Salt form of nicotinate compound, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a salt of a nicotinate compound, a crystal of the salt, and a preparation method therefor and a use thereof. The salt is selected from benzenesulfonate, phosphate, sulfate, hydrochloride, and methanesulfonate of a compound represented by formula (I). The crystal is crystal form A of the benzenesulfonate of the compound represented by formula (I), crystal form B of the benzenesulfonate of the compound represented by formula (I), crystal form A of the phosphate of the compound represented by formula (I), crystal form A of the sulfate of the compound represented by formula (I), crystal form A of the hydrochloride of the compound represented by formula (I), crystal form A of the methanesulfonate of the compound represented by formula (I), crystal form B of the methanesulfonate of the compound represented by formula (I), or an amorphous form of the methanesulfonate of the compound represented by formula (I).

Description

A salt form of a nicotinic acid ester compound and its preparation method and application

[0001] This application claims priority to a prior application, patent application number 202410107329.1, filed with the State Intellectual Property Office of China on January 25, 2024, entitled "A salt form of a nicotinic acid ester compound, preparation method thereof, and use thereof." The entire text of the prior application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of compounds, and in particular relates to a salt of a nicotinate compound, a crystal of the salt, and a preparation method and application thereof. Background Art

[0003] The androgen receptor (AR) is a steroid nuclear receptor that is a receptor for ligand-induced nuclear transcription factors. It is an important cellular regulatory protein that plays a crucial role in numerous physiological processes through endogenous androgens. With aging, androgen levels in the body decrease, leading to the development of age-related diseases. While androgen therapy can alleviate androgen deficiency to some extent, it is prone to side effects.

[0004] In order to replace androgen therapy, it is urgent to find and develop new drugs that can be used to prevent and / or treat diseases caused by androgen deficiency. In recent years, non-steroidal selective androgen receptor modulators (SARMs) have attracted increasing interest from academia and the pharmaceutical industry.

[0005] CN201410033958.0 discloses the compound (S)-1-(4-cyano-3-(trifluoromethyl)anilino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropanyl-2-nicotinate (also known as "(S)-1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylnicotinate"), the structure of which is shown in formula (I), but does not disclose the form of the compound.

[0006] Salt formation is one of the effective means to improve the physicochemical properties of drug molecules and enhance their drugability. It can change the solubility of the drug, improve its compliance, enhance its stability and bioavailability, and reduce its adverse reactions. Generally speaking, the crystal structure of the active ingredient of the drug and its salt not only affects the physical and chemical stability of the drug itself, but also affects the difficulty of the later drug preparation and the production cost. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound and its salt, and sometimes are accompanied by the production of other morphologies. In order to meet the further development of drugs, the research and development of salts of the compound, such as salt forms with improved stability and / or efficacy, so as to achieve good results in the pharmaceutical and medication stages, has become a technical problem that those skilled in the art are committed to solving. Summary of the Invention

[0007] The present invention provides a salt of a compound represented by formula (I), wherein the salt is one or more of benzenesulfonate, phosphate, sulfate, hydrochloride and methanesulfonate;

[0008] Preferably, the salt is selected from phosphates and sulfates;

[0009] According to an embodiment of the present invention, in the benzenesulfonate salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to the benzenesulfonic acid molecule is 1:0.9 to 1:1.4, for example, about 1:1.

[0010] According to an embodiment of the present invention, in the phosphate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to the phosphoric acid molecule is 1:0.9 to 1:1.4, for example, about 1:1.

[0011] According to an embodiment of the present invention, in the sulfate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to sulfuric acid is 1:0.9 to 1:1.4, for example, about 1:1.

[0012] According to an embodiment of the present invention, in the hydrochloride of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:0.9 to 1:1.4, for example, about 1:1.

[0013] According to an embodiment of the present invention, in the methanesulfonate salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to the methanesulfonic acid molecule is 1:0.9 to 1:1.4, for example, about 1:1.

[0014] According to an embodiment of the present invention, the above salt is a pharmaceutically acceptable salt.

[0015] The present invention also provides crystals of the above-mentioned salt, wherein the crystals are crystal form A of the benzenesulfonate salt of the compound represented by formula (I), crystal form B of the benzenesulfonate salt of the compound represented by formula (I), crystal form A of the phosphate salt of the compound represented by formula (I), crystal form A of the sulfate salt of the compound represented by formula (I), crystal form A of the hydrochloride salt of the compound represented by formula (I), crystal form A of the methanesulfonate salt of the compound represented by formula (I), crystal form B of the methanesulfonate salt of the compound represented by formula (I), or an amorphous form of the methanesulfonate salt of the compound represented by formula (I).

[0016] According to an embodiment of the present invention, the crystal is the A crystal form of the phosphate of the compound represented by formula (I) or the A crystal form of the sulfate of the compound represented by formula (I).

[0017] According to an embodiment of the present invention, the crystalline form A of the benzenesulfonate salt of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.4±0.20°, 10.1±0.20°, 19.4±0.20°, 20.3±0.20°, 20.9±0.20°, and 22.2±0.20°; further, it also has characteristic peaks at 11.1±0.20°, 12.2±0.20° and / or 23.6±0.20°; further, it also has characteristic peaks at 6.1±0.20°, 13.2±0.20°, 14.1±0.20°, 14.4±0.20°, 18.0±0.20° and / or 18.3±0.20°.

[0018] According to an embodiment of the present invention, the Form A of the benzenesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 2.

[0019] According to an embodiment of the present invention, the Form A of the benzenesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG2 .

[0020] According to an embodiment of the present invention, the crystal form A of the benzenesulfonate salt of the compound represented by formula (I) loses 11.0% of its weight before 150°C.

[0021] According to an embodiment of the present invention, the crystalline form A of the benzenesulfonate salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG3 and a DSC spectrum substantially as shown in FIG4 .

[0022] According to an embodiment of the present invention, the B crystalline form of the benzenesulfonate salt of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.6±0.20°, 6.6±0.20°, 7.5±0.20°, 8.6±0.20°, 14.9±0.20°, and 21.9±0.20°; further, it also has characteristic peaks at 18.3±0.20°, 18.7±0.20° and / or 21.1±0.20°; further, it also has characteristic peaks at 13.1±0.20°, 16.1±0.20°, 19.7±0.20°, 23.0±0.20°, 24.9±0.20° and / or 27.8±0.20°.

[0023] According to an embodiment of the present invention, the Form B of the benzenesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 4.

[0024] According to an embodiment of the present invention, the Form B of the benzenesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG6 .

[0025] According to an embodiment of the present invention, the decomposition temperature of the benzenesulfonate salt of the compound represented by formula (I) in Form B is about 269°C.

[0026] According to an embodiment of the present invention, the Form B of the benzenesulfonate salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG7 and a DSC spectrum substantially as shown in FIG8 .

[0027] According to an embodiment of the present invention, the crystal form A of the phosphate of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 9.9±0.20°, 12.3±0.20°, 14.2±0.20°, 17.1±0.20°, 19.1±0.20°, and 19.7±0.20°; further, it also has characteristic peaks at 6.5±0.20°, 13.1±0.20° and / or 21.1±0.20°; further, it also has characteristic peaks at 10.8±0.20°, 17.8±0.20°, 21.9±0.20°, 22.8±0.20°, 23.6±0.20° and / or 24.2±0.20°.

[0028] According to an embodiment of the present invention, the crystal form A of the phosphate of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 6.

[0029] According to an embodiment of the present invention, the crystal form A of the phosphate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG12 .

[0030] According to an embodiment of the present invention, the decomposition temperature of the crystal form A of the phosphate of the compound represented by formula (I) is about 259°C.

[0031] According to an embodiment of the present invention, the crystal form A of the phosphate of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG13 and a DSC spectrum substantially as shown in FIG14 .

[0032] According to an embodiment of the present invention, the crystal form A of the sulfate of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 9.9±0.20°, 11.0±0.20°, 12.7±0.20°, 15.3±0.20°, 17.6±0.20°, and 19.6±0.20°; further, it also has characteristic peaks at 13.2±0.20°, 13.7±0.20° and / or 14.4±0.20°; further, it also has characteristic peaks at 16.3±0.20°, 20.7±0.20°, 21.3±0.20°, 21.9±0.20°, 24.9±0.20° and / or 27.1±0.20°.

[0033] According to an embodiment of the present invention, the crystal form A of the sulfate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 8.

[0034] According to an embodiment of the present invention, the crystal form A of the sulfate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG17 .

[0035] According to an embodiment of the present invention, the crystal form A of the sulfate salt of the compound represented by formula (I) loses 3.9% of its weight before 150°C.

[0036] According to an embodiment of the present invention, the crystal form A of the sulfate salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG18 and a DSC spectrum substantially as shown in FIG19 .

[0037] According to an embodiment of the present invention, the crystal form A of the hydrochloride of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.6±0.20°, 9.5±0.20°, 11.5±0.20°, 12.7±0.20°, 15.0±0.20°, and 19.8±0.20°; further, it also has characteristic peaks at 14.0±0.20°, 17.7±0.20° and / or 23.1±0.20°; further, it also has characteristic peaks at 13.1±0.20°, 16.1±0.20°, 16.6±0.20°, 18.1±0.20°, 20.3±0.20° and / or 24.5±0.20°.

[0038] According to an embodiment of the present invention, the Form A of the hydrochloride salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 10.

[0039] According to an embodiment of the present invention, the Form A of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG. 22 .

[0040] According to an embodiment of the present invention, the crystal form A of the hydrochloride of the compound represented by formula (I) loses 12.1% of its weight before 150°C.

[0041] According to an embodiment of the present invention, the Form A of the hydrochloride salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG23 and a DSC spectrum substantially as shown in FIG24 .

[0042] According to an embodiment of the present invention, the crystal form A of the methanesulfonate of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 12.5±0.20°, 15.1±0.20°, 17.3±0.20°, 18.1±0.20°, 22.1±0.20°, and 23.1±0.20°; further, it also has characteristic peaks at 6.7±0.20°, 10.8±0.20° and / or 11.6±0.20°; further, it also has characteristic peaks at 18.6±0.20°, 19.6±0.20°, 20.1±0.20°, 25.4±0.20°, 26.2±0.20° and / or 27.2±0.20°.

[0043] According to an embodiment of the present invention, the crystal form A of the methanesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 14.

[0044] According to an embodiment of the present invention, the crystal form A of the methanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG34 .

[0045] According to an embodiment of the present invention, the decomposition temperature of the crystal form A of the methanesulfonate of the compound represented by formula (I) is about 261°C.

[0046] According to an embodiment of the present invention, the crystal form A of the methanesulfonate salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG35 and a DSC spectrum substantially as shown in FIG36 .

[0047] According to an embodiment of the present invention, the B crystalline form of the methanesulfonate of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.1±0.20°, 9.8±0.20°, 19.2±0.20°, 20.0±0.20°, 21.9±0.20°, and 23.3±0.20°; further, it also has characteristic peaks at 5.8±0.20°, 20.6±0.20° and / or 24.2±0.20°; further, it also has characteristic peaks at 10.8±0.20°, 12.9±0.20°, 13.8±0.20°, 16.9±0.20°, 17.8±0.20° and / or 25.2±0.20°.

[0048] According to an embodiment of the present invention, the Form B of the methanesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 15.

[0049] According to an embodiment of the present invention, the Form B of the methanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG40 .

[0050] According to an embodiment of the present invention, the crystal form B of the methanesulfonate of the compound represented by formula (I) loses 10.2% of its weight before 150°C.

[0051] According to an embodiment of the present invention, the Form B of the methanesulfonate of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG41 and a DSC spectrum substantially as shown in FIG42 .

[0052] The present invention also provides a method for preparing a salt of the compound represented by the above formula (I) or a crystal of the salt of the compound represented by the formula (I), comprising: reacting the compound represented by the formula (I) with benzenesulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid or methanesulfonic acid in a solvent to obtain the salt of the compound represented by the formula (I) or the crystal of the salt.

[0053] The present invention also provides a pharmaceutical composition comprising a salt or a crystal of the salt of the compound represented by the above formula (I).

[0054] According to an embodiment of the present invention, the pharmaceutical composition further comprises pharmaceutically acceptable excipients, such as, but not limited to, one or more of excipients, fillers, lubricants, binders, disintegrants, inorganic salts, solvents, dissolution aids, suspending agents, isotonic agents, buffers, preservatives, antioxidants, colorants, foaming agents and flavoring agents.

[0055] The present invention also provides use of the above salt, salt crystal or pharmaceutical composition in preparing pharmaceutical preparations.

[0056] According to an embodiment of the present invention, the pharmaceutical preparation is used for preventing and / or treating diseases caused by androgen deficiency.

[0057] According to an embodiment of the present invention, the diseases include androgenic alopecia, acute or chronic muscle wasting, muscle wasting, muscle atrophy, bone-related diseases, cancer (such as prostate cancer, breast cancer, etc.), AIDS, kidney disease, muscle wasting / muscle wasting / muscle atrophy caused by burns, anemia, obesity, diabetes, senile mood and cognitive changes, urinary incontinence (such as stress urinary incontinence), heart failure, dry eye syndrome, new coronavirus infectious diseases, etc.

[0058] The present invention also provides a pharmaceutical preparation containing the above salt, salt crystals or pharmaceutical composition.

[0059] According to an embodiment of the present invention, the pharmaceutical preparation can be in the form of powder, tablet (e.g., coated tablet, sustained-release or controlled-release tablet), lozenge, capsule (e.g., soft capsule or hard capsule), granule, pill, dispersible powder, suspension, solution, emulsion, elixir, syrup, aerosol, cream, ointment, gel, injection, lyophilized powder injection or suppository.

[0060] According to an embodiment of the present invention, the pharmaceutical preparation can be administered in any of the following ways: orally, buccal administration, sublingually, inhaled, topically applied, parenterally administered intravenously, subcutaneously, at acupuncture points or intramuscularly, or rectally.

[0061] The present invention also provides a method for preventing and / or treating diseases caused by androgen deficiency, comprising administering an effective amount of the above-mentioned salt, salt crystal, pharmaceutical composition or pharmaceutical preparation to a patient.

[0062] According to an embodiment of the present invention, the diseases include androgenic alopecia, acute or chronic muscle wasting, muscle wasting, muscle atrophy, bone-related diseases, cancer (such as prostate cancer, breast cancer, etc.), AIDS, kidney disease, muscle wasting / muscle wasting / muscle atrophy caused by burns, anemia, obesity, diabetes, senile mood and cognitive changes, urinary incontinence (such as stress urinary incontinence), heart failure, dry eye syndrome, new coronavirus infectious diseases, etc. Beneficial effects

[0063] The present invention provides salts of the compound represented by formula (I) and crystals of the salts, which have good stability and are suitable for pharmaceutical preparation.

[0064] Definitions and Explanations of Terms

[0065] Unless otherwise stated, the definitions of terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, and specific definitions in embodiments, may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of this specification.

[0066] The term "effective amount" refers to the amount of the crystalline form of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific active ingredient selected, the dosage regimen based on, whether to be administered in combination with other compounds, the time schedule of administration, the tissue to be administered, and the physical delivery system carried.

[0067] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1: XRPD pattern of the amorphous form of the compound represented by formula (I).

[0069] Figure 2: XRPD pattern of Form A of benzenesulfonate salt of the compound represented by formula (I).

[0070] Figure 3: TGA spectrum of Form A of benzenesulfonate salt of the compound represented by formula (I).

[0071] Figure 4: DSC spectrum of Form A of benzenesulfonate salt of the compound represented by formula (I).

[0072] Figure 5: Crystalline Form A of the benzenesulfonate salt of the compound represented by formula (I) 1 H NMR spectrum.

[0073] Figure 6: XRPD pattern of Form B of benzenesulfonate salt of the compound represented by formula (I).

[0074] Figure 7: TGA spectrum of Form B of benzenesulfonate salt of the compound represented by formula (I).

[0075] Figure 8: DSC spectrum of Form B of benzenesulfonate salt of the compound represented by formula (I).

[0076] Figure 9: DVS spectrum of Form B of benzenesulfonate salt of the compound represented by formula (I).

[0077] Figure 10: Isothermal adsorption curve of Form B of benzenesulfonate salt of the compound represented by formula (I).

[0078] Figure 11: Crystalline Form B of the benzenesulfonate salt of the compound represented by formula (I) 1 H NMR spectrum.

[0079] Figure 12: XRPD pattern of Form A of the phosphate salt of the compound represented by formula (I).

[0080] Figure 13: TGA spectrum of Form A of the phosphate salt of the compound represented by formula (I).

[0081] Figure 14: DSC spectrum of Form A of the phosphate salt of the compound represented by formula (I).

[0082] Figure 15: DVS spectrum of Form A of the phosphate salt of the compound represented by formula (I).

[0083] Figure 16: Isothermal adsorption curve of Form A of the phosphate salt of the compound represented by formula (I).

[0084] Figure 17: XRPD pattern of Form A of the sulfate salt of the compound represented by formula (I).

[0085] Figure 18: TGA spectrum of Form A of the sulfate salt of the compound represented by formula (I).

[0086] Figure 19: DSC spectrum of Form A of the sulfate salt of the compound represented by formula (I).

[0087] Figure 20: DVS spectrum of Form A of the sulfate salt of the compound represented by formula (I).

[0088] Figure 21: Isothermal adsorption curve of Form A of the sulfate salt of the compound represented by formula (I).

[0089] Figure 22: XRPD pattern of Form A of the hydrochloride salt of the compound represented by formula (I).

[0090] Figure 23: TGA spectrum of Form A of the hydrochloride salt of the compound represented by formula (I).

[0091] Figure 24: DSC spectrum of Form A of the hydrochloride salt of the compound represented by formula (I).

[0092] Figure 25: DVS spectrum of Form A of the hydrochloride salt of the compound represented by formula (I).

[0093] Figure 26: Isothermal adsorption curve of Form A of the hydrochloride salt of the compound represented by formula (I).

[0094] Figure 27: Crystalline Form A of the hydrochloride salt of the compound represented by formula (I) 1 H NMR spectrum.

[0095] Figure 28: XRPD pattern of the amorphous methanesulfonate salt of the compound represented by formula (I).

[0096] Figure 29: TGA spectrum of the amorphous methanesulfonate of the compound represented by formula (I).

[0097] Figure 30: DSC spectrum of the amorphous methanesulfonate of the compound represented by formula (I).

[0098] Figure 31: DVS spectrum of the amorphous methanesulfonate of the compound represented by formula (I).

[0099] Figure 32: Isothermal adsorption curve of the amorphous methanesulfonate of the compound represented by formula (I).

[0100] Figure 33: Amorphous methanesulfonate of the compound represented by formula (I) 1 H NMR spectrum.

[0101] Figure 34: XRPD pattern of Form A of the mesylate salt of the compound represented by formula (I).

[0102] Figure 35: TGA spectrum of Form A of the methanesulfonate salt of the compound represented by formula (I).

[0103] Figure 36: DSC spectrum of Form A of the methanesulfonate salt of the compound represented by formula (I).

[0104] Figure 37: DVS spectrum of Form A of the mesylate salt of the compound represented by formula (I).

[0105] Figure 38: Isothermal adsorption curve of Form A of the methanesulfonate salt of the compound represented by formula (I).

[0106] Figure 39: Crystalline Form A of the methanesulfonate salt of the compound represented by formula (I) 1 H NMR spectrum.

[0107] Figure 40: XRPD pattern of Form B of the mesylate salt of the compound represented by formula (I).

[0108] Figure 41: TGA spectrum of Form B of the methanesulfonate salt of the compound represented by formula (I).

[0109] Figure 42: DSC spectrum of Form B of the methanesulfonate salt of the compound represented by formula (I).

[0110] Figure 43: Crystalline Form B of the methanesulfonate salt of the compound represented by formula (I) 1 H NMR spectrum.

[0111] Figure 44: XRPD pattern of Form A of the phosphate salt of the compound represented by formula (I) at room temperature.

[0112] Figure 45: XRPD pattern of Form A of the phosphate salt of the compound represented by formula (I) under high temperature and high humidity conditions.

[0113] Figure 46: XRPD pattern of Form A of the phosphate salt of the compound represented by formula (I) under oxidizing conditions.

[0114] Figure 47: XRPD pattern of Form A of the phosphate salt of the compound represented by formula (I) under illumination conditions.

[0115] Figure 48: XRPD pattern of Form A of the sulfate salt of the compound represented by formula (I) at room temperature.

[0116] Figure 49: XRPD pattern of Form A of the sulfate salt of the compound represented by formula (I) under high temperature and high humidity conditions.

[0117] Figure 50: XRPD pattern of Form A of the sulfate salt of the compound represented by formula (I) under oxidizing conditions.

[0118] Figure 51: XRPD pattern of Form A of the sulfate salt of the compound represented by formula (I) under illumination conditions.

[0119] Figure 52: Comparative DSC spectra of Form A of the phosphate salt of the compound represented by formula (I) at 0 days and 5 days.

[0120] Figure 53: Comparative DSC spectra of Form A of the phosphate salt of the compound represented by formula (I) at 0 days and 10 days.

[0121] Figure 54: Comparative DSC spectra of Form A of the sulfate salt of the compound represented by formula (I) at 0 days and 5 days.

[0122] Figure 55: Comparative DSC spectra of Form A of the sulfate salt of the compound represented by formula (I) at 0 days and 10 days.

[0123] Figure 56: XRPD patterns of Form A of benzenesulfonate, Form B of benzenesulfonate, Form A of phosphate, Form A of sulfate, Form A of hydrochloride and amorphous form of methanesulfonate of the compound represented by formula (I) after stirring in water for 24 hours. DETAILED DESCRIPTION

[0124] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0125] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0126] The following are the instruments, parameters, characterizations, and test methods used in the examples:

[0127] Example 1 Preparation of the amorphous compound represented by formula (I)

[0128] Repeat the synthesis method of Example 1 in CN201911320125.1 to obtain a white solid, which is the compound represented by formula (I).

[0129] Weigh 1 g of the resulting white solid into a beaker, add 4 mL of purified water, and slurry the mixture at 10°C to 30°C for 40 hours. Filter the suspended white solid and dry it. XRPD analysis was performed using the same testing method as above. The results, shown in Figure 1, indicate that the white solid is amorphous.

[0130] Example 2 Salt screening test

[0131] In the salt screening experiment, the free form and the counter ion were fed at a molar ratio of 1:1.1-1:1.4. A total of 10 counter ions were selected for the salt screening experiment (benzenesulfonic acid, L-lactic acid, phosphoric acid, sulfuric acid, L-tartaric acid, fumaric acid, hydrochloric acid, maleic acid, methanesulfonic acid, and salicylic acid, where the mass fraction of hydrochloric acid was 36%-38%, the mass fraction of phosphoric acid was approximately 85%, the mass fraction of sulfuric acid was approximately 98%, and the mass fraction of lactic acid was approximately 85%). Various crystalline salt forms were discovered and obtained, as shown in Table 1.

[0132] Table 1. Summary of salt screening experimental data

[0133] Example 3 Preparation and Characterization of Form A of the Benzenesulfonate Salt of the Compound Represented by Formula (I)

[0134] 199.99 mg of the amorphous raw material of the compound represented by formula (I) obtained in Example 1 was taken, 10 mL of methyl tert-butyl ether was added, and ultrasonication was performed until the solution was clear. 77.40 mg of benzenesulfonic acid (about 1.2 equivalents) was taken, 0.4 mL of ethanol was added, and ultrasonication was performed to dissolve the solution. The ethanol solution of benzenesulfonic acid was added dropwise to the methyl tert-butyl ether solution under stirring at room temperature to precipitate a white solid. After stirring overnight, the mixture was centrifuged and dried in vacuo at 40°C for 5 hours to obtain 287.40 mg of Form A of benzenesulfonate. The XRPD spectrum is shown in Figure 2, and the analytical data are shown in Table 2 below.

[0135] Table 2

[0136] The obtained benzenesulfonate form A of the compound represented by formula (I) was subjected to TGA, DSC, 1 H NMR detection, the characterization results are shown in Table 3, and the spectra are shown in Figures 3-5.

[0137] Table 3. Characterization results of Form A of benzenesulfonate

[0138] Example 4 Preparation and Characterization of Form B of the Benzenesulfonate Salt of the Compound Represented by Formula (I)

[0139] 600.17 mg of the amorphous raw material of the compound represented by formula (I) obtained in Example 1 was taken, 15 mL of methyl tert-butyl ether was added, and ultrasonication was performed until the solution was clear. 240.24 mg of benzenesulfonic acid (about 1.2 equivalents) was added to 1.0 mL of methyl tert-butyl ether, and ultrasonication was performed to dissolve the solution. The methyl tert-butyl ether solution of benzenesulfonic acid was added dropwise to the methyl tert-butyl ether solution of the sample under stirring at room temperature to precipitate a white solid. After stirring for 10 days, the solid was filtered and dried in vacuo at 40°C overnight to obtain 771.45 mg of Form B of the benzenesulfonate salt. The XRPD spectrum is shown in Figure 6, and the analytical data are shown in Table 4 below.

[0140] Table 4

[0141] The obtained benzenesulfonate of the compound represented by formula (I) was subjected to TGA, DSC, DVS, 1 The characterization results of HNMR detection are shown in Table 5, and the spectra are shown in Figures 7-11.

[0142] Table 5. Characterization results of Form B of benzenesulfonate

[0143] Example 5 Preparation and Characterization of Crystal Form A of the Phosphate of the Compound Represented by Formula (I)

[0144] 199.97 mg of the amorphous raw material of the compound represented by formula (I) obtained in Example 1 was taken, 10 mL of methyl tert-butyl ether was added, and ultrasonication was performed until the solution was clear. 57.23 mg of phosphoric acid (about 1.2 equivalents) was taken, 0.4 mL of ethanol was added, and ultrasonication was performed to dissolve the solution. The ethanol solution of phosphoric acid was added dropwise to the methyl tert-butyl ether solution under stirring at room temperature to precipitate a white solid. After stirring overnight, the solid was centrifuged and dried in vacuo at 40°C for 5 hours to obtain 157.02 mg of Form A of the phosphate. The XRPD spectrum is shown in Figure 12, and the analytical data are shown in Table 6 below.

[0145] Table 6

[0146] The obtained crystal form A of the phosphate of the compound represented by formula (I) was subjected to TGA, DSC, DVS, and IC detection. The characterization results are shown in Table 7, and the spectra are shown in Figures 13-16.

[0147] Table 7. Characterization results of Form A of phosphate

[0148] Example 6 Preparation and Characterization of Crystal Form A of the Sulfate Salt of the Compound Represented by Formula (I)

[0149] 200.02 mg of the amorphous raw material of the compound represented by formula (I) obtained in Example 1 was taken, 10 mL of methyl tert-butyl ether was added, and ultrasonication was performed until the solution was clear. 51.13 mg of sulfuric acid (about 1.2 equivalents) was taken, 0.4 mL of ethanol was added, and ultrasonication was performed to dissolve the solution. The ethanol solution of sulfuric acid was added dropwise to the methyl tert-butyl ether solution under stirring at room temperature to precipitate a white solid. After stirring overnight, the solid was centrifuged and dried in vacuo at 40°C for 5 hours to obtain 248.64 mg of crystal form A of the sulfate salt. The XRPD spectrum is shown in Figure 17, and the analytical data are shown in Table 8 below.

[0150] Table 8

[0151] The obtained crystal form A of the sulfate salt of the compound represented by formula (I) was subjected to TGA, DSC, DVS, and SXRD detection. The characterization results are shown in Table 9, and the spectra are shown in Figures 18-21.

[0152] Table 9. Characterization results of Form A of sulfate

[0153] Example 7 Preparation and Characterization of Form A of the Hydrochloride Salt of the Compound Represented by Formula (I)

[0154] 600.12 mg of the amorphous raw material of the compound represented by formula (I) obtained in Example 1 was taken, 15 mL of methyl tert-butyl ether was added, and ultrasonication was performed until the solution was clear. 154.11 mg of concentrated hydrochloric acid (about 1.2 equivalents) was taken, 0.2 mL of ethanol was added, and ultrasonication was performed to dissolve the solution. The ethanol solution of hydrochloric acid was added dropwise to the methyl tert-butyl ether solution under stirring at room temperature to precipitate a white solid. After stirring overnight, it became oil. After removing the solvent, 10 mL of n-heptane was added to the oil and stirring was continued for about 8 days to obtain a white turbid substance. The solid was filtered and dried in vacuo at 40°C overnight to obtain 633.00 mg of Form A of the hydrochloride salt. The XRPD spectrum is shown in Figure 22, and the analytical data are shown in Table 10 below.

[0155] Table 10

[0156] The obtained A-type hydrochloride of the compound represented by formula (I) was subjected to TGA, DSC, DVS, IC, 1 H NMR detection and characterization results are shown in Table 11, and the spectra are shown in Figures 23-27.

[0157] Table 11. Characterization results of Form A of hydrochloride

[0158] Example 8 Preparation and Characterization of the Amorphous Methanesulfonate of the Compound Represented by Formula (I)

[0159] 600.07 mg of the amorphous raw material of the compound represented by formula (I) obtained in Example 1 was taken, 15 mL of methyl tert-butyl ether was added, and the mixture was ultrasonically stirred until the solution was clear. 138.33 mg of methanesulfonic acid (about 1.2 equivalents) was added to 1.0 mL of methyl tert-butyl ether. The methyl tert-butyl ether solution of methanesulfonic acid was added dropwise to the methyl tert-butyl ether solution under stirring at room temperature to precipitate a white solid. After stirring overnight, it became oil. After removing the solvent, 10 mL of n-heptane was added and stirring was continued for about 8 days to obtain a white turbid substance. The solid was filtered and dried in vacuo at 40°C overnight to obtain 695.64 mg of amorphous methanesulfonate. The XRPD spectrum is shown in Figure 28.

[0160] The obtained amorphous methanesulfonate of the compound represented by formula (I) was subjected to TGA, DSC, DVS, 1 The characterization results are shown in Table 12, and the spectra are shown in Figures 29-33.

[0161] Table 12. Characterization results of amorphous methanesulfonate

[0162] Example 9 Preparation and Characterization of Crystal Form A and Crystal Form B of the Methanesulfonate of the Compound Represented by Formula (I)

[0163] 15 mg to 20 mg of the amorphous mesylate was added to an appropriate amount of the corresponding solvent listed in Table 13 and slurried at room temperature for 3 days to obtain Form A and Form B of the mesylate. The XRPD patterns are shown in Figures 34 and 40, respectively, and the analytical data are shown in Tables 14 and 15, respectively.

[0164] Table 13

[0165] Table 14

[0166] Table 15

[0167] The obtained crystal forms A and B of the methanesulfonate of the compound represented by formula (I) were subjected to TGA, DSC, DVS, 1H NMR detection and characterization results are shown in Tables 16 and 17, respectively, and the spectra are shown in Figures 35-39 and Figures 40-43, respectively.

[0168] Table 16. Characterization results of Form A of mesylate

[0169] Table 17. Characterization results of Form B of mesylate

[0170] Test Example 1. Solubility Test

[0171] 40 mg each of benzenesulfonate Form A, benzenesulfonate Form B, phosphate Form A, sulfate Form A, hydrochloride Form A, and amorphous methanesulfonate were placed in a 5 mL glass vial. 2 mL of deionized water was added, stirred at room temperature for 24 hours, and centrifuged. The solid was collected for XRPD analysis, and the centrifuge was filtered through a membrane and its solubility was measured by HPLC. The results are shown in Table 18 and Figure 56.

[0172] The solubility was determined using a single-point external standard method. The experimental results showed that the undissolved solids of all samples turned into amorphous forms after 24 hours of stirring (the peak of the sample at 18°2θ may come from the stirrer). All new salt forms (except the B crystal form of the benzenesulfonate) had improved solubility, while the B crystal form of the benzenesulfonate showed color change during stirring, suspected decomposition.

[0173] Table 18. Statistics of stirring results in water for 24 hours

[0174] in conclusion

[0175] This application describes screening experiments with 10 counterions in different organic solvents and crystallization conditions, resulting in the discovery of five salt forms: benzenesulfonate, phosphate, sulfate, hydrochloride, and methanesulfonate, all of which are monosalts. The benzenesulfonate and methanesulfonate salts exhibited polymorphism during this salt screening process.

[0176] The main reference indicators for selecting the obtained salt form are: crystallinity, water solubility, hygroscopicity (here refers to "weight change from 0% RH to 80% RH") and thermal properties.

[0177] The solubility in water from high to low is as follows: 100 μg / mL>sulfate crystal form A>benzenesulfonate crystal form A>hydrochloride crystal form A>phosphate crystal form A>methanesulfonate amorphous form.

[0178] The hygroscopicity is in the following order from smallest to largest: 0.2% < phosphate crystal form A = methanesulfonate crystal form A < 2.0% < hydrochloride crystal form A < sulfate crystal form A < benzenesulfonate crystal form B < methanesulfonate amorphous form < 15%.

[0179] The melting points or desolvation temperatures (measured by DSC) are as follows from high to low: phosphate crystal form A > 150°C > methanesulfonate crystal form A > benzenesulfonate crystal form B > sulfate crystal form A (dehydrated) > hydrochloride crystal form A (dehydrated) > benzenesulfonate crystal form A (desolvated) > methanesulfonate crystal form B (desolvated).

[0180] XRPD crystallinity (peak intensity): Form A of benzenesulfonate, Form A of phosphate, Form A of sulfate, and Form A of hydrochloride have high crystallinity, while Form A of methanesulfonate and Form A of mesylate have slightly lower crystallinity.

[0181] Test Example 2. Solid-state stability test

[0182] Determination method

[0183] Sample and experimental preparation: Crystal Form A of the phosphate of the compound prepared in Example 5 and Crystal Form A of the sulfate of the phosphate of the compound prepared in Example 6; approximately 50 mg of each sample was placed in a 5 mL glass bottle.

[0184] Experimental conditions: room temperature (25°C, sealed and dry, away from light), high temperature and humidity (40°C / 75% RH, open and away from light), light (25°C, 4500 Lux ± 500 Lux, open) and oxidation (40°C, sealed container containing urea peroxide, open and away from light) conditions.

[0185] Detection time: Day 0, Day 5, Day 10.

[0186] Test items: crystal form (XRPD test), melting point (DSC test, except amorphous form) and purity (HPLC test).

[0187] The test results are shown in Table 19.

[0188] Table 19. Stability test results at room temperature

[0189] result

[0190] Crystal form

[0191] The crystal form A of phosphate and the crystal form A of sulfate showed no obvious change after being placed under room temperature, high temperature and humidity, light and oxidation conditions for 10 days.

[0192] Specific diagrams are shown in Figures 44 to 51.

[0193] Melting point

[0194] Compared with 0 days, the melting point of phosphate crystal form A on 5 days and 10 days under room temperature, high temperature and humidity and light conditions remained basically unchanged, with a temperature fluctuation of 1℃-2℃; the melting point on 5 days and 10 days under oxidizing conditions decreased by 7℃-8℃.

[0195] The A crystal form of sulfate is a hydrate, and dehydration is accompanied by melting. Under room temperature, high temperature, high humidity and light conditions, the dehydration temperature remains basically unchanged after 5 days and 10 days, decreasing by less than 5°C. Under oxidizing conditions, the dehydration temperature decreases after 5 days and 10 days, decreasing by 7°C-9°C.

[0196] See Figures 52 to 55 for specific diagrams.

[0197] purity

[0198] The purity of the crystal form A of the phosphate of the compound represented by formula (I) remains essentially unchanged after 5 days and 10 days under room temperature, high temperature and humidity, light and oxidation conditions, with a decrease of less than 0.3%.

[0199] The initial purity of the crystal form A of the sulfate of the compound represented by formula (I) is 92.10%. The purity remains basically unchanged after 5 days and 10 days under room temperature, high temperature and humidity, light and oxidation conditions, with a decrease of less than 0.5%.

[0200] in conclusion

[0201] The crystal form A of the phosphate of the compound represented by formula (I) and the crystal form A of the sulfate of the compound represented by formula (I) showed no significant changes in crystal form, melting point or dehydration temperature, purity, etc. under room temperature, high temperature and humidity and light conditions for 10 days. The melting point or dehydration temperature decreased under oxidizing conditions for 10 days.

[0202] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A salt of the compound represented by formula (I), wherein, The salt is selected from one or more of benzenesulfonate, phosphate, sulfate, hydrochloride, and mesylate; Preferably, the salt is selected from phosphates and sulfates; 2. The salt of the compound of formula (I) according to claim 1, wherein, In the benzenesulfonate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to the p-benzenesulfonic acid molecule is 1:0.9 to 1:1.4, for example, about 1:1; In the phosphate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to the phosphoric acid molecule is 1:0.9 to 1:1.4, for example, about 1:1; In the sulfate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to sulfuric acid is 1:0.9 to 1:1.4, for example, about 1:1; In the hydrochloride of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:0.9 to 1:1.4, for example, about 1:1; In the mesylate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to the mesylic acid molecule is 1:0.9 to 1:1.4, for example, about 1:1; Preferably, the salt is a pharmaceutically acceptable salt.

3. A crystal of a salt of the compound of formula (I) according to claim 1 or 2, wherein, The crystal is the A crystal form of the benzenesulfonate of the compound represented by formula (I), the B crystal form of the benzenesulfonate of the compound represented by formula (I), the A crystal form of the phosphate of the compound represented by formula (I), the A crystal form of the sulfate of the compound represented by formula (I), the A crystal form of the hydrochloride of the compound represented by formula (I), the A crystal form of the mesylate of the compound represented by formula (I), the B crystal form of the mesylate of the compound represented by formula (I), or the amorphous form of the mesylate of the compound represented by formula (I); Preferably, the crystal is the A crystal form of the phosphate of the compound represented by formula (I) or the A crystal form of the sulfate of the compound represented by formula (I).

4. The crystal of the salt of the compound represented by formula (I) according to claim 3, wherein, For the A crystal form of the phosphate of the compound represented by formula (I), the X-ray powder diffraction represented by the 2θ angle has characteristic peaks at 9.9±0.20°, 12.3±0.20°, 14.2±0.20°, 17.1±0.20°, 19.1±0.20°, and 19.7±0.20° using Cu-Kα radiation; Furthermore, it also has characteristic peaks at 6.5±0.20°, 13.1±0.20°, and / or 21.1±0.20°; Even further, it also has characteristic peaks at 10.8±0.20°, 17.8±0.20°, 21.9±0.20°, 22.8±0.20°, 23.6±0.20°, and / or 24.2±0.20°; Preferably, the A crystal form of the phosphate of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 6; Preferably, the A crystal form of the phosphate of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 12; Preferably, the decomposition temperature of the A crystal form of the phosphate of the compound represented by formula (I) is about 259°C; Preferably, the A crystal form of the phosphate of the compound represented by formula (I) has a TGA pattern substantially as shown in Figure 13 and a DSC pattern substantially as shown in Figure 14.

5. The crystal of the salt of the compound represented by formula (I) according to claim 3, wherein, The A crystal form of the sulfate salt of the compound represented by formula (I) has characteristic peaks in the X-ray powder diffraction expressed in 2θ angles at 9.9±0.20°, 11.0±0.20°, 12.7±0.20°, 15.3±0.20°, 17.6±0.20°, 19.6±0.20° using Cu-Kα radiation; Furthermore, it also has characteristic peaks at 13.2±0.20°, 13.7±0.20° and / or 14.4±0.20°; Even further, it also has characteristic peaks at 16.3±0.20°, 20.7±0.20°, 21.3±0.20°, 21.9±0.20°, 24.9±0.20° and / or 27.1±0.20°; Preferably, the A crystal form of the sulfate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 8; Preferably, the A crystal form of the sulfate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 17; Preferably, the A crystal form of the sulfate salt of the compound represented by formula (I) loses 3.9% of its weight before 150 °C; Preferably, the A crystal form of the sulfate salt of the compound represented by formula (I) has a TGA pattern substantially as shown in Figure 18 and a DSC pattern substantially as shown in Figure 19.

6. The crystal of the salt of the compound represented by formula (I) according to claim 3, wherein, The A crystal form of the benzenesulfonate salt of the compound represented by formula (I) has characteristic peaks in the X-ray powder diffraction expressed in 2θ angles at 8.4±0.20°, 10.1±0.20°, 19.4±0.20°, 20.3±0.20°, 20.9±0.20°, 22.2±0.20° using Cu-Kα radiation; Furthermore, it also has characteristic peaks at 11.1±0.20°, 12.2±0.20° and / or 23.6±0.20°; Even further, it also has characteristic peaks at 6.1±0.20°, 13.2±0.20°, 14.1±0.20°, 14.4±0.20°, 18.0±0.20° and / or 18.3±0.20°; Preferably, the A crystal form of the benzenesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 2; Preferably, the A crystal form of the benzenesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 2; Preferably, the A crystal form of the benzenesulfonate salt of the compound represented by formula (I) loses 11.0% of its weight before 150 °C. Preferably, the A crystal form of the benzenesulfonate salt of the compound represented by formula (I) has a TGA pattern substantially as shown in Figure 3 and a DSC pattern substantially as shown in Figure 4; The B crystal form of the benzenesulfonate salt of the compound represented by formula (I) has characteristic peaks in the X-ray powder diffraction expressed in 2θ angles at 4.6±0.20°, 6.6±0.20°, 7.5±0.20°, 8.6±0.20°, 14.9±0.20°, 21.9±0.20° using Cu-Kα radiation; Furthermore, it also has characteristic peaks at 18.3 ± 0.20°, 18.7 ± 0.20° and / or 21.1 ± 0.20°; Even further, it also has characteristic peaks at 13.1 ± 0.20°, 16.1 ± 0.20°, 19.7 ± 0.20°, 23.0 ± 0.20°, 24.9 ± 0.20° and / or 27.8 ± 0.20°; Preferably, the B crystal form of the benzenesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 4; Preferably, the B crystal form of the benzenesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 6; Preferably, the decomposition temperature of the B crystal form of the benzenesulfonate salt of the compound represented by formula (I) is about 269 °C; Preferably, the B crystal form of the benzenesulfonate salt of the compound represented by formula (I) has a TGA pattern substantially as shown in Figure 7 and a DSC pattern substantially as shown in Figure 8; For the A crystal form of the hydrochloride salt of the compound represented by formula (I), X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation has characteristic peaks at 6.6 ± 0.20°, 9.5 ± 0.20°, 11.5 ± 0.20°, 12.7 ± 0.20°, 15.0 ± 0.20°, 19.8 ± 0.20°; Furthermore, it also has characteristic peaks at 14.0 ± 0.20°, 17.7 ± 0.20° and / or 23.1 ± 0.20°; Even further, it also has characteristic peaks at 13.1 ± 0.20°, 16.1 ± 0.20°, 16.6 ± 0.20°, 18.1 ± 0.20°, 20.3 ± 0.20° and / or 24.5 ± 0.20°; Preferably, the A crystal form of the hydrochloride salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 10; Preferably, the A crystal form of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 22; Preferably, the A crystal form of the hydrochloride salt of the compound represented by formula (I) loses 12.1% of its weight before 150 °C; Preferably, the A crystal form of the hydrochloride salt of the compound represented by formula (I) has a TGA pattern substantially as shown in Figure 23 and a DSC pattern substantially as shown in Figure 24; For the A crystal form of the methanesulfonate salt of the compound represented by formula (I), X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation has characteristic peaks at 12.5 ± 0.20°, 15.1 ± 0.20°, 17.3 ± 0.20°, 18.1 ± 0.20°, 22.1 ± 0.20°, 23.1 ± 0.20°; Furthermore, it also has characteristic peaks at 6.7 ± 0.20°, 10.8 ± 0.20° and / or 11.6 ± 0.20°; Even further, it also has characteristic peaks at 18.6 ± 0.20°, 19.6 ± 0.20°, 20.1 ± 0.20°, 25.4 ± 0.20°, 26.2 ± 0.20° and / or 27.2 ± 0.20°; Preferably, the A crystal form of the mesylate salt of the compound represented by formula (I) has an XRPD analytical pattern substantially as shown in Table 14; Preferably, the A crystal form of the mesylate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 34; Preferably, the decomposition temperature of the A crystal form of the mesylate salt of the compound represented by formula (I) is about 261 °C; Preferably, the A crystal form of the mesylate salt of the compound represented by formula (I) has a TGA pattern substantially as shown in Figure 35 and a DSC pattern substantially as shown in Figure 36; For the B crystal form of the mesylate salt of the compound represented by formula (I), X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation has characteristic peaks at 8.1 ± 0.20°, 9.8 ± 0.20°, 19.2 ± 0.20°, 20.0 ± 0.20°, 21.9 ± 0.20°, 23.3 ± 0.20°; Furthermore, it further has characteristic peaks at 5.8 ± 0.20°, 20.6 ± 0.20° and / or 24.2 ± 0.20°; Even further, it further has characteristic peaks at 10.8 ± 0.20°, 12.9 ± 0.20°, 13.8 ± 0.20°, 16.9 ± 0.20°, 17.8 ± 0.20° and / or 25.2 ± 0.20°; Preferably, the B crystal form of the mesylate salt of the compound represented by formula (I) has an XRPD analytical pattern substantially as shown in Table 15; Preferably, the B crystal form of the mesylate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 40; Preferably, the B crystal form of the mesylate salt of the compound represented by formula (I) loses 10.2% of its weight before 150 °C; Preferably, the B crystal form of the mesylate salt of the compound represented by formula (I) has a TGA pattern substantially as shown in Figure 41 and a DSC pattern substantially as shown in Figure 42.

7. A method for preparing a salt of the compound represented by formula (I) according to claim 1 or 2 or a crystal of a salt of the compound represented by formula (I) according to any one of claims 3-6, comprising: React the compound represented by formula (I) with benzenesulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid or methanesulfonic acid in a solvent to obtain the salt or crystal of the salt of the compound represented by formula (I).

8. A pharmaceutical composition comprising the salt of the compound represented by formula (I) as claimed in claim 1 or 2 or the crystal of the salt of the compound represented by formula (I) as claimed in any one of claims 3 - 6; Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable pharmaceutical excipients, such as including but not limited to one or more of excipients, fillers, lubricants, binders, disintegrants, inorganic salts, solvents, solubilizing agents, suspending agents, isotonic agents, buffers, preservatives, antioxidants, colorants, foaming agents and flavoring agents, etc.

9. Use of the salt of the compound represented by formula (I) as claimed in claim 1 or 2, the crystal of the salt of the compound represented by formula (I) as claimed in any one of claims 3 - 6 or the pharmaceutical composition as claimed in claim 8 in the preparation of a pharmaceutical preparation; Preferably, the pharmaceutical preparation is used for preventing and / or treating diseases caused by androgen deficiency; Preferably, the diseases include androgenetic alopecia, acute or chronic muscle wasting, sarcopenia, muscle atrophy, bone-related disorders, cancers (such as prostate cancer, breast cancer, etc.), AIDS, kidney diseases, muscle wasting / sarcopenia / muscle atrophy caused by burn diseases, anemia, obesity, diabetes, senile emotional and cognitive changes, urinary incontinence (such as stress urinary incontinence), heart failure, dry eye disease, coronavirus disease 2019, etc.

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