New crystal forms of nucleoside compounds and their salts

Abstract

The present invention provides a novel crystalline form of nucleoside compounds and their salts, which belongs to the field of pharmaceutical technology. The said nucleoside compound is compound ATV014, the present invention focuses on whether compound ATV014 has various solid forms, and unexpectedly, we have found that compound ATV014 has various stable solid forms, including ATV-014 free base crystalline form I, ATV-014 hydrochloride crystalline form I, ATV-014 hydrochloride crystalline form II, ATV-014 hydrochloride crystalline form III, ATV-014 hydrochloride crystalline form IV, ATV-014 hydrobromide crystalline form I, and ATV-014 p-toluenesulfonate crystalline form I. The provided novel crystalline forms of compound ATV014 free base and its salts have good solubility and thermal stability, and have better bioavailability and dissolution curve in certain preparations. Good permeability and thermal stability are suitable for use in certain pharmaceutical preparations.

Description

[Technical field]

[0001] The present invention belongs to the field of pharmaceutical technology and relates to novel crystalline forms of nucleoside compounds and their salts. [Background technology]

[0002] SARS-CoV-2 is an enveloped, single-stranded RNA virus that belongs to the βcoronavirus genus. Similar to SARS and MERS, the SARS-CoV-2 genome encodes nonstructural proteins, such as 3C-like protease (3CLpro), papain-like protease (PLpro), helicase, and RNA-dependent RNA polymerase (RdRp). Structural proteins include spike glycoproteins and accessory proteins. SARS-CoV-2 infects human respiratory epithelial cells by binding to the angiotensin-converting enzyme (ACE2) receptor on the surface of human cells through the surface spike glycoproteins. After the virus enters the host cell, it disassembles and releases the nucleocapsid and viral RNA into the cytoplasm. The open reading frame (ORF1a / b) at the 5' end of the viral RNA encodes polyproteins (pp1a and pp1ab), which play an important role in the processing and maturation of enzymes required for viral replication. pp1a and pp1ab are cleaved by papain-like protease (PLpro) and 3C-like protease (3CLpro) to produce nonstructural proteins, including RNA-dependent RNA polymerase and helicase, which play a crucial role in the transcription and replication of the new coronavirus. At present, the surface spike glycoproteins for identifying coronavirus receptors, and the key proteins 3CLpro, PLpro and RdRp involved in the replication and transcription process, are very attractive targets for the research and development of antiviral drugs.

[0003] Through the applicant's early research on remdesivir and its prodrug compound GS-441524 (Li, et al., J. Med. Chem. 2020), it was discovered that the compound GS-441524 produced a better antiviral effect than remdesivir in mouse in vivo activity tests. The compound GS-441524 has a similar mechanism of action to remdesivir, but exhibits better safety. Therefore, the applicant has filed a patent application for a drug describing the compound GS-441524 in the prevention, mitigation and / or treatment of SARS-CoV-2 (application number or patent number 202011000517.2).

[0004] The structure of compound GS-441524 is shown below. [ka] The compound represented by formula ATV014 is a derivative of the compound GS-441524, and the inventors' research has found that the compound represented by formula ATV014 has better activity and bioavailability than the compound GS-441524.

[0005] The structure of compound ATV014 is as follows: [ka]

[0006] Pharmaceutical crystal polymorphism is a common phenomenon in pharmaceutical research and development, and is an important factor affecting the quality of pharmaceuticals. Different pharmaceutical crystal forms may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and may even have very large differences, which may have different effects on pharmaceutical storage transfer, application, stability, therapeutic effect, etc. In order to effectively obtain a crystal form that is favorable for production or pharmaceutical formulation, it is necessary to comprehensively consider the drug crystallization behavior and obtain a crystal form that meets production requirements.

[0007] The present invention has conducted a large amount of experimental research on compound ATV014 to obtain a new crystalline form of the compound and its salt, and the new crystalline form has excellent properties such as good stability, stability under light irradiation, high temperature and high humidity conditions, simple manufacturing process and easy operation, etc., and has advantages in industrial production. Research on the new crystalline form of compound ATV014 provides an opportunity to improve the overall performance of the pharmaceutical product (ease of synthesis and handling, improved dissolution, improved stability and shelf life, etc.), and at the same time expands the variety of materials that formulation scientists can use when designing the drug, which is of great importance to drug research and development. Summary of the Invention

[0008] The present invention aims to solve at least to some extent one of the technical problems in the related art.Therefore, one of the objectives of the present invention is to provide a new crystalline form of compound ATV014 free base and its salt and its preparation method, the present invention focuses on whether compound ATV014 has various solid forms, and unexpectedly, we have found that compound ATV014 has various stable solid forms, including ATV-014 free base crystalline form I, ATV-014 hydrochloride crystalline form I, ATV-014 hydrochloride crystalline form II, ATV-014 hydrochloride crystalline form III, ATV-014 hydrochloride crystalline form IV, ATV-014 hydrobromide crystalline form I, ATV-014 p-toluenesulfonate crystalline form I. Here, the structure of compound ATV014 is as follows: [ka]

[0009] The novel crystalline forms of the compound ATV014 free base and its salts provided by the present invention have good solubility and thermal stability, and have better bioavailability and dissolution curves in certain formulations. Its good permeability and thermal stability make it suitable for use in certain pharmaceutical formulations.

[0010] In order to solve the above problems, the present invention provides the following technical solutions: In a first aspect, a crystalline form of the free base or a salt thereof of the compound ATV-014 is provided. According to one aspect of the present invention, there are provided crystalline form I of the free base of compound ATV-014, crystalline form I of the hydrochloride salt of compound ATV-014, crystalline form II of the hydrochloride salt of compound ATV-014, crystalline form III of the hydrochloride salt of compound ATV-014, crystalline form IV of the hydrochloride salt of compound ATV-014, crystalline form I of the hydrobromide salt of compound ATV-014, and crystalline form I of the p-toluenesulfonate salt of compound ATV-014.

[0011] Crystalline Form I of the free base of compound ATV-014 In some embodiments, crystalline Form I of the free base of compound ATV-014 is provided, wherein crystalline Form I of the free base is anhydrous.

[0012] In some embodiments, the crystalline Form I of the free base of the compound ATV-014 has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG.

[0013] In some embodiments, the crystalline Form I of the free base of the compound ATV-014 has a differential scanning calorimetry curve (DSC) essentially as shown in FIG.

[0014] In some embodiments, the crystalline Form I of the free base of the compound ATV-014 has a thermogravimetry curve (TGA) essentially as shown in FIG.

[0015] In some embodiments, the crystalline Form I of the free base of compound ATV-014 has at least one, at least two, or all of the following characteristics: (a) a) a) crystalline form I of the free base of compound ATV-014; (a) Crystalline Form I has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. (b) Crystalline Form I has a differential scanning calorimetry curve (DSC) essentially as shown in FIG. (c) Crystalline Form I has a thermogravimetric analysis curve (TGA) essentially as shown in FIG.

[0016] In some embodiments, the crystalline Form I of the free base of the compound ATV-014 has the following properties: (a) Crystal Form I has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. (b) Crystal Form I has a differential scanning calorimetry curve (DSC) essentially as shown in Figure 8; and (c) Crystal Form I has a thermogravimetric analysis curve (TGA) essentially as shown in FIG.

[0017] In some embodiments, the crystalline Form I of the free base of compound ATV-014 has an XRPD pattern exhibiting at least 2, at least 3, at least 4, at least 5, or at least 6 2θ degree reflections, the maxima of which and the XRPD pattern are approximately as shown in FIG.

[0018] In some embodiments, the differential scanning calorimetry curve of crystalline Form I of the free base of the compound ATV-014 has an endothermic peak at 225°C-228°C.

[0019] In some embodiments, the thermogravimetric analysis curve for crystalline Form I of the free base of the compound ATV-014 exhibits a weight loss of 0.5% or less within the temperature range of 100° C.-200° C.

[0020] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 9.69, 18.70, and 23.88.

[0021] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 9.69, 18.70, and 23.88 ±0.2° 2θ, and one, two, or three of the following diffraction angles 9.84, 17.74, and 19.38 ±0.2° 2θ.

[0022] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 9.69, 18.70, and 23.88 ±0.2° 2θ, and one or two of the following diffraction angles 9.84, 17.74, and 19.38 ±0.2° 2θ.

[0023] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 9.69, 18.70, and 23.88 ±0.2° 2θ, and one of the following diffraction angles 9.84, 17.74, and 19.38 ±0.2° 2θ.

[0024] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 9.69, 18.70, and 23.88 ±0.2° 2θ, and two of the following diffraction angles 9.84, 17.74, and 19.38 ±0.2° 2θ.

[0025] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 9.69, 9.84, 17.74, 18.70, 19.38, and 23.88.

[0026] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at at least three of the following diffraction angles 2θ±0.2°: 9.69, 9.84, 17.74, 18.70, 19.38, and 23.88.

[0027] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 9.69, 9.84, 17.74, 18.70, 19.38, and 23.88, and one, two, or three of the following diffraction angles 2θ±0.2° at 13.19, 15.61, and 21.31.

[0028] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 9.69, 9.84, 17.74, 18.70, 19.38, and 23.88, and one or two of the following diffraction angles 2θ±0.2° at 13.19, 15.61, and 21.31.

[0029] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 9.69, 9.84, 17.74, 18.70, 19.38, and 23.88, and at one of diffraction angles 2θ±0.2° at 13.19, 15.61, and 21.31.

[0030] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 9.69, 9.84, 17.74, 18.70, 19.38, and 23.88, and two of the following diffraction angles 2θ±0.2° at 13.19, 15.61, and 21.31.

[0031] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 9.69, 9.84, 13.91, 15.61, 17.74, 18.70, 19.38, 21.31, and 23.88.

[0032] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at at least three of the following diffraction angles 2θ±0.2°: 9.69, 9.84, 13.91, 15.61, 17.74, 18.70, 19.38, 21.31, and 23.88.

[0033] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 9.69, 9.84, 13.91, 15.61, 17.74, 18.70, 19.38, 21.31, and 23.88, and one or two of the following diffraction angles 2θ±0.2° at 17.41 and 26.01.

[0034] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 9.69, 9.84, 13.91, 15.61, 17.74, 18.70, 19.38, 21.31, and 23.88, and at one of diffraction angles 2θ±0.2° at 17.41 and 26.01.

[0035] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free base of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 9.69, 9.84, 13.91, 15.61, 17.41, 17.74, 18.70, 19.38, 21.31, 23.88, and 26.01.

[0036] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the free salt of the compound ATV-014 has characteristic peaks at at least three positions within diffraction angles 2θ±0.2° at 9.69, 9.84, 13.91, 15.61, 17.41, 17.74, 18.70, 19.38, 21.31, 23.88, and 26.01.

[0037] Crystal form I of the hydrochloride salt of compound ATV-014 In some embodiments, crystalline Form I of the hydrochloride salt of compound ATV-014 is provided, wherein crystalline Form I of the hydrochloride salt is a solvate.

[0038] In some embodiments, crystalline Form I of the hydrochloride salt has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG.

[0039] In some embodiments, crystalline Form I of the hydrochloride salt has a differential scanning calorimetry curve (DSC) essentially as shown in FIG.

[0040] In some embodiments, crystalline Form I of the hydrochloride salt has a thermogravimetry curve (TGA) essentially as shown in FIG.

[0041] In some embodiments, the crystalline Form I of the hydrochloride salt of compound ATV-014 has at least one, at least two, or all of the following characteristics: (a) the crystalline form I is crystalline; (a) Crystal Form I has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. (b) Crystalline Form I has a differential scanning calorimetry curve (DSC) essentially as shown in FIG. (c) Crystalline Form I has a thermogravimetric analysis curve (TGA) essentially as shown in FIG.

[0042] In some embodiments, the crystalline form I of the hydrochloride salt of the compound ATV-014 has the following properties: (a) Crystal Form I has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. 2. (b) Crystal Form I has a differential scanning calorimetry curve (DSC) essentially as shown in Figure 9; and (c) The thermogravimetric analysis curve (TGA) of crystalline form I is approximately the same as that shown in FIG.

[0043] In some embodiments, the crystalline Form I of the hydrochloride salt of the compound ATV-014 has an XRPD pattern exhibiting at least 2, at least 3, at least 4, at least 5, or at least 6 2θ degree reflections, the maxima of which and the XRPD pattern are approximately shown in FIG.

[0044] In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the hydrochloride salt of the compound ATV-014 has an endothermic peak at 120° C.-170° C. In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the hydrochloride salt of the compound ATV-014 has an endothermic peak at 125° C.-165° C. In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the hydrochloride salt of the compound ATV-014 has an endothermic peak, and the peak value of the endothermic peak is 141° C.-151° C. or 143° C.-149° C. In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the hydrochloride salt of the compound ATV-014 is essentially similar to the differential scanning calorimetry curve of FIG.

[0045] In some examples, the differential scanning calorimetry curve for crystalline Form I of the hydrochloride salt of the compound ATV-014 exhibits a melting point of 136.55±5° C.

[0046] In some embodiments, the differential scanning calorimetry curve of crystalline Form I of the hydrochloride salt of the compound ATV-014 has an endothermic peak at 137° C.-146° C. with an enthalpy value of 81 J / g, and the desolvation overlaps with the melting peak.

[0047] In some embodiments, the thermogravimetric analysis curve of crystalline Form I of the hydrochloride salt of compound ATV-014 has a weight loss of less than 10%, or less than 9%, or less than 8% at 110° C.-170° C. In some embodiments, the thermogravimetric analysis curve of crystalline Form I of the hydrochloride salt of compound ATV-014 has a weight loss of 7.1% or less at 110° C.-170° C.

[0048] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 15.53, and 20.76.

[0049] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 15.53, and 20.76, and one, two, or three of diffraction angles 2θ±0.2° of 10.33, 22.75, and 24.19.

[0050] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 15.53, and 20.76, and one or two of diffraction angles 2θ±0.2° of 10.33, 22.75, and 24.19.

[0051] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 15.53, and 20.76, and one of diffraction angles 2θ±0.2° of 10.33, 22.75, and 24.19.

[0052] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 15.53, and 20.76, and two of the diffraction angles 2θ±0.2° of 10.33, 22.75, and 24.19.

[0053] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 10.33, 15.53, 20.76, 22.75, and 24.19.

[0054] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three of the diffraction angles 2θ±0.2° at 5.16, 10.33, 15.53, 20.76, 22.75, and 24.19.

[0055] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 10.33, 15.53, 20.76, 22.75, and 24.19, and one or two of diffraction angles 2θ±0.2° of 23.88 and 26.01.

[0056] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 5.16, 10.33, 15.53, 20.76, 22.75, and 24.19 ±0.2° 2θ, and one characteristic peak at diffraction angles 2θ±0.2° at 23.88 and 26.01.

[0057] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.16, 10.33, 15.53, 20.76, 22.75, 23.88, 24.19, and 26.01.

[0058] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three of the following diffraction angles 2θ±0.2°: 5.16, 10.33, 15.53, 20.76, 22.75, 23.88, 24.19, and 26.01.

[0059] Crystalline Form II of the hydrochloride salt of compound ATV-014 In some embodiments, crystalline Form II of the hydrochloride salt of compound ATV-014 is provided, wherein said crystalline Form II of the hydrochloride salt is a solvate / hydrate.

[0060] In some embodiments, crystalline Form II of the hydrochloride salt has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG.

[0061] In some embodiments, crystalline Form II of the hydrochloride salt has a differential scanning calorimetry (DSC) curve essentially as shown in FIG.

[0062] In some embodiments, crystalline Form II of the hydrochloride salt has a thermogravimetry curve (TGA) essentially as shown in FIG.

[0063] In some embodiments, the crystalline Form II of the hydrochloride salt of compound ATV-014 has at least one, at least two, or all of the following characteristics (a)-(c): (a) Crystalline Form II has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. (b) Crystalline Form II has a differential scanning calorimetry curve (DSC) essentially as shown in FIG. (c) Crystalline Form II has a thermogravimetric analysis curve (TGA) essentially as shown in FIG.

[0064] In some embodiments, the crystalline form II of the hydrochloride salt of the compound ATV-014 has the following properties: (a) Crystal Form II has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. (b) Crystalline Form II has a differential scanning calorimetry curve (DSC) essentially as shown in Figure 10; and (c) The thermogravimetric analysis curve (TGA) of the crystalline form II is approximately the same as that shown in FIG.

[0065] In some embodiments, the crystalline Form II of the hydrochloride salt of the compound ATV-014 has an XRPD pattern exhibiting at least 2, at least 3, at least 4, at least 5, or at least 6 2θ degree reflections, the maxima of which and the XRPD pattern are approximately shown in FIG.

[0066] In some embodiments, the differential scanning calorimetry curve of the crystalline form II of the hydrochloride salt of the compound ATV-014 has an endothermic peak at 100° C.-150° C. In some embodiments, the differential scanning calorimetry curve of the crystalline form II of the hydrochloride salt of the compound ATV-014 has an endothermic peak, the peak value of the endothermic peak is 135° C.-145° C. In some embodiments, the differential scanning calorimetry curve of the crystalline form II of the hydrochloride salt of the compound ATV-014 has an endothermic peak, the peak value of the endothermic peak is 136° C.-143° C. In some embodiments, the differential scanning calorimetry curve of the crystalline form II of the hydrochloride salt of the compound ATV-014 is essentially as shown in FIG. 10.

[0067] In some embodiments, the differential scanning calorimetry curve for crystalline Form II of the hydrochloride salt of the compound ATV-014 exhibits a melting point of 126.75±5° C.

[0068] In some embodiments, the thermogravimetric analysis curve of crystalline Form II of the hydrochloride salt of compound ATV-014 exhibits a weight loss of less than 10% from 70° C. to 170° C. In some embodiments, the thermogravimetric analysis curve of crystalline Form II of the hydrochloride salt of compound ATV-014 exhibits a weight loss of less than 8% from 70° C. to 170° C. In some embodiments, the thermogravimetric analysis curve of crystalline Form II of the hydrochloride salt of compound ATV-014 exhibits a weight loss of 5.6% or less from 70° C. to 170° C.

[0069] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 10.43, and 18.79.

[0070] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 10.43, and 18.79, and one, two, or three of diffraction angles 2θ±0.2° of 9.88, 14.05, and 22.28.

[0071] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 10.43, and 18.79, and one or two of diffraction angles 2θ±0.2° of 9.88, 14.05, and 22.28.

[0072] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 10.43, and 18.79, and one of diffraction angles 2θ±0.2° of 9.88, 14.05, and 22.28.

[0073] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 10.43, and 18.79, and two of the diffraction angles 2θ±0.2° of 9.88, 14.05, and 22.28.

[0074] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 9.88, 10.43, 14.05, 18.79, and 22.28.

[0075] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three of the diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 18.79, and 22.28.

[0076] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 9.88, 10.43, 14.05, 18.79, and 22.28, and has characteristic peaks at one, two, and three of diffraction angles 2θ±0.2° of 15.68, 19.46, and 21.38.

[0077] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 5.23, 9.88, 10.43, 14.05, 18.79, and 22.28 ±0.2° 2θ, and one or two characteristic peaks at diffraction angles 15.68, 19.46, and 21.38 ±0.2° 2θ.

[0078] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 5.23, 9.88, 10.43, 14.05, 18.79, and 22.28 ±0.2° 2θ, and one characteristic peak at diffraction angles 15.68, 19.46, and 21.38 ±0.2° 2θ.

[0079] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 18.79, and 22.28, and two characteristic peaks at diffraction angles 2θ±0.2° at 15.68, 19.46, and 21.38.

[0080] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38, and 22.28.

[0081] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three positions within diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38, and 22.28.

[0082] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38, and 22.28, and one, two, or three of the following diffraction angles 2θ±0.2° at 17.81, 20.37, and 23.96.

[0083] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38, and 22.28, and one or two of diffraction angles 2θ±0.2° at 17.81, 20.37, and 23.96.

[0084] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38, and 22.28, and two of the following diffraction angles 2θ±0.2° at 17.81, 20.37, and 23.96.

[0085] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38, and 22.28, and at one of diffraction angles 2θ±0.2° at 17.81, 20.37, and 23.96.

[0086] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, 21.38, 22.28, and 23.96.

[0087] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three of the following diffraction angles 2θ±0.2°: 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, 21.38, 22.28, and 23.96.

[0088] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, 21.38, 22.28, and 23.96, and at one or two of diffraction angles 2θ±0.2° at 22.81 and 37.05.

[0089] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, 21.38, 22.28, and 23.96, and one of diffraction angles 2θ±0.2° at 22.81 and 37.05.

[0090] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, 21.38, 22.28, 22.81, 23.96, and 37.05.

[0091] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three of the following diffraction angles 2θ±0.2°: 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, 21.38, 22.28, 22.81, 23.96, and 37.05.

[0092] Crystalline Form III of the hydrochloride salt of compound ATV-014 In some embodiments, crystalline Form III of the hydrochloride salt of compound ATV-014 is provided, wherein crystalline Form III of the hydrochloride salt is a solvate.

[0093] In some embodiments, crystalline Form III of the hydrochloride salt has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG.

[0094] In some embodiments, crystalline Form III of the hydrochloride salt has a differential scanning calorimetry curve (DSC) essentially as shown in FIG.

[0095] In some embodiments, crystalline Form III of the hydrochloride salt has a thermogravimetric analysis curve (TGA) essentially as shown in FIG.

[0096] In some embodiments, the crystalline Form III of the hydrochloride salt of compound ATV-014 has at least one, at least two, or all of the following characteristics: (a) the crystalline form III is crystalline; (a) Crystalline Form III has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. (b) Crystalline Form III has a differential scanning calorimetry curve (DSC) essentially as shown in FIG. (c) Crystalline Form III has a thermogravimetric analysis curve (TGA) essentially as shown in FIG.

[0097] In some embodiments, the crystalline Form III of the hydrochloride salt of compound ATV-014 has the following properties: (a) Crystalline Form III has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. (b) Crystalline Form III has a differential scanning calorimetry curve (DSC) essentially as shown in Figure 11; and (c) The thermogravimetric analysis curve (TGA) of the crystalline form III is approximately the same as that shown in FIG.

[0098] In some embodiments, the crystalline Form III of the hydrochloride salt of the compound ATV-014 has an XRPD pattern exhibiting at least 2, at least 3, at least 4, at least 5, or at least 6 2θ degree reflections, the maxima of which and the XRPD pattern are approximately shown in FIG.

[0099] In some embodiments, the differential scanning calorimetry curve of the crystalline Form III of the hydrochloride salt of the compound ATV-014 has an endothermic peak at 90° C.-170° C. In some embodiments, the differential scanning calorimetry curve of the crystalline Form III of the hydrochloride salt has an endothermic peak at 125° C.-170° C. In some embodiments, the differential scanning calorimetry curve of the crystalline Form III of the hydrochloride salt has an endothermic peak at 90° C.-125° C., the endothermic peak being a desolvation peak. In some embodiments, the differential scanning calorimetry curve of the crystalline Form III of the hydrochloride salt has an endothermic peak, the endothermic peak having a peak value of 101° C.-120 and / or 130° C.-138° C. In some embodiments, the differential scanning calorimetry curve of the crystalline Form III of the hydrochloride salt is essentially as shown in FIG. 11.

[0100] In some embodiments, the differential scanning calorimetry curve for crystalline Form III of the hydrochloride salt shows a melting point of 134.32±5° C.

[0101] In some embodiments, the thermogravimetric analysis curve of crystalline Form III of the hydrochloride salt has a weight loss of less than 10%, or less than 9% at 70° C.-170° C. In some embodiments, the thermogravimetric analysis curve of crystalline Form III of the hydrochloride salt of compound ATV-014 has a weight loss of 8.6% or less in the temperature range of 70-170° C. In some embodiments, the thermogravimetric analysis curve of crystalline Form III of the hydrochloride salt is essentially represented by the thermogravimetric analysis curve of FIG.

[0102] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 14.03, and 18.99.

[0103] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 5.28, 14.03, and 18.99 2θ±0.2°, and one, two, or three of the following diffraction angles 10.54, 15.84, and 21.16 2θ±0.2°.

[0104] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 5.28, 14.03, and 18.99 ±0.2° 2θ, and one or two of the following diffraction angles 10.54, 15.84, and 21.16 ±0.2° 2θ.

[0105] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 5.28, 14.03, and 18.99 degrees 2θ±0.2°, and one of the following diffraction angles 10.54, 15.84, and 21.16 degrees 2θ±0.2°.

[0106] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 5.28, 14.03, and 18.99 ±0.2° 2θ, and two of the following diffraction angles 10.54, 15.84, and 21.16 ±0.2° 2θ.

[0107] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 10.54, 14.03, 15.84, 18.99, and 21.16.

[0108] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three of the diffraction angles 2θ±0.2° at 5.28, 10.54, 14.03, 15.84, 18.99, and 21.16.

[0109] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 10.54, 14.03, 15.84, 18.99, and 21.16, and one, two, or three of the following diffraction angles 2θ±0.2° at 17.67, 22.49, and 27.51.

[0110] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 10.54, 14.03, 15.84, 18.99, and 21.16, and one or two of diffraction angles 2θ±0.2° at 17.67, 22.49, and 27.51.

[0111] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 10.54, 14.03, 15.84, 18.99, and 21.16, and one of diffraction angles 2θ±0.2° at 17.67, 22.49, and 27.51.

[0112] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 10.54, 14.03, 15.84, 18.99, and 21.16, and two of the following diffraction angles 2θ±0.2° at 17.67, 22.49, and 27.51.

[0113] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 10.54, 14.03, 15.84, 17.67, 18.99, 21.16, 22.49, and 27.51.

[0114] In some embodiments, the X-ray powder diffraction pattern of the crystalline form III of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three positions within a diffraction angle 2θ±0.2° at 5.28, 10.54, 14.03, 15.84, 17.67, 18.99, 21.16, 22.49, and 27.51.

[0115] Crystalline Form IV of the hydrochloride salt of compound ATV-014 In some embodiments, crystalline Form IV of the hydrochloride salt has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG.

[0116] In some embodiments, crystalline Form IV of the hydrochloride salt has a differential scanning calorimetry curve (DSC) essentially as shown in FIG.

[0117] In some embodiments, the crystalline Form IV of the hydrochloride salt has a thermogravimetry curve (TGA) essentially as shown in FIG.

[0118] In some embodiments, the crystalline Form IV of the hydrochloride salt of compound ATV-014 has at least one, at least two, or all of the following characteristics: (a) the crystalline Form IV is a hydrochloride salt of the compound ATV-014; (a) Crystalline Form IV has an X-ray powder diffraction pattern essentially as shown in FIG. 5 (XRPD pattern). (b) Crystalline Form IV has a differential scanning calorimetry curve (DSC) essentially as shown in FIG. (c) Crystalline Form IV has a thermogravimetric analysis curve (TGA) essentially as shown in FIG.

[0119] In some embodiments, the crystalline Form IV of the hydrochloride salt of compound ATV-014 has the following properties: (a) Crystalline Form IV has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. (b) Crystalline Form IV has a differential scanning calorimetry curve (DSC) essentially as shown in Figure 12; and (c) Crystalline Form IV has a thermogravimetric analysis curve (TGA) approximately similar to that shown in FIG.

[0120] In some embodiments, the differential scanning calorimetry curve of Form IV of the hydrochloride salt has an endothermic peak at 180° C.-200° C. In some embodiments, the differential scanning calorimetry curve of Form IV of the hydrochloride salt has an endothermic peak, the endothermic peak having a peak value of 183° C.-190° C. In some embodiments, the differential scanning calorimetry curve of Form IV of the hydrochloride salt is substantially similar to the differential scanning calorimetry curve of FIG.

[0121] In some embodiments, the differential scanning calorimetry curve for crystalline Form IV of the hydrochloride salt displays a melting point of 182.50±5°C.

[0122] In some embodiments, the thermogravimetric analysis curve for Form IV of the hydrochloride salt shows a weight loss of less than 2% from 30° C.-150° C. In some embodiments, the thermogravimetric analysis curve for Form IV of the hydrochloride salt shows a weight loss of less than 1% from 30° C.-150° C. In some embodiments, the thermogravimetric analysis curve for Form IV of the hydrochloride salt shows a weight loss of less than 0.5% from 30° C.-150° C. In some embodiments, the thermogravimetric analysis curve for Form IV of the hydrochloride salt shows a weight loss of less than 0.2% from 30° C.-150° C.

[0123] In some embodiments, the crystalline Form IV of the hydrochloride salt of the compound ATV-014 has an XRPD pattern exhibiting at least 2, at least 3, at least 4, at least 5, or at least 6 2θ degree reflections, the maxima of which and the XRPD pattern are approximately shown in FIG. 5.

[0124] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 10.63, and 19.13.

[0125] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 5.28, 10.63, and 19.13 ±0.2° 2θ, and one, two, or three of the following diffraction angles 9.63, 14.10, and 16.82 ±0.2° 2θ.

[0126] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 5.28, 10.63, and 19.13 ±0.2° 2θ, and one or two of the following diffraction angles 9.63, 14.10, and 16.82 ±0.2° 2θ.

[0127] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 5.28, 10.63, and 19.13 ±0.2° 2θ, and one of the following diffraction angles 9.63, 14.10, and 16.82 ±0.2° 2θ.

[0128] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 10.63, and 19.13, and two characteristic peaks at diffraction angles 2θ±0.2° of 9.63, 14.10, and 16.82.

[0129] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 9.63, 10.63, 14.10, 16.82, and 19.13.

[0130] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three of the following diffraction angles 2θ±0.2°: 5.28, 9.63, 10.63, 14.10, 16.82, and 19.13.

[0131] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 9.63, 10.63, 14.10, 16.82, and 19.13, and one, two, or three of the following diffraction angles 2θ±0.2° at 10.19, 15.99, and 17.62.

[0132] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 9.63, 10.63, 14.10, 16.82, and 19.13, and at one or two of diffraction angles 2θ±0.2° at 10.19, 15.99, and 17.62.

[0133] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 9.63, 10.63, 14.10, 16.82, and 19.13, and one of diffraction angles 2θ±0.2° at 10.19, 15.99, and 17.62.

[0134] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 5.28, 9.63, 10.63, 14.10, 16.82, and 19.13 ±0.2° 2θ, and two of the following diffraction angles 10.19, 15.99, and 17.62 ±0.2° 2θ.

[0135] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, and 19.13.

[0136] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three positions within a diffraction angle 2θ±0.2° at 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, and 19.13.

[0137] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, and 19.13, and one, two, or three of the following diffraction angles 2θ±0.2° at 22.27, 23.19, and 27.74.

[0138] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, and 19.13, and at one or two of diffraction angles 2θ±0.2° at 22.27, 23.19, and 27.74.

[0139] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, and 19.13, and at one of diffraction angles 2θ±0.2° at 22.27, 23.19, and 27.74.

[0140] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, and 19.13, and two of the following diffraction angles 2θ±0.2° at 22.27, 23.19, and 27.74.

[0141] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, 19.13, 22.27, 23.19, and 27.74.

[0142] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three positions within a diffraction angle 2θ±0.2° at 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, 19.13, 22.27, 23.19, and 27.74.

[0143] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, 19.13, 22.27, 22.56, 23.19, and 27.74.

[0144] In some embodiments, the X-ray powder diffraction pattern of crystalline Form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at at least three of the following diffraction angles 2θ±0.2°: 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, 19.13, 22.27, 22.56, 23.19, and 27.74.

[0145] Crystal form I of the hydrobromide salt of compound ATV-014 In some embodiments, crystalline Form I of the hydrobromide salt of compound ATV-014 is provided, wherein crystalline Form I of the hydrobromide salt is substantially acrystalline.

[0146] In some embodiments, crystalline Form I of the hydrobromide salt has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG.

[0147] In some embodiments, crystalline Form I of the Hydrobromide Salt has a Differential Scanning Calorimetry curve (DSC) essentially as shown in FIG.

[0148] In some embodiments, crystalline Form I of the Hydrobromide Salt has a thermogravimetric analysis curve (TGA) essentially as shown in FIG.

[0149] In some embodiments, the crystalline Form I of the hydrobromide salt of the compound ATV-014 has at least one, at least two, or all of the following characteristics: (a) the crystalline form I is a hydrobromide salt of the compound ATV-014; (a) Crystalline Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 7 (XRPD pattern). (b) Crystalline Form I has a differential scanning calorimetry curve (DSC) essentially as shown in FIG. (c) Crystalline Form I has a thermogravimetric analysis curve (TGA) essentially as shown in FIG.

[0150] In some embodiments, the crystalline form I of the hydrobromide salt of the compound ATV-014 has the following properties: (a) Crystal Form I has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. (b) Crystal Form I has a differential scanning calorimetry curve (DSC) essentially as shown in Figure 14; and (c) The thermogravimetric analysis curve (TGA) of crystalline form I is approximately the same as that shown in FIG.

[0151] In some embodiments, crystalline Form I of the hydrobromide salt of the compound ATV-014 has an XRPD pattern exhibiting at least 2, at least 3, at least 4, at least 5, or at least 6 2θ degree reflections, the maxima of which and the XRPD pattern are approximately shown in FIG. 7.

[0152] In some embodiments, the thermogravimetric curve of crystalline Form I of the hydrobromide salt of compound ATV-014 exhibits less than 2% weight loss at 100° C.-160° C. In some embodiments, the thermogravimetric curve of crystalline Form I of the hydrobromide salt of compound ATV-014 exhibits less than 1.5% weight loss at 100° C.-160° C. In some embodiments, the thermogravimetric curve of crystalline Form I of the hydrobromide salt of compound ATV-014 is essentially as shown in FIG.

[0153] In some embodiments, the thermogravimetric analysis curve of the crystalline form I of the hydrobromide salt of the compound ATV-014 does not show any obvious weight loss within the temperature range of room temperature-170°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the hydrobromide salt of the compound ATV-014 has an endothermic peak at 130°C-170°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the hydrobromide salt of the compound ATV-014 has an endothermic peak, the peak value of the endothermic peak is 138°C-145°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the hydrobromide salt of the compound ATV-014 has an endothermic peak, the peak value of the endothermic peak is 59°C-66°C, and the endothermic peak is a desolvation peak. In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the hydrobromide salt of the compound ATV-014 is substantially as shown in the differential scanning calorimetry curve of FIG. 14.

[0154] In some embodiments, the thermogravimetric analysis curve of crystalline Form I of the hydrobromide salt of the compound ATV-014 shows that its melting point is 132.75±5°C.

[0155] In some embodiments, the differential scanning calorimetry curve of crystalline form I of the hydrobromide salt of the compound ATV-014 has endothermic peaks at 64°C to 66°C and 179°C to 183°C.

[0156] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 3.78, 13.20, and 16.88.

[0157] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at diffraction angles 3.78, 13.20, and 16.88 2θ±0.2°, and one, two, or three of the following diffraction angles 15.41, 17.46, and 26.38 2θ±0.2°.

[0158] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at diffraction angles 3.78, 13.20, and 16.88 ±0.2° 2θ, and one or two characteristic peaks at diffraction angles 15.41, 17.46, and 26.38 ±0.2° 2θ.

[0159] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at diffraction angles 3.78, 13.20, and 16.88 ±0.2° 2θ, and one characteristic peak at diffraction angles 15.41, 17.46, and 26.38 ±0.2° 2θ.

[0160] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at diffraction angles 3.78, 13.20, and 16.88 2θ±0.2°, and two characteristic peaks at diffraction angles 15.41, 17.46, and 26.38 2θ±0.2°.

[0161] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 3.78, 13.20, 15.41, 16.88, 17.46, and 26.38.

[0162] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at at least three of the following diffraction angles 2θ±0.2°: 3.78, 13.20, 15.41, 16.88, 17.46, and 26.38.

[0163] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide salt crystalline Form I of the compound ATV-014 has characteristic peaks at diffraction angles 3.78, 13.20, 15.41, 16.88, 17.46, and 26.38 ±0.2° 2θ, and one or two of the following diffraction angles 25.52 and 26.79 ±0.2° 2θ.

[0164] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at diffraction angles 3.78, 13.20, 15.41, 16.88, 17.46, and 26.38 ±0.2° 2θ, and one characteristic peak at diffraction angles 2θ ±0.2° 2θ of 25.52 and 26.79.

[0165] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° at 3.78, 13.20, 15.41, 16.88, 17.46, 25.52, 26.38, and 26.79.

[0166] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at at least three of the following diffraction angles 2θ±0.2°: 3.78, 13.20, 15.41, 16.88, 17.46, 25.52, 26.38, and 26.79.

[0167] Crystal form I of the p-toluenesulfonate salt of compound ATV-014 In some embodiments, crystalline Form I of the p-toluenesulfonate salt of compound ATV-014 is provided, wherein crystalline Form I of the p-toluenesulfonate salt is a monohydrate.

[0168] In some embodiments, crystalline Form I of the p-toluenesulfonate salt has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG.

[0169] In some embodiments, the crystalline Form I of the p-toluenesulfonate salt has a differential scanning calorimetry (DSC) curve essentially as shown in FIG.

[0170] In some embodiments, the crystalline Form I of the p-toluenesulfonate salt has a thermogravimetric analysis (TGA) curve essentially as shown in FIG.

[0171] In some embodiments, crystalline Form I of the p-toluenesulfonate salt of compound ATV-014 has at least one, at least two, or all of the following characteristics: (a) a) a crystalline form I of the p-toluenesulfonate salt of compound ATV-014; (a) Crystalline Form I has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. (b) Crystalline Form I has a differential scanning calorimetry curve (DSC) essentially as shown in FIG. (c) Crystalline Form I has a thermogravimetric analysis curve (TGA) essentially as shown in FIG.

[0172] In some embodiments, crystalline Form I of the p-toluenesulfonic acid salt of the compound ATV-014 has the following properties: (a) Crystal Form I has an X-ray powder diffraction pattern (XRPD pattern) essentially as shown in FIG. (b) Crystalline Form I has a differential scanning calorimetry curve (DSC) essentially as shown in Figure 13; and (c) The thermogravimetric analysis curve (TGA) of crystalline form I is approximately the same as that shown in FIG.

[0173] In some embodiments, crystalline Form I of the p-toluenesulfonate salt of the compound ATV-014 has an XRPD pattern exhibiting at least 2, at least 3, at least 4, at least 5, or at least 6 2θ degree reflections, the maxima of which and the XRPD pattern are approximately shown in FIG.

[0174] In some embodiments, the thermogravimetric curve of crystalline Form I of p-toluenesulfonate of compound ATV-014 exhibits a weight loss of less than 10% at 60° C.-150° C. In some embodiments, the thermogravimetric curve of crystalline Form I of p-toluenesulfonate of compound ATV-014 exhibits a weight loss of less than 5% at 60° C.-150° C. In some embodiments, the thermogravimetric curve of crystalline Form I of p-toluenesulfonate of compound ATV-014 exhibits a weight loss of less than 4% at 60° C.-150° C. In some embodiments, the thermogravimetric curve of crystalline Form I of p-toluenesulfonate of compound ATV-014 is essentially the thermogravimetric curve of FIG.

[0175] In some embodiments, the thermogravimetric analysis curve of crystalline Form I of the p-toluenesulfonic acid salt of the compound ATV-014 shows that its melting point is 105.92±5°C.

[0176] In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the p-toluenesulfonate salt of the compound ATV-014 has an endothermic peak at 100° C.-140° C. In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the p-toluenesulfonate salt of the compound ATV-014 has an endothermic peak, and the peak value of the endothermic peak is 120° C.-127° C. In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the p-toluenesulfonate salt of the compound ATV-014 has an endothermic peak at 121° C.-126° C., and the enthalpy value is 66 J / g. In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the p-toluenesulfonate salt of the compound ATV-014 is essentially the same as the differential scanning calorimetry curve of FIG. 13.

[0177] In some embodiments, the thermogravimetric analysis curve for crystalline Form I of the p-toluenesulfonate salt of ATV-014 exhibits a weight loss of 3.2% or less within the temperature range of 65° C.-130° C.

[0178] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the p-toluenesulfonate salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 3.58, 10.89, and 16.59.

[0179] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of the p-toluenesulfonate salt of the compound ATV-014 has characteristic peaks at diffraction angles 3.58, 10.89, and 16.59 2θ±0.2°, and one or two characteristic peaks at diffraction angles 7.23 and 14.59 2θ±0.2°.

[0180] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the p-toluenesulfonate salt of the compound ATV-014 has characteristic peaks at diffraction angles 3.58, 10.89, and 16.59 2θ±0.2°, and one or two characteristic peaks at diffraction angles 7.23 and 14.59 2θ±0.2°.

[0181] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the p-toluenesulfonate salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 3.58, 7.23, 10.89, 14.59, and 16.59.

[0182] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the p-toluenesulfonate salt of the compound ATV-014 has characteristic peaks at at least three of the diffraction angles 2θ±0.2° at 3.58, 7.23, 10.89, 14.59, and 16.59.

[0183] The novel crystalline forms of the free base and salts thereof of the compound ATV014 of the present invention can be used to treat diseases associated with viral infections, or to prevent, alleviate and / or treat symptoms such as SARS-CoV-2-related diseases.

[0184] In a second aspect, a pharmaceutical composition is provided.

[0185] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the novel crystalline form of the free base of the compound ATV014 and its salts and a pharma- ceutically acceptable auxiliary material or excipient. Typically, a therapeutically effective amount of the novel crystalline form of the free base of the compound ATV014 and its salts is mixed or contacted with one or more pharma- ceutically acceptable excipients to prepare a pharmaceutical composition or formulation, which is prepared by a method well known in the pharmaceutical art. The pharmaceutical composition or formulation can be used for the treatment of a disease associated with a viral infection, or for the prevention, alleviation and / or treatment of symptoms, such as a disease associated with SARS-CoV-2.

[0186] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of crystalline Form I of the hydrochloride salt of compound ATV-014, a therapeutically effective amount of crystalline Form II of the hydrochloride salt of compound ATV-014, a therapeutically effective amount of crystalline Form III of the hydrochloride salt of compound ATV-014, a therapeutically effective amount of crystalline Form IV of the hydrochloride salt of compound ATV-014, a therapeutically effective amount of crystalline Form I of the hydrobromide salt of compound ATV-014, or a therapeutically effective amount of crystalline Form I of the p-toluenesulfonate salt of compound ATV-014, and any pharmaceutically acceptable excipients.

[0187] In some embodiments, a pharmaceutical composition comprising the free base of the compound ATV014, wherein at least 80% of the free base of the compound ATV014 is in crystalline Form I of the free base of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the free base of the compound ATV014, wherein at least 90% of the free base of the compound ATV014 is in crystalline Form I of the free base of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the free base of the compound ATV014, wherein at least 95% of the free base of the compound ATV014 is in crystalline Form I of the free base of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the free base of the compound ATV014, wherein at least 99% of the free base of the compound ATV014 is in crystalline Form I of the free base of the compound ATV014.

[0188] In some embodiments, a pharmaceutical composition comprising the hydrochloride salt of the compound ATV014, wherein at least 80% of the hydrochloride salt of the compound ATV014 is in crystalline form I of the hydrochloride salt of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrochloride salt of the compound ATV014, wherein at least 90% of the hydrochloride salt of the compound ATV014 is in crystalline form I of the hydrochloride salt of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrochloride salt of the compound ATV014, wherein at least 95% of the hydrochloride salt of the compound ATV014 is in crystalline form I of the hydrochloride salt of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrochloride salt of the compound ATV014, wherein at least 99% of the hydrochloride salt of the compound ATV014 is in crystalline form I of the hydrochloride salt of the compound ATV014.

[0189] In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 80% of the hydrochloride of the compound ATV014 is the crystalline form II of the hydrochloride of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 90% of the hydrochloride of the compound ATV014 is the crystalline form II of the compound ATV014 hydrochloride. In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 95% of the hydrochloride of the compound ATV014 is the crystalline form II of the compound ATV014 hydrochloride. In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 99% of the hydrochloride of the compound ATV014 is the crystalline form II of the compound ATV014 hydrochloride.

[0190] In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 80% of the hydrochloride of the compound ATV014 is in the hydrochloride crystalline form III of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 90% of the hydrochloride of the compound ATV014 is in the hydrochloride crystalline form III of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 95% of the hydrochloride of the compound ATV014 is in the hydrochloride crystalline form III of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 99% of the hydrochloride of the compound ATV014 is in the hydrochloride crystalline form III of the compound ATV014.

[0191] In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 80% of the hydrochloride of the compound ATV014 is in crystalline form IV of the hydrochloride of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 90% of the hydrochloride of the compound ATV014 is in crystalline form IV of the hydrochloride of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 95% of the hydrochloride of the compound ATV014 is in crystalline form IV of the hydrochloride of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrochloride of the compound ATV014, wherein at least 99% of the hydrochloride of the compound ATV014 is in crystalline form IV of the hydrochloride of the compound ATV014.

[0192] In some embodiments, a pharmaceutical composition comprising the hydrobromide salt of the compound ATV014, wherein at least 80% of the hydrobromide salt of the compound ATV014 is in crystalline form I of the hydrobromide salt of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrobromide salt of the compound ATV014, wherein at least 90% of the hydrobromide salt of the compound ATV014 is in crystalline form I of the hydrobromide salt of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrobromide salt of the compound ATV014, wherein at least 95% of the hydrobromide salt of the compound ATV014 is in crystalline form I of the hydrobromide salt of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the hydrobromide salt of the compound ATV014, wherein at least 99% of the hydrobromide salt of the compound ATV014 is in crystalline form I of the hydrobromide salt of the compound ATV014.

[0193] In some embodiments, a pharmaceutical composition comprising the p-toluenesulfonate salt of the compound ATV014, wherein at least 80% of the p-toluenesulfonate salt of the compound ATV014 is in crystalline form I of the p-toluenesulfonate salt of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the p-toluenesulfonate salt of the compound ATV014, wherein at least 90% of the p-toluenesulfonate salt of the compound ATV014 is in crystalline form I of the p-toluenesulfonate salt of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the p-toluenesulfonate salt of the compound ATV014, wherein at least 95% of the p-toluenesulfonate salt of the compound ATV014 is in crystalline form I of the p-toluenesulfonate salt of the compound ATV014. In some embodiments, a pharmaceutical composition comprising the p-toluenesulfonate salt of the compound ATV014, wherein at least 99% of the p-toluenesulfonate salt of the compound ATV014 is in crystalline form I of the p-toluenesulfonate salt of the compound ATV014.

[0194] In a third aspect, there is provided a use of the crystalline form or pharmaceutical composition described above. The use of the crystalline form I of the hydrochloride of the compound ATV-014 according to the first aspect, the crystalline form II of the hydrochloride of the compound ATV-014, the crystalline form III of the hydrochloride of the compound ATV-014, the crystalline form IV of the hydrochloride of the compound ATV-014, the crystalline form I of the hydrobromide of the compound ATV-014, or the crystalline form I of the p-toluenesulfonate of the compound ATV-014 according to the second aspect, in the manufacture of a medicament for treating a disease or condition associated with a viral infection.

[0195] The novel crystalline forms of the compound ATV014 free base and salts thereof of the present invention can be used for the prevention, alleviation and / or treatment of a disease or condition associated with a viral infection, or for use in a method for the prevention, alleviation and / or treatment of a disease or condition associated with SARS-CoV-2 or a mutant strain thereof.

[0196] The novel crystalline form provided by the present invention has not been reported yet. Through research, the inventors of the present invention have overcome this difficulty and found a novel crystalline form suitable for development. The novel crystalline form has better stability and solubility, and a more stable crystalline form is of great significance to the improvement of drug quality.

[0197] The novel crystalline form provided by the present invention has the characteristics of good stability in water, not easily deliquescing under high humidity conditions, and is convenient for long-term storage and storage of drugs. The crystalline form provided by the present invention has good stability, remarkable technical purification effect, and can effectively prevent the occurrence of crystal transition during drug storage and development, thus avoiding changes in bioavailability and efficacy, and has great economic value. Effect of the Invention

[0198] (1) The crystalline form I of the hydrobromide salt of the formula ATV-014 provided by the present invention absorbs 0.2% moisture when left under 70% RH (open) for one week, and absorbs 18.8% moisture when left under 90% RH (open) for one week. (2) The crystalline form I of p-toluenesulfonate salt of formula ATV-014 provided by the present invention is left under 30% RH (open) for one week, absorbs 0.4% moisture, and left under 90% RH (open) for one week, absorbs 0.5% moisture, without any change in crystalline form and chemical purity, and has good physical and chemical stability. (3) According to the results of DVS, the crystalline form I of the hydrobromide salt of ATV-014 is hygroscopic. After equilibration for 30-120 minutes under 70% RH conditions, the weight gain upon hygroscopic absorption was 0.2%. The hygroscopicity was relatively strong under conditions from 70% RH to 90% RH, and the weight gain upon hygroscopic absorption was 18.8% under 90% RH conditions. The sample transformed into an amorphous glassy solid during the DVS test process. (4) According to the DVS results, the crystalline form I of the p-toluenesulfonate salt of ATV-014 was found to be slightly hygroscopic. After equilibration for 30-120 minutes under 90% RH conditions, the hygroscopic weight gain was about 0.5%. No change in the crystalline form of the remaining solid was observed after the DVS test was completed. (5) The crystalline form of the hydrochloride salt of the formula ATV-014 provided by the present invention can be left at 40°C / 75%RH and RH (open) for one week without any change in crystalline form and chemical purity, and has good physical and chemical stability.

[0199] Definition of Terms Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings: The term "crystalline form" refers to a specific regular arrangement and / or conformation of the molecules within a compound lattice.

[0200] X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, crystallinity, and crystalline state, and is a commonly used means for identifying crystal forms. The peak positions of the XRPD pattern mainly depend on the structure of the crystal form and are relatively insensitive to experimental details, while the relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystal forms of the present invention are characterized by XRPD patterns with specific peak positions essentially as shown in the XRPDs provided in the drawings of the present invention. At the same time, the measurement of 2θ in the XRPD pattern may have experimental errors, and the measurement of 2θ in the XRPD pattern may vary slightly between different instruments and different samples, so the value of 2θ cannot be considered absolute. Due to the conditions of the instrument used in this test, the diffraction peaks are within ±0.2 o There is a margin of error.

[0201] Differential scanning calorimetry (DSC) curves were measured using samples and an inert reference (commonly α-AlO 3) It is a technique that measures the temperature change of the energy difference between the DSC peak and the DSC peak by heating or cooling under programmed control. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline forms of the present invention are characterized by DSC patterns having characteristic peak positions basically as shown in the DSC patterns provided in the drawings of the present invention. At the same time, the DSC pattern may have experimental errors, and the peak positions and peak values ​​of the DSC pattern may differ slightly between different instruments and different samples, so the peak value position or peak value value of the DSC endothermic peak cannot be considered absolute. Depending on the conditions of the instrument used in this test, the melting peak may have a deviation of ±3 o There is an error margin of error.

[0202] Glass transition refers to the transition of an amorphous material between a highly elastic state and a glassy state, and is an inherent property of this material. The corresponding transition temperature is the glass transition temperature (Tg), which is an important physical property of amorphous materials. Since glass transition is a phenomenon related to molecular motion, the glass transition temperature (Tg) depends mainly on the structure of the material and is relatively insensitive to experimental details. The melting peak was within ±3°C from the conditions of the apparatus used in this study. o There is an error margin of error.

[0203] Thermogravimetric analysis (TGA) is a technique to measure the mass change of a substance with temperature under program control, and is suitable for examining the process of solvent loss in crystals, sublimation and decomposition of samples, and estimating the presence of crystal water or crystal solvent in crystals. The mass change shown by the TGA curve depends on many factors, such as sample preparation and instrument. The mass change detected by TGA varies slightly between different instruments and different samples. The mass change has an error margin of ±0.1% depending on the instrument conditions used in this test.

[0204] For the purposes of this invention, all 2θ values ​​in X-ray powder diffraction patterns are in degrees (°).

[0205] When referring to data appearing in patterns and / or graphs, a "peak" refers to a feature recognizable by one of ordinary skill in the art that is not part of the background noise.

[0206] The term "essentially pure" refers to a crystalline form that is substantially free of one or more other crystalline forms, where the purity of the crystalline form is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%, or where the crystalline form contains other crystalline forms that are less than 20%, less than 10%, less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01 by total volume or weight percent of the other crystalline forms.

[0207] "Substantially free" of one or more other crystalline forms means that the content of other crystalline forms is less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% of the total volume or weight.

[0208] The term X-ray powder diffraction pattern is "essentially as shown" means that in the X-ray powder diffraction pattern, at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks are present in the pattern.

[0209] The term "relative intensity" refers to the ratio of the intensity of a peak to the intensity of the first intense peak among all diffraction peaks in an X-ray powder diffraction pattern, where the intensity of the first intense peak is 100%.

[0210] The term "anti-solvent" refers to a solvent that promotes supersaturation of the solution or crystallization. In certain embodiments, the free base of ATV014 has a solubility in the anti-solvent of less than 0.001 g / L, or less than 0.01 g / L, or less than 0.1 g / L, or less than 0.2 g / L, or less than 0.3 g / L, or less than 0.4 g / L, or less than 0.5 g / L, or less than 0.6 g / L, or less than 0.8 g / L, or less than 1 g / L, or less than 2 g / L, or less than 3 g / L, or less than 4 g / L, or less than 6 g / L, or less than 7 g / L, or less than 8 g / L, or less than 9 g / L, or less than 10 g / L.

[0211] The term "peak" of the patterns and / or data in the figures refers to features that do not belong to the background noise as would be understood by one skilled in the art.

[0212] The terms "optional," "optional," or "alternatively" mean that the subsequently described event or circumstance may occur, but need not occur. For example, "optionally a pharma- ceutically acceptable excipient" means that a "pharma-ceutically acceptable excipient" may or may not be present.

[0213] All numbers in this document are approximations, regardless of the use of phrases such as "about" or "approximately." The numerical values ​​of the numbers may vary, such as by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%. Whenever a numerical value having a value of N is disclosed, any numerical value having a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% is expressly disclosed, where "+ / -" means plus or minus. The lower limit R of the range of values ​​is L , and upper limit R U Whenever R is published, any value in the published range is explicitly published. Specifically, R = R L +K*(R U -R L ), where K is a variable from 1% to 100% in 1% increments, i.e., 1%, 2%, 3%, 4%, 5%, 50%, 51%, 52%, 95%, 96%, 97%, 98%, 99%, or 100%. Numeric ranges defined by the two R numbers above are also expressly disclosed herein.

[0214] "Room temperature" in the present invention refers to the ambient temperature, the temperature being from about 10° C. to about 40° C. In some embodiments, "room temperature" refers to a temperature from about 20° C. to about 30° C. In some embodiments, "room temperature" refers to a temperature from about 25° C. to about 30° C. In some embodiments, "room temperature" refers to 10° C., 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., etc.

[0215] The term "treatment" as used herein, unless otherwise specified, means reversing, alleviating, inhibiting the progression of, or preventing the disease, disorder, or one or more symptoms of such disease, disorder to which the term applies. As used herein, the term "treatment" refers to the act of treatment as defined above as "treatment".

[0216] In the context of this specification, "crystalline Form I of the hydrobromic acid of ATV-014" and "crystalline Form I of the hydrobromide salt of the compound ATV-014" have the same meaning, as do other crystalline forms.

[0217] Instrument parameters Unless parameters are otherwise specified, all of the following analyses are performed at room temperature.

[0218] X-ray powder diffraction studies X-ray powder diffraction patterns are collected using a zero-background sample disk on a German Bruker D8 Advance X-ray diffractometer equipped with an autosampler. The radiation source is Cu kα (λ=1.5418 Å), the light pipe voltage is set at 40 kV, and the light pipe current is set at 40 mA. The X-ray divergence slit is 0.6 mm. An appropriate amount of sample is taken and lightly pressed with a clean glass slide in the center of the zero-background sample disk under ambient conditions to obtain a flat surface, and the zero-background sample shelf is fixed. The sample is subjected to diffraction analysis in the range of 3-40° (2θ) with a scan step of 0.02° (2θ). The software used for data collection is DIFFRAC.COMMANDER, and the data is analyzed and presented with DIFFRAC.EVA.

[0219] Differential Scanning Calorimetry Curve (DSC) Samples are subjected to DSC analysis on a TA Instrument Discovery DSC 250 instrument with a perforated lidded aluminum disk. The aluminum disk is weighed (approximately 2-5 mg) and capped with Tzero, the sample amount is precisely recorded, and the sample is transferred to the instrument for measurement. The instrument is purged with nitrogen at 50 mL / min. Data is collected between 25°C and 300°C at a heating rate of 10°C / min. Data is analyzed and displayed in TRIOS.

[0220] Thermogravimetric analysis (TGA) Samples are subjected to TGA analysis on open aluminum disks using a TA Instrument Discovery TGA Model 55 instrument. 2-5 mg of sample is placed on a pre-equilibrated aluminum sample disk and heated from ambient temperature to 300°C at 10°C / min. The sample chamber is maintained with a nitrogen gas flow of 25 mL / min. In the TGA pattern, the horizontal axis represents temperature (°C) and the vertical axis represents the percentage of weight loss (Weight (%)).

[0221] High-performance liquid chromatography (HPLC) detection of crystalline forms The instrument used for the liquid chromatography analysis was an Agilent HPLC 1260 series.

[0222] [Table 1]

[0223] The above-mentioned various dosage forms of drugs can be prepared by conventional methods in the pharmaceutical field. In the present invention, the abbreviations of some compounds are shown in Table 2.

[0224] [Table 2]

[0225] In describing the experimental details, several abbreviations and acronyms have been used. While most of these will be understood by those skilled in the art, the following table contains a list of these abbreviations and acronyms.

[0226] [Table 3] [Brief description of the drawings]

[0227] [Figure 1] 1 shows the X-ray powder diffraction pattern of crystalline form I of the free base of compound ATV-014. [Diagram 2] 1 shows the X-ray powder diffraction pattern of crystalline form I of the hydrochloride salt of compound ATV-014. [Diagram 3] 1 shows the X-ray powder diffraction pattern of crystalline form II of the hydrochloride salt of compound ATV-014. [Figure 4] 1 shows the X-ray powder diffraction pattern of crystalline form III of the hydrochloride salt of compound ATV-014. [Diagram 5] 1 shows an X-ray powder diffraction pattern of crystalline form I of the hydrobromide salt of compound ATV-014. [Figure 6] 1 shows an X-ray powder diffraction pattern of crystalline form I of p-toluenesulfonate of compound ATV-014. [Figure 7] 1 shows the X-ray powder diffraction pattern of crystalline form IV of the hydrochloride salt of compound ATV-014. [Figure 8] 1 shows the differential scanning calorimetry pattern and the thermogravimetry pattern of crystalline form I of the free base of compound ATV-014. [Figure 9] 1 shows the differential scanning calorimetry pattern and the thermogravimetry pattern of crystalline form I of the hydrochloride salt of compound ATV-014. [Figure 10] 1 shows the differential scanning calorimetry pattern and the thermogravimetry pattern of crystalline form II of the hydrochloride salt of compound ATV-014. [Figure 11] 1 shows the differential scanning calorimetry pattern and the thermogravimetry pattern of crystalline form III of the hydrochloride salt of compound ATV-014. [Figure 12] 1 shows the differential scanning calorimetry pattern and the thermogravimetry pattern of crystalline form I of the hydrobromide salt of compound ATV-014. [Figure 13] 1 shows a differential scanning calorimetry pattern and a thermogravimetric analysis pattern of crystalline form I of p-toluenesulfonate of compound ATV-014. [Figure 14] 1 shows the differential scanning calorimetry pattern and the thermogravimetry pattern of crystalline form IV of the hydrochloride salt of compound ATV-014. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0228] In order for people skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to illustrate the present invention in more detail. All reagents used in the present invention are either commercially available or prepared by the methods described herein.

[0229] Example 1 Preparation of Crystalline Form I of the Hydrochloride Salt of ATV-014 25mg of ATV-014 free base crystalline form I is weighed out, 1mL of THF is added to make a saturated solution, 1.0 equivalent of hydrochloric acid is added to the solution to make a salt, then 1mL of MTBE is added as an antisolvent to precipitate a solid, the resulting suspension is stirred at room temperature for 20 hours, the solid is filtered and collected, and dried in vacuum at 50℃ for 3 hours to obtain ATV-014 hydrochloride crystalline form I. The obtained ATV-014 hydrochloride crystalline form I is measured by X-ray powder diffraction, DSC and TGA, and its X-ray powder diffraction pattern is shown in Figure 2, and its DSC and TGA patterns are shown in Figure 9.

[0230] Example 2 Preparation of Crystalline Form II of the Hydrochloride Salt of ATV-014 0.16 mL of concentrated hydrochloric acid is diluted to 3 mL with IPA. 94 mg of the crystalline form I of the free base of ATV-014 is added to 1.02 mL of the HCl-IPA solution (1.05 equivalents) and stirred at room temperature for about 10 minutes to make the mixture viscous. Then, 0.5 mL of IPA is further added, the suspension is stirred at room temperature for 2 hours, then 1 mL of MTBE is added, stirred for another 2 hours, and filtered to collect the solid. The solid is washed with 3 mL of MTBE, and then vacuum dried at 50 °C for 3 hours to obtain the crystalline form II of the hydrochloride salt of ATV-014. The obtained crystalline form II of the hydrochloride salt of ATV-014 is taken and subjected to X-ray powder diffraction, DSC and TGA measurements. The X-ray powder diffraction pattern is shown in Figure 3, and the DSC and TGA patterns are shown in Figure 10.

[0231] Example 3 Preparation of Crystalline Form III of the Hydrochloride Salt of ATV-014 69mg of ATV-014 free base crystalline form I was suspended in 1mL of dichloromethane, the resulting suspension was stirred at room temperature for about 10 minutes, then 1.0 equivalent of concentrated hydrochloric acid was added, the mixture was stirred for another 2 hours, the solid was filtered, and dried in vacuum at 50°C for 3 hours to obtain ATV-014 hydrochloride crystalline form III. The obtained ATV-014 hydrochloride crystalline form III was taken and subjected to X-ray powder diffraction, DSC and TGA measurements, the X-ray powder diffraction pattern of which is shown in Figure 4, and the DSC and TGA patterns of which are shown in Figure 11.

[0232] Example 4 Preparation of Crystalline Form I of the Hydrobromide Salt of ATV-014 Approximately 500 mg of the free base crystalline form I is suspended in 15 mL of ethyl acetate, the resulting suspension is stirred at room temperature for 10 minutes, and then 1 equivalent of hydrobromic acid is added and stirred at room temperature for 2 hours. The solid is collected by filtration and then vacuum dried overnight at 50°C to obtain the crystalline form I of hydrobromic acid of ATV-014. The obtained crystalline form I of hydrobromic acid of ATV-014 is subjected to X-ray powder diffraction, DSC and TGA measurements, and its X-ray powder diffraction pattern is shown in Figure 5, and its DSC and TGA patterns are shown in Figure 12.

[0233] Example 5 Preparation of Crystalline Form I of p-Toluenesulfonate of ATV-014 Approximately 500 mg of the free base crystalline form I is suspended in 15 mL of isopropanol, and then 1 equivalent of p-toluenesulfonic acid solid is added, dissolving most of the solid. The suspension is stirred at room temperature for 2 hours, but no further solid precipitates. Seed crystals of p-toluenesulfonic acid salt are added, followed by stirring for 2 hours, and the solid is collected by filtration. The resulting solid is dried overnight at room temperature, and then vacuum dried at 40°C for 2 hours to obtain crystalline form I of p-toluenesulfonic acid salt of ATV-014. The obtained crystalline form I of p-toluenesulfonic acid salt of ATV-014 is subjected to X-ray powder diffraction, DSC and TGA measurements, and its X-ray powder diffraction pattern is shown in Figure 6, and its DSC and TGA patterns are shown in Figure 13.

[0234] Example 6 Preparation of Crystalline Form IV of the Hydrochloride Salt of ATV-014 ATV014 (1g, 2.5 mmol) and 5 mL of methanol (almost insoluble) are added to a 50 mL single-mouth bottle, and 4.0 M hydrochloric acid methanol solution (0.9 mL, 3.75 mmol) is added dropwise under ice bath conditions. After 2 minutes, the addition is completed and the solution becomes clear and transparent. 20 mL of MTBE is added directly to the residue, and the mixture is stirred at room temperature for 2 hours to form a large amount of white solid. The solid is suction filtered and dried in vacuum at 45 ° C to obtain 1 g of ATV014 hydrochloride. The obtained crystalline form IV of ATV-014 hydrochloride is taken and X-ray powder diffraction, DSC and TGA are measured. The X-ray powder diffraction pattern is shown in Figure 7, and the DSC and TGA patterns are shown in Figure 14.

[0235] Example 7 Preparation of Crystalline Form I of the Free Base of ATV-014 [ka] A 500 mL reactor was equipped with a stirrer, a thermometer, and a constant pressure dropping funnel. GS-441524 (10 g, 0.03 mol) was added, followed by acetone (300 mL) dried over magnesium sulfate, and then 2,2-dimethoxypropane (17 g, 0.16 mol). Concentrated sulfuric acid (2.4 mL, 0.04 mol) was added dropwise to the system at room temperature. After 5 minutes, the addition was complete and the solid began to dissolve. The temperature was raised to 45°C and the reaction was continued for 4 hours. The reaction was found to be complete by HPLC (OD-3 column, transfer column). Phase: n-hexane / isopropanol = 80:20, flow rate: 0.8mL / min, sample injection amount 1μL) was monitored and the reaction was stopped and cooled in an ice bath, after which NaHCO3 solid (10g) and water (30mL) were added to the reaction solution, followed by adjusting the pH to 7-8 with sodium bicarbonate, removing the solvent by vacuum distillation, diluting the residue with ethyl acetate (300mL), washing the ethyl acetate layer with water (80mL) and saturated aqueous sodium chloride solution (80mL) respectively, and drying with anhydrous sodium sulfate. Suction filtration was performed, and the filtrate was distilled under reduced pressure until about 100mL of solvent remained, and the residue was slowly added to petroleum ether cooled in an ice bath and stirred vigorously to wash out a large amount of white solid, and suction filtration was performed to obtain 10.5g of white solid compound 1, with a yield of 91%.

[0236] Dissolve 15.0 g of compound 1 in 15 ml of dichloromethane, add cyclohexane carboxylic acid and 554.0 mg of 4-dimethylaminopyridine, stir for 10 minutes, add 10.2 g of dicyclohexylcarbodiimide, and stir at room temperature for 24 hours. Separate by column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain compound 2 (white solid). Dissolve compound 2 in 30 mL of 37% by mass aqueous hydrochloric acid solution and 150 mL of tetrahydrofuran, stir for 6 hours, add sodium carbonate to adjust the pH to 8, remove the organic solvent by rotary evaporation, and separate by column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 3) to obtain compound 2.8 g of ATV014 (crystalline form I of the free base, yield 49%) in a two-step yield of 45.8%. The obtained crystalline form I of the free base of ATV-014 was subjected to X-ray powder diffraction, DSC and TGA measurements, and the X-ray powder diffraction pattern is shown in Figure 1, and the DSC and TGA patterns are shown in Figure 8. The hydrogen pattern and carbon pattern of the obtained compound ATV014 were measured, and the results are as follows: Hydrogen Pattern: 1 H NMR (600 MHz, DMSO-d 6) δ(ppm):7.92 (s,1H), 7.86(br,1H), 6.92(d,J=4.5Hz,1H), 6.81(d,J=4.5Hz,1H), 6.33(d,J=5.9Hz,1H), 5.38(d,J=5.9Hz ,1H), 4.70(t,J=5.3Hz,1H), 4.32-4.29(dd,J=12.2Hz,2.6Hz,1H), 4.24-4.21(m,1H), 4.16-4.13(dd,J=12.3 Hz,4.8Hz,1H), 3.98-3.95(q,J=5.9Hz,1H), 2.26-2.22(m, 1H), 1.75-1.72(m, 2H), 1.64-1.56(m, 3H), 1.30-1.12(m, 5H). Carbon Pattern: 13 C NMR (150 MHz, DMSO-d 6)δ(ppm):175.34,156.06,148.4,124.0,117.4,117.0,110.7,101.2,81.7,79.4,74.5,70.6,63.0,42.6,29.0,28.9,25.7,25.2,25.1.

[0237] Example 8 Stability study of influencing factors Crystal form I of the free base of ATV-014, crystal form I of the hydrobromide salt of ATV-014, and crystal form I of the p-toluenesulfonate salt of ATV-014 were taken and left to stand at 40°C / 75%RH (open) and 60°C (sample bottle with lid), respectively, for 7 days. Measurements of high performance liquid chromatography and X-ray powder diffraction were performed on the 0th and 7th days, respectively, and the results are shown in Table 4.

[0238] [Table 4] Conclusion: The results show that: the purity and crystal form of the compound of ATV-014 free base and the crystal form of ATV-014 p-toluenesulfonate salt were not changed after 7 days under the experimental conditions (60℃ and 40℃ / 75%RH), and the physical and chemical stability was good. The purity and crystal form of the compound of ATV-014 hydrobromide salt were not changed after 7 days under the experimental conditions (60℃), and the crystal form was not changed. The sample was liquefied after 7 days at 40℃ / 75%RH.

[0239] Example 9 Solubility Studies Based on the results of the salt formation screening study, the solubility of Form I of the free base and Form I of the p-toluenesulfonate salt was measured at 0.5 hours, 2 hours, and 24 hours in FaSSIF, FeSSIF, SGF, and water at 37° C. The solubility and solution pH results are shown in Table 5.

[0240] [Table 5]

[0241] As a result, the solubility of the sample was pH-dependent, with high solubility at low pH, and the lower the pH, the higher the solubility of the sample. The solubility of the crystalline form I of the p-toluenesulfonate salt of ATV-014 was higher than 5 mg / mL, and the solubility of the crystalline form I of the free base of ATV-014 in SGF was 2.5-2.9 mg / mL. The solubility of the p-toluenesulfonate salt of ATV-014 in water was 30 times higher than that of the free base.

[0242] Although the method of the present invention has been described in terms of the preferred embodiment, it is obvious that those skilled in the art can make modifications or suitable modifications and combinations to the methods and applications described herein within the content, spirit and scope of the present invention in order to implement and apply the technology of the present invention. Those skilled in the art can appropriately improve and realize the process parameters by referring to the content of the present specification. It should be noted that all similar replacements and modifications are obvious to those skilled in the art and are considered to be included in the present invention.

Claims

1. The crystalline form I of the hydrochloride salt of compound ATV014 shown below: 【Chemistry 1】 The X-ray powder diffraction pattern of the crystalline form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 15.53, and 20.76; Alternatively, the X-ray powder diffraction pattern of crystalline form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 10.33, 15.53, 20.76, 22.75 and 24.19; Alternatively, the X-ray powder diffraction pattern of the crystalline form I of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 10.33, 15.53, 20.76, 22.75, 23.88, 24.19 and 26.

01.

2. The X-ray powder diffraction pattern of the crystalline form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 15.53, and 20.76; In addition, the diffraction angle 2θ±0.2° has characteristic peaks at one, two or three positions among 10.33, 22.75 and 24.19, Alternatively, the X-ray powder diffraction pattern of crystalline form I of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.16, 10.33, 15.53, 20.76, 22.75 and 24.19; The hydrochloride crystalline form I of the compound ATV014 according to claim 1, characterized in that it has characteristic peaks at one or two of the diffraction angles 2θ±0.2° of 23.88 and 26.

01.

3. The X-ray powder diffraction pattern of the crystalline form I of the hydrochloride salt of the compound ATV-014 is essentially as shown in FIG. and / or the differential scanning calorimetry curve of the crystalline form I of the hydrochloride of the compound ATV-014 has an endothermic peak at 120°C-170°C, or the differential scanning calorimetry curve of the crystalline form I of the hydrochloride of the compound ATV-014 has an endothermic peak at 125°C-165°C, or the differential scanning calorimetry curve of the crystalline form I of the hydrochloride of the compound ATV-014 has an endothermic peak, and the peak value of the endothermic peak is 141°C-151°C or 143°C-149°C, or the differential scanning calorimetry curve of the crystalline form I of the hydrochloride of the compound ATV-014 is essentially the differential scanning calorimetry curve of FIG. and / or the thermogravimetric analysis curve of the crystalline form I of the hydrochloride of the compound ATV-014 according to claim 1, wherein the weight loss at 110°C-170°C is less than 10%, less than 9%, or less than 8%, or the thermogravimetric analysis curve of the crystalline form I of the hydrochloride of the compound ATV-014 is essentially as shown in the thermogravimetric analysis curve of FIG.

4. The crystalline form II of the hydrochloride salt of compound ATV014 shown below: 【Chemistry 2】 The X-ray powder diffraction pattern of the crystalline form II of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 10.43 and 18.79, or the X-ray powder diffraction pattern of the crystalline form II of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 9.88, 10.43, 14.05, 18.79 and 22.28, or the X-ray powder diffraction pattern of the crystalline form II of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38 ... The X-ray powder diffraction pattern of the crystalline form II of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, 21.38, 22.28, and 23.96, or the X-ray powder diffraction pattern of the crystalline form II of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, 21.38, 22.28, 22.81, 23.96, and 37.

05.

5. The X-ray powder diffraction pattern of the crystalline form II of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 10.43 and 18.79, and has characteristic peaks at one, two or three of diffraction angles 2θ±0.2° of 9.88, 14.05 and 22.28, or the X-ray powder diffraction pattern of the crystalline form II of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 10.43 and 18.79, and has characteristic peaks at diffraction angles 2θ±0.2° of 9.88, 14.05 and 22.28, and the X-ray powder diffraction pattern of the crystalline form II of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.23, 9.88, 10.43, 14.05, 18.79 and 22.28, and has characteristic peaks at one, two or three positions among 15.68, 19.46 and 21.38, or the X-ray powder diffraction pattern of the crystalline form II of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.2 and the X-ray powder diffraction pattern of the crystalline form II of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 17.81, 20.37, and 23.

96. The crystalline form II of the hydrochloride salt of the compound ATV014 according to claim 4, characterized in that it has characteristic peaks at 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, 21.38, 22.28 and 23.96, and also has characteristic peaks at one or two of the diffraction angles 2θ±0.2° of 22.81 and 37.

05.

6. The X-ray powder diffraction pattern of the crystalline form II of the hydrochloride salt of the compound ATV-014 is essentially as shown in FIG. and / or the differential scanning calorimetry curve of the crystalline form II of the hydrochloride of the compound ATV-014 has an endothermic peak at 100°C-150°C, or the differential scanning calorimetry curve of the crystalline form II of the hydrochloride of the compound ATV-014 has an endothermic peak, and the peak value of the endothermic peak is 135°C-145°C or 136°C-143°C; Alternatively, the differential scanning calorimetry curve of the crystalline form II of the hydrochloride of the compound ATV-014 is basically shown as the differential scanning calorimetry curve in FIG. 10; and / or the thermogravimetric analysis curve of the crystalline form II of the hydrochloride salt of the compound ATV-014 shows a weight loss of less than 10% or less than 8% at 70°C-170°C; Or the crystalline form II of the hydrochloride of the compound ATV-014 according to claim 4, characterized in that the thermogravimetric analysis curve of the crystalline form II of the hydrochloride of the compound ATV-014 is essentially as shown in FIG.

10.

7. The following compound ATV014, hydrochloride salt, crystalline form III: 【Chemistry 3】 The X-ray powder diffraction pattern of the crystalline form III of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 14.03, and 18.99, or the X-ray powder diffraction pattern of the crystalline form III of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 10.54, 14.03, 15.84, 18.99, and 21.16, or the X-ray powder diffraction pattern of the crystalline form III of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 10.54, 14.03, 15.84, 17.67, 18.99, 21.16, 22.49, and 27.

51.

8. The crystalline form III of the hydrochloride of the compound ATV-014 according to claim 7, characterized in that the X-ray powder diffraction pattern of the crystalline form III of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 14.03, and 18.99, and has characteristic peaks at one, two, or three positions among 10.54, 15.84, and 21.16, or the X-ray powder diffraction pattern of the crystalline form III of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 10.54, 14.03, 15.84, 18.99, and 21.16, and has characteristic peaks at diffraction angles 2θ±0.2° of 17.67, 22.49, and 27.

51.

9. The X-ray powder diffraction pattern of the crystalline form III of the hydrochloride salt of the compound ATV-014 is essentially as shown in FIG. and / or the differential scanning calorimetry curve of the crystalline form III of the hydrochloride of the compound ATV-014 has an endothermic peak at 90°C-170°C, or the differential scanning calorimetry curve of the crystalline form III of the hydrochloride of the compound ATV-014 has an endothermic peak at 125°C-170°C, or the differential scanning calorimetry curve of the crystalline form III of the hydrochloride of the compound ATV-014 has an endothermic peak, the peak value of the endothermic peak being 130°C-138°C, or the differential scanning calorimetry curve of the crystalline form III of the hydrochloride of the compound ATV-014 is essentially as shown in the differential scanning calorimetry curve of FIG. and / or the thermogravimetric analysis curve of the crystalline form III of the hydrochloride salt of the compound ATV-014 shows a weight loss of less than 10% or less than 9% at 70°C-170°C; Alternatively, the crystalline form III of the hydrochloride of the compound ATV-014 according to claim 7, characterized in that the thermogravimetric analysis curve of the crystalline form III of the hydrochloride of the compound ATV-014 is essentially as shown in FIG.

11.

10. The crystalline form IV of the hydrochloride salt of compound ATV014 shown below: 【Chemistry 4】 The X-ray powder diffraction pattern of the crystalline form IV of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 10.63 and 19.13, or the X-ray powder diffraction pattern of the crystalline form IV of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 9.63, 10.63, 14.10, 16.82 and 19.13, or the X-ray powder diffraction pattern of the crystalline form IV of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5. or the X-ray powder diffraction pattern of the crystalline form IV of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, 19.13, 22.27, 23.19, and 27.

74.

11. The X-ray powder diffraction pattern of the crystalline form IV of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 10.63, and 19.13, and has characteristic peaks at one, two, or three of diffraction angles 2θ±0.2° of 9.63, 14.10, and 16.82, or the X-ray powder diffraction pattern of the crystalline form IV of the hydrochloride of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 9.63, 10.63, 14.10, 16.82, and 19.13, and has characteristic peaks at diffraction angles 2θ±0.2° of 10.19, 1 The crystalline form IV of the hydrochloride salt of the compound ATV-014 according to claim 10, characterized in that the X-ray powder diffraction pattern of the crystalline form IV of the hydrochloride salt of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62 and 19.13, and has characteristic peaks at diffraction angles 2θ±0.2° of 22.27, 23.19 and 27.

74.

12. The X-ray powder diffraction pattern of the crystalline form IV of the hydrochloride salt of the compound ATV-014 is essentially as shown in FIG. and / or the differential scanning calorimetry curve of the crystalline form IV of the hydrochloride of the compound ATV-014 has an endothermic peak at 180°C-200°C, or the differential scanning calorimetry curve of the crystalline form IV of the hydrochloride of the compound ATV-014 has an endothermic peak, and the peak value of the endothermic peak is 183°C-190°C, or the differential scanning calorimetry curve of the crystalline form IV of the hydrochloride of the compound ATV-014 is essentially as shown in the differential scanning calorimetry curve of FIG. and / or the thermogravimetric analysis curve of the crystalline form IV of the hydrochloride salt of the compound ATV-014 shows a weight loss of less than 2%, or less than 1%, or less than 0.5%, or less than 0.2% at 30°C-150°C; Alternatively, the crystalline form IV of the hydrochloride of the compound ATV-014 according to claim 10, characterized in that the thermogravimetric analysis curve of the crystalline form IV of the hydrochloride of the compound ATV-014 is essentially as shown in FIG.

12.

13. The crystalline form I of the hydrobromide salt of compound ATV014 shown below: 【Chemistry 5】 The X-ray powder diffraction pattern of the crystalline form I of the hydrobromide of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 3.78, 13.20, and 16.88, or the X-ray powder diffraction pattern of the crystalline form I of the hydrobromide of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 3.78, 13.20, 15.41, 16.88, 17.46, and 26.38, or the X-ray powder diffraction pattern of the crystalline form I of the hydrobromide of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 3.78, 13.20, 15.41, 16.88, 17.46, 25.52, 26.38, and 26.

79.

14. The crystalline form I of the hydrobromide salt of the compound ATV-014 according to claim 13, characterized in that the X-ray powder diffraction pattern of the crystalline form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at diffraction angles of 3.78, 13.20, and 16.88 at 2θ±0.2° and one, two, or three of 15.41, 17.46, and 26.38 at 2θ±0.2°, or the X-ray powder diffraction pattern of the crystalline form I of the hydrobromide salt of the compound ATV-014 has characteristic peaks at diffraction angles of 3.78, 13.20, 15.41, 16.88, 17.46, and 26.38 at 2θ±0.2° and one or two of 25.52 and 26.79 at 2θ±0.2°.

15. The X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of compound ATV-014 is approximately shown in FIG. and / or the differential scanning calorimetry curve of the crystalline form I of the hydrobromide salt of the compound ATV-014 has an endothermic peak at 130°C-170°C, or the differential scanning calorimetry curve of the crystalline form I of the hydrobromide salt of the compound ATV-014 has an endothermic peak, and the peak value of the endothermic peak is 138°C-145°C, or the differential scanning calorimetry curve of the crystalline form I of the hydrobromide salt of the compound ATV-014 is essentially the differential scanning calorimetry curve of FIG. 14; and / or the thermogravimetric analysis curve of the crystalline form I of the hydrobromide salt of the compound ATV-014 shows a weight loss of less than 2% or less than 1.5% at 100°C-160°C; Alternatively, the crystalline form I of the hydrobromide salt of the compound ATV-014 according to claim 13, characterized in that the thermogravimetric analysis curve of the crystalline form I of the hydrobromide salt of the compound ATV-014 is essentially the thermogravimetric analysis curve shown in FIG.

14.

16. The crystalline form I of p-toluenesulfonate of compound ATV014 shown below: 【Chemistry 6】 The X-ray powder diffraction pattern of the crystalline form I of p-toluenesulfonate of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 3.58, 10.89, and 16.59, or the X-ray powder diffraction pattern of the crystalline form I of p-toluenesulfonate of the compound ATV-014 has characteristic peaks at diffraction angles 2θ±0.2° of 3.58, 7.23, 10.89, 14.59, and 16.

59.

17. The X-ray powder diffraction pattern of crystalline Form I of the p-toluenesulfonate salt of the compound ATV-014 is approximately shown in FIG. and / or the differential scanning calorimetry curve of the crystalline form I of p-toluenesulfonate of the compound ATV-014 has an endothermic peak at 100°C-140°C, or the differential scanning calorimetry curve of the crystalline form I of p-toluenesulfonate of the compound ATV-014 has an endothermic peak, and the peak value of the endothermic peak is 120°C-127°C, or the differential scanning calorimetry curve of the crystalline form I of p-toluenesulfonate of the compound ATV-014 is essentially the differential scanning calorimetry curve of FIG. 13; and / or the thermogravimetric analysis curve of the crystalline form I of the p-toluenesulfonate salt of the compound ATV-014 shows a weight loss of less than 10%, less than 5%, or less than 4% at 60°C to 150°C; and / or the thermogravimetric analysis curve of the crystalline form I of p-toluenesulfonate of the compound ATV-014 is essentially as shown in FIG.

13.

18. 1. A pharmaceutical composition comprising: A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form I of the hydrochloride of the compound ATV-014 according to any one of claims 1 to 3, a therapeutically effective amount of the crystalline form II of the hydrochloride of the compound ATV-014 according to any one of claims 4 to 6, a therapeutically effective amount of the crystalline form III of the hydrochloride of the compound ATV-014 according to any one of claims 7 to 9, a therapeutically effective amount of the crystalline form IV of the hydrochloride of the compound ATV-014 according to any one of claims 10 to 12, a therapeutically effective amount of the crystalline form I of the hydrobromide of the compound ATV-014 according to any one of claims 13 to 15, or a therapeutically effective amount of the crystalline form I of the p-toluenesulfonate of the compound ATV-014 according to any one of claims 16 to 17, and optionally a pharma- ceutical acceptable excipient.

19. Use of the crystalline form I of the hydrochloride salt of compound ATV-014 according to any one of claims 1 to 3, the crystalline form II of the hydrochloride salt of compound ATV-014 according to any one of claims 4 to 6, the crystalline form III of the hydrochloride salt of compound ATV-014 according to any one of claims 7 to 9, the crystalline form IV of the hydrochloride salt of compound ATV-014 according to any one of claims 10 to 12, the crystalline form I of the hydrobromide salt of compound ATV-014 according to any one of claims 13 to 15, the crystalline form I of the p-toluenesulfonate salt of compound ATV-014 according to any one of claims 16 to 17, or the pharmaceutical composition according to claim 18, in the manufacture of a medicament for the prevention, alleviation and / or treatment of a disease or condition associated with a viral infection.

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