% at 80% RH, with a desorption weight gain of approximately 3.08%. XRPD results showed that the crystal structure of the sample after DVS testing was a mixed crystal of potassium salt form C and a small amount of free form B.

[0250] Example 12: Rat PK Study

[0251] Gavage administration: Nine male Wistar rats were divided into three groups. They were fasted overnight before the experiment but had free access to water. One hour after administration, all rats were fed. Compound free acid form A was administered at 3 mg / kg, while sodium salt form B and potassium salt form B were administered by gavage at equimolar doses of free acid form A. The gavage solvent was 0.5% methylcellulose. At 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24.0 h post-administration, 0.2 mL of blood was collected via the jugular vein, placed in EDTA-K2 anticoagulant tubes, gently mixed, placed on ice, and immediately centrifuged (4℃, 4000 rpm, 10 min). The plasma was separated and frozen at –80℃ for analysis. The concentration of free acid in the plasma was determined by LC-MS / MS, and pharmacokinetic parameters were calculated. The results are shown in Table 11.

[0252] Table 11 PK parameters for Wistar rats administered via gavage

[0253] PK parameters (ig) Free acid form A Sodium salt form B Potassium salt form B <![CDATA[t 1 / 2 (h)]]> 1.53 1.81 1.47 <![CDATA[T max (h)]]> 1.00 0.83 1.00 <![CDATA[C max (of mL) -1 )]]> 125.36 120.23 148.82 <![CDATA[AUC 0-t (ng·h·mL) -1 )]]> 255.50 313.92 460.78

[0254] The results showed that when the relatively stable sodium salt form B and potassium salt form B were administered to Wistar rats by gavage in equimolar amounts with the free acid form A, the absorption AUC in the rats was increased to a certain extent compared with that of the free acid form. This proves that salt formation can improve the water solubility of the compound and increase its bioavailability. This improvement has an important role in clinical drug use, which can reduce the dosage and reduce toxic side effects to a certain extent.

[0255] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A solid form of a compound of formula (II), characterized in that: The solid form is either amorphous or crystalline, and in formula (II), X is 0-10, and X is an integer multiple of 0.5:

2. The solid form according to claim 1, characterized in that: The amorphous structure is a type A amorphous structure, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-45° at the 2θ angle.

3. The solid form according to claim 2, characterized in that: The thermogravimetric analysis (TGA) spectrum of the type A amorphous structure shows a weight loss of 22.8 ± 0.2% when heated to 160 ± 2 °C; and / or, the differential scanning calorimetry (DSC) spectrum of the type A amorphous structure shows endothermic peaks at 77 ± 2 °C and 120 ± 2 °C, respectively.

4. The solid form according to claim 1, characterized in that: The crystal is of type B, and its X-ray powder diffraction pattern shows characteristic peaks at 2θ angles of 6.15°±0.2°, 10.66°±0.2°, 12.31°±0.2°, 13.75°±0.2°, 15.09°±0.2°, 16.29°±0.2°, 18.49°±0.2°, 20.45°±0.2°, 21.37°±0.2°, 22.26°±0.2°, 23.10°±0.2°, 23.93°±0.2°, 26.98°±0.2°, 28.40°±0.2°, and 29.74°±0.2°.

5. The solid form according to claim 4, characterized in that: The X-ray powder diffraction pattern of the B-type crystal also has characteristic peaks at one or more of the following 2θ angles: 24.71°±0.2°, 25.51°±0.2°, 26.23°±0.2°, 30.37°±0.2°, 31.05°±0.2°, 32.29°±0.2°, 33.51°±0.2°, 34.14°±0.2°, 34.64°±0.2°, 35.85°±0.2°, 37.54°±0.2°, 38.02°±0.2°, 39.01°±0.2°, 41.07°±0.2°, and 42.03°±0.2°.

6. The solid form according to claim 4 or 5, characterized in that: The thermogravimetric analysis (TGA) spectrum of the B-type crystal form shows a weight loss of 3.7 ± 0.2% when heated to 100 ± 2 °C and a weight loss of 3.3 ± 0.2% between 100 ± 2 °C and 160 ± 2 °C; and / or, the differential scanning calorimetry (DSC) spectrum of the B-type crystal form shows two endothermic peaks at 71 ± 2 °C and 136 ± 2 °C.

7. The solid form according to claim 4, characterized in that: In the B-type crystal form, X is 1-3; preferably, X is 1.

8. A method for preparing the solid form of the compound of formula (II) according to any one of claims 1-7, characterized in that: The preparation method includes: 1) Dissolve compound (I) in a solvent, add ligands to react, and remove the solvent by evaporation or lyophilization after the reaction to obtain an amorphous structure; or 2) Dissolve compound (I) in a solvent, add the ligand to react, and after the reaction is complete, add an antisolvent to the solvent to precipitate the solid. Filter or centrifuge to obtain the amorphous structure; or 3) Dissolve compound (I) in a solvent, add ligands to react, and after the reaction is complete, cool and crystallize under stirring, then filter or centrifuge to obtain the crystals; 4) The B-type crystal form is placed under conditions of humidity greater than or equal to 90% to undergo crystal transformation, thereby obtaining the A-type amorphous structure; Among them, compound (I) is The solvent is selected from one or more combinations of ether solvents, ester solvents, alcohol solvents, ketone solvents, nitrile solvents, halogenated hydrocarbons, aromatic hydrocarbons, or water; the antisolvent is selected from one or more combinations of ether solvents or alkanes; the ligand is selected from one or more combinations of sodium hydroxide, sodium methoxide, sodium ethoxide, and sodium tert-butoxide; preferably, the solvent is selected from one or more combinations of ethyl acetate, methyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, acetone, methyl ethyl ketone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol, acetonitrile, methyl tert-butyl ether, dioxane, and water; the antisolvent is selected from one or more combinations of petroleum ether, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, isopropyl ether, and diethyl ether.

9. A solid form of a compound of formula (III), characterized in that: The solid form is an amorphous structure or crystalline, and in formula (III), X is 0-10, and X is an integer multiple of 0.5:

10. The solid form according to claim 9, characterized in that: The amorphous structure is a type A amorphous structure, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-45° at the 2θ angle.

11. The solid form according to claim 10, characterized in that: The thermogravimetric analysis (TGA) spectrum of the type A amorphous structure shows a weight loss of 8.4 ± 0.2% when heated to 150 ± 2 °C; and / or, the differential scanning calorimetry (DSC) spectrum of the type A amorphous structure shows an endothermic peak at 78 ± 2 °C.

12. The solid form according to claim 10 or 11, characterized in that: In the type A amorphous structure, X is 0-3; preferably, X is 0.

13. The solid form according to claim 9, characterized in that: The crystal is of type B, and its X-ray powder diffraction pattern is observed at 2θ angles of 6.15°±0.2°, 10.62°±0.2°, 12.31°±0.2°, 13.73°±0.2°, 15.05°±0.2°, 15.48°±0.2°, 16.29°±0.2°, 16.66°±0.2°, 17.77°±0.2°, and 18°. Characteristic peaks are observed at 0.47°±0.2°, 19.81°±0.2°, 20.43°±0.2°, 20.74°±0.2°, 21.37°±0.2°, 21.66°±0.2°, 22.26°±0.2°, 23.10°±0.2°, 23.37°±0.2°, 23.91°±0.2°, and 26.96°±0.2°.

14. The solid form according to claim 13, characterized in that: The X-ray powder diffraction patterns of the B-type crystal form also show 2θ angles of 9.37°±0.2°, 12.76°±0.2°, 18.78°±0.2°, 24.73°±0.2°, 24.98°±0.2°, 25.72°±0.2°, 26.26°±0.2°, 26.52°±0.2°, 27.24°±0.2°, 27.86°±0.2°, 28.40°±0.2°, and 29.30°±0.2°. One or more of the following values ​​are characteristic peaks: 0.2°, 29.74°±0.2°, 30.64°±0.2°, 31.90°±0.2°, 32.46°±0.2°, 33.11°±0.2°, 34.29°±0.2°, 34.70°±0.2°, 35.44°±0.2°, 35.85°±0.2°, 36.53°±0.2°, 38.65°±0.2°, and 39.03°±0.2°.

15. The solid form according to claim 13 or 14, characterized in that: The thermogravimetric analysis (TGA) spectrum of the B-type crystal form shows a weight loss of 3.8±0.2% when heated to 60±2℃ and a weight loss of 2.9±0.2% between 60±2℃ and 160±2℃; and / or, the differential scanning calorimetry (DSC) spectrum of the B-type crystal form shows endothermic peaks at 42±2℃, 61±2℃, and 141±2℃, respectively.

16. The solid form according to claim 13 or 14, characterized in that: In the B-type crystal form, X is 1-3; preferably, X is 1.

17. The solid form according to claim 9, characterized in that: The crystal is of the C-type crystal form, and its X-ray powder diffraction pattern is observed at 2θ angles of 6.07°±0.2°, 9.39°±0.2°, 10.52°±0.2°, 11.18°±0.2°, 12.15°±0.2°, 12.74°±0.2°, 15.38°±0.2°, 16.10°±0.2°, 16.55°±0.2°, and 17.65°±0.2°. Characteristic peaks are observed at 2°, 18.86°±0.2°, 19.81°±0.2°, 20.59°±0.2°, 21.13°±0.2°, 21.48°±0.2°, 22.01°±0.2°, 26.25°±0.2°, 26.69°±0.2°, 26.98°±0.2°, 27.80°±0.2°, and 29.02°±0.2°.

18. The solid form according to claim 17, characterized in that: The X-ray powder diffraction patterns of the C-type crystal form also show 2θ angles of 10.85°±0.2°, 13.44°±0.2°, 13.71°±0.2°, 17.83°±0.2°, 18.59°±0.2°, 19.27°±0.2°, 23.21°±0.2°, 23.84°±0.2°, 24.44°±0.2°, 24.77°±0.2°, 25.66°±0.2°, 28.09°±0.2°, 28.50°±0.2°, 29.69°±0.2°, and 30.40°±0.2°. One or more of the following values ​​are characteristic peaks: 0.2°, 30.70°±0.2°, 31.07°±0.2°, 31.57°±0.2°, 32.17°±0.2°, 32.54°±0.2°, 32.85°±0.2°, 34.04°±0.2°, 34.29°±0.2°, 34.62°±0.2°, 35.09°±0.2°, 35.67°±0.2°, 36.20°±0.2°, 40.28°±0.2°, 42.30°±0.2°, and 43.52°±0.2°.

19. The solid form according to claim 17 or 18, characterized in that: The C-type crystal form, as determined by thermogravimetric analysis, shows a weight loss of 5.0±0.2% when heated to 100±2℃ and a weight loss of 2.7±0.2% between 100±2℃ and 160±2℃; and / or, the C-type crystal form, as determined by differential scanning calorimetry, shows endothermic peaks at 100±2℃ and 145±2℃, respectively.

20. The solid form according to claim 17 or 18, characterized in that: In the C-type crystal form, X is a multiple of 0.5 between 1 and 3; preferably, X is 2.

21. A method for preparing the solid form of the compound of formula (III) according to any one of claims 9-20, characterized in that: The preparation method includes: 1) Dissolve compound (I) in a solvent, add ligands to react, and remove the solvent by evaporation or lyophilization after the reaction to obtain an amorphous structure; or 2) Dissolve compound (I) in a solvent, add the ligand to react, and after the reaction is complete, add an antisolvent to the solvent to precipitate the solid. Filter or centrifuge to obtain the amorphous structure; or 3) Dissolve compound (I) in a solvent, add ligands to react, and after the reaction is complete, cool and crystallize under stirring, then filter or centrifuge to obtain the crystals; Among them, compound (I) is The solvent is selected from one or more combinations of ether solvents, ester solvents, alcohol solvents, ketone solvents, nitrile solvents, halogenated hydrocarbons, aromatic hydrocarbons, or water; the antisolvent is selected from one or more combinations of ether solvents or alkanes; the ligand is selected from one or more combinations of potassium hydroxide, potassium methoxide, potassium ethoxide, and potassium tert-butoxide; preferably, the solvent is selected from one or more combinations of ethyl acetate, methyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, acetone, methyl ethyl ketone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol, acetonitrile, methyl tert-butyl ether, dioxane, and water; the antisolvent is selected from one or more combinations of petroleum ether, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, isopropyl ether, and diethyl ether.

22. A solid form of a compound of formula (I), characterized in that: The solid form is either an amorphous structure or crystalline:

23. The solid form according to claim 22, characterized in that: The amorphous structure is a type A amorphous structure, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-45° at the 2θ angle.

24. The solid form according to claim 23, characterized in that: The thermogravimetric analysis (TGA) spectrum of the type A amorphous structure shows a weight loss of 7.5 ± 0.2% when heated to 150 ± 2 °C; and / or, the differential scanning calorimetry (DSC) spectrum of the type A amorphous structure shows endothermic peaks at 66 ± 2 °C and 114 ± 2 °C, respectively.

25. The solid form according to claim 22, characterized in that: The crystal is of type B, and its X-ray powder diffraction pattern shows characteristic peaks at 2θ angles of 9.63°±0.2°, 10.89°±0.2°, 13.48°±0.2°, 13.75°±0.2°, 15.32°±0.2°, 16.33°±0.2°, 16.84°±0.2°, 17.85°±0.2°, 18.63°±0.2°, 19.29°±0.2°, 19.50°±0.2°, 20.63°±0.2°, 23.25°±0.2°, 23.87°±0.2°, 24.90°±0.2°, and 26.32°±0.2°.

26. The solid form according to claim 25, characterized in that: The X-ray powder diffraction patterns of the B-type crystal form also show 2θ angles of 15.91°±0.2°, 18.18°±0.2°, 21.13°±0.2°, 21.50°±0.2°, 21.87°±0.2°, 22.49°±0.2°, 22.88°±0.2°, 24.50°±0.2°, 26.01°±0.2°, 26.73°±0.2°, and 27.14°± One or more of the following values ​​are characteristic peaks: 0.2°, 27.39°±0.2°, 27.72°±0.2°, 27.92°±0.2°, 28.66°±0.2°, 29.06°±0.2°, 29.90°±0.2°, 31.88°±0.2°, 32.74°±0.2°, 34.00°±0.2°, 35.85°±0.2°, and 37.01°±0.2°.

27. The solid form according to claim 25 or 26, characterized in that: The thermogravimetric analysis (TGA) spectrum of the B-type crystal form shows a weight loss of 0.3 ± 0.2% when heated to 150 ± 2 °C; and / or, the differential scanning calorimetry (DSC) spectrum of the B-type crystal form shows an endothermic peak, indicating that the melting point onset temperature of the B-type crystal form is 246 ± 2 °C.

28. A method for preparing the solid form of the compound of formula (I) according to any one of claims 22-27, characterized in that: The preparation method includes: 1) Dissolve compound (I) in a solvent, remove the solvent by evaporation or lyophilization to obtain an amorphous structure; or 2) Dissolve compound (I) in a solvent, add an antisolvent or water to the solvent to precipitate the solid, filter or centrifuge to obtain the amorphous structure; or 3) Dissolve compound (I) in a solvent, cool and crystallize while stirring, and then filter or centrifuge to obtain the crystal form; The solvent is selected from one or more combinations of ether solvents, ester solvents, alcohol solvents, ketone solvents, nitrile solvents, halogenated hydrocarbons, and aromatic hydrocarbons; the antisolvent is selected from one or more combinations of ether solvents, alkanes, and water; preferably, the solvent is selected from one or more combinations of ethyl acetate, methyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, acetone, methyl ethyl ketone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol, acetonitrile, methyl tert-butyl ether, and dioxane; the antisolvent is selected from one or more combinations of petroleum ether, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, isopropyl ether, diethyl ether, and water.

29. A pharmaceutical composition, characterized in that: Includes the solid form as described in any one of claims 1 to 28 and pharmaceutically acceptable carriers.

30. Use of the solid form according to any one of claims 1 to 28 in the preparation of an antiviral drug; preferably, the virus is HCMV virus.

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