Salt of dihydroorotate dehydrogenase inhibitor as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicinal chemistry, in particular to salt of a dihydroorotate dehydrogenase inhibitor as well as a preparation method and application of the salt. The salt of the dihydroorotate dehydrogenase inhibitor is a salt of a compound as shown in a formula (I), the salt is sulfate or hydrochloride. Compared with the compound shown in the formula (I), the salt of the compound shown in the formula (I) has better solubility and bioavailability, and has excellent stability.

Description

[0001] Related applications

[0002] This application claims priority to Chinese patent application No. 2025100890228, filed on January 21, 2025, entitled "Salts of dihydroorotate dehydrogenase inhibitors or crystal forms thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the field of medicinal chemistry technology, and in particular to salts of dihydroorotate dehydrogenase inhibitors, their preparation methods, and applications. Background Technology

[0004] Invasive fungal infections are infectious diseases caused by fungi invading human tissues or bloodstreams, triggering inflammatory responses and organ dysfunction. Because it is difficult to find drug targets compatible with the human body, currently used antifungal drugs mainly fall into four categories: polyenes (e.g., amphotericin B), azoles (e.g., itraconazole), allylamines (e.g., terbinafine), and echinocandins (e.g., micafungin). However, due to the overuse of broad-spectrum antibiotics, resistant strains to these four classes of antifungal drugs have gradually emerged in different fungal pathogens, prompting researchers to design new anti-infection strategies and drugs.

[0005] Dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in the fourth step of the pyrimidine-derived synthesis pathway. Pyrimidine uptake is an essential energy source for most life forms; therefore, inhibiting fungal DHODH can effectively block its proliferation. (S)-2-(1,5-dimethyl-3-phenyl-1H-pyrrolo-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-8-yl)-2-oxoacetamide (structure shown in formula (I)) is a DHODH inhibitor that selectively inhibits fungal DHODH, has minimal impact on human DHODH, and is highly safe for human use. However, the free base of compound (I) has low solubility, is almost insoluble in water, and has low absorption and bioavailability after oral administration, thus affecting its drug-like properties.

[0006] Therefore, it is necessary to improve the solubility, oral absorption and bioavailability of compounds of formula (I). Summary of the Invention

[0007] Based on this, one or more embodiments of this application provide salts of compounds of formula (I), methods for their preparation, and applications. Salts of compounds of formula (I) have the advantages of high solubility, good bioavailability, and good stability.

[0008] The technical solution of this application includes the following:

[0009] One or more embodiments of this application provide salts of the compounds shown in formula (I), wherein the salts are sulfates or hydrochlorides;

[0010] (I).

[0011] In some embodiments, the salt is in sulfate form B;

[0012] The X-ray powder diffraction pattern of the sulfate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 14.87°±0.2°, 17.79°±0.2°, 21.86°±0.2°, 24.23°±0.2°.

[0013] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 14.87°±0.2°, 17.51°±0.2°, 17.79°±0.2°, 21.37°±0.2°, 21.86°±0.2°, 24.23°±0.2°;

[0014] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form B exhibits characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 9.53°±0.2°, 14.87°±0.2°, 17.51°±0.2°, 17.79°±0.2°, 21.37°±0.2°, 21.86°±0.2°, 23.66°±0.2°, 24.23°±0.2°;

[0015] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 9.53°±0.2°, 13.33°±0.2°, 14.87°±0.2°, 17.21°±0.2°, 17.51°±0.2°, 17.79°±0.2°, 21.37°±0.2°, 21.86°±0.2°, 23.66°±0.2°, 24.23°±0.2°, and 25.80°±0.2°.

[0016] Furthermore, the differential scanning calorimetry (DSC) chromatogram of the sulfate contains endothermic peaks at 139.2°C ± 3°C and 191.3°C ± 3°C.

[0017] In some embodiments, the salt is in sulfate form C;

[0018] The X-ray powder diffraction pattern of the sulfate crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 17.84°±0.2°, 19.17°±0.2°, 21.33°±0.2°.

[0019] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 10.00°±0.2°, 17.84°±0.2°, 18.39°±0.2°, 19.17°±0.2°, 21.33°±0.2°;

[0020] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form C exhibits characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 10.00°±0.2°, 17.84°±0.2°, 18.39°±0.2°, 19.17°±0.2°, 21.33°±0.2°, 24.05°±0.2°, 24.21°±0.2°;

[0021] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 10.00°±0.2°, 14.57°±0.2°, 17.84°±0.2°, 18.39°±0.2°, 19.17°±0.2°, 21.33°±0.2°, 21.89°±0.2°, 24.05°±0.2°, 24.21°±0.2°, and 24.86°±0.2°.

[0022] Furthermore, the differential scanning calorimetry (DSC) chromatogram of the sulfate contains an endothermic peak at 215.1°C ± 3°C.

[0023] In some embodiments, the salt is in sulfate form D;

[0024] The X-ray powder diffraction pattern of the sulfate crystal form D has characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 24.00°±0.2°.

[0025] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form D has characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 22.67°±0.2°, 24.00°±0.2°;

[0026] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form D exhibits characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 16.04°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 21.81°±0.2°, 22.67°±0.2°, 24.00°±0.2°;

[0027] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form D exhibits characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 16.04°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 19.58°±0.2°, 21.81°±0.2°, 22.67°±0.2°, 22.81°±0.2°, 23.37°±0.2°, 24.00°±0.2°, 25.33°±0.2°;

[0028] Furthermore, the X-ray powder diffraction pattern of sulfate crystal form D exhibits characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 11.30°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 15.90°±0.2°, 16.04°±0.2°, 17.94°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 19.58°±0.2°, 21.81°±0.2°, 22.67°±0.2°, 22.81°±0.2°, 23.37°±0.2°, 24.00°±0.2°, 25.33°±0.2°, and 29.17°±0.2°.

[0029] Furthermore, the differential scanning calorimetry (DSC) chromatogram of the sulfate contains endothermic peaks at 214.0°C ± 3°C and 218.2°C ± 3°C.

[0030] In some embodiments, the salt is in the form of hydrochloride crystal form B;

[0031] The X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 18.57°±0.2°, 22.77°±0.2°.

[0032] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 11.45°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 18.33°±0.2°, 18.57°±0.2°, 22.77°±0.2°;

[0033] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 11.45°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 17.61°±0.2°, 18.33°±0.2°, 18.57°±0.2°, 22.77°±0.2°, 27.17°±0.2°;

[0034] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 11.45°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 17.61°±0.2°, 18.33°±0.2°, 18.57°±0.2°, 22.77°±0.2°, 23.68°±0.2°, 23.98°±0.2°, 26.01°±0.2°, and 27.17°±0.2°.

[0035] Furthermore, the differential scanning calorimetry (DSC) plot of the hydrochloride salt contains an endothermic peak at 173.0°C ± 3°C.

[0036] In some embodiments, the salt has a crystal form of hydrochloride crystal form C;

[0037] The X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.78°±0.2°, and 18.93°±0.2°.

[0038] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 11.14°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.78°±0.2°, 18.38°±0.2°, and 18.93°±0.2°.

[0039] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 11.14°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.78°±0.2°, 18.38°±0.2°, 18.93°±0.2°, 21.80°±0.2°, 24.17°±0.2°;

[0040] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 7.70°±0.2°, 11.14°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.16°±0.2°, 16.78°±0.2°, 18.38°±0.2°, 18.93°±0.2°, 21.8°±0.2°, and 24.17°±0.2°.

[0041] Furthermore, the differential scanning calorimetry (DSC) plot of the hydrochloride salt contains an endothermic peak at 144.0°C ± 3°C.

[0042] In some embodiments, the salt has a crystal form of hydrochloride crystal form D;

[0043] The X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 11.24°±0.2°, 14.96°±0.2°, 19.43°±0.2°, 24.22°±0.2°.

[0044] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 11.24°±0.2°, 14.96°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 24.22°±0.2°;

[0045] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 9.68°±0.2°, 11.24°±0.2°, 14.96°±0.2°, 17.99°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 20.28°±0.2°, 24.22°±0.2°;

[0046] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 9.68°±0.2°, 11.24°±0.2°, 12.75°±0.2°, 14.96°±0.2°, 17.99°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 20.28°±0.2°, 22.11°±0.2°, 24.22°±0.2°, 24.46°±0.2°;

[0047] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 9.38°±0.2°, 9.68°±0.2°, 11.24°±0.2°, 12.75°±0.2°, 14.96°±0.2°, 16.71°±0.2°, 17.23°±0.2°, 17.99°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 20.28°±0.2°, 22.11°±0.2°, 24.22°±0.2°, 24.46°±0.2°, 26.21°±0.2°.

[0048] Furthermore, the differential scanning calorimetry (DSC) plot of the hydrochloride salt contains endothermic peaks at 142.8°C ± 3°C and 191.3°C ± 3°C.

[0049] In some embodiments, the salt has a crystal form of hydrochloride crystal form E;

[0050] The X-ray powder diffraction pattern of the hydrochloride crystal form E has characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 14.95°±0.2°, 19.43°±0.2°, 19.72°±0.2°, 20.28°±0.2°, 24.20°±0.2°;

[0051] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form E has characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 12.75°±0.2°, 14.95°±0.2°, 19.43°±0.2°, 19.72°±0.2°, 20.28°±0.2°, 22.10°±0.2°, 24.20°±0.2°;

[0052] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form E has characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 12.75°±0.2°, 14.95°±0.2°, 16.71°±0.2°, 19.43°±0.2°, 19.72°±0.2°, 20.28°±0.2°, 22.10°±0.2°, 23.33°±0.2°, 24.20°±0.2°, 26.07°±0.2°;

[0053] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form E exhibits characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 12.75°±0.2°, 13.82°±0.2°, 14.95°±0.2°, 16.71°±0.2°, 19.43°±0.2°, and 19.72°±0.2°. , 20.28°±0.2°, 22.10°±0.2°, 22.86°±0.2°, 23.33°±0.2°, 24.20°±0.2°, 26.07°±0.2°, 26.33°±0.2°, 26.89°±0.2°, 28.49°±0.2°, 29.30°±0.2°, 30.28°±0.2°.

[0054] Furthermore, the differential scanning calorimetry (DSC) plot of the hydrochloride salt contains an endothermic peak at 186.8°C ± 3°C.

[0055] One or more embodiments of this application provide a method for preparing a salt of the compound represented by formula (I) described above, comprising the following steps:

[0056] A salt of the compound shown in formula (I) is prepared by mixing the compound, acid, and solvent.

[0057] Optionally, the acid is sulfuric acid or hydrochloric acid;

[0058] Optionally, the solvent includes one or more of acetone, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, acetonitrile, and ethanol.

[0059] One or more embodiments of this application provide pharmaceutical compositions comprising a salt of the compound represented by formula (I) as described above and pharmaceutically acceptable excipients;

[0060] Optionally, the excipients include one or more of a carrier, excipient, diluent, and auxiliaries.

[0061] One or more embodiments of this application provide the use of salts or pharmaceutical compositions of the compounds represented by formula (I) described above in the preparation of medicaments for treating and / or preventing fungal infections or diseases caused by fungal infections;

[0062] Further, the fungi include one or more of the following genera: *Absidia*, *Alternaria*, *Aspergillus*, *Bipolaris*, *Blastomyces*, *Blumeria*, *Cladosporium*, *Coccidioides*, *Colletotrichium*, *Encephalitozoon*, *Epicoccum*, *Epidermophyton*, *Exophiala*, *Exserohilum*, *Fusarium*, *Histoplasma*, and others. Genus *Leptosphaeria*, *Microsporum*, *Mycosphaerella*, *Neurospora*, *Paecilomyces*, *Penicillium*, *Phytophthora*, *Plasmopara*, *Pneumocystis*, *Pyricularia*, *Pythium*, *Puccinia*, *Rhizoctonia*, *Rhizomucor*, *sporium*, *Scopulariopsis*, *Trichophyton*, *Trichosporon*, *Ustilago*.

[0063] The salts of the compounds represented by formula (I) in this application exhibit superior solubility and higher oral bioavailability compared to the compounds represented by formula (I), and also possess excellent stability and better druggability. In some preferred embodiments, the hydrochloride salt has low hygroscopicity, which is beneficial for the production and storage of the product. In some preferred embodiments, hydrochloride crystal form D, hydrochloride crystal form E, and sulfate crystal form C have superior solubility and higher oral bioavailability; furthermore, hydrochloride crystal form E also has superior stability and lower hygroscopicity, thus exhibiting better druggability. Attached Figure Description

[0064] To more clearly illustrate the technical solutions in the specific embodiments of this application or the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0065] Figure 1 The image shows the X-ray powder diffraction (XRPD) pattern of the sulfate crystal form B of the compound represented by formula (I) of this application.

[0066] Figure 2 The differential scanning calorimetry (DSC) curve is shown for the sulfate crystal form B of the compound represented by formula (I) of this application.

[0067] Figure 3 The image shows the X-ray powder diffraction (XRPD) pattern of the sulfate crystal form C of the compound represented by formula (I) of this application.

[0068] Figure 4 The differential scanning calorimetry (DSC) curve is shown for the sulfate crystal form C of the compound represented by formula (I) of this application.

[0069] Figure 5 The image shows the X-ray powder diffraction (XRPD) pattern of the sulfate crystal form D of the compound represented by formula (I) of this application.

[0070] Figure 6 The differential scanning calorimetry (DSC) curve is shown for the sulfate crystal form D of the compound represented by formula (I) of this application.

[0071] Figure 7 The image shows the X-ray powder diffraction (XRPD) pattern of the hydrochloride crystal form B of the compound represented by formula (I) of this application.

[0072] Figure 8 The differential scanning calorimetry (DSC) curve is shown for the hydrochloride crystal form B of the compound represented by formula (I) of this application.

[0073] Figure 9 The image shows the X-ray powder diffraction (XRPD) pattern of the hydrochloride crystal form C of the compound represented by formula (I) of this application.

[0074] Figure 10 The differential scanning calorimetry (DSC) curve is shown for the hydrochloride crystal form C of the compound represented by formula (I) of this application.

[0075] Figure 11 The image shows the X-ray powder diffraction (XRPD) pattern of the hydrochloride crystal form D of the compound represented by formula (I) of this application.

[0076] Figure 12The differential scanning calorimetry (DSC) curve is shown for the hydrochloride crystal form D of the compound represented by formula (I) of this application.

[0077] Figure 13 The image shows the X-ray powder diffraction (XRPD) pattern of the hydrochloride crystal form E of the compound represented by formula (I) of this application.

[0078] Figure 14 The differential scanning calorimetry (DSC) curve is shown for the hydrochloride crystal form E of the compound represented by formula (I) of this application.

[0079] Figure 15 The image shows the X-ray powder diffraction (XRPD) pattern of the hydrobromide crystal form A of the compound represented by formula (I) of this application.

[0080] Figure 16 The differential scanning calorimetry (DSC) curve is shown for the hydrobromide crystal form A of the compound represented by formula (I) of this application.

[0081] Figure 17 The image shows the X-ray powder diffraction (XRPD) pattern of the p-toluenesulfonate crystal form A of the compound represented by formula (I) of this application.

[0082] Figure 18 The image shows a differential scanning calorimetry (DSC) curve of p-toluenesulfonate crystal form A of the compound represented by formula (I) of this application.

[0083] Figure 19 The image shows a dynamic moisture adsorption (DVS) diagram of the hydrochloride crystal form E of the compound represented by formula (I) of this application.

[0084] Figure 20 The image shows a dynamic moisture adsorption (DVS) diagram of the sulfate crystal form C of the compound represented by formula (I) of this application.

[0085] Figure 21 The diagram shows the dynamic water adsorption (DVS) of hydrobromide crystal form A of the compound represented by formula (Ⅰ) of this application.

[0086] Figure 22 The diagram shows the dynamic water adsorption (DVS) of p-toluenesulfonate crystal form A of the compound represented by formula (Ⅰ) of this application.

[0087] Figure 23 The image shows a dynamic moisture adsorption (DVS) diagram of the hydrochloride crystal form B of the compound represented by formula (I) of this application.

[0088] Figure 24 The image shows a dynamic moisture adsorption (DVS) diagram of the hydrochloride crystal form C of the compound represented by formula (I) of this application.

[0089] Figure 25The image shows a dynamic moisture adsorption (DVS) diagram of the hydrochloride crystal form D of the compound represented by formula (I) of this application.

[0090] Figure 26 The image shows a dynamic moisture adsorption (DVS) diagram of the sulfate crystal form D of the compound represented by formula (I) of this application. Detailed Implementation

[0091] The present application is further described below with reference to embodiments and examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Furthermore, it should be understood that after reading the teachings of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the protection scope of the appended claims.

[0092] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0093] The terms “comprising” and “having”, and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps and modules listed, but may optionally include steps not listed, and may optionally include other steps inherent to such process, method, product, or device.

[0094] The term "multiple" refers to two or more.

[0095] The term "and / and" describes the relationship between related objects, indicating that there can be three relationships. For example, A and / and B can represent: A alone, A and B simultaneously, or B alone. The character " / " generally indicates that the related objects are in an "and" relationship.

[0096] In this application, "solubility" refers to the equilibrium solubility of a substance, i.e., saturated solubility, which means the maximum amount of a substance that can be dissolved in a certain solvent under specific conditions. Referring to the USP shake flask method, it is used to compare the solubility of different crystal forms in the same solvent.

[0097] In this application, the X-ray powder diffraction pattern was acquired using a Panalytical Empyrean X-ray powder diffractometer. In some embodiments, the X-ray powder diffraction method parameters are as follows: X-ray reflection parameters: Cu, Kα; Kα1 (Å): 1.540598; Kα2 (Å): 1.544426; Kα2 / Kα1 intensity ratio: 0.50; voltage: 45 kV; current: 40 mA; scan range: 3.0 to 60.0 degrees; step size: 0.026° / sec.

[0098] In this application, the test parameters for differential scanning calorimetry (DSC) are as follows: scan rate: 10°C / min; start and end temperatures: room temperature - 300°C.

[0099] In this application, the dynamic moisture adsorption (DVS) graph for the hygroscopicity test was collected using an Intrinsic dynamic moisture adsorption analyzer manufactured by SMS (Surface Measurement Systems Ltd.). The method parameters for the dynamic moisture adsorption analyzer are as follows: temperature: 25°C; carrier gas flow rate: N2, 200 mL / min; mass change per unit time: 0.002% / min; relative humidity range: 0%RH-95%RH-0%RH; step size: 10%RH.

[0100] In this application, the compound represented by formula (I) is (S)-2-(1,5-dimethyl-3-phenyl-1H-pyrrolo-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-8-yl)-2-oxoacetamide.

[0101] One or more embodiments of this application provide salts of the compounds shown in formula (I), wherein the salts are sulfates or hydrochlorides;

[0102] (I).

[0103] In some embodiments, the salt is in sulfate form B;

[0104] The X-ray powder diffraction pattern of the sulfate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 14.87°±0.2°, 17.79°±0.2°, 21.86°±0.2°, 24.23°±0.2°.

[0105] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 14.87°±0.2°, 17.51°±0.2°, 17.79°±0.2°, 21.37°±0.2°, 21.86°±0.2°, 24.23°±0.2°;

[0106] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form B exhibits characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 9.53°±0.2°, 14.87°±0.2°, 17.51°±0.2°, 17.79°±0.2°, 21.37°±0.2°, 21.86°±0.2°, 23.66°±0.2°, 24.23°±0.2°;

[0107] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 9.53°±0.2°, 13.33°±0.2°, 14.87°±0.2°, 17.21°±0.2°, 17.51°±0.2°, 17.79°±0.2°, 21.37°±0.2°, 21.86°±0.2°, 23.66°±0.2°, 24.23°±0.2°, and 25.80°±0.2°.

[0108] Furthermore, the differential scanning calorimetry (DSC) chromatogram of the sulfate contains endothermic peaks at 139.2°C ± 3°C and 191.3°C ± 3°C.

[0109] In some embodiments, the salt is in sulfate form C;

[0110] The X-ray powder diffraction pattern of the sulfate crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 17.84°±0.2°, 19.17°±0.2°, 21.33°±0.2°.

[0111] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 10.00°±0.2°, 17.84°±0.2°, 18.39°±0.2°, 19.17°±0.2°, 21.33°±0.2°;

[0112] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form C exhibits characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 10.00°±0.2°, 17.84°±0.2°, 18.39°±0.2°, 19.17°±0.2°, 21.33°±0.2°, 24.05°±0.2°, 24.21°±0.2°;

[0113] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 10.00°±0.2°, 14.57°±0.2°, 17.84°±0.2°, 18.39°±0.2°, 19.17°±0.2°, 21.33°±0.2°, 21.89°±0.2°, 24.05°±0.2°, 24.21°±0.2°, and 24.86°±0.2°.

[0114] Furthermore, the differential scanning calorimetry (DSC) chromatogram of the sulfate contains an endothermic peak at 215.1°C ± 3°C.

[0115] In some embodiments, the salt is in sulfate form D;

[0116] The X-ray powder diffraction pattern of the sulfate crystal form D has characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 24.00°±0.2°.

[0117] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form D has characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 22.67°±0.2°, 24.00°±0.2°;

[0118] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form D exhibits characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 16.04°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 21.81°±0.2°, 22.67°±0.2°, 24.00°±0.2°;

[0119] Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form D exhibits characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 16.04°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 19.58°±0.2°, 21.81°±0.2°, 22.67°±0.2°, 22.81°±0.2°, 23.37°±0.2°, 24.00°±0.2°, 25.33°±0.2°;

[0120] Furthermore, the X-ray powder diffraction pattern of sulfate crystal form D exhibits characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 11.30°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 15.90°±0.2°, 16.04°±0.2°, 17.94°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 19.58°±0.2°, 21.81°±0.2°, 22.67°±0.2°, 22.81°±0.2°, 23.37°±0.2°, 24.00°±0.2°, 25.33°±0.2°, and 29.17°±0.2°.

[0121] Furthermore, the differential scanning calorimetry (DSC) chromatogram of the sulfate contains endothermic peaks at 214.0°C ± 3°C and 218.2°C ± 3°C.

[0122] In some embodiments, the salt is in the form of hydrochloride crystal form B;

[0123] The X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 18.57°±0.2°, 22.77°±0.2°.

[0124] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 11.45°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 18.33°±0.2°, 18.57°±0.2°, 22.77°±0.2°;

[0125] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 11.45°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 17.61°±0.2°, 18.33°±0.2°, 18.57°±0.2°, 22.77°±0.2°, 27.17°±0.2°;

[0126] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 11.45°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 17.61°±0.2°, 18.33°±0.2°, 18.57°±0.2°, 22.77°±0.2°, 23.68°±0.2°, 23.98°±0.2°, 26.01°±0.2°, and 27.17°±0.2°.

[0127] Furthermore, the differential scanning calorimetry (DSC) plot of the hydrochloride salt contains an endothermic peak at 173.0°C ± 3°C.

[0128] In some embodiments, the salt has a crystal form of hydrochloride crystal form C;

[0129] The X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.78°±0.2°, and 18.93°±0.2°.

[0130] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 11.14°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.78°±0.2°, 18.38°±0.2°, and 18.93°±0.2°.

[0131] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 11.14°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.78°±0.2°, 18.38°±0.2°, 18.93°±0.2°, 21.80°±0.2°, 24.17°±0.2°;

[0132] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 7.70°±0.2°, 11.14°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.16°±0.2°, 16.78°±0.2°, 18.38°±0.2°, 18.93°±0.2°, 21.8°±0.2°, and 24.17°±0.2°.

[0133] Furthermore, the differential scanning calorimetry (DSC) plot of the hydrochloride salt contains an endothermic peak at 144.0°C ± 3°C.

[0134] In some embodiments, the salt has a crystal form of hydrochloride crystal form D;

[0135] The X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 11.24°±0.2°, 14.96°±0.2°, 19.43°±0.2°, and 24.22°±0.2°.

[0136] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 11.24°±0.2°, 14.96°±0.2°, 19.43°±0.2°, 19.71°±0.2°, and 24.22°±0.2°.

[0137] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 9.68°±0.2°, 11.24°±0.2°, 14.96°±0.2°, 17.99°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 20.28°±0.2°, and 24.22°±0.2°.

[0138] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 9.68°±0.2°, 11.24°±0.2°, 12.75°±0.2°, 14.96°±0.2°, 17.99°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 20.28°±0.2°, 22.11°±0.2°, 24.22°±0.2°, 24.46°±0.2°;

[0139] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 9.38°±0.2°, 9.68°±0.2°, 11.24°±0.2°, 12.75°±0.2°, 14.96°±0.2°, 16.71°±0.2°, 17.23°±0.2°, 17.99°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 20.28°±0.2°, 22.11°±0.2°, 24.22°±0.2°, 24.46°±0.2°, 26.21°±0.2°.

[0140] Furthermore, the differential scanning calorimetry (DSC) plot of the hydrochloride salt contains endothermic peaks at 142.8°C ± 3°C and 191.3°C ± 3°C.

[0141] In some embodiments, the salt has a crystal form of hydrochloride crystal form E;

[0142] The X-ray powder diffraction pattern of the hydrochloride crystal form E has characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 14.95°±0.2°, 19.43°±0.2°, 19.72°±0.2°, 20.28°±0.2°, 24.20°±0.2°;

[0143] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form E has characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 12.75°±0.2°, 14.95°±0.2°, 19.43°±0.2°, 19.72°±0.2°, 20.28°±0.2°, 22.10°±0.2°, 24.20°±0.2°;

[0144] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form E has characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 12.75°±0.2°, 14.95°±0.2°, 16.71°±0.2°, 19.43°±0.2°, 19.72°±0.2°, 20.28°±0.2°, 22.10°±0.2°, 23.33°±0.2°, 24.20°±0.2°, 26.07°±0.2°;

[0145] Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form E exhibits characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 12.75°±0.2°, 13.82°±0.2°, 14.95°±0.2°, 16.71°±0.2°, 19.43°±0.2°, and 19.72°±0.2°. , 20.28°±0.2°, 22.10°±0.2°, 22.86°±0.2°, 23.33°±0.2°, 24.20°±0.2°, 26.07°±0.2°, 26.33°±0.2°, 26.89°±0.2°, 28.49°±0.2°, 29.30°±0.2°, 30.28°±0.2°.

[0146] Furthermore, the differential scanning calorimetry (DSC) plot of the hydrochloride salt contains an endothermic peak at 186.8°C ± 3°C.

[0147] One or more embodiments of this application provide a method for preparing a salt of the compound shown in formula (I) above, comprising the following steps:

[0148] A salt of the compound shown in formula (I) is prepared by mixing the compound, acid, and solvent.

[0149] Alternatively, the acid may be selected from hydrochloric acid or sulfuric acid;

[0150] Optionally, the solvent includes at least one of acetone, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, acetonitrile, and ethanol.

[0151] In the method for preparing the salt of the compound shown in formula (I) of this application, after mixing the compound shown in formula (I), the acid and the solvent, corresponding seed crystals may be added as needed to promote crystallization.

[0152] In some embodiments, the salt of the compound shown in formula (I) is a hydrochloride salt, and the preparation method of the hydrochloride salt includes the following steps:

[0153] The hydrochloride salt is prepared by mixing the compound shown in formula (I), hydrochloric acid, and solvent;

[0154] The solvent includes at least one of isopropyl acetate, ethyl acetate, ethanol, methyl isobutyl ketone, and acetone.

[0155] In some embodiments, the salt of the compound shown in formula (I) is a sulfate, and the method for preparing the sulfate includes the following steps:

[0156] Sulfates are prepared by mixing the compound shown in formula (I), sulfuric acid, and a solvent;

[0157] The solvent includes at least one of acetonitrile and acetone.

[0158] In some embodiments, the salt of the compound shown in formula (I) is a hydrobromide, and the preparation method of the hydrobromide includes the following steps:

[0159] Hydrobromate is prepared by mixing the compound shown in formula (I), hydrobromic acid, and a solvent;

[0160] The solvent is acetone.

[0161] In some embodiments, the salt of the compound shown in formula (I) is p-toluenesulfonate, and the preparation method of toluenesulfonate includes the following steps:

[0162] p-Toluenesulfonate salts are prepared by mixing the compound shown in formula (I), p-toluenesulfonic acid, and solvent;

[0163] The solvent is acetonitrile.

[0164] One or more embodiments of this application provide pharmaceutical compositions comprising a salt of a compound represented by formula (I) above and a pharmaceutically acceptable excipient;

[0165] Optionally, the excipients include at least one of a carrier, an excipient, a diluent, and an adjuvant.

[0166] One or more embodiments of this application provide the use of salts of compounds of formula (I) above or pharmaceutical compositions in the preparation of medicaments for treating and / or preventing fungal infections or diseases caused by fungal infections.

[0167] In some embodiments, fungi include one or more of the following genera: *Absidia*, *Alternaria*, *Aspergillus*, *Bipolaris*, *Blastomyces*, *Blumeria*, *Cladosporium*, *Coccidioides*, *Colletotrichium*, *Encephalitozoon*, *Epicoccum*, *Epidermophyton*, *Exophiala*, *Exserohilum*, *Fusarium*, *Histoplasma*, and others. Genus *Leptosphaeria*, *Microsporum*, *Mycosphaerella*, *Neurospora*, *Paecilomyces*, *Penicillium*, *Phytophthora*, *Plasmopara*, *Pneumocystis*, *Pyricularia*, *Pythium*, *Puccinia*, *Rhizoctonia*, *Rhizomucor*, *sporium*, *Scopulariopsis*, *Trichophyton*, *Trichosporon*, *Ustilago*.

[0168] The following are some specific examples.

[0169] Unless otherwise specified, the experimental methods described in the following examples are generally performed under conventional conditions and as recommended by the manufacturer; all commonly used chemical reagents are commercially available products.

[0170] In the following examples, six solvents were used in the solubility comparison test: a buffer solution with pH 1.5, a buffer solution with pH 2.2, a buffer solution with pH 4.0, a buffer solution with pH 4.5, a buffer solution with pH 6.8, and water.

[0171] The pH 1.5 buffer solution is a hydrochloric acid solution: take 3.73 ml of hydrochloric acid, dilute with water to 1000 ml, and shake well to obtain the solution.

[0172] The pH 2.2 buffer solution is a hydrochloric acid solution: take 0.70 ml of hydrochloric acid, dilute with water to 1000 ml, and shake well to obtain the solution.

[0173] The pH 4.0 buffer solution is an acetate solution: Take 120.0 g (114 ml) of glacial acetic acid and dilute it with water to 1000 mL to obtain a 2 mol / L acetic acid solution. Take 1.22 g of sodium acetate, add 20.5 ml of the 2 mol / L acetic acid solution, dissolve it in water and dilute it to 1000 ml, shake well, and you have the solution.

[0174] The pH 4.5 buffer solution is an acetate solution: Take 120.0 g (114 ml) of glacial acetic acid and dilute it with water to 1000 mL to obtain a 2 mol / L acetic acid solution. Take 2.99 g of sodium acetate, add 14.0 ml of the 2 mol / L acetic acid solution, dissolve and dilute with water to 1000 ml, and shake well to obtain the final solution.

[0175] The pH 6.8 buffer solution is a phosphate solution: Take 250 ml of 0.2 mol / L potassium dihydrogen phosphate solution and 112 ml of 0.2 mol / L sodium hydroxide solution, then dilute with water to 1000 ml, shake with a spoon, and the solution is ready.

[0176] Example 1

[0177] This embodiment provides a method for preparing the sulfate crystal form B of compound (I), the steps of which are as follows: 500.1 mg of the compound shown in formula (I) and 0.539 mL of sulfuric acid-acetonitrile solution (2 mol / L) are placed in a glass vial, 4 mL of acetonitrile is added, and the mixture is stirred to obtain a suspension. Then, another 4 mL of acetonitrile is added. After stirring at room temperature overnight, the suspension is filtered and separated, and the solid is dried under vacuum at 50 °C overnight.

[0178] The dried solid was subjected to X-ray powder diffraction analysis. The diffraction data are shown in Table 1, and its XRPD pattern is attached. Figure 1 As shown in the figure. X-ray powder diffraction analysis results show that the solid obtained in this embodiment is a crystalline substance.

[0179] Table 1. X-ray powder diffraction data of sulfate crystal form B of compound (I).

[0180]

[0181] DSC of sulfate crystal form B, such as Figure 2 As shown, the DSC exhibits endothermic peaks when heated to 136.16℃ and 191.28℃.

[0182] Example 2

[0183] This embodiment provides a method for preparing the sulfate crystal form C of the compound of formula (I), the steps of which are as follows: Take 2.99g of the compound of formula (I) and 90mL of acetone solution in a glass bottle, heat to 55℃ to dissolve, add 0.067mL of concentrated sulfuric acid, add 30.4mg of seed crystals, cool to 50℃, stir for 0.5h, add 0.604mL of concentrated sulfuric acid, stir for 1h, turn off the heating, let it cool naturally to room temperature, stir overnight, filter the suspension, and dry the solid under vacuum at 50℃ overnight.

[0184] The dried solid was subjected to X-ray powder diffraction analysis. The diffraction data are shown in Table 2, and its XRPD pattern is attached. Figure 3 As shown in the figure. X-ray powder diffraction analysis results show that the solid obtained in this embodiment is a crystalline substance.

[0185] Table 2. X-ray powder diffraction data of sulfate crystal form C of compound (I).

[0186]

[0187] DSC of sulfate crystal form C as follows Figure 4 As shown, the DSC exhibits an endothermic peak when heated to around 215.13℃.

[0188] Example 3

[0189] This embodiment provides a method for preparing the sulfate crystal form D of the compound of formula (I), the steps of which are as follows: Take 3.00 g of the compound of formula (I) and 80 mL of acetone solution in a glass bottle, heat to reflux until dissolved, add 0.4 mL of sulfuric acid aqueous solution (3.06 mol / L), add 30.2 mg of seed crystals, cool to 50 °C, stir for 0.5 h, add 3.6 mL of sulfuric acid aqueous solution (3.06 mol / L) dropwise, stir for 2.5 h, turn off the heating, let it cool naturally to room temperature, stir overnight, filter the suspension to separate, and dry the solid under vacuum at 50 °C overnight.

[0190] X-ray powder diffraction analysis was performed on the solid product. The diffraction data are shown in Table 3, and its XRPD pattern is attached. Figure 5 As shown in the figure. X-ray powder diffraction analysis results show that the solid obtained in this embodiment is a crystalline substance.

[0191] Table 3. X-ray powder diffraction data of hydrobromide of compound (I).

[0192]

[0193] DSC of sulfate crystal form D, such as Figure 6 As shown, DSC exhibits endothermic peaks at 214.02°C and 218.16°C when heated.

[0194] Example 4

[0195] This embodiment provides a method for preparing the hydrochloride crystal form B of compound (I), the steps of which are as follows: 400.7 mg of the compound shown in formula (I) and 10 mL of methyl isobutyl ketone solution are placed in a glass bottle, stirred until dissolved, 0.072 mL of concentrated hydrochloric acid is added, and the mixture is stirred overnight at room temperature. The suspension is then filtered and separated, and the solid is dried under vacuum at 50 °C for 4 h.

[0196] The dried solid was subjected to X-ray powder diffraction analysis. The diffraction data are shown in Table 4, and its XRPD pattern is attached. Figure 7 As shown in the figure. X-ray powder diffraction analysis results show that the solid obtained in this embodiment is a crystalline substance.

[0197] Table 4. X-ray powder diffraction data of the hydrochloride crystal form B of compound (I).

[0198]

[0199] DSC / TGA of hydrochloride crystal form B, such as Figure 8 As shown, the DSC exhibits an endothermic peak when heated to 172.96℃.

[0200] Example 5

[0201] This embodiment provides a method for preparing the hydrochloride crystal form C of compound (I), the steps of which are as follows: Take 500.1 mg of the compound shown in formula (I) and 0.539 mL of hydrochloric acid-acetone solution (2 mol / L) in a glass vial, add 4 mL of acetone, stir to obtain a suspension, and then add another 4 mL of acetone. After stirring at room temperature overnight, filter the suspension to separate the solid, and dry the solid under vacuum at 50 °C overnight.

[0202] The dried solid was subjected to X-ray powder diffraction analysis. The diffraction data are shown in Table 5, and its XRPD pattern is shown in the figure. Figure 9 As shown in the figure. X-ray powder diffraction analysis results show that the solid obtained in this embodiment is a crystalline substance.

[0203] Table 5. X-ray powder diffraction data of the hydrochloride crystal form C of compound (I).

[0204]

[0205] DSC of hydrochloride crystal form C as follows Figure 10 As shown, the DSC signal peak is endothermic when heated to 143.98℃.

[0206] Example 6

[0207] This embodiment provides a method for preparing the sulfate crystal form D of the compound of formula (I), the steps of which are as follows: Take 5.00g of the compound of formula (I) and 180mL of acetone solution in a glass bottle, add 10.3mL of hydrochloric acid acetone solution (2mol / L), stir overnight at room temperature, filter and separate the suspension, and dry the solid under vacuum at 50℃ overnight.

[0208] The dried solid was subjected to X-ray powder diffraction analysis. The diffraction data are shown in Table 6, and its XRPD pattern is shown in the figure. Figure 11 As shown in the figure. X-ray powder diffraction analysis results show that the solid obtained in this embodiment is a crystalline substance.

[0209] Table 6. X-ray powder diffraction data of the hydrochloride crystal form D of compound (I).

[0210]

[0211] DSC of hydrochloride crystal form D as follows Figure 12 As shown, the DSC exhibits endothermic signal peaks when heated to 142.82℃ and 191.29℃.

[0212] Example 7

[0213] This embodiment provides a method for preparing the hydrochloride crystal form E of the compound of formula (I), the steps of which are as follows: Take 3.01g of the compound of formula (I) and 75mL of isopropyl acetate solution in a glass bottle, add 0.54mL of concentrated hydrochloric acid, stir overnight at room temperature, filter and separate the suspension, and dry the solid under vacuum at 50℃ overnight.

[0214] The dried solid was subjected to X-ray powder diffraction analysis. The diffraction data are shown in Table 7, and its XRPD pattern is shown in the figure. Figure 13 As shown in the figure. X-ray powder diffraction analysis results show that the solid obtained in this embodiment is a crystalline substance.

[0215] Table 7. X-ray powder diffraction data of the hydrochloride crystal form E of compound (I).

[0216]

[0217] DSC of hydrochloride crystal form E as follows Figure 14 As shown, the DSC signal peak is endothermic at 186.77℃.

[0218] Comparative Example 1

[0219] This comparative example provides a method for preparing the hydrobromide crystal form A of compound (I), the steps of which are as follows: Take 4.97g of the compound shown in formula (I) and 90mL of acetone solution in a glass bottle, add 10.28mL of 2M hydrobromic acid acetone solution, stir overnight at room temperature, filter and separate the suspension, and dry the solid under vacuum at 50℃ overnight.

[0220] The dried solid was subjected to X-ray powder diffraction analysis. The diffraction data are shown in Table 8, and its XRPD pattern is shown in the figure. Figure 15 As shown in the figure. X-ray powder diffraction analysis results show that the solid obtained in this embodiment is a crystalline substance.

[0221] Table 8. X-ray powder diffraction data of hydrobromide crystal form A of compound (I).

[0222]

[0223] DSC of hydrobromide crystal form A as follows Figure 16 As shown, the DSC signal peak is at 239.30℃.

[0224] Comparative Example 2

[0225] This comparative example provides a method for preparing p-toluenesulfonate crystal form A of compound (I), comprising the following steps: 500.0 mg of the compound shown in formula (I) and 188.6 mg of p-toluenesulfonic acid are placed in a glass bottle, 3 mL of acetonitrile solution is added, and the mixture is stirred to obtain a suspension. Then, 4 mL of acetonitrile is added. The suspension is stirred overnight at room temperature, and the suspension is separated by filtration. The solid is then dried under vacuum at 50 °C overnight.

[0226] The dried solid was subjected to X-ray powder diffraction analysis. The diffraction data are shown in Table 9, and its XRPD pattern is shown in the figure. Figure 17 As shown in the figure. X-ray powder diffraction analysis results show that the solid obtained in this embodiment is a crystalline substance.

[0227] Table 9. X-ray powder diffraction data of p-toluenesulfonate crystal form A of compound (I).

[0228]

[0229] DSC of p-toluenesulfonate crystal form A as follows Figure 18 As shown, the DSC has an endothermic signal peak at 232.10℃.

[0230] Example 8

[0231] This embodiment is a test of the equilibrium solubility of the compound shown in formula (I) and its salt.

[0232] The compound shown in formula (I) (free base) and its sulfate crystal form C, sulfate crystal form D, hydrochloride crystal form B, hydrochloride crystal form C, hydrochloride crystal form D, hydrochloride crystal form E, hydrobromide crystal form A, and p-toluenesulfonate crystal form A (prepared in Examples 2-7 and Comparative Examples 1 and 2, respectively) were prepared into saturated solutions by shaking at 37°C for 24 hours with buffer solutions of pH 1.5, pH 2.2, pH 4.0, pH 4.5, and pH 6.8, respectively. The solubility of each saturated solution was determined by high performance liquid chromatography. The test results are shown in Table 10.

[0233] Table 10 shows the solubility of the compound and its salt shown in formula (I) under different pH conditions.

[0234]

[0235] As shown in Table 10, compared with the free base, the salts of the compounds shown in formula (I) all have improved solubility, among which the sulfate crystal form C, hydrochloride crystal form D, and hydrochloride crystal form E have the best solubility.

[0236] Example 9

[0237] This embodiment is a stability test of the salt of the compound shown in formula (I).

[0238] The sulfate crystal form C, sulfate crystal form D, hydrochloride crystal form B, hydrochloride crystal form D, hydrochloride crystal form E, hydrobromide crystal form A, and p-toluenesulfonate crystal form A of the compound shown in formula (I) (prepared in Examples 2, 3, 4, 6, 7 and Comparative Examples 1, 2, respectively) were placed under high temperature (60°C), high humidity (25°C / 90%RH) and light (illuminance of 4500±500 lx, ultraviolet light ≥0.7 w / m²) respectively. 2 The samples were placed under specific conditions, and samples were taken at 7 and 14 days to test their appearance, purity, and crystal form. The experimental results are shown in Table 11.

[0239] Table 11 shows the changes in crystal form and appearance of the salts of the compounds shown in formula (I) under different environmental conditions.

[0240]

[0241] Table 11 shows that hydrobromide crystal form A underwent slight degradation after 14 days, turning brown under light. Compared to hydrobromide crystal form A, hydrochloride crystal form E showed no change in purity, crystal form, or appearance after being placed under high temperature, high humidity, and light conditions, exhibiting good chemical and crystal form stability. Hydrochloride crystal form B showed no change in purity and crystal form after 14 days, but turned yellow under high temperature and light conditions. Sulfate crystal form D showed no change in purity and crystal form after 14 days, but turned brown under light conditions.

[0242] Example 10

[0243] This embodiment is a hygroscopic experiment on the salt of the compound shown in formula (I).

[0244] Dynamic water adsorption (DVS) tests were performed on the sulfate crystal forms C, D, B, C, D, E, A (hydrobromide crystal form A, and p-toluenesulfonate crystal form A) of the compound shown in formula (I). The experimental results are shown in Table 12. The hygroscopicity spectrum of hydrochloride crystal form E is shown in the figure below. Figure 19 As shown, the hygroscopicity spectrum of sulfate crystal form C is as follows: Figure 20 As shown, the hygroscopicity spectrum of hydrobromide crystal form A is as follows: Figure 21 As shown, the hygroscopicity spectrum of p-toluenesulfonate crystal form A is as follows: Figure 22 As shown, the hygroscopicity spectrum of hydrochloride crystal form B is as follows: Figure 23 As shown, the hygroscopicity spectrum of the C crystal form of hydrochloride is as follows: Figure 24 As shown, the hygroscopicity spectrum of hydrochloride crystal form D is as follows: Figure 25 As shown, the hygroscopicity spectrum of sulfate crystal form D is as follows: Figure 26 As shown.

[0245] Table 12 shows the hygroscopicity of the salts of the compounds shown in formula (I) under different humidity conditions.

[0246]

[0247] As shown in Table 12, compared with hydrobromide crystal form A, sulfate crystal form D, hydrochloride crystal form B and hydrochloride crystal form E have lower hygroscopicity, which is beneficial for the production and storage of products or preparations.

[0248] Example 11

[0249] This embodiment is an in vivo pharmacokinetic test of the compound shown in formula (I) and its salt.

[0250] The experimental animals used were male SD rats, 9 to 10 weeks old, weighing 250 to 350 g. Based on the rats' weight, they were randomly divided into 3 groups of 6 animals each. They were administered suspensions of the compound (free base) shown in formula (I) and the sulfate crystal form C and hydrochloride crystal form E of the compound shown in formula (I) by gavage, respectively, at a dose of 5 mg / kg.

[0251] Blood samples of 0.3 mL were collected at regular intervals via jugular vein puncture at 0 days, 5 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 1 day, and 2 days. The samples were transferred to EDTA-K2 anticoagulant tubes, gently inverted 5-10 times to mix, and temporarily stored in a pre-chilled CoolRack module. Plasma samples were then separated by centrifugation at 6800 g / min for 6 minutes at 4°C and stored frozen at -60°C to -90°C.

[0252] The drug concentration (ng / mL) in plasma samples at each time point was determined using LC-MS / MS. The methods and instruments used are as follows: Instrument: LC-MS / MS (Waters TQ-XS); Column: ACQUITY UPLC BEH C18 1.7μm 2.1*50mm; Mass spectrometry method: ESI positive; Mobile phase: 0.1% formic acid / water / 0.1% formic acid acetonitrile; Quantitative method: internal standard method; Sample preparation method: protein precipitation method. The experimental results are shown in Table 13.

[0253] Table 13 shows the PK parameters of the compounds and their salts represented by formula (I).

[0254]

[0255] As shown in Table 13, the sulfate and hydrochloride salts of the compound shown in formula (I) have a significant advantage in oral bioavailability compared to the compound (free base) shown in formula (I). Drugs with high oral bioavailability can achieve the expected efficacy at lower dosages; and lower dosages can reduce drug costs, indicating that the sulfate and hydrochloride salts of the compound shown in formula (I) have better drug-like properties.

[0256] Example 12: Competitive Pulping Experiment

[0257] Equal amounts of hydrochloride salts with different crystal forms prepared in the embodiments of the present invention were subjected to a competitive pulping experiment in an organic solvent. The experimental results are shown in Table 14.

[0258] Table 14

[0259]

[0260] As can be seen from the data in Table 14, the hydrochloride crystal forms B, C, and D in this invention will all transform into hydrochloride crystal form E when stirred at room temperature in the above solvents. Hydrochloride crystal form E is a thermodynamically stable crystal form.

[0261] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0262] The embodiments described above merely illustrate several implementation methods of this application and should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Furthermore, it should be understood that after reading the above teachings, those skilled in the art can make various alterations or modifications to this application, and the equivalent forms obtained also fall within the protection scope of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the protection scope of the appended claims. Therefore, the protection scope of this patent application should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A salt of the compound shown in formula (I), characterized in that, The salt is a sulfate or hydrochloride; （Ⅰ）。 2. The salt of the compound of formula (I) according to claim 1, characterized in that, The salt has the crystal form of sulfate B; The X-ray powder diffraction pattern of the sulfate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 14.87°±0.2°, 17.79°±0.2°, 21.86°±0.2°, 24.23°±0.2°. Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 14.87°±0.2°, 17.51°±0.2°, 17.79°±0.2°, 21.37°±0.2°, 21.86°±0.2°, 24.23°±0.2°; Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form B exhibits characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 9.53°±0.2°, 14.87°±0.2°, 17.51°±0.2°, 17.79°±0.2°, 21.37°±0.2°, 21.86°±0.2°, 23.66°±0.2°, 24.23°±0.2°; Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.89°±0.2°, 9.53°±0.2°, 13.33°±0.2°, 14.87°±0.2°, 17.21°±0.2°, 17.51°±0.2°, 17.79°±0.2°, 21.37°±0.2°, 21.86°±0.2°, 23.66°±0.2°, 24.23°±0.2°, and 25.80°±0.2°.

3. The salt of the compound of formula (I) according to claim 1, characterized in that, The salt has the crystal form of sulfate, crystal form C; The X-ray powder diffraction pattern of the sulfate crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 17.84°±0.2°, 19.17°±0.2°, 21.33°±0.2°. Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 10.00°±0.2°, 17.84°±0.2°, 18.39°±0.2°, 19.17°±0.2°, 21.33°±0.2°; Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form C exhibits characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 10.00°±0.2°, 17.84°±0.2°, 18.39°±0.2°, 19.17°±0.2°, 21.33°±0.2°, 24.05°±0.2°, 24.21°±0.2°; Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.56°±0.2°, 9.13°±0.2°, 10.00°±0.2°, 14.57°±0.2°, 17.84°±0.2°, 18.39°±0.2°, 19.17°±0.2°, 21.33°±0.2°, 21.89°±0.2°, 24.05°±0.2°, 24.21°±0.2°, and 24.86°±0.2°.

4. The salt of the compound of formula (I) according to claim 1, characterized in that, The salt has the crystal form of sulfate, crystal form D; The X-ray powder diffraction pattern of the sulfate crystal form D has characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 24.00°±0.2°. Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form D has characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 22.67°±0.2°, 24.00°±0.2°; Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form D exhibits characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 16.04°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 21.81°±0.2°, 22.67°±0.2°, 24.00°±0.2°; Furthermore, the X-ray powder diffraction pattern of the sulfate crystal form D exhibits characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 16.04°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 19.58°±0.2°, 21.81°±0.2°, 22.67°±0.2°, 22.81°±0.2°, 23.37°±0.2°, 24.00°±0.2°, 25.33°±0.2°; Furthermore, the X-ray powder diffraction pattern of sulfate crystal form D exhibits characteristic diffraction peaks at the following 2θ angles: 10.89°±0.2°, 11.30°±0.2°, 12.64°±0.2°, 14.68°±0.2°, 15.90°±0.2°, 16.04°±0.2°, 17.94°±0.2°, 18.69°±0.2°, 19.45°±0.2°, 19.58°±0.2°, 21.81°±0.2°, 22.67°±0.2°, 22.81°±0.2°, 23.37°±0.2°, 24.00°±0.2°, 25.33°±0.2°, and 29.17°±0.2°.

5. The salt of the compound of formula (I) according to claim 1, characterized in that, The salt has a hydrochloride crystal form B; The X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 18.57°±0.2°, 22.77°±0.2°. Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 11.45°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 18.33°±0.2°, 18.57°±0.2°, 22.77°±0.2°; Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 11.45°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 17.61°±0.2°, 18.33°±0.2°, 18.57°±0.2°, 22.77°±0.2°, 27.17°±0.2°; Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.2°, 11.45°±0.2°, 15.01°±0.2°, 16.69°±0.2°, 17.61°±0.2°, 18.33°±0.2°, 18.57°±0.2°, 22.77°±0.2°, 23.68°±0.2°, 23.98°±0.2°, 26.01°±0.2°, and 27.17°±0.2°.

6. The salt of the compound of formula (I) according to claim 1, characterized in that, The salt has the crystal form of hydrochloride crystal form C; The X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.78°±0.2°, and 18.93°±0.2°. Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 11.14°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.78°±0.2°, 18.38°±0.2°, and 18.93°±0.2°. Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 11.14°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.78°±0.2°, 18.38°±0.2°, 18.93°±0.2°, 21.80°±0.2°, 24.17°±0.2°; Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.15°±0.2°, 7.70°±0.2°, 11.14°±0.2°, 12.18°±0.2°, 14.41°±0.2°, 16.16°±0.2°, 16.78°±0.2°, 18.38°±0.2°, 18.93°±0.2°, 21.8°±0.2°, and 24.17°±0.2°.

7. The salt of the compound of formula (I) according to claim 1, characterized in that, The salt has a crystal form of hydrochloride crystal form D; The X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 11.24°±0.2°, 14.96°±0.2°, 19.43°±0.2°, 24.22°±0.2°. Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 11.24°±0.2°, 14.96°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 24.22°±0.2°; Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 9.68°±0.2°, 11.24°±0.2°, 14.96°±0.2°, 17.99°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 20.28°±0.2°, 24.22°±0.2°; Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 9.68°±0.2°, 11.24°±0.2°, 12.75°±0.2°, 14.96°±0.2°, 17.99°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 20.28°±0.2°, 22.11°±0.2°, 24.22°±0.2°, 24.46°±0.2°; Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form D has characteristic diffraction peaks at the following 2θ angles: 6.06°±0.2°, 8.21°±0.2°, 9.38°±0.2°, 9.68°±0.2°, 11.24°±0.2°, 12.75°±0.2°, 14.96°±0.2°, 16.71°±0.2°, 17.23°±0.2°, 17.99°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 20.28°±0.2°, 22.11°±0.2°, 24.22°±0.2°, 24.46°±0.2°, 26.21°±0.2°.

8. The salt of the compound of formula (I) according to claim 1, characterized in that, The salt has a hydrochloride crystal form, E. The X-ray powder diffraction pattern of the hydrochloride crystal form E has characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 14.95°±0.2°, 19.43°±0.2°, 19.72°±0.2°, 20.28°±0.2°, and 24.20°±0.2°. Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form E has characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 12.75°±0.2°, 14.95°±0.2°, 19.43°±0.2°, 19.72°±0.2°, 20.28°±0.2°, 22.10°±0.2°, 24.20°±0.2°; Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form E has characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 12.75°±0.2°, 14.95°±0.2°, 16.71°±0.2°, 19.43°±0.2°, 19.72°±0.2°, 20.28°±0.2°, 22.10°±0.2°, 23.33°±0.2°, 24.20°±0.2°, 26.07°±0.2°; Furthermore, the X-ray powder diffraction pattern of the hydrochloride crystal form E exhibits characteristic diffraction peaks at the following 2θ angles: 9.67°±0.2°, 11.23°±0.2°, 12.75°±0.2°, 13.82°±0.2°, 14.95°±0.2°, 16.71°±0.2°, 19.43°±0.2°, and 19.72°±0.2°. , 20.28°±0.2°, 22.10°±0.2°, 22.86°±0.2°, 23.33°±0.2°, 24.20°±0.2°, 26.07°±0.2°, 26.33°±0.2°, 26.89°±0.2°, 28.49°±0.2°, 29.30°±0.2°, 30.28°±0.2°.

9. A method for preparing a salt of the compound of formula (I) according to any one of claims 1-8, characterized in that, Includes the following steps: A salt of the compound shown in formula (I) is prepared by mixing the compound, acid, and solvent. Optionally, the acid is sulfuric acid or hydrochloric acid; Optionally, the solvent includes one or more of acetone, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, acetonitrile, and ethanol.

10. A pharmaceutical composition, characterized in that, Includes a salt of the compound of formula (I) as described in any one of claims 1-8 and a pharmaceutically acceptable excipient; Optionally, the excipients include one or more of a carrier, excipient, diluent, and auxiliaries.

11. The use of a salt of the compound of formula (I) according to any one of claims 1-8 or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating and / or preventing fungal infections or diseases caused by fungal infections; Further, the fungi include one or more of the following genera: *Absidia*, *Alternaria*, *Aspergillus*, *Bipolaris*, *Blastomyces*, *Blumeria*, *Cladosporium*, *Coccidioides*, *Colletotrichium*, *Encephalitozoon*, *Epicoccum*, *Epidermophyton*, *Exophiala*, *Exserohilum*, *Fusarium*, *Histoplasma*, and others. Genus *Leptosphaeria*, *Microsporum*, *Mycosphaerella*, *Neurospora*, *Paecilomyces*, *Penicillium*, *Phytophthora*, *Plasmopara*, *Pneumocystis*, *Pyricularia*, *Pythium*, *Puccinia*, *Rhizoctonia*, *Rhizomucor*, *sporium*, *Scopulariopsis*, *Trichophyton*, *Trichosporon*, *Ustilago*.

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