WO2023115796A1 - 一种核苷类化合物及其盐的新晶型 - Google Patents

一种核苷类化合物及其盐的新晶型 Download PDF

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WO2023115796A1
WO2023115796A1 PCT/CN2022/093342 CN2022093342W WO2023115796A1 WO 2023115796 A1 WO2023115796 A1 WO 2023115796A1 CN 2022093342 W CN2022093342 W CN 2022093342W WO 2023115796 A1 WO2023115796 A1 WO 2023115796A1
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crystal form
compound
atv
hydrochloride
characteristic peaks
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PCT/CN2022/093342
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English (en)
French (fr)
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李硕
李官官
刘新军
李迎君
周启璠
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深圳安泰维生物医药有限公司
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Publication of WO2023115796A1 publication Critical patent/WO2023115796A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the technical field of medicine and relates to a new crystal form of nucleoside compounds and salts thereof.
  • the new coronavirus is an enveloped single-stranded RNA virus belonging to the genus Betacoronavirus. Similar to SARS and MERS, the SARS-CoV-2 genome encodes non-structural proteins: 3C-like protease (3-chymotrypsin-like protease, 3CLpro), papain-like protease (papain-like protease, PLpro), helicase (helicase) and RNA-dependent RNA polymerase (RNA-dependent RNA polymerase, RdRp); structural proteins: such as spike glycoprotein and accessory proteins.
  • 3C-like protease 3-chymotrypsin-like protease, 3CLpro
  • papain-like protease papain-like protease
  • PLpro helicase
  • RNA-dependent RNA polymerase RNA-dependent RNA polymerase
  • the surface spike glycoprotein of the new coronavirus binds to the angiotensin-converting enzyme (ACE2) receptor on the surface of human cells to infect human respiratory epithelial cells. After the virus enters the host cell, it disintegrates and releases the nucleocapsid and viral RNA into the cytoplasm.
  • the open reading frame (ORF 1a/b) at the 5′ end of the viral RNA will encode polyproteins (pp1a and pp1ab), which are essential for viral replication. Enzyme processing and maturation play an important role.
  • pp1a and pp1ab can be cleaved by papain-like protease (PLpro) and 3C-like protease (3CLpro) to produce non-structural proteins, including RNA-dependent RNA polymerase and helicase, which play a key role in the transcription and replication of the new coronavirus role.
  • PLpro papain-like protease
  • 3CLpro 3C-like protease
  • the compound represented by the formula ATV014 is a derivative of the compound GS-441524.
  • Drug polymorphism is a common phenomenon in drug research and development, and is an important factor affecting drug quality.
  • Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, and bioavailability, and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug etc. have different effects; in order to obtain effective crystal forms that are beneficial to production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of drugs to obtain crystal forms that meet production requirements.
  • the present invention has obtained a new crystal form of the compound and its salt through a large number of experimental studies on the compound ATV014.
  • the new crystal form has good stability, is stable under high-temperature and high-humidity conditions under light, and the preparation process is simple and easy to operate. It is superior in industrial production.
  • Research on the new crystal form of compound ATV014 provides an opportunity to improve the overall performance of the pharmaceutical product (such as ease of synthesis or handling, improved dissolution rate, or improved stability and shelf life), while expanding the variety of materials available to formulation scientists when designing the drug , which is crucial for drug development.
  • an object of the present invention is to provide a new crystal form of the compound ATV014 free base and its salt and its preparation method.
  • the present invention focuses on whether the compound ATV014 has multiple solid forms.
  • the compound ATV014 has multiple A stable solid form, including: ATV-014 free base crystal form I, ATV-014 hydrochloride salt crystal form I, ATV-014 hydrochloride salt crystal form II, ATV-014 hydrochloride salt crystal form III, ATV-014 Hydrochloride salt form IV, ATV-014 hydrobromide salt form I, ATV-014 p-toluenesulfonate form I.
  • the structure of the compound ATV014 is as follows:
  • the new crystal form of the compound ATV014 free base and its salt provided by the present invention has good solubility and thermal stability, and has better bioavailability and dissolution curve in specific preparations; its good permeability and thermal stability Suitable for use in specific pharmaceutical preparations.
  • the present invention provides the following technical solutions.
  • a crystal form of compound ATV-014 free base or a salt thereof is provided.
  • the present invention provides: compound ATV-014 free base crystal form I, compound ATV-014 hydrochloride crystal form I, compound ATV-014 hydrochloride crystal form II, compound ATV-014 hydrochloride Salt crystal form III, compound ATV-014 hydrochloride salt crystal form IV, compound ATV-014 hydrobromide salt crystal form I, compound ATV-014 p-toluenesulfonate salt crystal form I.
  • compound ATV-014 free base crystal form I is provided, wherein the free base crystal form I is an anhydrous substance.
  • the compound ATV-014 free base crystalline form I has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 1 .
  • the compound ATV-014 free base crystalline form I has a differential scanning calorimetry curve (DSC) substantially as shown in FIG. 8 .
  • the compound ATV-014 free base crystal form I has a thermogravimetric analysis curve (TGA) substantially as shown in FIG. 8 .
  • At least one, at least two, or all of the following (a)-(c) of the compound ATV-014 free base crystal form I are applicable: (a) the crystal form I has basically The shown X-ray powder diffraction pattern (XRPD pattern); (b) the differential scanning calorimetry curve (DSC) that crystal form I has is basically as shown in Figure 8; (c) the thermogravimetric analysis curve that crystal form I has (TGA) is basically as shown in FIG. 8 .
  • the compound ATV-014 free base crystal form I has the following properties:
  • Form I has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in Figure 1;
  • Form I has a differential scanning calorimetry curve (DSC) substantially as shown in Figure 8.
  • thermogravimetric analysis curve (TGA) of the crystal form I is basically as shown in FIG. 8 .
  • the compound ATV-014 free base crystalline form I has an XRPD pattern showing at least 2, at least 3, at least 4, at least 5 or at least 6 reflections in 2 ⁇ degrees, the maximum intensity of which is the same as that of XRPD The pattern is roughly shown in Figure 1.
  • the differential scanning calorimetry curve of the free base crystal form I of the compound ATV-014 has an endothermic peak at 225°C-228°C.
  • thermogravimetric analysis curve of the free base crystal form I of the compound ATV-014 has a weight loss of less than 0.5% in the temperature range of 100°C-200°C.
  • the X-ray powder diffraction pattern of the free base crystal form I of the compound ATV-014 has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 9.69, 18.70 and 23.88.
  • the X-ray powder diffraction pattern of the free base crystal form I of the compound ATV-014 has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 9.69, 18.70 and 23.88, and at diffraction angles 2 ⁇ 0.2° of There are characteristic peaks at 1, 2 or 3 of 9.84, 17.74 and 19.38.
  • the X-ray powder diffraction pattern of the free base crystal form I of the compound ATV-014 has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 9.69, 18.70 and 23.88, and at diffraction angles 2 ⁇ 0.2° of One or two of 9.84, 17.74 and 19.38 have characteristic peaks.
  • the X-ray powder diffraction pattern of the free base crystal form I of the compound ATV-014 has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 9.69, 18.70 and 23.88, and at diffraction angles 2 ⁇ 0.2° of One of 9.84, 17.74 and 19.38 has a characteristic peak.
  • the X-ray powder diffraction pattern of the free base crystal form I of the compound ATV-014 has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 9.69, 18.70 and 23.88, and at diffraction angles 2 ⁇ 0.2° of Two of 9.84, 17.74 and 19.38 have characteristic peaks.
  • the X-ray powder diffraction pattern of the free base crystal form I of the compound ATV-014 has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 9.69, 9.84, 17.74, 18.70, 19.38 and 23.88.
  • the X-ray powder diffraction pattern of the free base crystal form I of the compound ATV-014 has characteristic peaks at least three of the diffraction angles 2 ⁇ 0.2° of 9.69, 9.84, 17.74, 18.70, 19.38 and 23.88 .
  • the X-ray powder diffraction pattern of the compound ATV-014 free base crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 9.69, 9.84, 17.74, 18.70, 19.38 and 23.88, and in the diffraction Angle 2 ⁇ 0.2° is one of 13.19, 15.61 and 21.31, and there are characteristic peaks at 2 or 3.
  • the X-ray powder diffraction pattern of the compound ATV-014 free base crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 9.69, 9.84, 17.74, 18.70, 19.38 and 23.88, and in the diffraction Angle 2 ⁇ 0.2° has characteristic peaks at 1 or 2 of 13.19, 15.61 and 21.31.
  • the X-ray powder diffraction pattern of the compound ATV-014 free base crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 9.69, 9.84, 17.74, 18.70, 19.38 and 23.88, and in the diffraction There is a characteristic peak at one of the angles 2 ⁇ 0.2° at 13.19, 15.61 and 21.31.
  • the X-ray powder diffraction pattern of the compound ATV-014 free base crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 9.69, 9.84, 17.74, 18.70, 19.38 and 23.88, and in the diffraction Two of the angles 2 ⁇ 0.2° are 13.19, 15.61 and 21.31 have characteristic peaks.
  • the X-ray powder diffraction pattern of the free base crystal form I of the compound ATV-014 has: Characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 free base crystal form I is 9.69, 9.84, 13.91, 15.61, 17.74, 18.70, 19.38, 21.31 and 23.88 at diffraction angles 2 ⁇ 0.2° There are at least three characteristic peaks.
  • the X-ray powder diffraction pattern of the free base crystal form I of the compound ATV-014 has: There are characteristic peaks, and there are characteristic peaks at one or two of the diffraction angles 2 ⁇ 0.2° of 17.41 and 26.01.
  • the X-ray powder diffraction pattern of the free base crystal form I of the compound ATV-014 has: There are characteristic peaks, and there is a characteristic peak at 1 of 17.41 and 26.01 at the diffraction angle 2 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the compound ATV-014 free base crystal form I is 9.69, 9.84, 13.91, 15.61, 17.41, 17.74, 18.70, 19.38, 21.31, 23.88 at the diffraction angle 2 ⁇ 0.2° And there are characteristic peaks at 26.01.
  • the X-ray powder diffraction pattern of the compound ATV-014 free base crystal form I is 9.69, 9.84, 13.91, 15.61, 17.41, 17.74, 18.70, 19.38, 21.31, 23.88 at the diffraction angle 2 ⁇ 0.2° and 26.01 have at least three characteristic peaks.
  • compound ATV-014 hydrochloride salt form I is provided, wherein the hydrochloride salt form I is a solvate.
  • the hydrochloride salt form I has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 2 .
  • the hydrochloride salt form I has a differential scanning calorimetry curve (DSC) substantially as shown in the differential scanning calorimetry curve in FIG. 9 .
  • DSC differential scanning calorimetry curve
  • the hydrochloride salt form I has a thermogravimetric analysis curve (TGA) substantially as shown in the thermogravimetric analysis curve in FIG. 9 .
  • At least one, at least two, or all of the following (a)-(c) of the compound ATV-014 hydrochloride crystal form I are applicable: (a) crystal form I has basically The X-ray powder diffraction pattern (XRPD pattern) shown in 2; (b) the differential scanning calorimetry curve (DSC) that crystal form I has is basically as shown in the differential scanning calorimetry curve in Fig. 9; (c) crystal form I Form I has a thermogravimetric analysis curve (TGA) substantially as shown in the thermogravimetric analysis curve in FIG. 9 .
  • XRPD pattern X-ray powder diffraction pattern
  • DSC differential scanning calorimetry curve
  • TGA thermogravimetric analysis curve
  • the compound ATV-014 hydrochloride crystal form I has the following properties:
  • Form I has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in Figure 2;
  • Form I has a differential scanning calorimetry curve (DSC) substantially as shown in the differential scanning calorimetry curve in Figure 9;
  • thermogravimetric analysis curve (TGA) of crystal form I is basically as shown in the thermogravimetric analysis curve in FIG. 9 .
  • the compound ATV-014 hydrochloride salt form I has an XRPD pattern showing at least 2, at least 3, at least 4, at least 5 or at least 6 reflections in 2 ⁇ degrees, the maximum intensity of which is the same as The XRPD pattern is roughly shown in Figure 2.
  • the differential scanning calorimetry curve of the compound ATV-014 hydrochloride crystal form I has an endothermic peak at 120°C-170°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form I of the compound ATV-014 hydrochloride has an endothermic peak at 125°C-165°C. In some embodiments, the differential scanning calorimetry curve of the compound ATV-014 hydrochloride salt form I 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 compound ATV-014 hydrochloride is substantially as shown in the differential scanning calorimetry curve in FIG. 9 .
  • the differential scanning calorimetry curve of the compound ATV-014 hydrochloride crystal form I shows that its melting point is 136.55 ⁇ 5°C.
  • the differential scanning calorimetry curve of the compound ATV-014 hydrochloride crystal form I has an endothermic peak at 137°C-146°C, and the enthalpy value is 81J/g, which is a combination of desolvation melting peak.
  • the weight loss of the compound ATV-014 hydrochloride crystal form I thermogravimetric analysis curve at 110°C-170°C is less than 10%, or less than 9%, or less than 8%. In some embodiments, the weight loss in the temperature range of 110°C-170°C in the thermogravimetric analysis curve of the compound ATV-014 hydrochloride crystal form I is less than 7.1%.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride salt form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.16, 15.53 and 20.76.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.16, 15.53 and 20.76, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 1, 2 or 3 of 10.33, 22.75 and 24.19.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.16, 15.53 and 20.76, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 1 or 2 of 10.33, 22.75 and 24.19.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.16, 15.53 and 20.76, and at diffraction angles 2 ⁇ 0.2°
  • One of 10.33, 22.75 and 24.19 has a characteristic peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.16, 15.53 and 20.76, and at diffraction angles 2 ⁇ 0.2° There are two characteristic peaks in 10.33, 22.75 and 24.19.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride salt form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.16, 10.33, 15.53, 20.76, 22.75 and 24.19.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form I has at least three features in the diffraction angle 2 ⁇ 0.2° of 5.16, 10.33, 15.53, 20.76, 22.75 and 24.19 peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.16, 10.33, 15.53, 20.76, 22.75 and 24.19, and at The diffraction angle 2 ⁇ 0.2° has characteristic peaks at one or two of 23.88 and 26.01.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.16, 10.33, 15.53, 20.76, 22.75 and 24.19, and at One of the diffraction angles 2 ⁇ 0.2° is 23.88 and 26.01 has a characteristic peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form I has characteristics at diffraction angles 2 ⁇ 0.2° of 5.16, 10.33, 15.53, 20.76, 22.75, 23.88, 24.19 and 26.01 peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form I is at least one of 5.16, 10.33, 15.53, 20.76, 22.75, 23.88, 24.19 and 26.01 at a diffraction angle 2 ⁇ 0.2° There are three characteristic peaks.
  • compound ATV-014 hydrochloride salt form II is provided, wherein the hydrochloride salt form II is a solvate/hydrate.
  • the hydrochloride salt form II has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 3 .
  • the hydrochloride salt form II has a differential scanning calorimetry curve (DSC) substantially as shown in the differential scanning calorimetry curve in FIG. 10 .
  • DSC differential scanning calorimetry curve
  • the hydrochloride salt form II has a thermogravimetric analysis curve (TGA) substantially as shown in FIG. 10 .
  • At least one, at least two, or all of the following (a)-(c) of the compound ATV-014 hydrochloride crystal form II are applicable: (a) crystal form II has basically The X-ray powder diffraction pattern (XRPD pattern) shown in 3; (b) the differential scanning calorimetry curve (DSC) that crystal form II has is basically as shown in the differential scanning calorimetry curve in Fig. 10; (c) crystal form II Form II has a thermogravimetric analysis curve (TGA) substantially as shown in the thermogravimetric analysis curve in FIG. 10 .
  • XRPD pattern X-ray powder diffraction pattern
  • DSC differential scanning calorimetry curve
  • TGA thermogravimetric analysis curve
  • the compound ATV-014 hydrochloride crystal form II has the following properties:
  • Form II has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in Figure 3;
  • Form II has a differential scanning calorimetry curve (DSC) substantially as shown in the differential scanning calorimetry curve in Figure 10;
  • thermogravimetric analysis curve (TGA) of crystal form II is basically as shown in the thermogravimetric analysis curve in FIG. 10 .
  • the compound ATV-014 hydrochloride salt form II has an XRPD pattern showing at least 2, at least 3, at least 4, at least 5 or at least 6 2 ⁇ reflections, the maximum intensity of which is the same as The XRPD pattern is roughly as shown in FIG. 3 .
  • the differential scanning calorimetry curve of the compound ATV-014 hydrochloride crystal form II has an endothermic peak at 100°C-150°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form II of the compound ATV-014 hydrochloride has an endothermic peak, and 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 compound ATV-014 hydrochloride has an endothermic peak, and the peak value of the endothermic peak is 136°C-143°C. In some embodiments, the differential scanning calorimetry curve of the compound ATV-014 hydrochloride salt form II is substantially as shown in the differential scanning calorimetry curve in FIG. 10 .
  • the differential scanning calorimetry curve of the crystalline form II of the compound ATV-014 hydrochloride shows that its melting point is 126.75 ⁇ 5°C.
  • the weight loss of the compound ATV-014 hydrochloride salt form II thermogravimetric analysis curve at 70°C-170°C is less than 10%. In some embodiments, the weight loss of the compound ATV-014 hydrochloride salt form II thermogravimetric analysis curve at 70°C-170°C is less than 8%. In some embodiments, the weight loss at 70-170°C in the thermogravimetric analysis curve of the compound ATV-014 hydrochloride crystal form II is less than 5.6%.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride salt form II has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.23, 10.43 and 18.79.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.23, 10.43 and 18.79, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 1, 2 or 3 of 9.88, 14.05 and 22.28.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.23, 10.43 and 18.79, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 1 or 2 of 9.88, 14.05 and 22.28.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.23, 10.43 and 18.79, and at diffraction angles 2 ⁇ 0.2° One of 9.88, 14.05 and 22.28 has a characteristic peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.23, 10.43 and 18.79, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 2 of 9.88, 14.05 and 22.28.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.23, 9.88, 10.43, 14.05, 18.79 and 22.28.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II has at least three features in the diffraction angle 2 ⁇ 0.2° of 5.23, 9.88, 10.43, 14.05, 18.79 and 22.28 peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.23, 9.88, 10.43, 14.05, 18.79 and 22.28, and at The diffraction angle 2 ⁇ 0.2° is one of 15.68, 19.46 and 21.38, and there are characteristic peaks at 2 or 3.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.23, 9.88, 10.43, 14.05, 18.79 and 22.28, and at There are characteristic peaks at one or two of the diffraction angles 2 ⁇ 0.2° at 15.68, 19.46 and 21.38.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.23, 9.88, 10.43, 14.05, 18.79 and 22.28, and at One of the diffraction angles 2 ⁇ 0.2° at 15.68, 19.46 and 21.38 has a characteristic peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.23, 9.88, 10.43, 14.05, 18.79 and 22.28, and at Two of the diffraction angles 2 ⁇ 0.2° are 15.68, 19.46 and 21.38 have characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II is at diffraction angles 2 ⁇ 0.2° of 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38 and 22.28 have characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride salt form II is 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38 and 22.28 at diffraction angles 2 ⁇ 0.2° There are at least three characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II is 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38 and 22.28 at the diffraction angle 2 ⁇ 0.2°, And there are characteristic peaks at 1, 2 or 3 of the diffraction angles 2 ⁇ 0.2° of 17.81, 20.37 and 23.96.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II is at diffraction angles 2 ⁇ 0.2° of 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38 and 22.28 There are characteristic peaks, and there are characteristic peaks at one or two of the diffraction angles 2 ⁇ 0.2° of 17.81, 20.37 and 23.96.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II is at diffraction angles 2 ⁇ 0.2° of 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38 and 22.28 There are characteristic peaks, and there are characteristic peaks at 2 of the diffraction angles 2 ⁇ 0.2° of 17.81, 20.37 and 23.96.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II is at diffraction angles 2 ⁇ 0.2° of 5.23, 9.88, 10.43, 14.05, 15.68, 18.79, 19.46, 21.38 and 22.28 There are characteristic peaks, and there are characteristic peaks at one of the diffraction angles 2 ⁇ 0.2° of 17.81, 20.37 and 23.96.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II is 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, There are characteristic peaks at 21.38, 22.28 and 23.96.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II is 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, At least three of 21.38, 22.28 and 23.96 have characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II is 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, There are characteristic peaks at 21.38, 22.28 and 23.96, and there are characteristic peaks at one or two of 22.81 and 37.05 where the diffraction angle 2 ⁇ 0.2° is.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II is 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, There are characteristic peaks at 21.38, 22.28 and 23.96, and there is a characteristic peak at one of 22.81 and 37.05 where the diffraction angle 2 ⁇ 0.2° is.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II is 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, There are characteristic peaks at 21.38, 22.28, 22.81, 23.96 and 37.05.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form II is 5.23, 9.88, 10.43, 14.05, 15.68, 17.81, 18.79, 19.46, 20.37, At least three of 21.38, 22.28, 22.81, 23.96 and 37.05 have characteristic peaks.
  • compound ATV-014 hydrochloride salt form III is provided, wherein the hydrochloride salt form III is a solvate.
  • the hydrochloride salt form III has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 4 .
  • the hydrochloride salt form III has a differential scanning calorimetry curve (DSC) substantially as shown in the differential scanning calorimetry curve in FIG. 11 .
  • DSC differential scanning calorimetry curve
  • the hydrochloride salt form III has a thermogravimetric analysis curve (TGA) substantially as shown in FIG. 11 .
  • At least one, at least two, or all of the following (a)-(c) of the compound ATV-014 hydrochloride crystal form III are applicable: (a) crystal form III has basically The X-ray powder diffraction pattern (XRPD pattern) shown in 4; (b) the differential scanning calorimetry curve (DSC) that crystal form III has is basically as shown in the differential scanning calorimetry curve in Fig. 11; (c) crystal form III Form III has a thermogravimetric analysis curve (TGA) substantially as shown in the thermogravimetric analysis curve in FIG. 11 .
  • XRPD pattern X-ray powder diffraction pattern
  • DSC differential scanning calorimetry curve
  • TGA thermogravimetric analysis curve
  • the compound ATV-014 hydrochloride salt form III has the following properties:
  • Form III has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in Figure 4;
  • Form III has a differential scanning calorimetry curve (DSC) substantially as shown in the differential scanning calorimetry curve in Figure 11;
  • thermogravimetric analysis curve (TGA) of crystal form III is basically as shown in the thermogravimetric analysis curve in FIG. 11 .
  • the compound ATV-014 hydrochloride salt form III has an XRPD pattern showing at least 2, at least 3, at least 4, at least 5 or at least 6 reflections in 2 ⁇ degrees, the maximum intensity of which is the same as The XRPD pattern is roughly as shown in FIG. 4 .
  • the differential scanning calorimetry curve of the compound ATV-014 hydrochloride crystal form III has an endothermic peak at 90°C-170°C. In some embodiments, the differential scanning calorimetry curve of the hydrochloride salt form III has an endothermic peak at 125°C-170°C. In some embodiments, the differential scanning calorimetry curve of the hydrochloride salt form III has an endothermic peak at 90°C-125°C, and the endothermic peak is a desolvation peak. In some embodiments, the differential scanning calorimetry curve of the hydrochloride salt form III has an endothermic peak, and the peak value of the endothermic peak is 101°C-120 and/or 130°C-138°C. In some embodiments, the differential scanning calorimetry curve of the hydrochloride salt form III is substantially as shown in the differential scanning calorimetry curve in FIG. 11 .
  • the differential scanning calorimetry curve of the hydrochloride salt form III shows that its melting point is 134.32 ⁇ 5°C.
  • the weight loss of the thermogravimetric analysis curve of the hydrochloride salt form III at 70°C-170°C is less than 10% or less than 9%. In some embodiments, the weight loss in the temperature range of 70-170° C. in the thermogravimetric analysis curve of the compound ATV-014 hydrochloride crystal form III is less than 8.6%. In some embodiments, the thermogravimetric analysis curve of the hydrochloride salt form III is substantially as shown in the thermogravimetric analysis curve in FIG. 11 .
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride salt form III has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 14.03 and 18.99.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.28, 14.03 and 18.99, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 1, 2 or 3 of 10.54, 15.84 and 21.16.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.28, 14.03 and 18.99, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 1 or 2 of 10.54, 15.84 and 21.16.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.28, 14.03 and 18.99, and at diffraction angles 2 ⁇ 0.2°
  • One of 10.54, 15.84 and 21.16 has a characteristic peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.28, 14.03 and 18.99, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 2 of 10.54, 15.84 and 21.16.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 10.54, 14.03, 15.84, 18.99 and 21.16.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III has at least three features in the diffraction angle 2 ⁇ 0.2° of 5.28, 10.54, 14.03, 15.84, 18.99 and 21.16 peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 10.54, 14.03, 15.84, 18.99 and 21.16, and at The diffraction angle 2 ⁇ 0.2° is 1 of 17.67, 22.49 and 27.51, and there are characteristic peaks at 2 or 3.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 10.54, 14.03, 15.84, 18.99 and 21.16, and at The diffraction angle 2 ⁇ 0.2° has characteristic peaks at one or two of 17.67, 22.49 and 27.51.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 10.54, 14.03, 15.84, 18.99 and 21.16, and at One of the diffraction angles 2 ⁇ 0.2° at 17.67, 22.49 and 27.51 has a characteristic peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 10.54, 14.03, 15.84, 18.99 and 21.16, and at Two of the diffraction angles 2 ⁇ 0.2° are 17.67, 22.49 and 27.51 have characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III is at diffraction angles 2 ⁇ 0.2° of 5.28, 10.54, 14.03, 15.84, 17.67, 18.99, 21.16, 22.49 and 27.51 have characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form III is in the diffraction angle 2 ⁇ 0.2° of 5.28, 10.54, 14.03, 15.84, 17.67, 18.99, 21.16, 22.49 and 27.51 There are at least three characteristic peaks.
  • the crystalline form IV of the hydrochloride salt has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 5 .
  • the hydrochloride salt form IV has a differential scanning calorimetry curve (DSC) substantially as shown in the differential scanning calorimetry curve in FIG. 12 .
  • DSC differential scanning calorimetry curve
  • the hydrochloride salt form IV has a thermogravimetric analysis curve (TGA) substantially as shown in FIG. 12 .
  • TGA thermogravimetric analysis curve
  • At least one, at least two, or all of the following (a)-(c) of the compound ATV-014 hydrochloride crystal form IV are applicable: (a) crystal form IV has basically The X-ray powder diffraction pattern (XRPD pattern) shown in 5; (b) the differential scanning calorimetry curve (DSC) that crystal form IV has is basically as shown in the differential scanning calorimetry curve in Fig. 12; (c) crystal form IV Form IV has a thermogravimetric analysis curve (TGA) substantially as shown in the thermogravimetric analysis curve in FIG. 12 .
  • XRPD pattern X-ray powder diffraction pattern
  • DSC differential scanning calorimetry curve
  • TGA thermogravimetric analysis curve
  • the compound ATV-014 hydrochloride crystalline form IV has the following properties:
  • Form IV has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in Figure 5;
  • Form IV has a differential scanning calorimetry curve (DSC) substantially as shown in the differential scanning calorimetry curve in Figure 12;
  • thermogravimetric analysis curve (TGA) of crystal form IV is basically as shown in the thermogravimetric analysis curve in FIG. 12 .
  • the differential scanning calorimetry curve of the hydrochloride salt form IV has an endothermic peak at 180°C-200°C. In some embodiments, the differential scanning calorimetry curve of the hydrochloride salt form IV has an endothermic peak, and the peak value of the endothermic peak is 183°C-190°C. In some embodiments, the differential scanning calorimetry curve of the hydrochloride salt form IV is substantially as shown in the differential scanning calorimetry curve in FIG. 12 .
  • the differential scanning calorimetry curve of the hydrochloride salt form IV shows that its melting point is 182.50 ⁇ 5°C.
  • the weight loss of the thermogravimetric analysis curve of the hydrochloride salt form IV at 30°C-150°C is less than 2%. In some embodiments, the weight loss of the thermogravimetric analysis curve of the hydrochloride salt form IV at 30°C-150°C is less than 1%. In some embodiments, the weight loss of the thermogravimetric analysis curve of the hydrochloride salt form IV at 30°C-150°C is less than 0.5%. In some embodiments, the weight loss of the thermogravimetric analysis curve of the hydrochloride salt form IV at 30°C-150°C is less than 0.2%.
  • the compound ATV-014 hydrochloride salt form IV has an XRPD pattern showing at least 2, at least 3, at least 4, at least 5 or at least 6 2 ⁇ reflections, the maximum intensity of which is the same as The XRPD pattern is roughly as shown in FIG. 5 .
  • the X-ray powder diffraction pattern of the crystalline form IV of the compound ATV-014 hydrochloride has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 10.63 and 19.13.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.28, 10.63 and 19.13, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 1, 2 or 3 of 9.63, 14.10 and 16.82.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.28, 10.63 and 19.13, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 1 or 2 of 9.63, 14.10 and 16.82.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.28, 10.63 and 19.13, and at diffraction angles 2 ⁇ 0.2° One of 9.63, 14.10 and 16.82 has a characteristic peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 5.28, 10.63 and 19.13, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 2 of 9.63, 14.10 and 16.82.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride salt form IV has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 9.63, 10.63, 14.10, 16.82 and 19.13.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV has at least three features in the diffraction angle 2 ⁇ 0.2° of 5.28, 9.63, 10.63, 14.10, 16.82 and 19.13 peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 9.63, 10.63, 14.10, 16.82 and 19.13, and at The diffraction angle 2 ⁇ 0.2° is one of 10.19, 15.99 and 17.62, and there are characteristic peaks at 2 or 3.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 9.63, 10.63, 14.10, 16.82 and 19.13, and at There are characteristic peaks at one or two of the diffraction angles 2 ⁇ 0.2° at 10.19, 15.99 and 17.62.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 9.63, 10.63, 14.10, 16.82 and 19.13, and at One of the diffraction angles 2 ⁇ 0.2° at 10.19, 15.99 and 17.62 has a characteristic peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 5.28, 9.63, 10.63, 14.10, 16.82 and 19.13, and at Two of the diffraction angles 2 ⁇ 0.2° are 10.19, 15.99 and 17.62 have characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV is at diffraction angles 2 ⁇ 0.2° of 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62 and 19.13 have characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV has diffraction angles 2 ⁇ 0.2° of 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62 and 19.13 There are at least three characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV is at diffraction angles 2 ⁇ 0.2° of 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62 and 19.13 There are characteristic peaks, and there are characteristic peaks at 1, 2 or 3 of the diffraction angles 2 ⁇ 0.2° of 22.27, 23.19 and 27.74.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV is at diffraction angles 2 ⁇ 0.2° of 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62 and 19.13 There are characteristic peaks, and there are characteristic peaks at one or two of the diffraction angles 2 ⁇ 0.2° of 22.27, 23.19 and 27.74.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV is at diffraction angles 2 ⁇ 0.2° of 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62 and 19.13 There are characteristic peaks, and there are characteristic peaks at one of the diffraction angles 2 ⁇ 0.2° of 22.27, 23.19 and 27.74.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV is at diffraction angles 2 ⁇ 0.2° of 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62 and 19.13 There are characteristic peaks, and there are characteristic peaks at 2 of the diffraction angles 2 ⁇ 0.2° of 22.27, 23.19 and 27.74.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV is 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, 19.13, There are characteristic peaks at 22.27, 23.19 and 27.74.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV is 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, 19.13, At least three of 22.27, 23.19 and 27.74 have characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV is 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, 19.13, There are characteristic peaks at 22.27, 22.56, 23.19 and 27.74.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrochloride crystal form IV is 5.28, 9.63, 10.19, 10.63, 14.10, 15.99, 16.82, 17.62, 19.13, At least three of 22.27, 22.56, 23.19 and 27.74 have characteristic peaks.
  • compound ATV-014 hydrobromide salt crystalline form I is provided, wherein the hydrobromide salt crystalline form I is a substantially anhydrous crystalline form.
  • the hydrobromide salt form I has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 7 .
  • the hydrobromide salt form I has a differential scanning calorimetry curve (DSC) substantially as shown in the differential scanning calorimetry curve in FIG. 14 .
  • DSC differential scanning calorimetry curve
  • the hydrobromide salt form I has a thermogravimetric analysis curve (TGA) substantially as shown in FIG. 14 .
  • TGA thermogravimetric analysis curve
  • At least one, at least two, or all of the following (a)-(c) of the compound ATV-014 hydrobromide salt crystal form I are applicable: (a) crystal form I has substantially the following The X-ray powder diffraction pattern (XRPD pattern) shown in Fig. 7; (b) the differential scanning calorimetry curve (DSC) that crystal form I has is basically shown in the differential scanning calorimetry curve in Fig. 14; (c) The thermogravimetric analysis curve (TGA) of the crystal form I is basically as shown in the thermogravimetric analysis curve in FIG. 14 .
  • the compound ATV-014 hydrobromide salt crystal form I has the following properties:
  • Form I has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 7;
  • Form I has a differential scanning calorimetry curve (DSC) substantially as shown in the differential scanning calorimetry curve in Figure 14;
  • thermogravimetric analysis curve (TGA) of crystal form I is basically as shown in the thermogravimetric analysis curve in FIG. 14 .
  • the compound ATV-014 hydrobromide salt form I has an XRPD pattern showing at least 2, at least 3, at least 4, at least 5 or at least 6 reflections in 2 ⁇ degrees, the maximum intensity of which is The XRPD pattern is roughly as shown in Figure 7.
  • the weight loss of the thermogravimetric analysis curve of the compound ATV-014 hydrobromide salt form I at 100°C-160°C is less than 2%. In some embodiments, the weight loss of the thermogravimetric analysis curve of the compound ATV-014 hydrobromide salt form I at 100°C-160°C is less than 1.5%. In some embodiments, the thermogravimetric analysis curve of the compound ATV-014 hydrobromide salt form I is substantially as shown in the thermogravimetric analysis curve in FIG. 14 .
  • thermogravimetric analysis curve of the hydrobromide salt crystal form I of the compound ATV-014 has no obvious weight loss in the temperature range from room temperature to 170°C.
  • the differential scanning calorimetry curve of the compound ATV-014 hydrobromide salt form I has an endothermic peak at 130°C-170°C.
  • the differential scanning calorimetry curve of the compound ATV-014 hydrobromide salt form I has an endothermic peak, and the peak value of the endothermic peak is 138°C-145°C.
  • the differential scanning calorimetry curve of the compound ATV-014 hydrobromide salt crystal form I has an endothermic peak, and the peak value of the endothermic peak is 59°C-66°C. The peak is the desolvation peak.
  • the differential scanning calorimetry curve of the compound ATV-014 hydrobromide salt form I is substantially as shown in the differential scanning calorimetry curve in FIG. 14 .
  • thermogravimetric analysis curve of the compound ATV-014 hydrobromide salt form I shows that its melting point is 132.75 ⁇ 5°C.
  • the differential scanning calorimetry curve of the compound ATV-014 hydrobromide salt form I has endothermic peaks at 64°C-66°C and 179-183°C.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrobromide salt form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 3.78, 13.20 and 16.88.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrobromide salt crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 3.78, 13.20 and 16.88, and at diffraction angles 2 ⁇ 0.2° ° is 1 of 15.41, 17.46 and 26.38, and there are characteristic peaks at 2 or 3.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrobromide salt crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 3.78, 13.20 and 16.88, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at one or two of °15.41, 17.46 and 26.38.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrobromide salt crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 3.78, 13.20 and 16.88, and at diffraction angles 2 ⁇ 0.2° One of °15.41, 17.46 and 26.38 has a characteristic peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrobromide salt crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° at 3.78, 13.20 and 16.88, and at diffraction angles 2 ⁇ 0.2° There are characteristic peaks at 2 of °15.41, 17.46 and 26.38.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrobromide salt form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 3.78, 13.20, 15.41, 16.88, 17.46 and 26.38.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrobromide salt crystal form I has at least three of the diffraction angles 2 ⁇ 0.2° of 3.78, 13.20, 15.41, 16.88, 17.46 and 26.38. Characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrobromide salt crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 3.78, 13.20, 15.41, 16.88, 17.46 and 26.38, and There are characteristic peaks at one or two of the diffraction angles 2 ⁇ 0.2° of 25.52 and 26.79.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrobromide salt crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 3.78, 13.20, 15.41, 16.88, 17.46 and 26.38, and There is a characteristic peak at one of the diffraction angles 2 ⁇ 0.2° of 25.52 and 26.79.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrobromide salt crystal form I has diffraction angles 2 ⁇ 0.2° of 3.78, 13.20, 15.41, 16.88, 17.46, 25.52, 26.38 and 26.79. Characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 hydrobromide salt crystal form I is 3.78, 13.20, 15.41, 16.88, 17.46, 25.52, 26.38 and 26.79 at diffraction angles 2 ⁇ 0.2° There are at least three characteristic peaks.
  • compound ATV-014 p-toluenesulfonate salt form I is provided, wherein the p-toluenesulfonate salt form I is a monohydrate.
  • the p-toluenesulfonate salt form I has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 6 .
  • the p-toluenesulfonate salt form I has a differential scanning calorimetry curve (DSC) substantially as shown in FIG. 13 .
  • DSC differential scanning calorimetry curve
  • the p-toluenesulfonate salt form I has a thermogravimetric analysis curve (TGA) substantially as shown in the differential scanning calorimetry curve in FIG. 13 .
  • TGA thermogravimetric analysis curve
  • At least one, at least two or all of the following (a)-(c) of the compound ATV-014 tosylate crystal form I are applicable: (a) crystal form I has essentially X-ray powder diffraction pattern (XRPD pattern) as shown in Figure 6; (b) the differential scanning calorimetry curve (DSC) that crystal form I has is substantially as shown in the differential scanning calorimetry curve in Figure 13; (c ) The thermogravimetric analysis curve (TGA) of the crystal form I is basically as shown in the thermogravimetric analysis curve in FIG. 13 .
  • the compound ATV-014 tosylate salt form I has the following properties:
  • Form I has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in Figure 6;
  • Form I has a differential scanning calorimetry curve (DSC) substantially as shown in the differential scanning calorimetry curve in Figure 13;
  • thermogravimetric analysis curve (TGA) of crystal form I is basically as shown in the thermogravimetric analysis curve in FIG. 13 .
  • the compound ATV-014 p-toluenesulfonate salt form I has an XRPD pattern showing at least 2, at least 3, at least 4, at least 5 or at least 6 2 ⁇ degree reflections, the maximum of which is The intensity and XRPD pattern are roughly shown in FIG. 6 .
  • thermogravimetric analysis curve of the compound ATV-014 p-toluenesulfonate salt form I has a weight loss of less than 10% at 60°C-150°C. In some embodiments, the thermogravimetric analysis curve of the compound ATV-014 p-toluenesulfonate salt form I has a weight loss of less than 5% at 60°C-150°C. In some embodiments, the thermogravimetric analysis curve of the compound ATV-014 p-toluenesulfonate salt form I has a weight loss of less than 4% at 60°C-150°C. In some embodiments, the thermogravimetric analysis curve of the compound ATV-014 tosylate salt Form I is substantially as shown in the thermogravimetric analysis curve in FIG. 13 .
  • thermogravimetric analysis curve of the compound ATV-014 tosylate salt form I shows that its melting point is 105.92 ⁇ 5°C.
  • the differential scanning calorimetry curve of the tosylate salt form I of the compound ATV-014 has an endothermic peak at 100°C-140°C. In some embodiments, the differential scanning calorimetry curve of the tosylate salt form I 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 ATV-014 p-toluenesulfonate salt form I has an endothermic peak at 121°C-126°C, and the enthalpy value is 66J/g. In some embodiments, the differential scanning calorimetry curve of the tosylate salt form I of the compound ATV-014 is substantially as shown in the differential scanning calorimetry curve in FIG. 13 .
  • thermogravimetric analysis curve of the ATV-014 p-toluenesulfonate salt form I has a weight loss of less than 3.2% in the temperature range of 65°C-130°C.
  • the X-ray powder diffraction pattern of the compound ATV-014 p-toluenesulfonate salt form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 3.58, 10.89 and 16.59.
  • the X-ray powder diffraction pattern of the compound ATV-014 p-toluenesulfonate salt crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 3.58, 10.89 and 16.59, and at diffraction angles 2 ⁇ 0.2° 0.2° means that one or two of 7.23 and 14.59 have characteristic peaks.
  • the X-ray powder diffraction pattern of the compound ATV-014 p-toluenesulfonate salt crystal form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 3.58, 10.89 and 16.59, and at diffraction angles 2 ⁇ 0.2° 0.2° means that one of 7.23 and 14.59 has a characteristic peak.
  • the X-ray powder diffraction pattern of the compound ATV-014 tosylate salt form I has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 3.58, 7.23, 10.89, 14.59 and 16.59.
  • the X-ray powder diffraction pattern of the compound ATV-014 p-toluenesulfonate salt crystal form I has at least three features in the diffraction angle 2 ⁇ 0.2° of 3.58, 7.23, 10.89, 14.59 and 16.59 peak.
  • the new crystal form of the compound ATV014 free base and its salts described in the present invention can be used to treat diseases related to viral infection, or to prevent, alleviate and/or treat symptoms such as diseases related to SARS-CoV-2.
  • a pharmaceutical composition is provided.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the new crystal form of the compound ATV014 free base and its salt and pharmaceutically acceptable adjuvants or excipients.
  • the new crystal form of the compound ATV014 free base and its salt in a therapeutically effective amount is mixed or contacted with one or more pharmaceutical excipients to prepare a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is well known in the field of pharmacy prepared in a manner.
  • the pharmaceutical composition or preparation can be used to treat diseases related to viral infection, or to prevent, alleviate and/or treat symptoms such as diseases related to SARS-CoV-2.
  • a pharmaceutical composition which contains a therapeutically effective amount of the hydrochloride crystal form I of the compound ATV-014, a therapeutically effective amount of the hydrochloride crystal form of the compound ATV-014 II.
  • a pharmaceutical composition comprising the compound ATV014 free base, wherein at least 80% of the compound ATV014 free base is the crystalline form I of the compound ATV014 free base. In some embodiments, a pharmaceutical composition comprises the compound ATV014 free base, wherein at least 90% of the compound ATV014 free base is the compound ATV014 free base crystal form I. In some embodiments, a pharmaceutical composition comprises the compound ATV014 free base, wherein at least 95% of the compound ATV014 free base is the compound ATV014 free base crystal form I. In some embodiments, a pharmaceutical composition comprising compound ATV014 free base, wherein at least 99% of the compound ATV014 free base is said compound ATV014 free base crystal form I.
  • a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 80% of the compound ATV014 hydrochloride is the crystalline form I of the compound ATV014 hydrochloride. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 90% of the compound ATV014 hydrochloride is the crystalline form I of the compound ATV014 hydrochloride. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 95% of the compound ATV014 hydrochloride is the crystalline form I of the compound ATV014 hydrochloride. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 99% of the compound ATV014 hydrochloride is the crystalline form I of the compound ATV014 hydrochloride.
  • a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 80% of the compound ATV014 hydrochloride is the crystalline form II of the compound ATV014 hydrochloride. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 90% of the compound ATV014 hydrochloride is the crystalline form II of the compound ATV014 hydrochloride. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 95% of the compound ATV014 hydrochloride is the crystalline form II of the compound ATV014 hydrochloride. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 99% of the compound ATV014 hydrochloride is the crystalline form II of the compound ATV014 hydrochloride.
  • a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 80% of the compound ATV014 hydrochloride is the compound ATV014 hydrochloride crystal form III. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 90% of the compound ATV014 hydrochloride is the compound ATV014 hydrochloride crystal form III. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 95% of the compound ATV014 hydrochloride is the compound ATV014 hydrochloride crystal form III. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 99% of the compound ATV014 hydrochloride is the compound ATV014 hydrochloride crystal form III.
  • a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 80% of the compound ATV014 hydrochloride is the crystalline form IV of the compound ATV014 hydrochloride. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 90% of the compound ATV014 hydrochloride is the crystalline form IV of the compound ATV014 hydrochloride. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 95% of the compound ATV014 hydrochloride is the crystalline form IV of the compound ATV014 hydrochloride. In some embodiments, a pharmaceutical composition contains the compound ATV014 hydrochloride, wherein at least 99% of the compound ATV014 hydrochloride is the crystalline form IV of the compound ATV014 hydrochloride.
  • a pharmaceutical composition comprises the compound ATV014 hydrobromide salt, wherein at least 80% of the compound ATV014 hydrobromide salt is the crystalline form I of the compound ATV014 hydrobromide salt.
  • a pharmaceutical composition contains the compound ATV014 hydrobromide salt, wherein at least 90% of the compound ATV014 hydrobromide salt is the compound ATV014 hydrobromide salt crystal form I.
  • a pharmaceutical composition comprises the compound ATV014 hydrobromide salt, wherein at least 95% of the compound ATV014 hydrobromide salt is the compound ATV014 hydrobromide salt form I.
  • a pharmaceutical composition comprises the compound ATV014 hydrobromide salt, wherein at least 99% of the compound ATV014 hydrobromide salt is the compound ATV014 hydrobromide salt crystalline form I.
  • a pharmaceutical composition comprises the compound ATV014 p-toluenesulfonate salt, wherein at least 80% of the compound ATV014 p-toluenesulfonate salt is Form I of the compound ATV014 p-toluenesulfonate salt.
  • a pharmaceutical composition contains the compound ATV014 p-toluenesulfonate, wherein at least 90% of the compound ATV014 p-toluenesulfonate is the compound ATV014 p-toluenesulfonate crystal form I.
  • a pharmaceutical composition comprises the compound ATV014 p-toluenesulfonate salt, wherein at least 95% of the compound ATV014 p-toluenesulfonate salt is the crystalline form I of the compound ATV014 p-toluenesulfonate salt. In some embodiments, a pharmaceutical composition comprises the compound ATV014 p-toluenesulfonate salt, wherein at least 99% of the compound ATV014 p-toluenesulfonate salt is Form I of the compound ATV014 p-toluenesulfonate salt.
  • the new crystal form of the present invention containing the compound ATV014 free base and its salts can be used to prevent, alleviate and/or treat diseases or symptoms related to viral infection, or can be used in the prevention, mitigation and/or treatment of SARS-CoV-2 or In the method of related diseases and other symptoms of its mutant strains.
  • the new crystal form provided by the present invention has not been reported at present.
  • the inventors of the present invention have broken through this problem through research and found a new crystal form suitable for development.
  • the new crystal form has better stability and good solubility.
  • a more stable crystal form is of great significance for improving the quality of drugs.
  • the new crystal form provided by the invention has good stability in water, is not easy to deliquesce under high humidity conditions, and is convenient for long-term storage and placement of drugs.
  • the crystal form provided by the invention has good stability, remarkable process purification effect, can well avoid crystal transformation during drug storage and development, thereby avoiding changes in bioavailability and drug efficacy, and has strong economic value.
  • hydrobromide salt form I of the formula ATV-014 provided by the present invention absorbs 0.2% moisture for one week at 70% RH (open), and absorbs 18.8% moisture at 90% RH (open) for one week.
  • the p-toluenesulfonate crystal form I of the formula ATV-014 provided by the present invention is placed under the condition of 30% RH (open) for one week, absorbing 0.4% of moisture, and placed under the condition of 90% RH (open) for one week, absorbing 0.5% of moisture , the crystal form and chemical purity have not changed, and the physical and chemical stability is good.
  • crystalline form refers to a unique ordered arrangement and/or conformation of molecules in the crystal lattice of a compound.
  • X-ray powder diffraction can detect information such as changes in crystal forms, crystallinity, crystal structure state, etc., and is a common method for identifying crystal forms.
  • the peak positions of an XRPD pattern mainly depend on the structure of the crystalline form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention.
  • the measurement of 2 ⁇ in the XRPD pattern may have experimental errors, and the measurement of 2 ⁇ in the XRPD pattern may be slightly different between different instruments and different samples, so the value of 2 ⁇ in the XRPD pattern cannot be regarded as absolute. According to the condition of the instrument used in this test, there is an error tolerance of ⁇ 0.2° for the diffraction peaks.
  • DSC Differential Scanning Calorimetry
  • the DSC spectrum may have experimental errors, and the peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the condition of the instrument used in this test, there is an error margin of ⁇ 3° for the melting peak.
  • the glass transition refers to the transition between the high elastic state and the glass state of the amorphous substance, which is an inherent property of the substance; its corresponding transition temperature is the glass transition temperature (Tg), which is an important aspect of the amorphous substance. physical properties. Glass transition is a phenomenon related to molecular motion. Therefore, the glass transition temperature (Tg) mainly depends on the structure of the substance, and is relatively insensitive to experimental details. According to the condition of the instrument used in this test, there is an error margin of ⁇ 3° for the melting peak.
  • Thermogravimetric analysis is a technique for determining the quality of a substance as a function of temperature under program control. It is suitable for checking the loss of solvent in the crystal or the process of sublimation and decomposition of the sample. It can be speculated that the crystal contains crystal water or crystal solvent. Case.
  • the mass change shown by the TGA curve depends on many factors such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. There is a ⁇ 0.1% error margin for mass variation depending on the condition of the instrumentation used in this test.
  • 2 ⁇ values in X-ray powder diffraction patterns are all in degrees (°).
  • Pheak when referring to a spectrum and/or data appearing in a graph refers to a feature that one skilled in the art would recognize and would not attribute to background noise.
  • substantially pure means that a crystalline form is substantially free of one or more other crystalline forms, and its crystalline form has a purity of at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or Its crystal form contains other crystal forms, and the total volume or weight percentage of the other crystal forms in the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1% , or less than 0.5%, or less than 0.1%, or less than 0.01.
  • substantially free of one or more other crystal forms means that the content of other crystal forms is less than 20%, or less than 10%, or less than 5%, or less than 4% in the total volume or weight. %, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • substantially as shown in the X-ray powder diffraction pattern means that the X-ray powder diffraction pattern is 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 appear in its graph.
  • relative intensity refers to the ratio of the intensity of other peaks to the intensity of the first strong peak among all the diffraction peaks in the X-ray powder diffraction pattern when the intensity of the first strong peak is 100%.
  • anti-solvent refers to a solvent that promotes supersaturation or crystallization of a solution.
  • solubility of ATV014 free base in the antisolvent is 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 0.4g/L, or less than 0.5g/L, or less than 0.6g/L, or less than 0.8g/L, or less than 1g/L, or less than 2g/L, or less than 3g/L, or less than 4g/L , or less than 5g/L, or less than 6g/L, or less than 7g/L, or less than 8g/L, or less than 9g/L, or less than 10g/L.
  • peak when referring to a spectrum and/or data in a graph refers to a feature that one skilled in the art would not attribute to background noise.
  • R R L + K * (R U - R L ), where K is a variable from 1% to 100% in increments of 1% , namely: 1%, 2%, 3%, 4%, 5%, 50%, 51%, 52%... 95%, 96%, 97%, 98%, 99% or 100%.
  • K is a variable from 1% to 100% in increments of 1% , namely: 1%, 2%, 3%, 4%, 5%, 50%, 51%, 52%... 95%, 96%, 97%, 98%, 99% or 100%.
  • room temperature refers to ambient temperature, and the temperature is from about 10°C to about 40°C.
  • room temperature refers to a temperature from about 20°C to about 30°C; in other embodiments, “room temperature” refers to a temperature from about 25°C to about 30°C; in still other embodiments
  • room temperature refers to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C and the like.
  • treating means reversing, alleviating, alleviating, or inhibiting, the disorder or disorder or one or more symptoms of such a disorder or disorder to which the term applies. progress of a symptom or prevent the disorder or disorder or one or more symptoms thereof.
  • treatment refers to the act of treatment, as “treatment” is defined immediately above.
  • ATV-014 hydrobromide salt crystal form I and “compound ATV-014 hydrobromide salt crystal form I” mean the same meaning, and other crystal forms can be deduced by analogy.
  • X-ray powder diffraction patterns were collected on a German Bruker D8 Advance X-ray diffractometer equipped with an autosampler using a zero background sample pan.
  • the radiation source used is Cu k ⁇
  • the light tube voltage is set at 40KV, and the light tube current is set at 40mA.
  • the X-ray divergence slit is 0.6mm. Take an appropriate amount of sample in the center of the zero-background sample tray under ambient conditions, press lightly with a clean glass slide to obtain a flat plane, and fix the zero-background sample holder.
  • the samples were subjected to diffraction analysis in the range of 3-40° (2 ⁇ ) with a scan step size of 0.02° (2 ⁇ ).
  • the software used for data collection is DIFFRAC.COMMANDER, and the data is analyzed and displayed with DIFFRAC.EVA.
  • Samples were subjected to DSC analysis using a TA Instrument Discovery DSC 250 instrument with perforated covered aluminum pans.
  • Samples were analyzed by TGA using a TA Instrument Discovery TGA 55 instrument with open aluminum pans. Typically 2-5 mg of sample is placed into a pre-equilibrated aluminum sample pan and heated from ambient to 300°C at 10°C/min. The sample chamber maintains a nitrogen flow of 25 mL/min.
  • the abscissa indicates the temperature (Temperature, °C), and the ordinate indicates the percentage of weight loss (Weight (%)).
  • Figure 1 shows the X-ray powder diffraction detection spectrum of compound ATV-014 free base crystal form I.
  • Figure 2 shows the X-ray powder diffraction detection spectrum of compound ATV-014 hydrochloride crystal form I.
  • Figure 3 shows the X-ray powder diffraction detection spectrum of compound ATV-014 hydrochloride crystal form II.
  • Figure 4 shows the X-ray powder diffraction detection spectrum of compound ATV-014 hydrochloride crystal form III.
  • Fig. 5 shows the X-ray powder diffraction detection spectrum of compound ATV-014 hydrobromide salt crystal form I.
  • Figure 6 shows the X-ray powder diffraction detection spectrum of compound ATV-014 tosylate salt crystal form I.
  • Fig. 7 shows the X-ray powder diffraction detection spectrum of compound ATV-014 hydrochloride crystal form IV.
  • Figure 8 shows the differential scanning calorimetry detection spectrum and thermogravimetric analysis spectrum of compound ATV-014 free base crystal form I.
  • Figure 9 shows the differential scanning calorimetry detection spectrum and thermogravimetric analysis spectrum of compound ATV-014 hydrochloride crystal form I.
  • Figure 10 shows the differential scanning calorimetry detection spectrum and thermogravimetric analysis spectrum of compound ATV-014 hydrochloride crystal form II.
  • FIG. 11 Compound ATV-014 shows the differential scanning calorimetry detection spectrum and thermogravimetric analysis spectrum of hydrochloride crystal form III.
  • Figure 12 shows the differential scanning calorimetry detection spectrum and thermogravimetric analysis spectrum of compound ATV-014 hydrobromide salt crystal form I.
  • Figure 13 shows the differential scanning calorimetry detection spectrum and thermogravimetric analysis spectrum of compound ATV-014 p-toluenesulfonate crystal form I.
  • Figure 14 shows the differential scanning calorimetry detection spectrum and thermogravimetric analysis spectrum of compound ATV-014 hydrochloride crystal form IV.
  • the reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.
  • ATV-014 free base crystal form I was tested for X-ray powder diffraction, DSC and TGA, and its X-ray powder diffraction spectrum is shown in Figure 2, and its DSC and TGA spectrum is shown in Figure 9.
  • ATV-014 hydrochloride salt form II was tested for X-ray powder diffraction, DSC and TGA, and its X-ray powder diffraction spectrum is shown in Figure 3, and its DSC and TGA spectrum are shown in Figure 10.
  • ATV-014 hydrochloride salt form III was tested for X-ray powder diffraction, DSC and TGA, and its X-ray powder diffraction spectrum is shown in Figure 4, and its DSC and TGA spectrum are shown in Figure 11.
  • ATV-014 hydrobromide salt form I was tested for X-ray powder diffraction, DSC and TGA, and its X-ray powder diffraction spectrum is shown in Figure 5, and its DSC and TGA spectrum are shown in Figure 12.
  • ATV-014 p-toluenesulfonate salt crystal Form I was tested for X-ray powder diffraction, DSC and TGA, and its X-ray powder diffraction spectrum is shown in Figure 6, and its DSC and TGA spectrum are shown in Figure 13.
  • ATV014 (1g, 2.5mmol) and 5mL methanol (substantially insoluble) to a 50mL single-necked bottle, add 4.0M hydrochloric acid methanol solution (0.9mL, 3.75mmol) dropwise under ice bath conditions, after 2min, the solution is clear and transparent.
  • the obtained ATV-014 hydrochloride crystal form IV was tested for X-ray powder diffraction, DSC and TGA, and its X-ray powder diffraction spectrum is shown in Figure 7, and its DSC and TGA spectrum is shown in Figure 14.
  • Embodiment 8 Influencing factor stability research
  • ATV-014 free base crystal form I Take ATV-014 free base crystal form I, ATV-014 hydrobromide salt crystal form I and ATV-014 p-toluenesulfonate salt crystal form I, respectively at 40°C/75%RH (open) and 60°C (covered Sample bottle) was placed for 7 days, and HPLC detection and X-ray powder diffraction detection were carried out on 0 day and 7 days respectively, and the results are shown in Table 4.
  • solubility of the free base crystal form I and p-toluenesulfonate salt form I at 0.5 hours, 2 hours and 24 hours was determined in FaSSIF, FeSSIF, SGF and water at 37°C. Solubility and solution pH value results are shown in: table.
  • the solubility of ATV-014 tosylate salt form I is higher than 5 mg/mL, while the solubility of ATV-014 free base form I in SGF is 2.5-2.9 mg/mL.
  • the solubility of ATV-014 p-toluenesulfonate in water is 30 times higher than that of free base.

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Abstract

提供了一种核苷类化合物及其盐的新晶型，属于医药技术领域。所述核苷类化合物为化合物ATV014，重点考察了化合物ATV014是否存在多种固体形态，意外的，我们发现了化合物ATV014存在多种稳定的固体形态，包括：ATV-014游离碱晶型I、ATV-014盐酸盐晶型I、ATV-014盐酸盐晶型II、ATV-014盐酸盐晶型III、ATV-014盐酸盐晶型IV、ATV-014氢溴酸盐晶型I、ATV-014对甲苯磺酸盐晶型I。所提供的化合物ATV014游离碱及其盐的新晶型具有良好的溶解性和热稳定性，在特定的制剂具有更好的生物利用度和溶出曲线；其良好的渗透性和热稳定性适于在特定的药物制剂中使用。

Description

一种核苷类化合物及其盐的新晶型 技术领域
本发明属于医药技术领域，涉及一种核苷类化合物及其盐的新晶型。
背景技术
新冠病毒是一种具有包膜的单链RNA病毒，为β属冠状病毒。与SARS和MERS类似，SARS-CoV-2基因组编码非结构蛋白：3C样蛋白酶(3-chymotrypsin-like protease，3CLpro)、木瓜蛋白酶样蛋白酶(papain-likeprotease，PLpro)、解旋酶(helicase)和RNA依赖RNA聚合酶(RNA-dependent RNA polymerase，RdRp)；结构蛋白：如棘突糖蛋白(spike glycoprotein)和附属蛋白(accessory proteins)。新冠病毒的表面棘突糖蛋白与人体细胞表面血管紧张素转换酶(ACE2)受体的结合从而感染人的呼吸道上皮细胞。病毒在进入宿主细胞后解体，将核衣壳和病毒RNA释放到细胞质中，病毒RNA 5′末端开放阅读框(ORF 1a/b)将编码多聚蛋白质(pp1a和pp1ab)，它们对病毒复制所需酶的加工、成熟起重要作用。pp1a和pp1ab可被木瓜蛋白酶样蛋白酶(PLpro)和3C样蛋白酶(3CLpro)裂解，产生非结构蛋白，包括RNA依赖性RNA聚合酶和解螺旋酶等，它们对于新冠病毒的转录和复制的起着关键的作用。目前，冠状病毒识别受体的表面棘突糖蛋白、参与复制及转录过程的重要蛋白3CLpro、PLpro与RdRp是四个十分具有抗病毒药物研发吸引力的靶点。
通过申请人前期对瑞德西韦及其前药化合物GS-441524的研究(Li，et al.，J.Med.Chem.2020)，发现化合物GS-441524在小鼠体内的活性测试中产生了优于瑞德西韦的抗病毒作用。化合物GS-441524虽然与瑞德西韦的作用机理类似，但其显示了更好的安全性。因此，申请人已申请了描述化合物GS-441524在预防、缓解和/或治疗SARS-CoV-2的药物的应用专利(申请号或专利号202011000517.2)。
化合物GS-441524其结构如下所示：
Figure PCTCN2022093342-appb-000001
式ATV014所示化合物是化合物GS-441524的一种衍生物，经发明人研究发现，式ATV014所示化合物相比化合物GS-441524具有更好的活性和生物利用度。
化合物ATV014其结构如下所示：
Figure PCTCN2022093342-appb-000002
药物多晶型是药品研发中的常见现象，是影响药品质量的重要因素。同一药物的不同晶型在外观、流动性、溶解度、储存稳定性、生物利用度等理化性质方面可能会有显著不同，可能存在极大差异，会对药物的储存转移、应用、稳定性、疗效等产生不同的影响；为了得到有效的利于生产或利于药物制剂的晶型，需要对药物的结晶行为进行全面的考察，以得到满足生产要求的晶型。
本发明通过对化合物ATV014进行大量实验研究，得到了该化合物及其盐的新晶型，该新晶型具有稳定性好，光照高温高湿条件下稳定，制备工艺简单易操作等优越性质，在工业生产中具有优越性。对化合物ATV014新晶型的研究，提供了提高该医药产品整体性能(如易于合成或处理、提高溶出度或提高稳定性和保质期)的机会，同时扩大了制剂科学家设计该药品时可用的材料品种，对药物研发至关重要。
发明内容
发明概述
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的一个目的在于提供化合物ATV014游离碱及其盐的新晶型及其制备方法，本发明重点考察了化合物ATV014是否存在多种固体形态，意外的，我们发现了化合物ATV014存在多种稳定的固体形态，包括：ATV-014游离碱晶型I、ATV-014盐酸盐晶型I、ATV-014盐酸盐晶型II、ATV-014盐酸盐晶型III、ATV-014盐酸盐晶型IV、ATV-014氢溴酸盐晶型I、ATV-014对甲苯磺酸盐晶型I。
其中，化合物ATV014其结构如下所示：
Figure PCTCN2022093342-appb-000003
本发明所提供的化合物ATV014游离碱及其盐的新晶型具有良好的溶解性和热稳定性，在特定的制剂具有更好的生物利用度和溶出曲线；其良好的渗透性和热稳定性适于在特定的药物制剂中使用。
发明详述
为解决上述问题，本发明提供以下技术方案。
第一方面，提供一种化合物ATV-014游离碱或其盐的晶型。
根据本发明的一个方面，本发明提供了：化合物ATV-014游离碱晶型I、化合物ATV-014盐酸盐晶型I、化合物ATV-014盐酸盐晶型II、化合物ATV-014盐酸盐晶型III、化合物ATV-014盐酸盐晶型IV、化合物ATV-014氢溴酸盐晶型I、化合物ATV-014对甲苯磺酸盐晶型I。
化合物ATV-014游离碱晶型I
在一些实施方式中，提供了化合物ATV-014游离碱晶型I，其中，所述游离碱晶型I为无水物。
在一些实施方式中，所述化合物ATV-014游离碱晶型I具有基本上如图1所示的X射线粉末衍射图谱(XRPD图谱)。
在一些实施方式中，所述化合物ATV-014游离碱晶型I具有的差示扫描量热曲线(DSC)基本上如图8所示。
在一些实施方式中，所述化合物ATV-014游离碱晶型I具有的热重分析曲线(TGA)基本上如图8所示。
在一些实施方式中，所述化合物ATV-014游离碱晶型I至少有一种、至少两种或下列所有的(a)-(c)均适用：(a)晶型I具有基本上如图1所示的X射线粉末衍射图谱(XRPD图谱)；(b)晶型I具有的差示扫描量热曲线(DSC)基本上如图8所示；(c)晶型I具有的热重分析曲线(TGA)基本上如图8所示。
在一些实施方式中，所述化合物ATV-014游离碱晶型I具有如下属性：
(a)晶型I具有基本上如图1所示的X射线粉末衍射图谱(XRPD图谱)；
(b)晶型I具有的差示扫描量热曲线(DSC)基本上如图8所示；和
(c)晶型I具有的热重分析曲线(TGA)基本上如图8所示。
在一些实施方式中，所述化合物ATV-014游离碱晶型I具有至少显示2个、至少3个、至少4个、至少5个或至少6个2θ度反射的XRPD图案，其最大强度与XRPD图案大致如图1所示。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的差示扫描量热曲线中在225℃-228℃处具有吸热峰。
在一些实施例中，所述化合物ATV-014游离碱晶型I的热重分析曲线中在100℃-200℃的温度范围内有0.5％以下的失重。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、18.70和23.88处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、18.70和23.88处有特征峰，并且在衍射角2θ±0.2°为9.84、17.74和19.38中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、18.70和23.88处有特征峰，并且在衍射角2θ±0.2°为9.84、17.74和19.38中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、18.70和23.88处有特征峰，并且在衍射角2θ±0.2°为9.84、17.74和19.38中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、18.70和23.88处有特征峰，并且在衍射角2θ±0.2°为9.84、17.74和19.38中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、17.74、18.70、19.38和23.88处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、17.74、18.70、19.38和23.88中的至少有三处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、17.74、18.70、19.38和23.88处有特征峰，并且在衍射角2θ±0.2°为13.19、15.61和21.31中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、17.74、18.70、19.38和23.88处有特征峰，并且在衍射角2θ±0.2°为13.19、15.61和21.31中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、17.74、18.70、19.38和23.88处有特征峰，并且在衍射角2θ±0.2°为13.19、15.61和21.31中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、17.74、18.70、19.38和23.88处有特征峰，并且在衍射角2θ±0.2°为13.19、15.61和21.31中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、13.91、15.61、17.74、18.70、19.38、21.31和23.88处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、13.91、15.61、17.74、18.70、19.38、21.31和23.88中的至少有三处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、13.91、15.61、17.74、18.70、19.38、21.31和23.88处有特征峰，并且在衍射角2θ±0.2°为17.41和26.01中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、13.91、15.61、17.74、18.70、19.38、21.31和23.88处有特征峰，并且在衍射角2θ±0.2°为17.41和26.01中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、13.91、15.61、17.41、17.74、18.70、19.38、21.31、23.88和26.01处有特征峰。
在一些实施方式中，所述化合物ATV-014游离碱晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为9.69、9.84、13.91、15.61、17.41、17.74、18.70、19.38、21.31、23.88和26.01中的至少有三处有特征峰。
化合物ATV-014盐酸盐晶型I
在一些实施方式中，提供了化合物ATV-014盐酸盐晶型I，其中，所述盐酸盐晶型I为溶剂化物。
在一些实施方式中，所述盐酸盐晶型I具有基本上如图2所示的X射线粉末衍射图谱(XRPD图谱)。
在一些实施方式中，所述盐酸盐晶型I具有的差示扫描量热曲线(DSC)基本上如图9中差示扫描量热曲线所示。
在一些实施方式中，所述盐酸盐晶型I具有的热重分析曲线(TGA)基本上如图9中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I至少有一种、至少两种或下列所有的(a)-(c)均适用：(a)晶型I具有基本上如图2所示的X射线粉末衍射图谱(XRPD图谱)；(b)晶型I具有的差示扫描量热曲线(DSC)基本上如图9中差示扫描量热曲线所示；(c)晶型I具有的热重分析曲线(TGA)基本上如图9中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I具有如下属性：
(a)晶型I具有基本上如图2所示的X射线粉末衍射图谱(XRPD图谱)；
(b)晶型I具有的差示扫描量热曲线(DSC)基本上如图9中差示扫描量热曲线所示；和
(c)晶型I具有的热重分析曲线(TGA)基本上如图9中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I具有至少显示2个、至少3个、至少4个、至少5个或至少6个2θ度反射的XRPD图案，其最大强度与XRPD图案大致如图2所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的差示扫描量热曲线在120℃-170℃有吸热峰。在一些实施例中，所述化合物ATV-014盐酸盐晶型I的差示扫描量热曲线在125℃-165℃有吸热峰。在一些实施例中，所述化合物ATV-014盐酸盐晶型I的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为141℃-151℃或143℃-149℃。在一些实施例中，所述化合物ATV-014盐酸盐晶型I的差示扫描量热曲线基本上如图9中差示扫描量热曲线所示。
在一些实施例中，所述化合物ATV-014盐酸盐晶型I的差示扫描量热曲线中显示其熔点为136.55±5℃。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的差示扫描量热曲线中在137℃-146℃处具有吸热峰，热焓值为81J/g，为脱溶剂合并熔融峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的热重分析曲线在110℃-170℃的失重小于10％或者小于9％或者小于8％。在一些实施例中，所述化合物ATV-014盐酸盐晶型I的热重分析曲线中在110℃-170℃的温度范围的失重在7.1％以下。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、15.53和20.76处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、15.53和20.76处有特征峰，并且在衍射角2θ±0.2°为10.33、22.75和24.19中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、15.53和20.76处有特征峰，并且在衍射角2θ±0.2°为10.33、22.75和24.19中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、15.53和20.76处有特征峰，并且在衍射角2θ±0.2°为10.33、22.75和24.19中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、15.53和20.76处有特征峰，并且在衍射角2θ±0.2°为10.33、22.75和24.19中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、10.33、15.53、20.76、22.75和24.19处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、10.33、15.53、20.76、22.75和24.19中的至少有三处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、10.33、15.53、20.76、22.75和24.19处有特征峰，并且在衍射角2θ±0.2°为23.88和26.01中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、10.33、15.53、20.76、22.75和24.19处有特征峰，并且在衍射角2θ±0.2°为23.88和26.01中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、10.33、15.53、20.76、22.75、23.88、24.19和26.01处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、10.33、15.53、20.76、22.75、23.88、24.19和26.01中的至少有三处有特征峰。
化合物ATV-014盐酸盐晶型II
在一些实施方式中，提供了化合物ATV-014盐酸盐晶型II，其中，所述盐酸盐晶型II为溶剂化物/水合物。
在一些实施方式中，所述盐酸盐晶型II具有基本上如图3所示的X射线粉末衍射图谱(XRPD图谱)。
在一些实施方式中，所述盐酸盐晶型II具有的差示扫描量热曲线(DSC)基本上如图10中差示扫描量热曲线所示。
在一些实施方式中，所述盐酸盐晶型II具有的热重分析曲线(TGA)基本上如图10中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II至少有一种、至少两种或下列所有的(a)-(c)均适用：(a)晶型II具有基本上如图3所示的X射线粉末衍射图谱(XRPD图谱)；(b)晶型II具有的差示扫描量热曲线(DSC)基本上如图10中差示扫描量热曲线所示；(c)晶型II具有的热重分析曲线(TGA)基本上如图10中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II具有如下属性：
(a)晶型II具有基本上如图3所示的X射线粉末衍射图谱(XRPD图谱)；
(b)晶型II具有的差示扫描量热曲线(DSC)基本上如图10中差示扫描量热曲线所示；和
(c)晶型II具有的热重分析曲线(TGA)基本上如图10中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II具有至少显示2个、至少3个、 至少4个、至少5个或至少6个2θ度反射的XRPD图案，其最大强度与XRPD图案大致如图3所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的差示扫描量热曲线在100℃-150℃有吸热峰。在一些实施例中，所述化合物ATV-014盐酸盐晶型II的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为135℃-145℃。在一些实施例中，所述化合物ATV-014盐酸盐晶型II的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为136℃-143℃。在一些实施例中，所述化合物ATV-014盐酸盐晶型II的差示扫描量热曲线基本上如图10中差示扫描量热曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的差示扫描量热曲线显示其熔点为126.75±5℃。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的热重分析曲线在70℃-170℃的失重小于10％。在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的热重分析曲线在70℃-170℃的失重小于8％。在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的热重分析曲线中在70-170℃的失重在5.6％以下。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、10.43和18.79处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、10.43和18.79处有特征峰，并且在衍射角2θ±0.2°为9.88、14.05和22.28中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、10.43和18.79处有特征峰，并且在衍射角2θ±0.2°为9.88、14.05和22.28中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、10.43和18.79处有特征峰，并且在衍射角2θ±0.2°为9.88、14.05和22.28中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、10.43和18.79处有特征峰，并且在衍射角2θ±0.2°为9.88、14.05和22.28中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、18.79和22.28处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、18.79和22.28中的至少有三处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、18.79和22.28处有特征峰，并且在衍射角2θ±0.2°为15.68、19.46和21.38中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、18.79和22.28处有特征峰，并且在衍射角2θ±0.2°为15.68、19.46和21.38中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、18.79和22.28处有特征峰，并且在衍射角2θ±0.2°为15.68、19.46和21.38中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、18.79和22.28处有特征峰，并且在衍射角2θ±0.2°为15.68、19.46和21.38中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、18.79、19.46、21.38和22.28处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、18.79、19.46、21.38和22.28中的至少有三处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、18.79、19.46、21.38和22.28，并且在衍射角2θ±0.2°为17.81、20.37和23.96中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、18.79、19.46、21.38和22.28处有特征峰，并且在衍射角2θ±0.2°为17.81、20.37和23.96中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、18.79、19.46、21.38和22.28处有特征峰，并且在衍射角2θ±0.2°为17.81、20.37和23.96中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、18.79、19.46、21.38和22.28处有特征峰，并且在衍射角2θ±0.2°为17.81、20.37和23.96中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、17.81、18.79、19.46、20.37、21.38、22.28和23.96处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、17.81、18.79、19.46、20.37、21.38、22.28和23.96中的至少有三处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、17.81、18.79、19.46、20.37、21.38、22.28和23.96处有特征峰，并且在衍射角2θ±0.2°为22.81和37.05中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、17.81、18.79、19.46、20.37、21.38、22.28和23.96处有特征峰，并且在衍射角2θ±0.2°为22.81和37.05中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为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和37.05处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为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和37.05中的至少有三处有特征峰。
化合物ATV-014盐酸盐晶型III
在一些实施方式中，提供了化合物ATV-014盐酸盐晶型III，其中，所述盐酸盐晶型III为溶剂化物。
在一些实施方式中，所述盐酸盐晶型III具有基本上如图4所示的X射线粉末衍射图谱(XRPD图谱)。
在一些实施方式中，所述盐酸盐晶型III具有的差示扫描量热曲线(DSC)基本上如图11中差示扫描量热曲线所示。
在一些实施方式中，所述盐酸盐晶型III具有的热重分析曲线(TGA)基本上如图11中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III至少有一种、至少两种或下列所有的(a)-(c)均适用：(a)晶型III具有基本上如图4所示的X射线粉末衍射图谱(XRPD图谱)；(b)晶型III具有的差示扫描量热曲线(DSC)基本上如图11中差示扫描量热曲线所示；(c)晶型III具有的热重分析曲线(TGA)基本上如图11中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III具有如下属性：
(a)晶型III具有基本上如图4所示的X射线粉末衍射图谱(XRPD图谱)；
(b)晶型III具有的差示扫描量热曲线(DSC)基本上如图11中差示扫描量热曲线所示； 和
(c)晶型III具有的热重分析曲线(TGA)基本上如图11中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III具有至少显示2个、至少3个、至少4个、至少5个或至少6个2θ度反射的XRPD图案，其最大强度与XRPD图案大致如图4所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的差示扫描量热曲线在90℃-170℃有吸热峰。在一些实施方式中，所述盐酸盐晶型III的差示扫描量热曲线在125℃-170℃有吸热峰。在一些实施方式中，所述盐酸盐晶型III的差示扫描量热曲线在90℃-125℃有吸热峰，所述吸热峰为脱溶剂峰。在一些实施方式中，所述盐酸盐晶型III的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为101℃-120和/或130℃-138℃。在一些实施方式中，所述盐酸盐晶型III的差示扫描量热曲线基本上如图11中差示扫描量热曲线所示。
在一些实施方式中，所述盐酸盐晶型III的差示扫描量热曲线显示其熔点为134.32±5℃。
在一些实施方式中，所述盐酸盐晶型III的热重分析曲线在70℃-170℃的失重小于10％或者小于9％。在一些实施例中，所述化合物ATV-014盐酸盐晶型III的热重分析曲线中在70-170℃的温度范围的失重在8.6％以下。在一些实施方式中，所述盐酸盐晶型III的热重分析曲线基本上如图11中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、14.03和18.99处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、14.03和18.99处有特征峰，并且在衍射角2θ±0.2°为10.54、15.84和21.16中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、14.03和18.99处有特征峰，并且在衍射角2θ±0.2°为10.54、15.84和21.16中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、14.03和18.99处有特征峰，并且在衍射角2θ±0.2°为10.54、15.84和21.16中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、14.03和18.99处有特征峰，并且在衍射角2θ±0.2°为10.54、15.84和21.16中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.54、14.03、15.84、18.99和21.16处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.54、14.03、15.84、18.99和21.16中的至少有三处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.54、14.03、15.84、18.99和21.16处有特征峰，并且在衍射角2θ±0.2°为17.67、22.49和27.51中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.54、14.03、15.84、18.99和21.16处有特征峰，并且在衍射角2θ±0.2°为17.67、22.49和27.51中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.54、14.03、15.84、18.99和21.16处有特征峰，并且在衍射角2θ±0.2°为17.67、22.49和27.51中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.54、14.03、15.84、18.99和21.16处有特征峰，并且在衍射角2θ±0.2°为17.67、22.49和27.51中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.54、14.03、15.84、17.67、18.99、21.16、22.49和27.51处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.54、14.03、15.84、17.67、18.99、21.16、22.49和27.51中的至少有三处有特征峰。
化合物ATV-014盐酸盐晶型IV
在一些实施方式中，所述盐酸盐晶型IV具有基本上如图5所示的X射线粉末衍射图谱(XRPD图谱)。
在一些实施方式中，所述盐酸盐晶型IV具有的差示扫描量热曲线(DSC)基本上如图12中差示扫描量热曲线所示。
在一些实施方式中，所述盐酸盐晶型IV具有的热重分析曲线(TGA)基本上如图12中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV至少有一种、至少两种或下列所有的(a)-(c)均适用：(a)晶型IV具有基本上如图5所示的X射线粉末衍射图谱(XRPD图谱)；(b)晶型IV具有的差示扫描量热曲线(DSC)基本上如图12中差示扫描量热曲线所示；(c)晶型IV具有的热重分析曲线(TGA)基本上如图12中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV具有如下属性：
(a)晶型IV具有基本上如图5所示的X射线粉末衍射图谱(XRPD图谱)；
(b)晶型IV具有的差示扫描量热曲线(DSC)基本上如图12中差示扫描量热曲线所示；和
(c)晶型IV具有的热重分析曲线(TGA)基本上如图12中热重分析曲线所示。
在一些实施方式中，所述盐酸盐晶型IV的差示扫描量热曲线在180℃-200℃有吸热峰。在一些实施方式中，所述盐酸盐晶型IV的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为183℃-190℃。在一些实施方式中，所述盐酸盐晶型IV的差示扫描量热曲线基本上如图12中差示扫描量热曲线所示。
在一些实施方式中，所述盐酸盐晶型IV的差示扫描量热曲线显示其熔点为182.50±5℃。
在一些实施方式中，所述盐酸盐晶型IV的热重分析曲线在30℃-150℃的失重小于2％。在一些实施方式中，所述盐酸盐晶型IV的热重分析曲线在30℃-150℃的失重小于1％。在一些实施方式中，所述盐酸盐晶型IV的热重分析曲线在30℃-150℃的失重小于0.5％。在一些实施方式中，所述盐酸盐晶型IV的热重分析曲线在30℃-150℃的失重小于0.2％。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV具有至少显示2个、至少3个、至少4个、至少5个或至少6个2θ度反射的XRPD图案，其最大强度与XRPD图案大致如图5所示。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.63和19.13处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.63和19.13处有特征峰，并且在衍射角2θ±0.2°为9.63、14.10和16.82中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.63和19.13处有特征峰，并且在衍射角2θ±0.2°为9.63、14.10和16.82中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.63和19.13处有特征峰，并且在衍射角2θ±0.2°为9.63、14.10和16.82中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.63和19.13处有特征峰，并且在衍射角2θ±0.2°为9.63、14.10和16.82中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.63、14.10、16.82和19.13处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.63、14.10、16.82和19.13中的至少有三处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.63、14.10、16.82和19.13处有特征峰，并且在衍射角2θ±0.2°为10.19、15.99和17.62中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.63、14.10、16.82和19.13处有特征峰，并且在衍射角2θ±0.2°为10.19、15.99和17.62中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.63、14.10、16.82和19.13处有特征峰，并且在衍射角2θ±0.2°为10.19、15.99和17.62中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.63、14.10、16.82和19.13处有特征峰，并且在衍射角2θ±0.2°为10.19、15.99和17.62中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62和19.13处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62和19.13中的至少有三处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62和19.13处有特征峰，并且在衍射角2θ±0.2°为22.27、23.19和27.74中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62和19.13处有特征峰，并且在衍射角2θ±0.2°为22.27、23.19和27.74中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62和19.13处有特征峰，并且在衍射角2θ±0.2°为22.27、23.19和27.74中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62和19.13处有特征峰，并且在衍射角2θ±0.2°为22.27、23.19和27.74中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射 角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62、19.13、22.27、23.19和27.74处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62、19.13、22.27、23.19和27.74中的至少有三处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62、19.13、22.27、22.56、23.19和27.74处有特征峰。
在一些实施方式中，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62、19.13、22.27、22.56、23.19和27.74中的至少有三处有特征峰。
化合物ATV-014氢溴酸盐晶型I
在一些实施方式中，提供了化合物ATV-014氢溴酸盐晶型I，其中，所述氢溴酸盐晶型I为基本上无水晶型。
在一些实施方式中，所述氢溴酸盐晶型I具有基本上如图7所示的X射线粉末衍射图谱(XRPD图谱)。
在一些实施方式中，所述氢溴酸盐晶型I具有的差示扫描量热曲线(DSC)基本上如图14中差示扫描量热曲线所示。
在一些实施方式中，所述氢溴酸盐晶型I具有的热重分析曲线(TGA)基本上如图14中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I至少有一种、至少两种或下列所有的(a)-(c)均适用：(a)晶型I具有基本上如图7所示的X射线粉末衍射图谱(XRPD图谱)；(b)晶型I具有的差示扫描量热曲线(DSC)基本上如图14中差示扫描量热曲线所示；(c)晶型I具有的热重分析曲线(TGA)基本上如图14中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I具有如下属性：
(a)晶型I具有基本上如图7所示的X射线粉末衍射图谱(XRPD图谱)；
(b)晶型I具有的差示扫描量热曲线(DSC)基本上如图14中差示扫描量热曲线所示；和
(c)晶型I具有的热重分析曲线(TGA)基本上如图14中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I具有至少显示2个、至少3个、至少4个、至少5个或至少6个2θ度反射的XRPD图案，其最大强度与XRPD图案大致如图7所示。
在一些实施方式中，所述化合物ATV-014氢溴酸酸盐晶型I的热重分析曲线在100℃-160℃的失重小于2％。在一些实施方式中，所述化合物ATV-014氢溴酸酸盐晶型I的热重分析曲线在100℃-160℃的失重小于1.5％。在一些实施方式中，所述化合物ATV-014氢溴酸酸盐晶型I的热重分析曲线基本上如图14中的热重分析曲线所示。
在一些实施例中，所述化合物ATV-014氢溴酸盐晶型I的热重分析曲线中在室温-170℃的温度范围内没有明显失重。在一些实施方式中，所述化合物ATV-014氢溴酸酸盐晶型I的差示扫描量热曲线在130℃-170℃有吸热峰。在一些实施方式中，所述化合物ATV-014氢溴酸酸盐晶型I的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为138℃-145℃。在一些实施方式中，所述化合物ATV-014氢溴酸酸盐晶型I的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为59℃-66℃，所述吸热峰为脱溶剂峰。在一些实施方式中，所述化合物ATV-014氢溴酸酸盐晶型I的差示扫描量热曲线基本上如图14中差示扫描量热曲线所示。
在一些实施方式中，所述化合物ATV-014氢溴酸酸盐晶型I的热重分析曲线显示其熔点为132.75±5℃。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的差示扫描量热曲线中在64℃-66℃和179-183℃处具有吸热峰。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20和16.88处有特征峰。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20和16.88处有特征峰，并且在衍射角2θ±0.2°为15.41、17.46和26.38中的1处，2处或3处有特征峰。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20和16.88处有特征峰，并且在衍射角2θ±0.2°为15.41、17.46和26.38中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20和16.88处有特征峰，并且在衍射角2θ±0.2°为15.41、17.46和26.38中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20和16.88处有特征峰，并且在衍射角2θ±0.2°为15.41、17.46和26.38中的2处有特征峰。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20、15.41、16.88、17.46和26.38处有特征峰。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20、15.41、16.88、17.46和26.38中的至少有三处有特征峰。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20、15.41、16.88、17.46和26.38处有特征峰，并且在衍射角2θ±0.2°为25.52和26.79中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20、15.41、16.88、17.46和26.38处有特征峰，并且在衍射角2θ±0.2°为25.52和26.79中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20、15.41、16.88、17.46、25.52、26.38和26.79处有特征峰。
在一些实施方式中，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20、15.41、16.88、17.46、25.52、26.38和26.79中的至少有三处有特征峰。
化合物ATV-014对甲苯磺酸盐晶型I
在一些实施方式中，提供了化合物ATV-014对甲苯磺酸盐晶型I，其中，所述对甲苯磺酸盐晶型I为一水合物。
在一些实施方式中，所述对甲苯磺酸盐晶型I具有基本上如图6所示的X射线粉末衍射图谱(XRPD图谱)。
在一些实施方式中，所述对甲苯磺酸盐晶型I具有的差示扫描量热曲线(DSC)基本上如图13所示。
在一些实施方式中，所述对甲苯磺酸盐晶型I具有的热重分析曲线(TGA)基本上如图13中差示扫描量热曲线所示。
在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I至少有一种、至少两种或下列所有的(a)-(c)均适用：(a)晶型I具有基本上如图6所示的X射线粉末衍射图谱(XRPD图谱)；(b)晶型I具有的差示扫描量热曲线(DSC)基本上如图13中差示扫描量热曲线所示；(c)晶型I具有的热重分析曲线(TGA)基本上如图13中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I具有如下属性：
(a)晶型I具有基本上如图6所示的X射线粉末衍射图谱(XRPD图谱)；
(b)晶型I具有的差示扫描量热曲线(DSC)基本上如图13中差示扫描量热曲线所示；和
(c)晶型I具有的热重分析曲线(TGA)基本上如图13中热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I具有至少显示2个、至少3个、至少4个、至少5个或至少6个2θ度反射的XRPD图案，其最大强度与XRPD图案大致如图6所示。
在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的热重分析曲线在60℃-150℃的失重小于10％。在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的热重分析曲线在60℃-150℃的失重小于5％。在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的热重分析曲线在60℃-150℃的失重小于4％。在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的热重分析曲线基本上如图13中的热重分析曲线所示。
在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的热重分析曲线显示其熔点为105.92±5℃。
在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的差示扫描量热曲线在100℃-140℃有吸热峰。在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为120℃-127℃。在一些实施方式中，所述ATV-014对甲苯磺酸盐晶型I的差示扫描量热曲线中在121℃-126℃处具有吸热峰，热焓值为66J/g。在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的差示扫描量热曲线基本上如图13中差示扫描量热曲线所示。
在一些实施例中，所述ATV-014对甲苯磺酸盐晶型I的热重分析曲线中在65℃-130℃的温度范围内有3.2％以下的失重。
在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.58、10.89和16.59处有特征峰。
在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.58、10.89和16.59处有特征峰，并且在衍射角2θ±0.2°为7.23和14.59中的1处或2处有特征峰。
在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.58、10.89和16.59处有特征峰，并且在衍射角2θ±0.2°为7.23和14.59中的1处有特征峰。
在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.58、7.23、10.89、14.59和16.59处有特征峰。
在一些实施方式中，所述化合物ATV-014对甲苯磺酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.58、7.23、10.89、14.59和16.59中的至少有三处有特征峰。
本发明所述的化合物ATV014游离碱及其盐的新晶型，可用于治疗病毒感染相关疾病，或可在预防、缓解和/或治疗SARS-CoV-2相关疾病等症状。
第二方面，提供一种药物组合物。
本发明的另一个目的在于提供包含治疗有效量的化合物ATV014游离碱及其盐的新晶型和药学上可接受的辅料或赋形剂的药物组合物。一般是将治疗有效量的化合物ATV014游离碱及其盐的新晶型与一种或多种药用辅料混合或接触制成药物组合物或制剂，该药物组 合物或制剂是以制药领域中熟知的方式进行制备的。所述药物组合物或制剂可以用于治疗病毒感染相关疾病，或在预防、缓解和/或治疗SARS-CoV-2相关疾病等症状。
在一些实施方式中，一种药物组合物，其含有治疗有效量的所述的化合物ATV-014的盐酸盐晶型I、治疗有效量的所述的化合物ATV-014的盐酸盐晶型II、治疗有效量的化合物ATV-014的盐酸盐晶型III、治疗有效量的化合物ATV-014的盐酸盐晶型IV、治疗有效量的化合物ATV-014的氢溴酸酸盐晶型I或治疗有效量的化合物ATV-014的对甲苯磺酸盐晶型I，和任选地药学上可接受的赋形剂。
在一些实施方式中，一种药物组合物，含有化合物ATV014游离碱，其中至少80％的化合物ATV014游离碱为所述化合物ATV014游离碱晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014游离碱，其中至少90％的化合物ATV014游离碱为所述化合物ATV014游离碱晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014游离碱，其中至少95％的化合物ATV014游离碱为所述化合物ATV014游离碱晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014游离碱，其中至少99％的化合物ATV014游离碱为所述化合物ATV014游离碱晶型I。
在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少80％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少90％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少95％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少99％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型I。
在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少80％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型II。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少90％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型II。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少95％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型II。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少99％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型II。
在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少80％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型III。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少90％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型III。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少95％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型III。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少99％的化合物 ATV014盐酸盐为所述化合物ATV014盐酸盐晶型III。
在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少80％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型IV。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少90％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型IV。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少95％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型IV。在一些实施方式中，一种药物组合物，含有化合物ATV014盐酸盐，其中至少99％的化合物ATV014盐酸盐为所述化合物ATV014盐酸盐晶型IV。
在一些实施方式中，一种药物组合物，含有化合物ATV014氢溴酸盐，其中至少80％的化合物ATV014氢溴酸盐为所述化合物ATV014氢溴酸盐晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014氢溴酸盐，其中至少90％的化合物ATV014氢溴酸盐为所述化合物ATV014氢溴酸盐晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014氢溴酸盐，其中至少95％的化合物ATV014氢溴酸盐为所述化合物ATV014氢溴酸盐晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014氢溴酸盐，其中至少99％的化合物ATV014氢溴酸盐为所述化合物ATV014氢溴酸盐晶型I。
在一些实施方式中，一种药物组合物，含有化合物ATV014对甲苯磺酸盐，其中至少80％的化合物ATV014对甲苯磺酸盐为所述化合物ATV014对甲苯磺酸盐晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014对甲苯磺酸盐，其中至少90％的化合物ATV014对甲苯磺酸盐为所述化合物ATV014对甲苯磺酸盐晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014对甲苯磺酸盐，其中至少95％的化合物ATV014对甲苯磺酸盐为所述化合物ATV014对甲苯磺酸盐晶型I。在一些实施方式中，一种药物组合物，含有化合物ATV014对甲苯磺酸盐，其中至少99％的化合物ATV014对甲苯磺酸盐为所述化合物ATV014对甲苯磺酸盐晶型I。
第三方面，提供前述晶型或药物组合物的用途。
一种第一方面所述化合物ATV-014的盐酸盐晶型I、所述的化合物ATV-014的盐酸盐晶型II、所述的化合物ATV-014的盐酸盐晶型III、所述的化合物ATV-014的盐酸盐晶型IV、所述的化合物ATV-014的氢溴酸酸盐晶型I、所述的化合物ATV-014的对甲苯磺酸盐晶型I或者第二方面所述的药物组合物在制备用于治疗病毒感染相关疾病或症状的药物中的应用。
本发明所述的含有化合物ATV014游离碱及其盐的新晶型，可用于预防、缓解和/或治疗病毒感染相关疾病或症状，或可在预防、缓解和/或治疗SARS-CoV-2或其突变株的相关疾病等症状的方法中。
本发明提供的新晶型，目前尚无报道，本发明的发明人经过研究，突破了这一难题，找到了适合开发的新晶型，该新晶型具有稳定性更好，溶解性好，而更稳定的晶型对于提高药物质量具有重要意义。
本发明提供的新晶型，具有在水中稳定性好，不易在高湿条件下潮解，方便药物长期贮存放置。本发明提供的晶型稳定性好，工艺提纯效果显著，能很好的避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变，具有很强的经济价值。
本发明的有益效果为：
(1)本发明所提供的式ATV-014氢溴酸盐晶型I在70％RH(开口)条件下放置一周，吸湿0.2％，90％RH(开口)条件下放置一周，吸湿18.8％。
(2)本发明所提供的式ATV-014对甲苯磺酸盐晶型I在30％RH(开口)条件下放置一周，吸湿0.4％，90％RH(开口)条件下放置一周，吸湿0.5％，晶型和化学纯度没有发生改变，物理和化学稳定性良好。
(3)DVS结果表明，ATV-014氢溴酸盐晶型I具有吸湿性；在70％RH条件下平衡30至120min后，其吸湿增重为0.2％；在70％RH至90％RH条件下吸湿较强，在90％RH条件下的吸湿增重量为18.8％。样品在DVS测试过程中转变为无定型玻璃态固体。
(4)DVS结果表明，ATV-014对甲苯磺酸盐晶型I具有轻微吸湿性；在90％RH条件下平衡30至120min后，其吸湿增重约为0.5％。DVS测试结束后，剩余固体的晶型未见改变。
(5)本发明所提供的式ATV-014盐酸盐晶型在40℃/75％RH，RH(开口)条件下放置一周，晶型和化学纯度没有发生改变，物理和化学稳定性良好。
术语定义
除非另外说明，否则如本文使用的以下术语和短语意图具有以下含义：
术语“晶型”是指在化合物晶格中的分子的一个独特有序排列和/或构象。
X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施方案中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为绝对的。根据本试验所用仪器状况，衍射峰存在±0.2°的误差容限。
差示扫描量热(DSC)是在程序控制下，通过不断加热或降温，测量样品与惰性参比物(常用α-Al 2O 3)之间的能量差随温度变化的一种技术。DSC曲线的熔化峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明所述晶型的特征在于具有特征峰位置的DSC图，其基本上如本发明附图中提供的DSC图所示。同时，DSC图谱可以有实验误差，不同仪器以及不同样品之间，DSC图谱的峰位置和峰值可能会略有差别，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本试验所用仪器状况，熔化峰存在±3°的误差容限。
玻璃态转变是指非晶态物质在高弹态和玻璃态之间的转变，是该物质的固有性质；它所对应的转变温度为玻璃化转变温度(Tg)，是非晶态物质的一个重要物理性质。玻璃化转变是与分子运动有关的现象，因而，玻璃化转变温度(Tg)主要取决于物质的结构，而对实验细节等相对不敏感。根据本试验所用仪器状况，熔化峰存在±3°的误差容限。
热重分析(TGA)是在程序控制下，测定物质的质量随温度变化的一种技术，适用于检查晶体中溶剂的丧失或样品升华、分解的过程，可推测晶体中含结晶水或结晶溶剂的情况。TGA曲线显示的质量变化取决于样品制备和仪器等许多因素；不同仪器以及不同样品之间，TGA检测的质量变化略有差别。根据本试验所用的仪器状况，质量变化存在±0.1％的误差容限。
在本发明的上下文中，X-射线粉末衍射图中的2θ值均以度(°)为单位。
当提及谱图或/和出现在图中的数据时，“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。
术语“基本上纯净的”是指一种晶型基本上不含有一种或多种其它晶型，其晶型纯度至少60％，或至少70％，或至少80％，或至少85％，或至少90％，或至少93％，或至少95％，或至少98％，或至少99％，或至少99.5％，或至少99.6％，或至少99.7％，或至少99.8％，或至少99.9％，或其晶型含有其它晶型，所述其他晶型在晶型的总体积或重量百分比少于20％，或少于10％，或少于5％，或少于3％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01。
术语“基本上不含有”一种或多种其它晶型是指其它晶型的含量在总体积或重量中百分比少于20％，或少于10％，或少于5％，或少于4％，或少于3％，或少于2％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。
术语X-射线粉末衍射图“基本上如图所示”是指X-射线粉末衍射图中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰出现在其图中。
术语“相对强度”是指X-射线粉末衍射图的所有衍射峰中第一强峰的强度为100％时，其它峰的强度与第一强峰的强度的比值。
术语“反溶剂”是指能促进溶液达到过度饱和状态或结晶的溶剂。在一些实施例中，ATV014游离碱在反溶剂中的溶解度小于0.001g/L，或小于0.01g/L，或小于0.1g/L，或小于0.2g/L，或小于0.3g/L，或小于0.4g/L，或小于0.5g/L，或小于0.6g/L，或小于0.8g/L，或小于1g/L，或小于2g/L，或小于3g/L，或小于4g/L，或小于5g/L，或小于6g/L，或小于7g/L，或小于8g/L，或小于9g/L，或小于10g/L。
当指图谱和/或图中数据的术语“峰”是指本领域的技术人员不会归属于背景噪音的一个特征。
术语“任选”、“任选的”或“任选地”是指随后描述的事件或情形可以但不一定出现。例如，“任选地药学上可接受的赋形剂”表示“药学上可接受的赋形剂”可以存在或者不存在。
本发明中的数字均为近似值，无论有否使用“大约”或“约”等字眼。数字的数值有可能会出现1％、2％、5％、7％、8％、10％、15％或20％等差异。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％，N+/-10％，N+/-15％或N+/-20％值的数字会被明确地公开，其中“+/-”是指加或减。每当公开一个数值范围的一个下限，R L，和一个上限，R U，时，任何处于该公开了的范围之内的数值会被明确地公开。特别是，包含了以下该范围内明确地公开的数值：R＝R L+K＊(R U-R L)，其中K是一个按1％的增量增加的从1％到100％的变量，即：1％、2％、3％、4％、5％、50％、51％、52％……95％、96％、97％、98％、99％或100％。另外，还明确地在此公开了上述以两个R数字定义的数值范围。
本发明中“室温”指的是环境温度，温度由大约10℃到大约40℃。在一些实施例中，“室温”指的是温度由大约20℃到大约30℃；在另一些实施例中，“室温”指的是温度由大约25℃到大约30℃；在又一些实施例中，“室温”指的是10℃、15℃、20℃、25℃、30℃、35℃、40℃等。
本文使用的术语“治疗”，除非另外表明，否则意指逆转、减轻该术语所适用的病症或疾患或这样的病症或疾患的一个或多个症状、抑制所述病症或疾患或其一个或多个症状的进展或防止所述病症或疾患或其一个或多个症状。如本文使用的术语“治疗”是指治疗行为，如“治疗”在上文刚定义的。
本发明上下文中“ATV-014氢溴酸盐晶型I”和“化合物ATV-014氢溴酸盐晶型I”表示同一含义，其他晶型以此类推。
仪器参数
除非参数中另行规定，以下所有分析都在室温下进行。
X-射线粉末衍射研究
使用零背景样品盘，在装配有自动进样器的德国Bruker D8 Advance X射线衍射仪上收集X-射线粉末衍射图谱。所用辐射源为Cu kα
Figure PCTCN2022093342-appb-000004
其中光管电压设定在40KV，光管电流设定在40mA。X-射线的发散狭缝为0.6mm。取适量样品在环境条件下于零背景样品盘中央，用洁净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定。将样品以0.02°(2θ)的扫描步长在3-40°(2θ)范围内进行衍射分析。用于数据收集的软件为DIFFRAC.COMMANDER，数据用DIFFRAC.EVA分析和展示。
差示扫描量热法(DSC)
使用TA Insturment Discovery DSC 250型仪器，用带孔的加盖铝盘对样品进行DSC分析。
将样品(约2-5mg)在铝盘中称量，用Tzero压盖，精密记录样品量，并将样品转移至仪器中进行测量。仪器用氮气以50mL/min吹扫。在25℃到300℃之间以10℃/min的加热速率收集数据。数据用TRIOS分析和展示。
热重分析法(TGA)
使用TA Instrument Discovery TGA 55型仪器，用开口的铝盘对样品进行TGA分析。通常将2-5mg样品放入预平衡的铝制样品盘中，并以10℃/min从环境温度加热至300℃。样品室保持25mL/min的氮气流。在TGA图谱中，横坐标标示温度(Temperature，℃)，纵坐标表示失重的百分含量(Weight(％))。
晶型的高效液相色谱(HPLC)检测
液相色谱分析所用到的仪器为安捷伦HPLC 1260系列，
表1.用于稳定性研究的HPLC方法
Figure PCTCN2022093342-appb-000005
上述各种剂型的药物均可以按照药学领域的常规方法制备。
本发明中，一些化合物的缩写所表示的化合物结构，表2：
Figure PCTCN2022093342-appb-000006
在描述实验细节时，使用了某些缩写和缩略词。尽管它们中的大多数能被本领域技术人员所理解，但下表包含了这些缩写和缩略词的列表，表3
缩写 含义
ACN 乙腈
DCC 二环己基碳二亚胺
DCM 二氯甲烷
DMAP 4-二甲氨基吡啶
EDMA N，N-二甲基乙胺
PE 石油醚
rt 室温
TEA 三乙胺
TLC 薄层色谱法
MeOH 甲醇
EtOH 乙醇
IPA 异丙醇
NBA 正丁醇
MEK 丁酮
MTBE 甲基叔丁基醚
EA 乙酸乙酯
IPAc 乙酸异丙酯
Tol 甲苯
Hept 正庚烷
THF 四氢呋喃
DMSO 二甲基亚砜
附图说明
图1示化合物ATV-014游离碱晶型I的X射线粉末衍射检测谱图。
图2示化合物ATV-014盐酸盐晶型I的X射线粉末衍射检测谱图。
图3示化合物ATV-014盐酸盐晶型II的X射线粉末衍射检测谱图。
图4示化合物ATV-014盐酸盐晶型III的X射线粉末衍射检测谱图。
图5示化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射检测谱图。
图6示化合物ATV-014对甲苯磺酸盐晶型I的X射线粉末衍射检测谱图。
图7示化合物ATV-014盐酸盐晶型IV的X射线粉末衍射检测谱图。
图8示化合物ATV-014游离碱晶型I的差示扫描量热检测谱图和热重分析谱图。
图9示化合物ATV-014盐酸盐晶型I的差示扫描量热检测谱图和热重分析谱图。
图10示化合物ATV-014盐酸盐晶型II的差示扫描量热检测谱图和热重分析谱图。
图11化合物ATV-014示盐酸盐晶型III的差示扫描量热检测谱图和热重分析谱图。
图12示化合物ATV-014氢溴酸盐晶型I的差示扫描量热检测谱图和热重分析谱图。
图13示化合物ATV-014对甲苯磺酸盐晶型I的差示扫描量热检测谱图和热重分析谱图。
图14示化合物ATV-014盐酸盐晶型IV的差示扫描量热检测谱图和热重分析谱图。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例以对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
实施例1 ATV-014盐酸盐晶型I的制备
称取25mg的ATV-014游离碱晶型I，加入1mL THF制成饱和溶液，将1.0当量的盐酸加入上述药液中进行成盐，然后加入1mL MTBE作为反溶剂，析出固体，所得混悬液在室温下继续搅拌20h，固体经过滤收集，并在50℃真空干燥3h得到ATV-014盐酸盐晶型I。取所得ATV-014盐酸盐晶型I检测X射线粉末衍射、DSC和TGA，其X射线粉末衍射谱图如图2所示，其DSC和TGA谱图如图9所示。
实施例2 ATV-014盐酸盐晶型II的制备
将0.16mL的浓盐酸用IPA稀释至3mL。将94mg的ATV-014游离碱晶型I加入1.02mL的HCl-IPA溶液(1.05当量)，室温下搅拌约十分钟，混合液变得粘稠，再加入0.5mL的IPA，混悬液在室温下搅拌2h后加入1mL MTBE，再继续搅拌2小时，过滤并收集固体。用3mL的MTBE洗涤固体，随后在50℃真空干燥3h得到ATV-014盐酸盐晶型II。取所得ATV-014盐酸盐晶型II检测X射线粉末衍射、DSC和TGA，其X射线粉末衍射谱图如图3所示，其DSC和TGA谱图如图10所示。
实施例3 ATV-014盐酸盐晶型III的制备
将69mg的ATV-014游离碱晶型I混悬于1mL的二氯甲烷中，所得混悬液在室温搅拌约10分钟后，再加入1.0当量的浓盐酸，再搅拌2小时，过滤固体，并在真空50℃干燥3h得到ATV-014盐酸盐晶型III。取所得ATV-014盐酸盐晶型III检测X射线粉末衍射、DSC和TGA，其X射线粉末衍射谱图如图4所示，其DSC和TGA谱图如图11所示。
实施例4 ATV-014氢溴酸盐晶型I的制备
约500mg游离碱晶型I混悬于15mL乙酸乙酯中，所得混悬液室温搅拌10分钟，然后加入1当量的氢溴酸，并室温搅拌2小时。过滤并收集固体，然后在50℃真空干燥过夜得到ATV-014氢溴酸盐晶型I。取所得ATV-014氢溴酸盐晶型I检测X射线粉末衍射、DSC和TGA，其X射线粉末衍射谱图如图5所示，其DSC和TGA谱图如图12所示。
实施例5 ATV-014对甲苯磺酸盐晶型I的制备
约500mg游离碱晶型I混悬于15mL异丙醇中，然后加入1当量对甲苯磺酸固体，固体大部分溶解。混悬液在室温条件下搅拌2小时，没有更多固体析出。加入对甲苯磺酸盐的晶种，然后继续搅拌2小时后，过滤并收集固体。所得固体室温晾干过夜，然后在40℃真空干燥2小时得到ATV-014对甲苯磺酸盐晶型I。取所得ATV-014对甲苯磺酸盐晶型I检测X射线粉末衍射、DSC和TGA，其X射线粉末衍射谱图如图6所示，其DSC和TGA谱图如图13所示。
实施例6 ATV-014盐酸盐晶型IV的制备
向50mL单口瓶中加入ATV014(1g，2.5mmol)，5mL甲醇(基本不溶)，于冰浴条件下滴加4.0M盐酸甲醇溶液(0.9mL，3.75mmol)，2min后滴毕，溶液澄清透明，直接向剩余物中加入20mL MTBE，于室温下搅拌2h，形成大量白色固体，抽滤，45℃下真空干燥，得到1g ATV014盐酸盐。取所得ATV-014盐酸盐晶型IV检测X射线粉末衍射、DSC和TGA，其X射线粉末衍射谱图如图7所示，其DSC和TGA谱图如图14所示。
实施例7 ATV-014游离碱晶型I的制备
Figure PCTCN2022093342-appb-000007
在500mL反应器中，安装好搅拌器、温度计、恒压滴液漏斗，加入GS-441524(10g，0.03mol)，加入经硫酸镁干燥后的丙酮(300mL)，再加入2，2-二甲氧基丙烷(17g，0.16mol)，于室温下向体系中滴加浓硫酸(2.4mL，0.04mol)，5min后滴加完毕，固体开始溶解，升温至45℃继续反应4h，HPLC监测反应完全(OD-3柱，流动相：正己烷/异丙醇＝80∶20，流速：0.8mL/min，进样量1μL)，停止反应，冰浴冷却后，向反应液中加入NaHCO 3固体(10g)，水(30mL)，继续用碳酸氢钠调pH至7-8、减压蒸馏去除溶剂，剩余物用乙酸乙酯 (300mL)稀释，乙酸乙酯层分别用水(80mL)，饱和氯化钠水溶液(80mL)洗涤，无水硫酸钠干燥。抽滤，滤液减压蒸馏至剩余100mL左右溶剂，将剩余物缓慢倒入冰浴冷却的石油醚中，并剧烈搅拌，洗出大量白色固体，抽滤得到10.5g白色固体的化合物1，收率为91％。
将15。0g的化合物1溶于15ml的二氯甲烷中，再加入环己甲酸和554.0mg的4-二甲氨基吡啶，搅拌10min后，加入10.2g的二环己基碳二亚胺，室温搅拌24h。经过柱层析分离(洗脱液为：石油醚/乙酸乙酯(V/V)＝1/1)，得到化合物2(白色固体)。将化合物2溶于30mL质量百分比为37％的盐酸水溶液和150mL的四氢呋喃中，搅拌6小时后，加入碳酸钠调节pH至8，旋转蒸发除去有机溶剂，经过柱层析分离(洗脱液为：石油醚/乙酸乙酯(V/V)＝1/3)，得到化合物2.8g ATV014(游离碱晶型I，产率49％)，两步收率为45.8％。取所得ATV-014游离碱晶型I检测X射线粉末衍射、DSC和TGA，其X射线粉末衍射谱图如图1所示，其DSC和TGA谱图如图8所示。取得到的化合物ATV014检测氢谱和碳谱，结果如下：
氢谱： 1H NMR(600MHz，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＝12.3Hz，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).
碳谱： 13C NMR(150MHz，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.
实施例8 影响因素稳定性研究
取ATV-014游离碱晶型I、ATV-014氢溴酸盐晶型I和ATV-014对甲苯磺酸盐晶型I，分别于40℃/75％RH(开口)和60℃(加盖样品瓶)条件下放置7天，分别于0天和7天进行高效液相色谱检测和X射线粉末衍射检测，结果如表4所示。
表4：影响因素稳定性研究
Figure PCTCN2022093342-appb-000008
结论：结果显示，ATV-014游离碱晶型I和ATV-014对甲苯磺酸盐晶型I在实验条件(60℃ 和40℃/75％RH)下放置7天，化合物纯度不变，晶型不变，其物理和化学稳定性良好；ATV-014氢溴酸盐晶型I在实验条件下(60℃)下放置7天，化合物纯度不变，晶型不变；在40℃/75％RH下放置7天，样品液化。
实施例9 溶解度研究
根据成盐筛选研究结果，在FaSSIF、FeSSIF、SGF和水中，于37℃条件下测定了游离碱晶型I和对甲苯磺酸盐晶型I在0.5小时、2小时和24小时的溶解度。溶解度及溶液pH值结果见：表。
表5.生物相关介质中的溶解度结果
Figure PCTCN2022093342-appb-000009
结果表明，样品溶解度呈现出pH依赖性，低pH条件下呈现出高溶解度，样品的溶解度越高。ATV-014对甲苯磺酸盐晶型I的溶解度高于5mg/mL，而ATV-014游离碱晶型I在SGF的溶解度为2.5-2.9mg/mL。另外，ATV-014对甲苯磺酸盐在水的溶解度比游离 碱高30倍。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。

Claims (19)

  1. 一种如下所示化合物ATV014的盐酸盐晶型I：
    Figure PCTCN2022093342-appb-100001
    其特征在于，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、15.53和20.76处有特征峰；或所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、10.33、15.53、20.76、22.75和24.19处有特征峰；或所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、10.33、15.53、20.76、22.75、23.88、24.19和26.01处有特征峰。
  2. 权利要求1所述的化合物ATV-014盐酸盐晶型I，其特征在于，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、15.53和20.76处有特征峰，还在衍射角2θ±0.2°为10.33、22.75和24.19中的1处，2处或3处有特征峰；或所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为5.16、10.33、15.53、20.76、22.75和24.19处有特征峰，还在衍射角2θ±0.2°为23.88和26.01中的1处或2处有特征峰。
  3. 权利要求1所述的化合物ATV-014盐酸盐晶型I，其特征在于，所述化合物ATV-014盐酸盐晶型I的X射线粉末衍射图谱基本如图2所示；和/或
    所述化合物ATV-014盐酸盐晶型I的差示扫描量热曲线在120℃-170℃有吸热峰；或者所述化合物ATV-014盐酸盐晶型I的差示扫描量热曲线在125℃-165℃有吸热峰；或者所述化合物ATV-014盐酸盐晶型I的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为141℃-151℃或143℃-149℃；或者所述化合物ATV-014盐酸盐晶型I的差示扫描量热曲线基本上如图9中差示扫描量热曲线所示；和/或
    所述化合物ATV-014盐酸盐晶型I的热重分析曲线在110℃-170℃的失重小于10％或者小于9％或者小于8％；或者所述化合物ATV-014盐酸盐晶型I的热重分析曲线基本上如图9中的热重分析曲线所示。
  4. 一种如下所示化合物ATV014的盐酸盐晶型II：
    Figure PCTCN2022093342-appb-100002
    其特征在于，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、10.43和18.79处有特征峰；或所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、18.79和22.28处有特征峰；或所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、18.79、19.46、21.38和22.28处有特征峰；或所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角26±0.2°为5.23、9.88、10.43、14.05、15.68、17.81、18.79、19.46、20.37、21.38、22.28和23.96处有特征峰；或所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为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和37.05处有特征峰。
  5. 权利要求4所述的化合物ATV-014盐酸盐晶型II，其特征在于，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、10.43和18.79处有特征峰，还在衍射角2θ±0.2°为9.88、14.05和22.28中的1处，2处或3处有特征峰；或所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、18.79和22.28处有特征峰，还在衍射角2θ±0.2°为15.68、19.46和21.38中的1处，2处或3处有特征峰；或所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、18.79、19.46、21.38和22.28处有特征峰，还在衍射角2θ±0.2°为17.81、20.37和23.96中的1处，2处或3处有特征峰；或所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱在衍射角2θ±0.2°为5.23、9.88、10.43、14.05、15.68、17.81、18.79、19.46、20.37、21.38、22.28和23.96处有特征峰，还在衍射角2θ±0.2°为22.81和37.05中的1处或2处有特征峰。
  6. 权利要求4所述的化合物ATV-014盐酸盐晶型II，其特征在于，所述化合物ATV-014盐酸盐晶型II的X射线粉末衍射图谱基本如图3所示；和/或
    所述化合物ATV-014盐酸盐晶型II的差示扫描量热曲线在100℃-150℃有吸热峰；或者所述化合物ATV-014盐酸盐晶型II的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为135℃-145℃或136℃-143℃；或者所述化合物ATV-014盐酸盐晶型II的差示扫描量热曲线基本上如图10中差示扫描量热曲线所示；和/或所述化合物ATV-014盐酸盐晶型II的热重分析曲线在70℃-170℃的失重小于10％或者小于8％；
    或者所述化合物ATV-014盐酸盐晶型II的热重分析曲线基本上如图10中热重分析曲线 所示。
  7. 一种如下所示化合物ATV014的盐酸盐晶型III：
    Figure PCTCN2022093342-appb-100003
    其特征在于，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、14.03和18.99处有特征峰；或所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.54、14.03、15.84、18.99和21.16处有特征峰；或所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.54、14.03、15.84、17.67、18.99、21.16、22.49和27.51处有特征峰。
  8. 权利要求7所述的化合物ATV-014盐酸盐晶型III，其特征在于，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、14.03和18.99处有特征峰，还在衍射角2θ±0.2°为10.54、15.84和21.16中的1处，2处或3处有特征峰；或所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.54、14.03、15.84、18.99和21.16处有特征峰，还在衍射角2θ±0.2°为17.67、22.49和27.51中的1处，2处或3处有特征峰。
  9. 权利要求7所述的化合物ATV-014盐酸盐晶型III，其特征在于，所述化合物ATV-014盐酸盐晶型III的X射线粉末衍射图谱基本如图4所示；和/或
    所述化合物ATV-014盐酸盐晶型III的差示扫描量热曲线在90℃-170℃有吸热峰；或者所述化合物ATV-014盐酸盐晶型III的差示扫描量热曲线在125℃-170℃有吸热峰；或者所述化合物ATV-014盐酸盐晶型III的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为130℃-138℃；或者所述化合物ATV-014盐酸盐晶型III的差示扫描量热曲线基本上如图11中差示扫描量热曲线所示；和/或
    所述化合物ATV-014盐酸盐晶型III的热重分析曲线在70℃-170℃的失重小于10％或者小于9％；
    或者所述化合物ATV-014盐酸盐晶型III的热重分析曲线基本上如图11中热重分析曲线所示。
  10. 一种如下所示化合物ATV014的盐酸盐晶型IV：
    Figure PCTCN2022093342-appb-100004
    其特征在于，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.63和19.13处有特征峰；或所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.63、14.10、16.82和19.13处有特征峰；或所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62和19.13处有特征峰；或所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62、19.13、22.27、23.19和27.74处有特征峰。
  11. 权利要求10所述的化合物ATV-014盐酸盐晶型IV，其特征在于，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、10.63和19.13处有特征峰，还在衍射角2θ±0.2°为9.63、14.10和16.82中的1处，2处或3处有特征峰；或所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.63、14.10、16.82和19.13处有特征峰，还在衍射角2θ±0.2°为10.19、15.99和17.62中的1处，2处或3处有特征峰；或所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱在衍射角2θ±0.2°为5.28、9.63、10.19、10.63、14.10、15.99、16.82、17.62和19.13处有特征峰，还在衍射角2θ±0.2°为22.27、23.19和27.74中的1处，2处或3处有特征峰。
  12. 权利要求10所述的化合物ATV-014盐酸盐晶型IV，其特征在于，所述化合物ATV-014盐酸盐晶型IV的X射线粉末衍射图谱基本如图5所示；和/或
    所述化合物ATV-014盐酸盐晶型IV的差示扫描量热曲线在180℃-200℃有吸热峰；或者所述化合物ATV-014盐酸盐晶型IV的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为183℃-190℃；或者所述化合物ATV-014盐酸盐晶型IV的差示扫描量热曲线基本上如图12中差示扫描量热曲线所示；和/或
    所述化合物ATV-014盐酸盐晶型IV的热重分析曲线在30℃-150℃的失重小于2％或者小于1％或者小于0.5％或者小于0.2％；
    或者所述化合物ATV-014盐酸盐晶型IV的热重分析曲线基本上如图12中的热重分析曲线所示。
  13. 一种如下所示化合物ATV014的氢溴酸酸盐晶型I：
    Figure PCTCN2022093342-appb-100005
    其特征在于，所述化合物ATV-014氢溴酸酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20和16.88处有特征峰；或所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20、15.41、16.88、17.46和26.38处有特征峰；或所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20、15.41、16.88、17.46、25.52、26.38和26.79处有特征峰。
  14. 权利要求13所述的化合物ATV-014氢溴酸酸盐晶型I，其特征在于，所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20和16.88处有特征峰，还在衍射角2θ±0.2°为15.41、17.46和26.38中的1处，2处或3处有特征峰；或所述化合物ATV-014氢溴酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.78、13.20、15.41、16.88、17.46和26.38处有特征峰，还在衍射角2θ±0.2°为25.52和26.79中的1处或2处有特征峰。
  15. 权利要求13所述的化合物ATV-014氢溴酸酸盐晶型I，其特征在于，所述化合物ATV-014氢溴酸酸盐晶型I的X射线粉末衍射图谱基本如图7所示；和/或
    所述化合物ATV-014氢溴酸酸盐晶型I的差示扫描量热曲线在130℃-170℃有吸热峰；或者所述化合物ATV-014氢溴酸酸盐晶型I的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为138℃-145℃；或者所述化合物ATV-014氢溴酸酸盐晶型I的差示扫描量热曲线基本上如图14中差示扫描量热曲线所示；和/或
    所述化合物ATV-014氢溴酸酸盐晶型I的热重分析曲线在100℃-160℃的失重小于2％或者小于1.5％；或者所述化合物ATV-014氢溴酸酸盐晶型I的热重分析曲线基本上如图14中的热重分析曲线所示。
  16. 一种如下所示化合物ATV014的对甲苯磺酸盐晶型I：
    Figure PCTCN2022093342-appb-100006
    其特征在于，所述化合物ATV-014对甲苯磺酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2°为3.58、10.89和16.59处有特征峰；或所述化合物ATV-014对甲苯磺酸盐晶型I的X射线粉末衍射图谱在衍射角2θ±0.2° 为3.58、7.23、10.89、14.59和16.59处有特征峰。
  17. 权利要求16所述的化合物ATV-014对甲苯磺酸盐晶型I，其特征在于，所述化合物ATV-014对甲苯磺酸盐晶型I的X射线粉末衍射图谱基本如图6所示；和/或
    所述化合物ATV-014对甲苯磺酸盐晶型I的差示扫描量热曲线在100℃-140℃有吸热峰；或者所述化合物ATV-014对甲苯磺酸盐晶型I的差示扫描量热曲线有吸热峰，所述吸热峰的峰值为120℃-127℃；或者所述化合物ATV-014对甲苯磺酸盐晶型I的差示扫描量热曲线基本上如图13中差示扫描量热曲线所示；和/或
    所述化合物ATV-014对甲苯磺酸盐晶型I的热重分析曲线在60℃-150℃的失重小于10％或者小于5％或者小于4％；和/或
    所述化合物ATV-014对甲苯磺酸盐晶型I的热重分析曲线基本上如图13中的热重分析曲线所示。
  18. 一种药物组合物，所述的药物组合物包含治疗有效量的权利要求1-3任一所述的化合物ATV-014的盐酸盐晶型I、治疗有效量的权利要求4-6任一所述的化合物ATV-014的盐酸盐晶型II、治疗有效量的权利要求7-9任一所述的化合物ATV-014的盐酸盐晶型III、治疗有效量的权利要求10-12任一所述的化合物ATV-014的盐酸盐晶型IV、治疗有效量的权利要求13-15任一所述的化合物ATV-014的氢溴酸酸盐晶型I或治疗有效量的权利要求16-17任一所述的化合物ATV-014的对甲苯磺酸盐晶型I，和任选地药学上可接受的赋形剂。
  19. 一种权利要求1-3任一所述的化合物ATV-014的盐酸盐晶型I、权利要求4-6任一所述的化合物ATV-014的盐酸盐晶型II、权利要求7-9任一所述的化合物ATV-014的盐酸盐晶型III、权利要求10-12任一所述的化合物ATV-014的盐酸盐晶型IV、权利要求13-15任一所述的化合物ATV-014的氢溴酸酸盐晶型I、权利要求16-17任一所述的化合物ATV-014的对甲苯磺酸盐晶型I或者权利要求18所述的药物组合物在制备用于预防、缓解和/或治疗病毒感染相关疾病或症状的药物中的应用。
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