WO2023274242A1 - 苯基[a]吲哚[2,3-g]并喹嗪类化合物的晶型、其盐和盐的晶型及其制备方法和应用 - Google Patents

苯基[a]吲哚[2,3-g]并喹嗪类化合物的晶型、其盐和盐的晶型及其制备方法和应用 Download PDF

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WO2023274242A1
WO2023274242A1 PCT/CN2022/101986 CN2022101986W WO2023274242A1 WO 2023274242 A1 WO2023274242 A1 WO 2023274242A1 CN 2022101986 W CN2022101986 W CN 2022101986W WO 2023274242 A1 WO2023274242 A1 WO 2023274242A1
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formula
crystal form
compound
represented
compound represented
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李永国
王春娟
贾国慧
舒诗会
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广州嘉越医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular, the present invention relates to a crystal form of a phenyl[a]indole[2,3-g]quinoquinazine compound, a salt thereof, a crystal form of the salt and a preparation method thereof and application.
  • Hyperlipidemia is the main risk factor for cardiovascular disease. Excessive blood lipid levels can directly cause some diseases that seriously endanger human health, such as atherosclerosis, coronary heart disease and so on.
  • the clinical manifestations of hyperlipidemia are mainly xanthoma caused by lipid deposition in the dermis and arteriosclerosis caused by lipid deposition in the vascular endothelium.
  • hyperlipidemia can cause xanthoma, its incidence is not very high; and the occurrence and development of atherosclerosis is a slow and gradual process. Therefore, under normal circumstances, most patients have no obvious symptoms and abnormal signs. Many people are found to have elevated plasma lipoprotein levels when blood biochemical tests are performed for other reasons. Cardiovascular disease accounts for a quarter of all deaths, equivalent to one death from cardiovascular disease every three minutes.
  • statins the main lipid-lowering drugs.
  • statins the main lipid-lowering drugs
  • PCSK9 is mainly regulated by the transcription factor Sterol Response Element Binding Protein-2 (SREBP-2), and exists in the endoplasmic reticulum of liver cells in the form of precursors of soluble zymogens, and undergoes autocatalysis Hydrolyzed to form mature PCSK9 and secreted into plasma.
  • SREBP-2 Sterol Response Element Binding Protein-2
  • Plasma LDL-c is taken up by LDLR expressed on the surface of liver cells, endocytized into cells, and degraded in lysosomes.
  • PCSK9 can compete with LDL-c to bind to LDLR, mediate the degradation of LDLR, and cause the increase of plasma LDL-c level. Therefore, PCSK9 plays a key regulatory role in maintaining cholesterol homeostasis in the body, and inhibiting PCSK9 can significantly reduce the level of LDL-C in the body.
  • PCSK9 inhibitors including Sanofi, Amgen, Novartis, Pfizer and Bristol-Myers Squibb.
  • PCSK9 monoclonal antibody has many advantages, such as: high specificity to the target, longer half-life, and greatly reduced frequency of medication. More importantly, PCSK9 monoclonal antibodies have shown promising results in pre-clinical trials.
  • PCSK9 can quickly , Lower plasma LDL-C level stably, none of the 270 cases had obvious adverse reactions, and there will be no discomfort or ineffectiveness caused by statin drug tolerance.
  • PCSK9 monoclonal antibody can also improve other lipoprotein indicators that cause cardiovascular risk, such as non-HDL-C, apolipoprotein B, lipoprotein a, etc.
  • the technical problem to be solved by the present invention is to improve the physical and chemical properties of phenyl [a] indole [2,3-g] quinozine compounds in the prior art, thereby providing a phenyl [a] indole Crystal forms of [2,3-g]quinoquinazine compounds, salts thereof, crystal forms of salts, preparation methods and applications thereof.
  • the crystal form of phenyl [a] indole [2,3-g] quinozine compound, its salt and each crystal form of the present invention have one or more of the following advantages: better solubility, stable properties, It has good wettability and has a good prospect of being a medicine.
  • the present invention provides a compound represented by formula II (that is, the hydrochloride salt of the compound represented by formula I), its crystal form or hydrate;
  • the present invention also provides a crystal form A of the compound represented by formula II, and its X-ray powder diffraction pattern represented by 2 ⁇ angle has Diffraction peaks.
  • the crystal form A of the compound represented by formula II has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 5.78 ⁇ 0.2°, 10.11 ⁇ 0.2°, 11.51 ⁇ 0.2°, 13.73 ⁇ 0.2 °, 16.97 ⁇ 0.2°, 17.77 ⁇ 0.2° have diffraction peaks.
  • the crystal form A of the compound represented by formula II has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 5.78 ⁇ 0.2°, 7.12 ⁇ 0.2°, 8.29 ⁇ 0.2°, 10.11 ⁇ 0.2 °, 11.51 ⁇ 0.2°, 12.21 ⁇ 0.2°, 13.73 ⁇ 0.2°, 14.19 ⁇ 0.2°, 14.85 ⁇ 0.2°, 16.97 ⁇ 0.2°, 17.28 ⁇ 0.2°, 17.77 ⁇ 0.2°, 18.53 ⁇ 0.2°, 19.19 ⁇ 0.2 °, 19.88 ⁇ 0.2°, 20.25 ⁇ 0.2°, 20.76 ⁇ 0.2°, 21.34 ⁇ 0.2°, 23.09 ⁇ 0.2°, 23.47 ⁇ 0.2°, 24.68 ⁇ 0.2°, 25.89 ⁇ 0.2°, 26.51 ⁇ 0.2°, 27.16 ⁇ 0.2 °, 28.52 ⁇ 0.2°, 29.26 ⁇ 0.2°, 31.27 ⁇ 0.2°, 31.62 ⁇ 0.2°, 33.52 ⁇ 0.2°, 35.05 ⁇ 0.2°, 38.78 ⁇ 0.2° have diffraction peaks.
  • the crystal form A of the compound represented by formula II has the diffraction peaks shown in Table 1 below in its X-ray powder diffraction pattern represented by the 2 ⁇ angle:
  • the crystal form A of the compound represented by formula II has an X-ray powder diffraction (XRPD) pattern as shown in FIG. 1 .
  • XRPD X-ray powder diffraction
  • the differential scanning calorimetry (DSC) curve of the crystalline form A of the compound represented by formula II has endothermic peaks at 235.4°C and 249.3°C.
  • the differential scanning calorimetry curve of the crystal form A of the compound represented by formula II is as shown in FIG. 2 .
  • thermogravimetric analysis curve (TGA) of the crystalline form A of the compound represented by the formula II shows a weight loss of 1.2% from 27.7°C to 150°C.
  • thermogravimetric analysis curve of the crystal form A of the compound represented by formula II is shown in FIG. 2 .
  • the XRPD of the crystal form A of the compound represented by formula II uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form A of the compound represented by formula II is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry analysis (TGA) method of the crystal form A of the compound represented by formula II is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention provides a crystal form B of the compound represented by formula II, which has diffraction peaks at 6.54 ⁇ 0.2°, 16.60 ⁇ 0.2° and 25.35 ⁇ 0.2° in the X-ray powder diffraction pattern represented by 2 ⁇ angle.
  • the crystal form B of the compound represented by formula II has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 6.54 ⁇ 0.2°, 15.34 ⁇ 0.2°, 16.60 ⁇ 0.2°, 20.40 ⁇ 0.2° , There is a diffraction peak at 25.35 ⁇ 0.2°.
  • the crystal form B of the compound represented by formula II has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 6.54 ⁇ 0.2°, 10.57 ⁇ 0.2°, 12.60 ⁇ 0.2°, 13.10 ⁇ 0.2° , 14.04 ⁇ 0.2°, 15.34 ⁇ 0.2°, 16.60 ⁇ 0.2°, 18.61 ⁇ 0.2°, 18.92 ⁇ 0.2°, 20.40 ⁇ 0.2°, 21.21 ⁇ 0.2°, 23.11 ⁇ 0.2°, 23.52 ⁇ 0.2°, 25.35 ⁇ 0.2° , There is a diffraction peak at 26.53 ⁇ 0.2°.
  • the crystal form B of the compound represented by the formula II has the diffraction peaks shown in Table 2 below in its X-ray powder diffraction pattern represented by the 2 ⁇ angle:
  • the X-ray powder diffraction (XRPD) of the crystal form B of the compound represented by the formula II is shown in FIG. 3 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form B of the compound represented by formula II has endothermic peaks at 211.4°C, 223.4°C and 253.7°C.
  • the differential scanning calorimetry curve of the crystal form B of the compound represented by formula II is shown in FIG. 4 .
  • thermogravimetric analysis curve (TGA) of the crystalline form B of the compound represented by formula II shows a weight loss of 1.4% in the temperature range from 29.1°C to 150°C.
  • thermogravimetric analysis curve of the crystal form B of the compound represented by formula II is as shown in FIG. 4 .
  • the XRPD of the crystal form B of the compound represented by formula II uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form B of the compound represented by formula II is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry (TGA) method of the crystal form B of the compound represented by formula II is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a crystal form K of the compound represented by formula II, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 6.59 ⁇ 0.2°, 13.16 ⁇ 0.2°, 15.06 ⁇ 0.2°, 16.10 ⁇ 0.2°, 16.86 There are diffraction peaks at ⁇ 0.2°, 17.36 ⁇ 0.2°, 18.15 ⁇ 0.2°, 20.50 ⁇ 0.2°, 21.53 ⁇ 0.2°, 24.84 ⁇ 0.2°, 26.85 ⁇ 0.2°.
  • the crystal form K of the compound represented by formula II has an X-ray powder diffraction pattern represented by 2 ⁇ angle at 6.59 ⁇ 0.2°, 13.16 ⁇ 0.2°, 15.06 ⁇ 0.2°, 16.10 ⁇ 0.2° , 16.86 ⁇ 0.2°, 17.36 ⁇ 0.2°, 18.15 ⁇ 0.2°, 20.50 ⁇ 0.2°, 21.53 ⁇ 0.2°, 22.39 ⁇ 0.2°, 24.84 ⁇ 0.2°, 26.85 ⁇ 0.2° have diffraction peaks.
  • the crystal form K of the compound represented by formula II has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 5.01 ⁇ 0.2°, 6.59 ⁇ 0.2°, 7.57 ⁇ 0.2°, 9.06 ⁇ 0.2° , 10.50 ⁇ 0.2°, 11.52 ⁇ 0.2°, 12.74 ⁇ 0.2°, 13.16 ⁇ 0.2°, 13.78 ⁇ 0.2°, 15.06 ⁇ 0.2°, 16.10 ⁇ 0.2°, 16.86 ⁇ 0.2°, 17.36 ⁇ 0.2°, 18.15 ⁇ 0.2° , 20.50 ⁇ 0.2°, 21.53 ⁇ 0.2°, 22.39 ⁇ 0.2°, 24.07 ⁇ 0.2°, 24.84 ⁇ 0.2°, 25.50 ⁇ 0.2°, 26.09 ⁇ 0.2°, 26.85 ⁇ 0.2°, 27.68 ⁇ 0.2°, 29.46 ⁇ 0.2° , There is a diffraction peak at 34.15 ⁇ 0.2°.
  • the crystal form K of the compound represented by the formula II has an X-ray powder diffraction pattern represented by 2 ⁇ angles with diffraction peaks as shown in Table 3 below:
  • the X-ray powder diffraction (XRPD) pattern of the crystal form K of the compound represented by the formula II is shown in FIG. 15 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form K of the compound represented by formula II has endothermic peaks at 83.8°C and 247.0°C.
  • the differential scanning calorimetry curve of the crystal form K of the compound represented by formula II is shown in FIG. 16 .
  • thermogravimetric analysis curve (TGA) of the crystal form K of the compound represented by the formula II shows a weight loss of 3.7% in the temperature range from 19.9°C to 150°C.
  • thermogravimetric analysis curve of the crystal form K of the compound represented by formula II is shown in FIG. 16 .
  • the XRPD of the crystal form K of the compound represented by formula II uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form K of the compound represented by formula II is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry (TGA) method of the crystal form K of the compound represented by formula II is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a hydrate represented by formula XX, wherein n is 1-3;
  • the present invention also provides a hydrate shown in formula III:
  • the present invention also provides a crystal form C of the hydrate shown in formula III, and its X-ray powder diffraction pattern represented by 2 ⁇ angle has Diffraction peaks.
  • the crystal form C of the hydrate shown in formula III has an X-ray powder diffraction pattern represented by 2 ⁇ angle at 6.90 ⁇ 0.2°, 10.53 ⁇ 0.2°, 13.79 ⁇ 0.2°, 19.94 ⁇ There are diffraction peaks at 0.2°, 20.74 ⁇ 0.2°, 21.12 ⁇ 0.2°, 26.25 ⁇ 0.2°.
  • the crystal form C of the hydrate shown in formula III has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 6.90 ⁇ 0.2°, 7.97 ⁇ 0.2°, 10.53 ⁇ 0.2°, 12.98 ⁇ 0.2°, 13.79 ⁇ 0.2°, 14.15 ⁇ 0.2°, 15.23 ⁇ 0.2°, 17.37 ⁇ 0.2°, 18.11 ⁇ 0.2°, 18.26 ⁇ 0.2°, 18.98 ⁇ 0.2°, 19.94 ⁇ 0.2°, 20.74 ⁇ 0.2°, 21.12 ⁇ 0.2°, 22.23 ⁇ 0.2°, 23.16 ⁇ 0.2°, 23.52 ⁇ 0.2°, 24.98 ⁇ 0.2°, 26.25 ⁇ 0.2°, 27.75 ⁇ 0.2°, 28.22 ⁇ 0.2°, 29.07 ⁇ 0.2°, 32.14 ⁇ 0.2°, 32.90 ⁇ There are diffraction peaks at 0.2°, 34.40 ⁇ 0.2°, 35.82 ⁇ 0.2°, 38.54 ⁇ 0.2°.
  • the crystalline form C of the hydrate represented by the formula III has the diffraction peaks shown in the following table 4 in the X-ray powder diffraction pattern represented by the 2 ⁇ angle:
  • the X-ray powder diffraction (XRPD) pattern of the crystalline form C of the hydrate represented by formula III is shown in FIG. 5 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form C of the hydrate represented by formula III has endothermic peaks at 85.8°C, 99.2°C, 169.5°C and 192.9°C.
  • the differential scanning calorimetry curve of the crystal form C of the hydrate shown in formula III is shown in FIG. 6 .
  • thermogravimetric analysis curve (TGA) of the crystalline form C of the hydrate represented by the formula III shows a weight loss of 9.2% in the temperature range from 21.3°C to 150°C.
  • thermogravimetric analysis curve of the crystal form C of the hydrate shown in formula III is shown in FIG. 6 .
  • the XRPD of the crystal form C of the hydrate shown in formula III uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form C of the hydrate represented by formula III is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry analysis (TGA) method of the crystalline form C of the hydrate represented by formula III is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a hydrate shown in formula IV:
  • the present invention also provides a crystal form D of the hydrate shown in formula IV, and its X-ray powder diffraction pattern represented by 2 ⁇ angle has diffraction peaks at 6.62 ⁇ 0.2° and 7.64 ⁇ 0.2°.
  • the crystal form D of the hydrate shown in formula IV has an X-ray powder diffraction pattern represented by 2 ⁇ angle at 6.62 ⁇ 0.2°, 7.64 ⁇ 0.2°, 13.22 ⁇ 0.2°, 13.79 ⁇ There is a diffraction peak at 0.2°.
  • the crystal form D of the hydrate shown in formula IV has an X-ray powder diffraction pattern represented by 2 ⁇ angle at 6.62 ⁇ 0.2°, 7.64 ⁇ 0.2°, 11.43 ⁇ 0.2°, 13.22 ⁇ There are diffraction peaks at 0.2° and 13.79 ⁇ 0.2°.
  • the crystal form D of the hydrate shown in the formula IV has an X-ray powder diffraction pattern represented by 2 ⁇ angles with diffraction peaks as shown in Table 5 below:
  • the X-ray powder diffraction (XRPD) pattern of the crystal form D of the hydrate shown in formula IV is shown in FIG. 7 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form D of the hydrate represented by formula IV has endothermic peaks at 106.9°C and 200.3°C.
  • the differential scanning calorimetry curve of the crystal form D of the hydrate shown in formula IV is as shown in FIG. 8 .
  • thermogravimetric analysis curve (TGA) of the crystal form D of the hydrate represented by the formula IV shows a weight loss of 7.8% in the temperature range from 17.5°C to 150°C.
  • thermogravimetric analysis curve of the crystal form D of the hydrate shown in Formula IV is shown in FIG. 8 .
  • the XRPD of the crystal form D of the hydrate shown in formula IV uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystalline form D of the hydrate represented by formula IV is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry analysis (TGA) method of the crystalline form D of the hydrate represented by formula IV is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a hydrate shown in formula V:
  • the present invention also provides a crystal form E of the hydrate shown in formula V, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 6.49 ⁇ 0.2°, 7.20 ⁇ 0.2°, 8.42 ⁇ 0.2°, 10.41 ⁇ 0.2°, There are diffraction peaks at 11.56 ⁇ 0.2°, 16.87 ⁇ 0.2°, and 19.11 ⁇ 0.2°.
  • the crystal form E of the hydrate shown in formula V has an X-ray powder diffraction pattern represented by 2 ⁇ angle at 6.49 ⁇ 0.2°, 7.20 ⁇ 0.2°, 8.42 ⁇ 0.2°, 10.41 ⁇ There are diffraction peaks at 0.2°, 11.56 ⁇ 0.2°, 16.87 ⁇ 0.2°, 19.11 ⁇ 0.2°, 19.56 ⁇ 0.2°.
  • the crystal form E of the hydrate shown in formula V has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 6.49 ⁇ 0.2°, 7.20 ⁇ 0.2°, 7.61 ⁇ 0.2°, 8.42 ⁇ 0.2°, 10.41 ⁇ 0.2°, 11.56 ⁇ 0.2°, 12.78 ⁇ 0.2°, 14.34 ⁇ 0.2°, 16.10 ⁇ 0.2°, 16.56 ⁇ 0.2°, 16.87 ⁇ 0.2°, 19.11 ⁇ 0.2°, 19.56 ⁇ 0.2°, 21.11 ⁇ There are diffraction peaks at 0.2°, 22.71 ⁇ 0.2°, 23.19 ⁇ 0.2°, 25.15 ⁇ 0.2°.
  • the crystal form E of the hydrate shown in the formula V has an X-ray powder diffraction pattern represented by a 2 ⁇ angle with diffraction peaks as shown in Table 6 below:
  • the X-ray powder diffraction (XRPD) pattern of the crystal form E of the hydrate shown in formula V is shown in FIG. 9 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form E of the hydrate represented by formula V has endothermic peaks at 70.4°C, 114.8°C and 218.9°C.
  • the differential scanning calorimetry curve of the crystal form E of the hydrate shown in formula V is shown in FIG. 10 .
  • thermogravimetric analysis curve (TGA) of the crystalline form E of the hydrate represented by the formula V shows a weight loss of 7.0% in the temperature range from 28.5°C to 150°C.
  • thermogravimetric analysis curve of the crystal form E of the hydrate shown in formula V is shown in FIG. 10 .
  • the XRPD of the crystal form E of the hydrate shown in formula V uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystalline form E of the hydrate represented by formula V is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry (TGA) method of the crystalline form E of the hydrate represented by formula V is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a hydrate shown in formula VI:
  • the present invention also provides a crystal form I of the hydrate shown in formula VI, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 6.72 ⁇ 0.2°, 7.97 ⁇ 0.2°, 10.46 ⁇ 0.2°, 13.65 ⁇ 0.2°, There are diffraction peaks at 17.22 ⁇ 0.2° and 20.22 ⁇ 0.2°.
  • the crystal form I of the hydrate shown in the formula VI has an X-ray powder diffraction pattern represented by a 2 ⁇ angle with diffraction peaks as shown in Table 7 below:
  • the X-ray powder diffraction (XRPD) pattern of the crystal form I of the hydrate shown in formula VI is shown in FIG. 11 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form I of the hydrate represented by formula VI has endothermic peaks at 94.6°C and 213.2°C.
  • the differential scanning calorimetry curve of the crystal form I of the hydrate shown in formula VI is shown in FIG. 12 .
  • thermogravimetric analysis curve (TGA) of the crystalline form I of the hydrate represented by the formula VI shows a weight loss of 5.2% in the temperature range from 29.4°C to 150°C.
  • thermogravimetric analysis curve of the crystal form I of the hydrate shown in formula VI is shown in FIG. 12 .
  • the XRPD of the crystal form I of the hydrate shown in formula VI uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystalline form I of the hydrate represented by formula VI is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry (TGA) method of the crystalline form I of the hydrate represented by formula VI is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a hydrate shown in formula VII:
  • the present invention also provides a crystalline form J of the hydrate shown in formula VII, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 6.55 ⁇ 0.2°, 12.42 ⁇ 0.2°, 13.13 ⁇ 0.2°, 16.82 ⁇ 0.2°, There are diffraction peaks at 17.73 ⁇ 0.2° and 19.66 ⁇ 0.2°.
  • the crystal form J of the hydrate shown in formula VII has an X-ray powder diffraction pattern represented by 2 ⁇ angle at 5.14 ⁇ 0.2°, 6.55 ⁇ 0.2°, 12.07 ⁇ 0.2°, 12.42 ⁇ There are diffraction peaks at 0.2°, 13.13 ⁇ 0.2°, 16.82 ⁇ 0.2°, 17.73 ⁇ 0.2°, 19.66 ⁇ 0.2°.
  • the crystal form J of the hydrate shown in formula VII has an X-ray powder diffraction pattern represented by 2 ⁇ angle at 5.14 ⁇ 0.2°, 6.55 ⁇ 0.2°, 9.84 ⁇ 0.2°, 12.07 ⁇ 0.2°, 12.42 ⁇ 0.2°, 13.13 ⁇ 0.2°, 13.70 ⁇ 0.2°, 14.87 ⁇ 0.2°, 16.82 ⁇ 0.2°, 17.73 ⁇ 0.2°, 19.66 ⁇ 0.2°, 20.53 ⁇ 0.2°, 21.44 ⁇ 0.2°, 23.21 ⁇ There is a diffraction peak at 0.2°.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the crystal form J of the hydrate represented by the formula VII has the diffraction peaks shown in Table 8 below:
  • the X-ray powder diffraction (XRPD) pattern of the crystal form J of the hydrate represented by the formula VII is shown in FIG. 13 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form J of the hydrate represented by formula VII has endothermic peaks at 102.2°C and 247.6°C.
  • the differential scanning calorimetry curve of the crystal form J of the hydrate shown in formula VII is as shown in FIG. 14 .
  • thermogravimetric analysis curve (TGA) of the crystal form J of the hydrate represented by the formula VII shows a weight loss of 3.9% in the temperature range from 19.6°C to 150°C.
  • thermogravimetric analysis curve of the crystal form J of the hydrate shown in the formula VII is as shown in FIG. 14 .
  • the XRPD of the crystal form J of the hydrate shown in formula VII uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form J of the hydrate represented by formula VII is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry (TGA) method of the crystal form J of the hydrate shown in VII is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a compound shown in formula VIII (i.e. the maleate salt of the compound shown in formula I), its crystal form or hydrate:
  • the present invention also provides a crystal form A of the compound represented by formula VIII, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 6.33 ⁇ 0.2°, 11.56 ⁇ 0.2°, 14.41 ⁇ 0.2°, 16.64 ⁇ 0.2°, 17.45 ⁇ There are diffraction peaks at 0.2°, 18.21 ⁇ 0.2°, 18.45 ⁇ 0.2°, 21.19 ⁇ 0.2°, 23.46 ⁇ 0.2°, 24.20 ⁇ 0.2°.
  • the crystal form A of the compound represented by the formula VIII has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 6.33 ⁇ 0.2°, 11.56 ⁇ 0.2°, 14.41 ⁇ 0.2°, 16.64 ⁇ 0.2 °, 17.45 ⁇ 0.2°, 18.21 ⁇ 0.2°, 18.45 ⁇ 0.2°, 20.22 ⁇ 0.2°, 21.19 ⁇ 0.2°, 23.46 ⁇ 0.2°, 24.20 ⁇ 0.2°, 25.04 ⁇ 0.2° have diffraction peaks.
  • the crystal form A of the compound represented by the formula VIII has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 6.33 ⁇ 0.2°, 11.15 ⁇ 0.2°, 11.56 ⁇ 0.2°, 12.71 ⁇ 0.2 °, 14.41 ⁇ 0.2°, 14.60 ⁇ 0.2°, 16.64 ⁇ 0.2°, 16.81 ⁇ 0.2°, 17.45 ⁇ 0.2°, 18.21 ⁇ 0.2°, 18.45 ⁇ 0.2°, 18.79 ⁇ 0.2°, 19.18 ⁇ 0.2°, 20.22 ⁇ 0.2 °, 21.19 ⁇ 0.2°, 21.58 ⁇ 0.2°, 22.45 ⁇ 0.2°, 23.46 ⁇ 0.2°, 24.20 ⁇ 0.2°, 24.52 ⁇ 0.2°, 25.04 ⁇ 0.2°, 26.68 ⁇ 0.2°, 27.88 ⁇ 0.2°, 28.08 ⁇ 0.2 °, 28.82 ⁇ 0.2°, 29.88 ⁇ 0.2°, 31.01 ⁇ 0.2°, 35.20 ⁇ 0.2° have diffraction peaks.
  • the crystal form A of the compound represented by the formula VIII has the diffraction peaks shown in the following table 9 in the X-ray powder diffraction pattern represented by the 2 ⁇ angle:
  • the X-ray powder diffraction (XRPD) pattern of the crystal form A of the compound represented by the formula VIII is shown in FIG. 17 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form A of the compound represented by formula VIII has endothermic peaks at 45.8°C, 204.0°C and 206.1°C.
  • the differential scanning calorimetry curve of the crystal form A of the compound represented by the formula VIII is shown in FIG. 18 .
  • the crystalline form A of the compound represented by formula VIII has a thermogravimetric analysis curve (TGA) of 6.9% weight loss in the temperature range from 28.8°C to 150°C.
  • TGA thermogravimetric analysis curve
  • thermogravimetric analysis curve of the crystal form A of the compound represented by the formula VIII is shown in FIG. 18 .
  • the XRPD of the crystal form A of the compound represented by formula VIII uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form A of the compound represented by formula VIII is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry analysis (TGA) method of the crystal form A of the compound represented by VIII is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a crystal form B of the compound represented by formula VIII, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 11.59 ⁇ 0.2°, 16.89 ⁇ 0.2°, 17.37 ⁇ 0.2°, 18.24 ⁇ 0.2°, 22.60 There are diffraction peaks at ⁇ 0.2°, 23.66 ⁇ 0.2°, and 23.89 ⁇ 0.2°.
  • the crystal form B of the compound represented by formula VIII has an X-ray powder diffraction pattern represented by 2 ⁇ angle at 11.59 ⁇ 0.2°, 11.79 ⁇ 0.2°, 14.39 ⁇ 0.2°, 16.89 ⁇ 0.2° , 17.37 ⁇ 0.2°, 18.24 ⁇ 0.2°, 21.30 ⁇ 0.2°, 22.60 ⁇ 0.2°, 23.66 ⁇ 0.2°, 23.89 ⁇ 0.2° have diffraction peaks.
  • the crystal form B of the compound represented by the formula VIII has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 6.28 ⁇ 0.2°, 10.96 ⁇ 0.2°, 11.59 ⁇ 0.2°, 11.79 ⁇ 0.2° , 14.39 ⁇ 0.2°, 16.53 ⁇ 0.2°, 16.89 ⁇ 0.2°, 17.37 ⁇ 0.2°, 17.93 ⁇ 0.2°, 18.24 ⁇ 0.2°, 18.66 ⁇ 0.2°, 19.04 ⁇ 0.2°, 19.38 ⁇ 0.2°, 19.94 ⁇ 0.2° , 21.30 ⁇ 0.2°, 21.70 ⁇ 0.2°, 22.60 ⁇ 0.2°, 23.25 ⁇ 0.2°, 23.66 ⁇ 0.2°, 23.89 ⁇ 0.2°, 24.33 ⁇ 0.2°, 25.03 ⁇ 0.2°, 25.43 ⁇ 0.2°, 26.83 ⁇ 0.2° , 27.62 ⁇ 0.2°, 27.92 ⁇ 0.2°, 28.76 ⁇ 0.2°, 29.72 ⁇ 0.2° have diffraction peaks.
  • the crystal form B of the compound represented by the formula VIII has an X-ray powder diffraction pattern represented by 2 ⁇ angles with diffraction peaks as shown in Table 10 below:
  • the X-ray powder diffraction (XRPD) pattern of the crystal form B of the compound represented by the formula VIII is shown in FIG. 19 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form B of the compound represented by formula VIII has endothermic peaks at 142.9°C and 204.1°C.
  • the differential scanning calorimetry curve of the crystal form B of the compound represented by formula VIII is shown in FIG. 20 .
  • thermogravimetric analysis curve (TGA) of the crystalline form B of the compound represented by the formula VIII shows a weight loss of 4.0% in the temperature range from 29.1°C to 170°C.
  • thermogravimetric analysis curve of the crystal form B of the compound represented by the formula VIII is as shown in FIG. 20 .
  • the XRPD of the crystal form B of the compound represented by formula VIII uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form B of the compound represented by formula VIII is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry (TGA) method of the crystal form B of the compound represented by VIII is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a compound of formula IX (i.e. the citrate of the compound shown in formula I), its crystal form or hydrate:
  • the present invention also provides a crystal form A of the compound of formula IX, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 5.09 ⁇ 0.2°, 8.16 ⁇ 0.2°, 10.13 ⁇ 0.2°, 15.22 ⁇ 0.2°, 18.27 ⁇ 0.2 °, there are diffraction peaks at 21.05 ⁇ 0.2°.
  • the crystal form A of the compound of formula IX has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 5.09 ⁇ 0.2°, 8.16 ⁇ 0.2°, 9.11 ⁇ 0.2°, 10.13 ⁇ 0.2°, 15.22 There are diffraction peaks at ⁇ 0.2°, 18.27 ⁇ 0.2°, 18.75 ⁇ 0.2°, 21.05 ⁇ 0.2°.
  • the crystal form A of the compound of formula IX has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 4.57 ⁇ 0.2°, 5.09 ⁇ 0.2°, 8.16 ⁇ 0.2°, 9.11 ⁇ 0.2°, 10.13 ⁇ 0.2°, 12.25 ⁇ 0.2°, 12.85 ⁇ 0.2°, 13.65 ⁇ 0.2°, 15.22 ⁇ 0.2°, 16.35 ⁇ 0.2°, 16.59 ⁇ 0.2°, 18.27 ⁇ 0.2°, 18.75 ⁇ 0.2°, 19.76 ⁇ 0.2°, 20.47 There are diffraction peaks at ⁇ 0.2°, 21.05 ⁇ 0.2°, 21.50 ⁇ 0.2°, 22.43 ⁇ 0.2°, 24.27 ⁇ 0.2°, 25.49 ⁇ 0.2°.
  • the crystal form A of the compound of formula IX has the diffraction peaks shown in Table 11 below in its X-ray powder diffraction pattern represented by 2 ⁇ angle:
  • the crystalline form A of the compound of formula IX has an X-ray powder diffraction (XRPD) pattern as shown in FIG. 21 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form A of the compound of formula IX has an endothermic peak at 189.5°C.
  • the differential scanning calorimetry curve of the crystalline form A of the compound of formula IX is shown in FIG. 22 .
  • thermogravimetric analysis curve (TGA) of the crystal form A of the compound of formula IX shows a weight loss of 1.6% in the temperature range from 27.3°C to 150°C.
  • thermogravimetric analysis curve of the crystal form A of the compound of formula IX is shown in FIG. 22 .
  • the XRPD of Form A of the compound of formula IX uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form A of the compound of formula IX is as follows: the heating rate is 10°C/min and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry (TGA) method of the crystal form A of the compound of formula IX is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a crystal form I of the compound represented by formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 15.03 ⁇ 0.2°, 18.91 ⁇ 0.2°, 19.83 ⁇ 0.2°, 20.40 ⁇ 0.2°, 21.11 There are diffraction peaks at ⁇ 0.2°;
  • the crystal form I of the compound represented by formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 9.64 ⁇ 0.2°, 11.16 ⁇ 0.2°, 12.53 ⁇ 0.2°, 15.03 ⁇ 0.2° , 18.91 ⁇ 0.2°, 19.83 ⁇ 0.2°, 20.40 ⁇ 0.2°, 21.11 ⁇ 0.2° have diffraction peaks.
  • the crystal form I of the compound represented by formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angle at 7.94 ⁇ 0.2°, 9.64 ⁇ 0.2°, 11.16 ⁇ 0.2°, 11.92 ⁇ 0.2° , 12.53 ⁇ 0.2°, 14.26 ⁇ 0.2°, 15.03 ⁇ 0.2°, 16.48 ⁇ 0.2°, 16.79 ⁇ 0.2°, 17.51 ⁇ 0.2°, 18.91 ⁇ 0.2°, 19.33 ⁇ 0.2°, 19.83 ⁇ 0.2°, 20.40 ⁇ 0.2° , 21.11 ⁇ 0.2°, 22.56 ⁇ 0.2°, 23.43 ⁇ 0.2°, 23.93 ⁇ 0.2°, 24.17 ⁇ 0.2°, 25.16 ⁇ 0.2°, 26.68 ⁇ 0.2°, 28.60 ⁇ 0.2°, 29.63 ⁇ 0.2°, 30.57 ⁇ 0.2° , 31.62 ⁇ 0.2°, 32.71 ⁇ 0.2°, 33.66 ⁇ 0.2° have diffraction peaks.
  • the crystal form I of the compound represented by the formula I has the diffraction peaks shown in the following table 12 in the X-ray powder diffraction pattern represented by the 2 ⁇ angle:
  • the X-ray powder diffraction (XRPD) pattern of the crystalline form I of the compound represented by formula I is shown in FIG. 23 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form I of the compound represented by formula I has an endothermic peak at 244.0°C.
  • the differential scanning calorimetry curve of the crystalline form I of the compound represented by formula I is shown in FIG. 24 .
  • thermogravimetric analysis curve (TGA) of the crystal form I of the compound represented by formula I shows a weight loss of 1.9% in the temperature range from 29.8°C to 200°C.
  • thermogravimetric analysis curve of the crystal form I of the compound represented by formula I is shown in FIG. 24 .
  • the XRPD of the crystal form I of the compound represented by formula I uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form I of the compound represented by formula I is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry analysis (TGA) method of the crystal form I of the compound represented by formula I is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a crystal form II of the compound represented by formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle has Diffraction peaks.
  • the crystal form II of the compound represented by formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angle at 7.83 ⁇ 0.2°, 9.09 ⁇ 0.2°, 9.79 ⁇ 0.2°, 17.99 ⁇ 0.2 °, 18.19 ⁇ 0.2°, 19.59 ⁇ 0.2°, 19.90 ⁇ 0.2°, 23.55 ⁇ 0.2° have diffraction peaks.
  • the crystal form II of the compound represented by formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 7.83 ⁇ 0.2°, 8.56 ⁇ 0.2°, 9.09 ⁇ 0.2°, 9.79 ⁇ 0.2 °, 11.07 ⁇ 0.2°, 11.74 ⁇ 0.2°, 13.86 ⁇ 0.2°, 15.18 ⁇ 0.2°, 15.65 ⁇ 0.2°, 17.15 ⁇ 0.2°, 17.99 ⁇ 0.2°, 18.19 ⁇ 0.2°, 19.59 ⁇ 0.2°, 19.90 ⁇ 0.2 °, 20.62 ⁇ 0.2°, 23.55 ⁇ 0.2°, 24.31 ⁇ 0.2°, 27.41 ⁇ 0.2°, 29.02 ⁇ 0.2°, 31.17 ⁇ 0.2°, 31.57 ⁇ 0.2°, 35.74 ⁇ 0.2°, 36.79 ⁇ 0.2°, 38.38 ⁇ 0.2 ° has a diffraction peak.
  • the crystal form II of the compound represented by formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angle with diffraction peaks as shown in Table 13 below:
  • the X-ray powder diffraction (XRPD) pattern of the crystalline form II of the compound represented by formula I is shown in FIG. 25 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form II of the compound represented by formula I has an endothermic peak at 244.9°C.
  • the differential scanning calorimetry curve of the crystalline form II of the compound represented by formula I is shown in FIG. 26 .
  • thermogravimetric analysis curve (TGA) of the crystal form II of the compound represented by formula I shows a weight loss of 1.1% in the temperature range from 25.1°C to 150°C.
  • thermogravimetric analysis curve of the crystal form II of the compound represented by formula I is shown in FIG. 26 .
  • the XRPD of the crystal form II of the compound represented by formula I uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form II of the compound represented by formula I is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry (TGA) method of the crystal form II of the compound represented by formula I is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a crystal form III of the compound represented by formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 4.50 ⁇ 0.2°, 6.89 ⁇ 0.2°, 7.24 ⁇ 0.2°, 13.42 ⁇ 0.2°, 14.46 There are diffraction peaks at ⁇ 0.2° and 20.72 ⁇ 0.2°.
  • the crystal form III of the compound represented by formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 4.50 ⁇ 0.2°, 6.89 ⁇ 0.2°, 7.24 ⁇ 0.2°, 13.42 ⁇ There are diffraction peaks at 0.2°, 14.46 ⁇ 0.2°, 15.47 ⁇ 0.2°, 20.72 ⁇ 0.2°, 21.92 ⁇ 0.2°.
  • the crystal form III of the compound represented by formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 4.50 ⁇ 0.2°, 6.89 ⁇ 0.2°, 7.24 ⁇ 0.2°, 9.88 ⁇ 0.2°, 12.56 ⁇ 0.2°, 13.42 ⁇ 0.2°, 14.46 ⁇ 0.2°, 15.47 ⁇ 0.2°, 16.73 ⁇ 0.2°, 17.58 ⁇ 0.2°, 19.25 ⁇ 0.2°, 19.81 ⁇ 0.2°, 20.72 ⁇ 0.2°, 21.45 ⁇ There are diffraction peaks at 0.2°, 21.92 ⁇ 0.2°, 23.34 ⁇ 0.2°, 26.25 ⁇ 0.2°, 27.65 ⁇ 0.2°, 30.69 ⁇ 0.2°.
  • the crystal form III of the compound represented by formula I has the diffraction peaks shown in Table 14 below in its X-ray powder diffraction pattern represented by 2 ⁇ angle:
  • the crystal form III of the compound represented by formula I has an X-ray powder diffraction (XRPD) pattern as shown in FIG. 27 .
  • XRPD X-ray powder diffraction
  • the differential scanning calorimetry (DSC) curve of the crystalline form III of the compound represented by formula I has endothermic peaks at 135.1°C and 244.1°C.
  • the differential scanning calorimetry curve of the crystal form III of the compound represented by formula I is shown in FIG. 28 .
  • thermogravimetric analysis curve (TGA) of the crystalline form III of the compound represented by formula I shows a weight loss of 4.3% in the temperature range from 26.5°C to 150°C.
  • thermogravimetric analysis curve of the crystal form III of the compound represented by formula I is as shown in FIG. 28 .
  • the XRPD of the crystal form III of the compound represented by formula I uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form III of the compound represented by formula I is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry (TGA) method of the crystal form III of the compound represented by formula I is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a crystal form V of the compound represented by formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 4.19 ⁇ 0.2°, 7.47 ⁇ 0.2°, 12.44 ⁇ 0.2°, 14.35 ⁇ 0.2°, 16.60 There are diffraction peaks at ⁇ 0.2° and 20.79 ⁇ 0.2°.
  • the crystal form V of the compound represented by formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 4.19 ⁇ 0.2°, 7.47 ⁇ 0.2°, 12.44 ⁇ 0.2°, 14.35 ⁇ 0.2 °, 15.17 ⁇ 0.2°, 16.60 ⁇ 0.2°, 20.79 ⁇ 0.2°, 26.86 ⁇ 0.2° have diffraction peaks.
  • the crystal form V of the compound represented by formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 4.19 ⁇ 0.2°, 7.47 ⁇ 0.2°, 12.44 ⁇ 0.2°, 14.35 ⁇ 0.2 °, 15.17 ⁇ 0.2°, 16.60 ⁇ 0.2°, 17.29 ⁇ 0.2°, 18.99 ⁇ 0.2°, 19.93 ⁇ 0.2°, 20.79 ⁇ 0.2°, 21.55 ⁇ 0.2°, 25.29 ⁇ 0.2°, 26.23 ⁇ 0.2°, 26.86 ⁇ 0.2 ° has a diffraction peak.
  • the crystal form V of the compound represented by formula I has the diffraction peaks shown in Table 15 in the X-ray powder diffraction pattern represented by the 2 ⁇ angle:
  • the X-ray powder diffraction (XRPD) pattern of the crystal form V of the compound represented by formula I is shown in FIG. 29 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form V of the compound represented by formula I has endothermic peaks at 132.3°C and 242.9°C.
  • the differential scanning calorimetry curve of the crystal form V of the compound represented by formula I is shown in FIG. 30 .
  • thermogravimetric analysis curve (TGA) of the crystal form V of the compound represented by formula I shows a weight loss of 5.9% in the temperature range from 22.0°C to 150°C.
  • thermogravimetric analysis curve of the crystal form V of the compound represented by formula I is shown in FIG. 30 .
  • the XRPD of the crystal form V of the compound represented by formula I uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form V of the compound represented by formula I is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry (TGA) method of the crystal form V of the compound represented by formula I is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a crystal form VI of the compound represented by formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 4.36 ⁇ 0.2°, 8.49 ⁇ 0.2°, 14.64 ⁇ 0.2°, 15.34 ⁇ 0.2°, 18.94 There are diffraction peaks at ⁇ 0.2°, 19.74 ⁇ 0.2°, 20.13 ⁇ 0.2°, 21.08 ⁇ 0.2°.
  • the crystal form VI of the compound represented by formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 4.36 ⁇ 0.2°, 8.49 ⁇ 0.2°, 13.03 ⁇ 0.2°, 14.64 ⁇ 0.2 °, 15.34 ⁇ 0.2°, 18.94 ⁇ 0.2°, 19.74 ⁇ 0.2°, 20.13 ⁇ 0.2°, 21.08 ⁇ 0.2°, 21.81 ⁇ 0.2° have diffraction peaks.
  • the crystal form VI of the compound represented by formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 4.36 ⁇ 0.2°, 6.96 ⁇ 0.2°, 8.49 ⁇ 0.2°, 12.23 ⁇ 0.2 °, 13.03 ⁇ 0.2°, 14.64 ⁇ 0.2°, 15.34 ⁇ 0.2°, 16.16 ⁇ 0.2°, 17.91 ⁇ 0.2°, 18.94 ⁇ 0.2°, 19.74 ⁇ 0.2°, 20.13 ⁇ 0.2°, 21.08 ⁇ 0.2°, 21.81 ⁇ 0.2 °, 25.07 ⁇ 0.2°, 26.01 ⁇ 0.2° have diffraction peaks.
  • the crystal form VI of the compound represented by formula I has the diffraction peaks shown in Table 16 below in its X-ray powder diffraction pattern represented by 2 ⁇ angle:
  • the X-ray powder diffraction (XRPD) pattern of the crystal form VI of the compound represented by formula I is shown in FIG. 31 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form VI of the compound represented by formula I has endothermic peaks at 134.3°C, 140.9°C and 240.8°C.
  • the differential scanning calorimetry curve of the crystalline form VI of the compound represented by formula I is shown in FIG. 32 .
  • the crystalline form VI of the compound represented by formula I has a thermogravimetric analysis curve (TGA) of 7.0% weight loss in the temperature range from 28.5°C to 150°C.
  • TGA thermogravimetric analysis curve
  • thermogravimetric analysis curve of the crystal form VI of the compound represented by formula I is shown in FIG. 32 .
  • the XRPD of the crystal form VI of the compound represented by formula I uses Cu,K ⁇ radiation.
  • thermogravimetric analysis (TGA) method of the crystal form VI of the compound represented by formula I is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the differential scanning calorimetry (TGA) method of the crystal form VI of the compound represented by formula I is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°C.
  • the present invention also provides a preparation method of a salt of a compound shown in formula I, wherein the salt of a compound shown in formula I is a compound shown in formula II as described above (ie the hydrochloride salt of a compound shown in formula I) , the compound shown in formula VIII (ie the maleate of the compound shown in formula I) or the compound of formula IX (ie the citrate of the compound shown in formula I), which comprises the steps of: mixing the compound shown in formula I and the acid in The salt-forming reaction can be carried out in the solvent; the acid is HCl, maleic acid or citric acid.
  • the solvent in the preparation method of the salt of the compound represented by formula I, can be selected from methanol, ethanol, isopropanol, n-butanol, acetonitrile, water, dichloromethane, methyl tert-butyl ether, dimethyl sulfoxide, chloroform, tetrahydrofuran, 2-methylfuran, ethyl acetate, isopropyl acetate, 1,4-dioxane, N,N-dimethylformamide , one or more of water, cyclohexane, acetone, N-methylpyrrolidone, butanone, methyl isobutyl ketone, toluene and anisole.
  • the solvent in the preparation method of the salt of the compound shown in formula I, can be selected from methanol, ethanol, isopropanol, acetonitrile, water, dichloromethane, methyl tert-butyl ether , dimethylsulfoxide, chloroform, tetrahydrofuran, 2-methylfuran, ethyl acetate, isopropyl acetate, 1,4-dioxane, N,N-dimethylformamide, water and acetone one or more of.
  • the solvent in the preparation method of the salt of the compound represented by formula I, can be selected from methanol, acetone, ethyl acetate, dimethyl sulfoxide, tetrahydrofuran, 1,4-diox Hexacyclic, acetonitrile, N,N-dimethylformamide, isopropanol, acetonitrile/ethyl acetate solution, acetonitrile in water, acetone/water in water, dichloromethane/methyl tert-butyl ether solution and chloroform/ethanol one or more in solution.
  • the present invention also provides a method for preparing crystal form A of the compound represented by formula II as described above, which includes the following steps: reacting and crystallizing the compound represented by formula I and HCl in a solvent to obtain the compound represented by formula II Crystal form A of the compound;
  • the solvent is an organic solvent or a mixed solvent of an organic solvent and water;
  • the organic solvent is one or more of dichloromethane, methanol, ethanol and isopropanol.
  • the molar ratio of the compound shown in formula I to HCl can be 1:(1-2.5), for example 1:1 or 1: 2.5.
  • the mass volume ratio of the compound represented by the formula I to the solvent can be 10-50 mg/mL; for example, 10, 15, 20 , 30 or 40 mg/mL.
  • the organic solvent in the preparation method of the crystal form A of the compound represented by formula II, is one of methanol, ethanol and isopropanol or more, such as a mixed solvent of methanol and water.
  • the solvent in the preparation method of the crystal form A of the compound represented by formula II, is a mixed solvent of methanol and water or a mixed solvent of dichloromethane and ethanol, preferably dichloromethane and ethanol mixed solvents.
  • the volume ratio of methanol and water may be (100-110):1.
  • the volume ratio of dichloromethane and ethanol can be (5-7):1, such as 6:1.
  • the operation of reaction crystallization may include the following steps: reacting the mixed solution of the compound shown in the formula I, HCl, methanol and water ( For example, react at room temperature first, and then react at 50°C; for example, react at room temperature for 3 days, then transfer to 50°C for 3 hours) After that, the solid in the system is separated to obtain the crystal form of the compound shown in formula II a. Preferably, the solid is further dried after separation, for example: first vacuum drying at 25° C. (for example, for 2 hours), and then vacuum drying at 50° C. (for example, for 2 hours).
  • the reaction crystallization operation may include the following steps: mixing the mixed solution of the compound shown in formula I, HCl, dichloromethane and ethanol After the reaction (for example, reaction at 20-30° C.; for example, reaction at 20-30° C. for 24 hours), the solid in the system is separated to obtain the crystal form A of the compound represented by the formula II. Preferably, the solid is further dried after separation, for example, vacuum drying at 50° C. (for example, for 2 hours).
  • the present invention also provides a method for preparing crystal form B of the compound represented by formula II as described above, which comprises the following steps: reacting and crystallizing the compound represented by formula I with HCl in a mixed solvent of acetone and water, The crystal form B of the compound represented by formula II was obtained.
  • the molar ratio of the compound represented by formula I to HCl may be 1:(1-1.05), preferably 1:1.
  • the mass volume ratio of the compound represented by formula I to acetone may be 20-60 mg/mL, preferably 50 mg/mL.
  • the volume ratio of acetone and water may be (100-120):1.
  • the operation of reaction crystallization may include the following steps: mixing the mixed solution of the compound shown in the formula I, HCl, acetone and water at room temperature (for example, react at room temperature first, then react at 50°C; for example, react at room temperature for 3 days, then transfer to 50°C for 2 hours) and then separate the solid in the system to obtain the compound shown in the formula II Crystalline Form B.
  • the solid is further dried after separation, for example, vacuum drying at 25° C. (for example, for 12 hours).
  • the present invention also provides a method for preparing the crystal form K of the compound represented by the formula II as described above, which comprises the following steps: purging the crystal form J of the hydrate represented by the formula VII under N2 conditions for 20 min, The temperature was raised to 120° C., and the temperature was lowered to 30° C. to obtain the crystal form K of the compound represented by formula II.
  • the present invention also provides a method for preparing the crystalline form C of the hydrate shown in formula III as described above, which comprises the following steps: mixing the compound shown in formula II (such as compound crystal form A shown in formula II) in acetonitrile and ethyl acetate in a mixed solvent (for example, stirring at 5-50° C. for 24 hours), to obtain the crystal form C of the hydrate represented by formula III.
  • a mixed solvent for example, stirring at 5-50° C. for 24 hours
  • the mass volume ratio of the crystal form A of the compound shown in formula II to the mixed solvent of acetonitrile and ethyl acetate is 20 - 200 mg/mL; preferably 100 mg/mL.
  • the volume ratio of the acetonitrile to ethyl acetate can be (2 -5):1; preferably 3:1.
  • the following step may be further included after stirring: separating the solid in the mixed solution to obtain the hydrate represented by the formula III Crystal Form C.
  • the solid is further dried after separation, for example: vacuum drying at 50°C (for example, for 2 hours).
  • the present invention also provides a method for preparing the crystalline form D of the hydrate shown in the formula IV as described above, which comprises the following steps: adding the compound shown in the formula II (such as the crystal form A of the compound shown in the formula II) in Stirring in a mixed solvent of acetonitrile and water (for example, stirring at 25° C. for 24 hours) to obtain the crystal form D of the hydrate represented by formula IV.
  • adding the compound shown in the formula II such as the crystal form A of the compound shown in the formula II
  • a mixed solvent of acetonitrile and water for example, stirring at 25° C. for 24 hours
  • the mass volume ratio of the crystalline form A of the compound shown in the formula II to the mixed solvent of acetonitrile and water is 20-200 mg /mL; preferably 100 mg/mL.
  • the volume ratio of acetonitrile to water is (5-20):1; preferably is 12:1.
  • the following steps may also be included: separating the solid in the mixed solution to obtain the hydrate shown in the formula IV Crystal form D.
  • the solid is further dried after separation, for example, vacuum drying at 50° C. (for example, for 2 hours).
  • the present invention also provides a method for preparing the crystal form E of the hydrate shown in formula V as described above, which comprises the following steps: mixing the compound shown in formula II (such as the crystal form A of the compound shown in formula II) in Stir and volatilize in a mixed solvent of acetone and water (for example, stir and volatilize at 25° C. for 24 hours), to obtain the crystal form E of the hydrate shown in formula V.
  • a mixed solvent of acetone and water for example, stir and volatilize at 25° C. for 24 hours
  • the mass volume ratio of the crystal form A of the compound shown in formula II to the mixed solvent of acetone and water is 20-200mg /mL; preferably 100 mg/mL.
  • the volume ratio of acetone to water is (5-12):1, preferably It is 9:1.
  • the following steps may be further included after stirring and volatilizing: separating the solid in the mixed solution to obtain the hydrated hydrate shown in formula V
  • the crystal form E of the compound Preferably, the solid is further dried after separation, for example, vacuum drying at 50° C. (for example, for 2 hours).
  • the present invention also provides a method for preparing the crystal form I of the hydrate shown in the formula VI, which comprises the following steps: purging the crystal form E of the hydrate shown in the formula V under N2 conditions, Raise the temperature to 80°C-150°C, cool down to 30°C, and expose to the air to obtain the crystal form I of the hydrate shown in formula VI.
  • the present invention also provides a method for preparing the crystal form J of the hydrate shown in formula VII as described above, which comprises the following steps: mixing the crystal form A of the compound shown in formula II in dichloromethane and methyl tert-butyl Stirring in a mixed solvent of base ether (for example, stirring at 25° C. for 24 hours), the crystal form J of the hydrate represented by formula VII was obtained.
  • the crystal form A of the compound shown in the formula II and the mixed solvent of dichloromethane and methyl tert-butyl ether The mass to volume ratio is 20-200 mg/mL; preferably 100 mg/mL.
  • ether volume ratio is (1-10):1; preferably 5:1.
  • the following steps may be further included: separating the solid in the mixed solution to obtain the hydrate shown in the formula VII
  • the crystal form J Preferably, the solid is further dried after separation, for example, vacuum drying at 50° C. (for example, for 2 hours).
  • the present invention also provides a method for preparing crystal form A of the compound represented by formula VIII as described above, which includes the following steps: reacting and crystallizing the compound represented by formula I and maleic acid in methanol to obtain formula VIII Form A of the compound shown.
  • the molar ratio of the compound shown in formula I to maleic acid can be 1:(1-1.1), preferably 1:1 .
  • the mass volume ratio of the compound represented by formula I to methanol may be 20-60 mg/mL, preferably 50 mg/mL.
  • the operation of reaction crystallization may include the following steps: reacting the mixed solution of the compound shown in the formula I, maleic acid and methanol ( For example, react at room temperature first, and then react at 50°C; for example, react at room temperature for 3 days, then transfer to 50°C for 2 hours) After that, the solid in the system is separated to obtain the crystal form of the compound shown in formula VIII a. Preferably, the solid is further dried after separation, for example, vacuum drying at 25° C. (for example, for 12 hours).
  • the present invention also provides a method for preparing crystal form B of the compound represented by formula VIII as described above, which comprises the following steps: reacting and crystallizing the compound represented by formula I and maleic acid in acetone to obtain formula VIII Form B of the compound shown.
  • the molar ratio of the compound shown in formula I to maleic acid can be 1:(1-1.1), preferably 1:1 .
  • the mass volume ratio of the compound represented by formula I to methanol may be 20-60 mg/mL, preferably 50 mg/mL.
  • the operation of reaction crystallization may include the following steps: reacting the mixed solution of the compound shown in the formula I, maleic acid and acetone ( For example, react at room temperature first, and then react at 50°C; for example, react at room temperature for 3 days, then transfer to 50°C for 2 hours) After that, the solid in the system is separated to obtain the crystal form of the compound shown in formula VIII b. Preferably, the solid is further dried after separation, for example, vacuum drying at 25° C. (for example, for 12 hours).
  • the present invention also provides a method for preparing crystal form A of the aforementioned compound of formula IX, which comprises the following steps: reacting and crystallizing the compound shown in formula I with citric acid in ethyl acetate to obtain the compound of formula IX Crystal Form A.
  • the molar ratio of the compound shown in formula I to maleic acid can be 1:(1-1.1), preferably 1:1.
  • the mass volume ratio of the compound represented by formula I to methanol may be 20-60 mg/mL, preferably 50 mg/mL.
  • the reaction crystallization operation may include the following steps: reacting a mixed solution of the compound shown in formula I, maleic acid and methanol (for example, first React at room temperature, and then react at 50°C; for example, react at room temperature for 3 days, then transfer to 50°C for 2 hours), and then the solid in the system is separated to obtain the crystal form A of the compound of formula IX.
  • the solid is further dried after separation, for example, vacuum drying at 25° C. (for example, for 12 hours).
  • the present invention also provides a method for preparing crystal form I of the compound shown in formula I as described above, which comprises the following steps: obtaining the crystal form of the compound shown in formula I by anti-solvent crystallization of the compound shown in formula I I, wherein the positive solvent in the anti-solvent crystallization method is DMSO, and the anti-solvent is methanol.
  • the operation of the anti-solvent crystallization method may include the following steps: adding an anti-solvent to the solution of the compound represented by the formula I in the positive solvent, and The solid in the system is separated to obtain the crystal form I of the compound represented by formula I.
  • the solid is further dried after separation, for example, vacuum drying at 25° C. (for example, for 12 hours).
  • the volume ratio of the positive solvent to the anti-solvent may be (1.5-2):1, for example, 8:5.
  • the mass volume ratio of the compound represented by the formula I to the positive solvent may be 10-100 mg/mL, and the formula I The mass volume ratio of the indicated compound to anti-solvent is 90-120 mg/mL.
  • the mass volume ratio of the compound represented by the formula I to the positive solvent is 62.5 mg/mL, and the mass volume ratio of the compound represented by the formula I to the anti-solvent is 100:1 mg/mL.
  • the present invention also provides a method for preparing crystal form II of the compound shown in formula I as described above, which comprises the following steps: preparing the compound shown in formula I (such as the crystal form I of the compound shown in formula I) in three Volatile crystallization was carried out in a mixed solvent of methyl chloride and ethanol to obtain the crystal form II of the compound represented by formula I.
  • the mass volume ratio of the crystal form I of the compound shown in formula I to the mixed solvent of chloroform and ethanol is 20-50mg /mL; preferably 50 mg/mL.
  • the volume ratio of chloroform to ethanol is (1-5): 1; preferably 1:1.
  • the operation of volatile crystallization may include the following steps: mixing the crystal form I of the compound shown in formula I in a mixed solvent of chloroform and ethanol Volatilize at medium temperature (for example, at 50° C.) to no solvent to obtain the crystal form II of the compound represented by formula I.
  • the present invention also provides a method for preparing the crystal form III of the compound shown in formula I as described above, which comprises the following steps: adding tetrahydrofuran to the compound shown in formula I (such as the crystal form I of the compound shown in formula I) The solution was diffused in gas-liquid in the atmosphere of isopropyl acetate to obtain the crystal form III of the compound represented by formula I.
  • the mass volume ratio of the compound represented by formula I to tetrahydrofuran is 20-60 mg/mL; preferably 50 mg/mL.
  • the present invention also provides a method for preparing crystal form V of the compound represented by formula I as described above, which includes the following steps: mixing the compound represented by formula I (such as the crystal form I of the compound represented by formula I) in 1 , in a mixed solvent of 4-dioxane and acetonitrile for volatile crystallization to obtain the crystal form V of the compound shown in formula I.
  • the preparation method of the crystal form V of the compound represented by the formula I comprises the following steps: dissolving the compound represented by the formula I in a mixed solvent of 1,4-dioxane and acetonitrile at room temperature (for example 25°C) to obtain the crystal form V of the compound represented by formula I by volatile crystallization.
  • the preparation method of the crystal form V of the compound represented by formula I comprises the following steps: dissolving the compound represented by formula I in a mixed solvent of 1,4-dioxane and acetonitrile at 5°C Stir (for example, stirring for 12 hours), and then carry out volatile crystallization at room temperature (for example, 25° C.) to obtain the crystal form V of the compound represented by formula I.
  • 1,4-dioxane and acetonitrile in the preparation method of the crystal form V of the compound represented by formula I, in the mixed solvent of 1,4-dioxane and acetonitrile, 1,4-dioxane and acetonitrile
  • the volume ratio is (1.5-2):1, for example 8:5.
  • the mass volume ratio of the compound represented by formula I to 1,4-dioxane is 20-50 mg/mL, so The mass volume ratio of the compound shown in formula I to acetonitrile is 10-30 mg/mL.
  • the mass volume ratio of the compound represented by formula I to 1,4-dioxane is 40 mg/mL, and the mass volume ratio of the compound represented by formula I to acetonitrile is 20 mg/mL.
  • the present invention also provides a method for preparing crystal form VI of the compound represented by formula I as described above, which comprises the following steps: mixing the compound represented by formula I (such as the crystal form I of the compound represented by formula I) in N , cooling and crystallizing in a mixed solvent of N-dimethylformamide and isopropanol to obtain the crystal form VI of the compound shown in formula I.
  • the preparation method of the crystal form VI of the compound represented by the formula I comprises the following steps: dissolving the compound represented by the formula I in a mixed solvent of N,N-dimethylformamide and isopropanol in- Cooling crystallization at 20°C (optionally, under stirring at -20°C) yields the crystal form VI of the compound represented by formula I.
  • the compound represented by formula I is stirred in a mixed solvent of N,N-dimethylformamide and isopropanol at 5°C (for example, stirring for 12 hours).
  • N,N-dimethylformamide in the preparation method of the crystal form VI of the compound represented by formula I, in the mixed solvent of N,N-dimethylformamide and isopropanol, N,N-dimethylformamide
  • the volume ratio of amide and isopropanol is (1.5-2):1, for example 8:5.
  • the mass volume ratio of the compound represented by formula I to N,N-dimethylformamide is 20-50 mg/mL
  • the mass volume ratio of the compound represented by the formula I to the anti-solvent isopropanol is 10-30 mg/mL.
  • the mass volume ratio of the compound represented by the formula I to N,N-dimethylformamide is 40 mg/mL
  • the mass volume ratio of the compound represented by the formula I to the anti-solvent isopropanol is 20 mg/mL .
  • the present invention also provides an application of the above-mentioned compound, hydrate or crystal form in the preparation of a medicament for treating diseases related to proprotein convertase subtilisin Kexin-9 (PCSK9).
  • PCSK9 proprotein convertase subtilisin Kexin-9
  • the disease associated with proprotein convertase subtilisin Kexin-9 type is a metabolic disease, such as hyperlipidemia, hypercholesterolemia, hyperglycerol Triesteremia, fatty liver deformation, atherosclerosis, obesity, etc.
  • the crystal form of the present invention can be identified by one or several solid-state analysis methods. Such as X-ray powder diffraction, single crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric curve, etc. Those skilled in the art should understand that the peak intensity and/or peak situation of X-ray powder diffraction may be different due to different experimental conditions. At the same time, due to the different accuracy of the instrument, the measured 2 ⁇ value will have an error of about ⁇ 0.2°. The relative intensity value of the peak is more dependent on certain properties of the measured sample than the position of the peak, such as the size of the crystal and the degree of purity, so the measured peak intensity may have a deviation of about ⁇ 20%.
  • the intermediate compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention. If the reaction temperature is not specified in the present invention, the reaction temperature is room temperature, and the room temperature is generally 20-35°C.
  • the X-ray powder diffraction patterns are all measured using the K ⁇ line of the Cu target.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention lies in: the hydrochloride crystal form A, the hydrochloride crystal form B, the hydrochloride salt crystal form K, the hydrochloride hydrate crystal form C, the hydrochloride hydrate Crystal form D, hydrochloride hydrate form E, hydrochloride hydrate form I, hydrochloride hydrate form J, maleate form A, maleate form B, citrate form A.
  • Free crystal form I, free crystal form II, free crystal form III, free crystal form V, and free crystal form VI have one or more of the following advantages: (1) stable properties; (2) good hygroscopicity; (3) Good bioavailability (4) good drug prospect (5) free crystal form and salt form have better stability than amorphous form.
  • Fig. 1 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form A of the hydrochloride salt of the compound of formula I.
  • Fig. 2 is the TGA/DSC spectrum of the crystal form A of the hydrochloride salt of the compound of formula I.
  • Fig. 3 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form B of the hydrochloride salt of the compound of formula I.
  • Fig. 4 is the TGA/DSC spectrum of the crystal form B of the hydrochloride salt of the compound of formula I.
  • Fig. 5 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form C of the hydrochloride salt of the compound of formula I.
  • Fig. 6 is the TGA/DSC spectrum of the crystal form C of the hydrochloride salt of the compound of formula I.
  • Fig. 7 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form D of the hydrochloride salt of the compound of formula I.
  • Fig. 8 is the TGA/DSC spectrum of the crystal form D of the hydrochloride salt of the compound of formula I.
  • Fig. 9 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form E of the hydrochloride salt of the compound of formula I.
  • Fig. 10 is the TGA/DSC spectrum of the crystal form E of the hydrochloride salt of the compound of formula I.
  • Fig. 11 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form I of the hydrochloride salt of the compound of formula I.
  • Fig. 12 is the TGA/DSC spectrum of the crystal form I of the hydrochloride salt of the compound of formula I.
  • Fig. 13 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form J of the hydrochloride salt of the compound of formula I.
  • Fig. 14 is a TGA/DSC spectrum of the crystal form J of the hydrochloride salt of the compound of formula I.
  • Fig. 15 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form K of the hydrochloride salt of the compound of formula I.
  • Fig. 16 is the TGA/DSC spectrum of the crystal form K of the hydrochloride salt of the compound of formula I.
  • Figure 17 is the Cu-K ⁇ radiation XRPD spectrum of Form A of the maleate salt of the compound of formula I.
  • Figure 18 is a TGA/DSC spectrum of Form A of the maleate salt of the compound of formula I.
  • Fig. 19 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form B of the maleate salt of the compound of formula I.
  • Fig. 20 is the TGA/DSC spectrum of the crystalline form B of the maleate salt of the compound of formula I.
  • Fig. 21 is the Cu-K ⁇ radiation XRPD spectrum of the crystalline form A of the citrate salt of the compound of formula I.
  • Figure 22 is the TGA/DSC spectrum of Form A of the citrate salt of the compound of formula I.
  • Fig. 23 is the Cu-K ⁇ radiation XRPD spectrum of free crystal form I of the compound of formula I.
  • Fig. 24 is the TGA/DSC spectrum of the free crystal form I of the compound of formula I.
  • Fig. 25 is the Cu-K ⁇ radiation XRPD spectrum of the free crystalline form II of the compound of formula I.
  • Fig. 26 is the TGA/DSC spectrum of the free crystal form II of the compound of formula I.
  • Fig. 27 is the Cu-K ⁇ radiation XRPD spectrum of free crystal form III of the compound of formula I.
  • Fig. 28 is the TGA/DSC spectrum of the free crystal form III of the compound of formula I.
  • Fig. 29 is the Cu-K ⁇ radiation XRPD spectrum of free crystal form V of the compound of formula I.
  • Fig. 30 is a TGA/DSC spectrum of free form V of the compound of formula I.
  • Fig. 31 is the Cu-K ⁇ radiation XRPD spectrum of the free crystalline form VI of the compound of formula I.
  • Fig. 32 is a TGA/DSC spectrum of the free crystal form VI of the compound of formula I.
  • Figure 33 is the XRPD spectrum of the free state amorphous Cu-K ⁇ radiation of the compound of formula I.
  • Figure 34 is the Cu-K ⁇ radiation XRPD spectrum of Form A of the L-malate salt of the compound of formula I.
  • thermogravimetric analysis (TGA) test conditions As shown in Table 19, thermogravimetric analysis (TGA) test conditions and differential scanning calorimetry (DSC) analysis conditions:
  • TGA Differential Scanning Calorimetry
  • DSC Differential Scanning Calorimetry
  • the Chinese and English names comparison table of solvent for use in the present invention is as shown in table 21:
  • the compound represented by formula I in the present invention is provided by Guangzhou Jiayue Pharmaceutical Technology Co., Ltd. and prepared according to the preparation method described in the patent PCT/CN2017/078616
  • the preparation method of the crystal form A of the hydrochloride salt of the compound shown in formula I (that is, the crystal form A of the compound shown in formula II) is: methanol (6.5mL) of concentrated hydrochloric acid (110mg, 12mol/L) The solution was added to a methanol (4 mL) solution of the compound represented by formula I (500 mg), stirred at room temperature for 3 days, then transferred to 50° C. and stirred for 3 hours, filtered, and vacuum-dried at 50° C. for 2 h to obtain 387.4 mg of Form A.
  • the XRPD pattern is shown in Figure 1, and the TGA and DSC results are shown in Figure 2.
  • the TGA results show that the sample weight loss is 1.2% from room temperature to 150°C; hot peak.
  • IC/HPLC results showed that the acid-base molar ratio was 1:1.
  • the preparation method of the crystal form B of the hydrochloride salt of the compound shown in formula I (that is, the crystal form B of the compound shown in formula II) is as follows: acetone (5mL) of concentrated hydrochloric acid (99.8mg, 12mol/L) The solution was added to the acetone (5 mL) solution of the compound represented by formula I (505 mg), stirred at room temperature for 3 days, then transferred to 50°C and stirred for 2 hours, filtered, and vacuum-dried at 25°C for 12 hours to obtain 417.5 mg of Form B of the hydrochloride salt.
  • the XRPD pattern is shown in Figure 3, and the TGA and DSC results are shown in Figure 4.
  • the TGA results show that the sample weight loss is 1.4% from room temperature to 150°C; the DSC curve is at 211.4°C, 223.4°C and 253.7°C (peak temperature) An endothermic peak was observed.
  • IC/HPLC results showed that the acid-base molar ratio was 1:0.9.
  • the preparation method of the crystal form C of the hydrochloride salt of the compound shown in the formula I is as follows: the hydrochloride crystal form A (500 mg) of the compound shown in the formula I Dissolve in acetonitrile/ethyl acetate (5mL, the volume ratio of acetonitrile/ethyl acetate is 3:1), suspend and stir at 5-50°C for 24h, filter, and dry under vacuum at 50°C for 2h to obtain crystal C of hydrochloride Type 419.8mg.
  • the XRPD pattern is shown in Figure 5, and the TGA and DSC results are shown in Figure 6.
  • the TGA results show that the sample weight loss is 9.2% from room temperature to 150°C; peak temperature) and an endothermic peak was observed.
  • IC/HPLC results showed that the acid-base molar ratio was 1:1.
  • the C crystal form of hydrochloride is a hydrate crystal form, specifically three waters.
  • the preparation method of the crystal form D of the hydrochloride salt of the compound shown in the formula I (that is, the crystal form D of the formula IV hydrate) is as follows: the compound hydrochloride crystal form A (500mg) shown in the formula I is dissolved in In acetonitrile/water (5 mL, volume ratio of acetonitrile/water: 92:8), suspend and stir at 25°C for 24h, filter, and vacuum-dry at 50°C for 2h to obtain 413.5mg of crystal form D of hydrochloride.
  • the XRPD pattern is shown in Figure 7, and the TGA and DSC results are shown in Figure 8.
  • the TGA results show that the sample weight loss is 7.8% from room temperature to 150°C; the DSC curve is observed at 106.9°C and 200.3°C (peak temperature) endothermic peak.
  • IC/HPLC results showed that the acid-base molar ratio was 1:1.
  • the crystal form D of hydrochloride is a hydrate crystal form, specifically 2.5 hydrates.
  • the preparation method of the crystal form E of the hydrochloride salt of the compound shown in the formula I (that is, the crystal form E of the formula V hydrate) is as follows: the compound hydrochloride crystal form A (500mg) shown in the formula I is dissolved in Acetone/water (5mL, volume ratio of acetone/water is 9:1) solution, stirred and volatilized at 25°C for 24h, filtered, and vacuum dried at 50°C for 2h to obtain 417.7mg of Form E hydrochloride.
  • the XRPD pattern is shown in Figure 9, and the TGA and DSC results are shown in Figure 10.
  • the TGA results show that the sample weight loss is 7.0% from room temperature to 150°C; the DSC curve is at 70.4°C, 114.8°C and 218.9°C (peak temperature) An endothermic peak was observed.
  • IC/HPLC results showed that the acid-base molar ratio was 1:1.
  • the E crystal form of hydrochloride is a hydrate crystal form, specifically 2.3 hydrates.
  • the preparation method of the crystal form I of the hydrochloride salt of the compound shown in formula I is: the hydrochloride crystal form E sample is purged under N2 conditions 1. Raise the temperature to 80°C-150°C, cool down to 30°C, and expose to the air to obtain the crystal form I of hydrochloride.
  • the XRPD pattern is shown in Figure 11, and the TGA and DSC results are shown in Figure 12.
  • the TGA results show that the weight loss of the sample is 5.2% from room temperature to 150°C; the DSC curve is observed at 94.6°C and 213.2°C (peak temperature) endothermic peak.
  • IC/HPLC results showed that the acid-base molar ratio was 1:1.
  • the crystal form I of hydrochloride is a hydrate crystal form, specifically 1.7 hydrates.
  • the preparation method of the crystal form J of the hydrochloride salt of the compound shown in the formula I is as follows: the hydrochloride crystal form A (500 mg) of the compound shown in the formula I Dissolve in dichloromethane/methyl tert-butyl ether (5mL, the volume ratio of dichloromethane/methyl tert-butyl ether is 5:1), suspend and stir at 25°C for 24h, filter, and vacuum-dry at 50°C for 2h, 415.1 mg of Form J of hydrochloride was obtained.
  • the XRPD pattern is shown in Figure 13, and the TGA and DSC results are shown in Figure 14.
  • the TGA results show that the weight loss of the sample is 3.9% from room temperature to 150°C; the DSC curve is observed at 102.2°C and 247.6°C (peak temperature) endothermic peak.
  • IC/HPLC results showed that the acid-base molar ratio was 1:1.
  • the J crystal form of hydrochloride is a hydrate crystal form, specifically 1.2 hydrates.
  • the preparation method of the crystal form K of the hydrochloride salt of the compound shown in formula I (that is, the crystal form K of the compound shown in formula II ) is as follows: the hydrochloride crystal form J is purged under N for 20min, Raise the temperature to 120°C and cool down to 30°C to obtain hydrochloride salt form K.
  • the XRPD pattern is shown in Figure 15, and the TGA and DSC results are shown in Figure 16.
  • the TGA results show that the weight loss of the sample is 3.7% from room temperature to 150°C; the DSC curve is observed at 83.8°C and 247.0°C (peak temperature) endothermic peak.
  • IC/HPLC results showed that the acid-base molar ratio was 1:1.
  • the preparation method of the crystal form A of the maleate salt of the compound shown in formula I (that is, the crystal form A of the compound shown in formula VIII) is as follows: the methanol (5mL) solution of maleic acid (116mg) is added to A methanol (5 mL) solution of the compound represented by Formula I (503 mg) was stirred at room temperature for three days, then transferred to 50°C and stirred for 2 hours, filtered, and vacuum-dried at 25°C for 12 hours to obtain 526 mg of Form A of the maleate salt.
  • the XRPD pattern is shown in Figure 17, and the TGA and DSC results are shown in Figure 18.
  • the TGA results show that the sample weight loss is 6.9% from room temperature to 150°C; the DSC curve is at 45.8°C, 204.0°C and 206.1°C (peak temperature) An endothermic signal was observed.
  • IC/HPLC results showed that the acid-base molar ratio was 1:1.
  • the preparation method of the crystal form B of the maleate salt of the compound shown in formula I (that is, the crystal form B of the compound shown in formula VIII) is: the acetone (5mL) solution of maleic acid (113mg) is added to A solution of the compound represented by formula I (500 mg) in acetone (5 mL) was stirred at room temperature for three days, then transferred to 50° C. and stirred for 2 hours, filtered, and vacuum-dried at 25° C. for 12 hours to obtain 521 mg of Form B of the maleate salt.
  • the XRPD pattern is shown in Figure 19, and the TGA and DSC results are shown in Figure 20.
  • the TGA results show that the sample weight loss is 4.0% from room temperature to 170°C; heat signal.
  • IC/HPLC results showed that the acid-base molar ratio was 1:1.
  • the preparation method of the crystal form A of the citrate salt of the compound shown in formula I (that is, the crystal form A of the compound of formula IX) is as follows: the ethyl acetate (5mL) solution of citric acid (210mg) is added to the formula I The indicated compound (504mg) in ethyl acetate (5mL) solution was stirred at room temperature for three days, then transferred to 50°C and stirred for 2 hours, filtered, and vacuum-dried at 25°C for 12h to obtain 620mg of crystal form A of citrate.
  • the XRPD pattern is shown in Figure 21, and the TGA and DSC results are shown in Figure 22.
  • the TGA results show that the sample weight loss was 1.6% from room temperature to 150°C; the DSC curve observed an endothermic peak at 189.5°C (peak temperature) .
  • IC/HPLC results showed that the acid-base molar ratio was 1:1.
  • the preparation method of the free crystal form I of the compound represented by the formula I (that is, the crystal form I of the compound represented by the formula I) is: under the condition of nitrogen protection at 25°C, add the compound represented by the formula I (500 mg) to DMSO After dissolving in (8mL), methanol (5mL) was added, cooled to 10°C and stirred for 20 hours, filtered, and vacuum-dried at 25°C for 12h to obtain 473mg of free crystal form I.
  • the XRPD pattern is shown in Figure 23, and the TGA and DSC results are shown in Figure 24.
  • the TGA results show that the sample weight loss is 1.9% from room temperature to 200°C; the DSC curve has an endothermic peak at 243.0°C (initial temperature) .
  • the preparation method of the free crystal form II of the compound shown in formula I (that is, the crystal form II of the compound shown in formula I) is as follows: the free crystal form I (500mg) is dissolved in chloroform/ethanol (10mL, trichloro The volume ratio of methane/ethanol is 1:1), and slowly evaporated to no solvent at 50°C to obtain 491 mg of free crystal form II.
  • the XRPD pattern is shown in Figure 25, and the TGA and DSC results are shown in Figure 26.
  • the TGA results show that the weight loss of the sample is 1.1% when the temperature is raised from room temperature to 200°C; an endothermic peak (peak temperature) is observed in the DSC curve at 244.9°C.
  • the preparation method of the free crystal form III of the compound shown in formula I (that is, the crystal form III of the compound shown in formula I) is as follows: after dissolving the free crystal form I (500mg) in tetrahydrofuran (10mL) in acetic acid Obtained by gas-liquid diffusion in an isopropyl ester atmosphere to obtain 471.4 mg of free crystal form III.
  • the XRPD pattern is shown in Figure 27, and the TGA and DSC results are shown in Figure 28.
  • the TGA results show that the sample weight loss was 4.3% from room temperature to 200°C; the DSC curve observed endothermic peaks at 135.1°C and 244.1°C (peak temperature).
  • the preparation method of the free crystal form V of the compound shown in formula I (that is, the crystal form V of the compound shown in formula I) is as follows: dissolving the free crystal form I (500 mg) in 1,4-dioxane ( 8mL) and anti-solvent (5mL, ACN as anti-solvent) was added, and the obtained clear solution was transferred to 5°C and stirred for 12h, then volatilized at room temperature (25°C) to obtain 480.6mg of free crystal form V.
  • the XRPD pattern is shown in Figure 29, and the TGA and DSC results are shown in Figure 30.
  • the TGA results showed that the sample weight loss was 5.9% from room temperature to 200°C; the DSC curve observed endothermic peaks at 132.3°C and 242.9°C (peak temperature).
  • the preparation method of the free crystal form VI of the compound shown in formula I (that is, the crystal form VI of the compound shown in formula I) is as follows: dissolving the free crystal form I (500 mg) in N,N-dimethylformamide (8mL) and anti-solvent (5mL, isopropanol as anti-solvent) was added, the clear solution was transferred to 5°C and stirred for 12h, then placed at -20°C and stirred for 12h, filtered, and vacuum-dried at 50°C for 12h to obtain Free crystal form VI 482.2mg.
  • the XRPD pattern is shown in Figure 31, and the TGA and DSC results are shown in Figure 32.
  • the TGA results show that the weight loss of the sample is 7.0% when the temperature rises from room temperature to 200°C; endotherms are observed at 134.3°C, 140.9°C and 240.8°C in the DSC curve peak (peak temperature).
  • FaSSIF stock buffer Weigh 340.9 mg of sodium dihydrogen phosphate, 41.7 mg of sodium hydroxide and 620.5 mg of sodium chloride into a 100-mL volumetric flask. Add qs purified water and sonicate to dissolve the solid. Add purified water to close to the target volume, adjust the pH to 6.5, and mix the purified water to volume.
  • FaSSIF solution can be stored at 4°C for 7 days, and needs to be equilibrated at room temperature for 2 hours before use.
  • FeSSIF stock buffer Take 0.820mL glacial acetic acid, 404.2mg sodium hydroxide and 1187.9mg sodium chloride in a 100-mL volumetric flask. An appropriate amount of purified water was added to dissolve the solid. Then add purified water to reach the target volume, adjust the pH to 5.0, and mix at a constant volume.
  • the hygroscopicity of the hydrochloride salt form A was evaluated by DVS.
  • the water adsorption capacity of the sample at 25°C/80%RH was 0.08%, indicating that it had almost no hygroscopicity, and the crystal form of the sample did not change after the DVS test.
  • Embodiment 20 solid state stability
  • the solid-state stability of the hydrochloride form A sample was further evaluated, including extending the storage time to 12 weeks under the conditions of 25°C/60%RH and 40°C/75%RH, while increasing the stability at 80°C/closed Place the test for 48 hours.
  • the solid-state stability of the hydrochloride form B, maleate form A and citrate form A samples was further evaluated, including storage at 25°C/60%RH and 40°C/75%RH time extended to 1 week.
  • the solid-state stability of free form I samples was further evaluated, including storage time extended to 24 months at 25°C/60%RH and 6 months at 40°C/75%RH.
  • a group of rats is established, with 6 rats in each group, half male and half male. Fasting for no less than 12 hours before administration, drinking water freely, eating uniformly 4 hours after administration, intravenously administering 20 mg/kg of the compound hydrochloride crystal form A shown in formula I, and the administration volume is 10ml/kg; before administration and After administration, 0.2ml of blood was collected at 5min (intravenous group), 15min (intravenous group), 0.5, 1.0, 2.0, 4.0, 6.0, 10, 24, and 48h, and placed in an EDTA-K2 anticoagulant test tube, centrifuged at 11000rpm for 5min (4°C). ), separate the plasma, and store it at -70°C until testing.
  • the present invention has also done salt-forming screening about D-glucuronic acid and L-malic acid.
  • D-glucuronic acid and L-malic acid were selected as acidic Ligand (the molar feed ratio of free state/acidic ligand is 1:1) and 5 kinds of solvent systems as shown in Table 26, screening test.
  • the specific steps of the screening test are as follows: Weigh about 20 mg of free crystal form I and different ligands in equimolar amounts into an HPLC vial, add 0.5 mL of solvent and mix to obtain a suspension, the liquid acid is first diluted with the corresponding solvent and then mixed with the starting sample mix. After suspension and stirring at room temperature for about 4 days, the solid was separated by centrifugation and vacuum-dried at room temperature for about 4 hours. The results are shown in Table 26.

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Abstract

提供一种苯基[a]吲哚[2,3-g]并喹嗪类化合物的晶型、其盐和盐的晶型及其制备方法和应用。该苯基[a]吲哚[2,3-g]并喹嗪类化合物的结构如下式(I)所示。所述苯基[a]吲哚[2,3-g]并喹嗪类化合物的晶型、其盐以及各晶型具有以下一个或多个优点：较好的溶解性、性质稳定、引湿性好、具有良好的成药前景。

Description

苯基[a]吲哚[2,3-g]并喹嗪类化合物的晶型、其盐和盐的晶型及其制备方法和应用
本申请要求申请日为2021/6/28的中国专利申请2021107171608的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及药物化学领域，具体地，本发明涉及一种苯基[a]吲哚[2,3-g]并喹嗪类化合物的晶型、其盐和盐的晶型及其制备方法和应用。
背景技术
高血脂症是造成心血管疾病的主要危险因素，血脂水平过高，可直接引起一些严重危害人体健康的疾病，如动脉粥样硬化、冠心病等等。高脂血症的临床表现主要是脂质在真皮内沉积所引起的黄色瘤和脂质在血管内皮沉积所引起的动脉硬化。尽管高脂血症可引起黄色瘤，但其发生率并不是很高；而动脉粥样硬化的发生和发展又是一种缓慢渐进的过程。因此在通常情况下，多数患者并无明显症状和异常体征。不少人是由于其他原因进行血液生化检验时才发现有血浆脂蛋白水平升高。由心血管疾病造成的死亡占所有死亡人数的四分之一，相当于每三分钟就有一人死于心血管疾病。
目前主要的降血脂类药物为他汀类药物。但是在临床使用过程中发现，大约有20％的患者都不能耐受他汀类药物的副作用，比如肌肉酸痛及健忘等。
近年来以PCSK9为代表的新的降脂靶点受到越来越多的关注，在研的PCSK9抑制剂研究也取得了令人瞩目的进展，有望上市成为新的革命性降脂药物。PCSK9主要是受转录因子胆固醇调节元件结合蛋白2(Sterol Response Element Binding Protein-2，SREBP-2)的调节，以可溶性酶原的前体形式存在于肝细胞等的内质网中，经过自身催化水解，形成成熟的PCSK9并分泌至血浆。血浆LDL-c被肝细胞表面表达的LDLR摄取，内吞进入细胞，在溶酶体中降解。而PCSK9可与LDL-c竞争性结合LDLR，介导LDLR的降解，引起血浆LDL-c水平升高。因此PCSK9对于维持体内胆固醇稳态发挥着关键的调节作用，抑制PCSK9可以显著降低体内LDL-C水平，上述发现引起了人们研发PCSK9抑制剂类药物的兴趣。
目前大约有10家制药公司在生产研发PCSK9抑制剂，包括赛诺菲、安进、诺华、辉瑞以及施贵宝等。其中，大约半数的PCSK9抑制剂属于单克隆抗体，并处于药物临床研究的领先阶段。PCSK9单克隆抗体作为降脂药物本身有诸多优势，如：对靶目标高度特异、半衰期更长、用药频率大大减低等。更重要的是，PCSK9单克隆抗体在前期临床试验中展现出可喜结果。根据2015年美国脂质协会(NLA)临床血脂学年度总结报告，在国内医院调查270名高脂血症及冠心病患者，无论PCSK9是作为他汀类药物的辅助用药还是作为单一疗法用药都可快速、稳定地降低血浆LDL-C水平，270病例中无一出现明显不良反应，也不会出现像他汀药物耐受性引起的不适或无效。PCSK9单克隆抗体还可改善造成心血管风险的其他脂蛋白指标如非HDL-C、载脂蛋白B、脂蛋白a等，应考虑治疗范围逐步扩展 的可能性，如治疗早发冠心病以及载脂蛋白B、脂蛋白a水平升高，甚至可将人群扩大至糖尿病、代谢综合征患者。未来尤其适用于服用他汀不能达到降脂目标或不能耐受他汀的高危患者，以及家族性高胆固醇血症患者。但是，单克隆抗体药物存在以下两点问题：价格昂贵，如此高昂的价格，令患者望而却步；一般不能口服，剂型单一；许多患者尤其是无症状的高脂血症，每2或4周长期接受皮下或静脉注射治疗存在不便。然而，小分子PCSK9抑制剂的研发相对较少，开发获得结构新颖的PCSK9小分子抑制剂是目前降脂药物的研究热点。
众所周知，作为药用活性成分的晶型结构往往影响到该药物的化学和物理稳定性。结晶条件及储存条件的不同有可能导致化合物的晶体结构的变化。基于前期的研究，式I所示化合物具有良好的成药性，为了进一步改善该化合物的理化性质，提高暴露量，我们对式I所示化合物进行了晶型和成盐研究，目前未见式I所示化合物的晶型、其盐及晶型的报道。一般来说，无定型的药物产品没有规则的晶体结构，往往具有其它缺陷，比如热力学稳定性较差等。因此，改善上述化合物的各方面性质是很有必要的。
Figure PCTCN2022101986-appb-000001
发明内容
本发明所要解决的技术问题为改善现有技术中苯基[a]吲哚[2,3-g]并喹嗪类化合物的物理和化学性质，从而提供了一种苯基[a]吲哚[2,3-g]并喹嗪类化合物的晶型、其盐和盐的晶型及其制备方法和应用。本发明的苯基[a]吲哚[2,3-g]并喹嗪类化合物的晶型、其盐以及各晶型具有以下一个或多个优点：较好的溶解性、性质稳定、引湿性好、具有良好的成药前景。
本发明提供了一种式II所示化合物(即式I所示化合物的盐酸盐)、其晶型或水合物；
Figure PCTCN2022101986-appb-000002
本发明还提供了一种式II所示化合物的晶型A，其以2θ角表示的X射线粉末衍射图在5.78±0.2°、11.51±0.2°、16.97±0.2°、17.77±0.2°处有衍射峰。
在一些实施方案中，所述的式II所示化合物的晶型A，其以2θ角表示的X-射线粉末衍射图在5.78±0.2°、10.11±0.2°、11.51±0.2°、13.73±0.2°、16.97±0.2°、17.77±0.2°处有衍射峰。
在一些实施方案中，所述的式II所示化合物的晶型A，其以2θ角表示的X-射线粉末衍射图在5.78±0.2°、7.12±0.2°、8.29±0.2°、10.11±0.2°、11.51±0.2°、12.21±0.2°、13.73±0.2°、14.19±0.2°、14.85±0.2°、16.97±0.2°、17.28±0.2°、17.77±0.2°、18.53±0.2°、19.19±0.2°、19.88±0.2°、20.25±0.2°、20.76±0.2°、21.34±0.2°、23.09±0.2°、23.47±0.2°、24.68±0.2°、25.89±0.2°、26.51±0.2°、27.16±0.2°、28.52±0.2°、29.26±0.2°、31.27±0.2°、31.62±0.2°、33.52±0.2°、35.05±0.2°、38.78±0.2°处有衍射峰。
在一些实施方案中，所述的式II所示化合物的晶型A，其以2θ角表示的X-射线粉末衍射图具有如下表1所示的衍射峰：
表1
Figure PCTCN2022101986-appb-000003
Figure PCTCN2022101986-appb-000004
在一些实施方案中，所述的式II所示化合物的晶型A，其X射线粉末衍射(XRPD)图谱如图1所示。
在一些实施方案中，所述的式II所示化合物的晶型A，其差示扫描量热(DSC)曲线在235.4℃及249.3℃处具有吸热峰。
在一些实施方案中，所述的式II所示化合物的晶型A，其差示扫描量热曲线如图2中所示。
在一些实施方案中，所述的式II所示化合物的晶型A，其热重分析曲线(TGA)显示从27.7℃至150℃温度范围失重1.2％。
在一些实施方案中，所述的式II所示化合物的晶型A，其热重分析曲线如图2中所示。
在一些实施方案中，所述的式II所示化合物的晶型A，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式II所示化合物的晶型A的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式II所示化合物的晶型A的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明提供了一种式II所示化合物的晶型B，其以2θ角表示的X射线粉末衍射图在6.54±0.2°、16.60±0.2°和25.35±0.2°处有衍射峰。
在一些实施方案中，所述的式II所示化合物的晶型B，其以2θ角表示的X射线粉末衍射图在6.54±0.2°、15.34±0.2°、16.60±0.2°、20.40±0.2°、25.35±0.2°处有衍射峰。
在一些实施方案中，所述的式II所示化合物的晶型B，其以2θ角表示的X射线粉末衍射图在6.54±0.2°、10.57±0.2°、12.60±0.2°、13.10±0.2°、14.04±0.2°、15.34±0.2°、16.60±0.2°、18.61±0.2°、18.92±0.2°、20.40±0.2°、21.21±0.2°、23.11±0.2°、23.52±0.2°、25.35±0.2°、26.53±0.2°处有衍射峰。
在一些实施方案中，所述的式II所示化合物的晶型B，其以2θ角表示的X-射线粉末衍射图具有如下表2所示的衍射峰：
表2
Figure PCTCN2022101986-appb-000005
Figure PCTCN2022101986-appb-000006
在一些实施方案中，所述的式II所示化合物的晶型B，其X射线粉末衍射(XRPD)如图3所示。
在一些实施方案中，所述的式II所示化合物的晶型B，其差示扫描量热(DSC)曲线在211.4℃、223.4℃和253.7℃处具有吸热峰。
在一些实施方案中，所述的式II所示化合物的晶型B，其差示扫描量热曲线如图4中所示。
在一些实施方案中，所述的式II所示化合物的晶型B，其热重分析曲线(TGA)显示在29.1℃至150℃温度范围失重1.4％。
在一些实施方案中，所述的式II所示化合物的晶型B，其热重分析曲线如图4中所示。
在一些实施方案中，所述的式II所示化合物的晶型B，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式II所示化合物的晶型B的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式II所示化合物的晶型B的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式II所示化合物的晶型K，其以2θ角表示的X射线粉末衍射图在6.59±0.2°、13.16±0.2°、15.06±0.2°、16.10±0.2°、16.86±0.2°、17.36±0.2°、18.15±0.2°、20.50±0.2°、21.53±0.2°、24.84±0.2°、26.85±0.2°处有衍射峰。
在一些实施方案中，所述的式II所示化合物的晶型K，其以2θ角表示的X射线粉末衍射图在6.59±0.2°、13.16±0.2°、15.06±0.2°、16.10±0.2°、16.86±0.2°、17.36±0.2°、18.15±0.2°、20.50±0.2°、21.53±0.2°、22.39±0.2°、24.84±0.2°、26.85±0.2°处有衍射峰。
在一些实施方案中，所述的式II所示化合物的晶型K，其以2θ角表示的X射线粉末衍射图在5.01±0.2°、6.59±0.2°、7.57±0.2°、9.06±0.2°、10.50±0.2°、11.52±0.2°、12.74±0.2°、13.16±0.2°、13.78±0.2°、15.06±0.2°、16.10±0.2°、16.86±0.2°、17.36±0.2°、18.15±0.2°、20.50±0.2°、21.53±0.2°、22.39±0.2°、24.07±0.2°、24.84±0.2°、25.50±0.2°、26.09±0.2°、26.85±0.2°、27.68±0.2°、29.46±0.2°、34.15±0.2°处有衍射峰。
在一些实施方案中，所述的式II所示化合物的晶型K，其以2θ角表示的X-射线粉末衍射图具有如下表3所示的衍射峰：
表3
Figure PCTCN2022101986-appb-000007
Figure PCTCN2022101986-appb-000008
在一些实施方案中，所述的式II所示化合物的晶型K，其X射线粉末衍射(XRPD)图谱如图15所示。
在一些实施方案中，所述的式II所示化合物的晶型K，其差示扫描量热(DSC)曲线在83.8℃和247.0℃处具有吸热峰。
在一些实施方案中，所述的式II所示化合物的晶型K，其差示扫描量热曲线如图16中所示。
在一些实施方案中，所述的式II所示化合物的晶型K，其热重分析曲线(TGA)显示在19.9℃至150℃温度范围失重3.7％。
在一些实施方案中，所述的式II所示化合物的晶型K，其热重分析曲线如图16中所示。
在一些实施方案中，所述的式II所示化合物的晶型K，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式II所示化合物的晶型K的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式II所示化合物的晶型K的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式XX所示水合物，其中n为1-3；
Figure PCTCN2022101986-appb-000009
本发明还提供了一种式III所示水合物：
Figure PCTCN2022101986-appb-000010
本发明还提供一种式III所示水合物的晶型C，其以2θ角表示的X射线粉末衍射图在6.90±0.2°、10.53±0.2°、13.79±0.2°、21.12±0.2°处有衍射峰。
在一些实施方案中，所述的式III所示水合物的晶型C，其以2θ角表示的X-射线粉末衍射图在6.90±0.2°、10.53±0.2°、13.79±0.2°、19.94±0.2°、20.74±0.2°、21.12±0.2°、26.25±0.2°处有衍射峰。
在一些实施方案中，所述的式III所示水合物的晶型C，其以2θ角表示的X-射线粉末衍射图在 6.90±0.2°、7.97±0.2°、10.53±0.2°、12.98±0.2°、13.79±0.2°、14.15±0.2°、15.23±0.2°、17.37±0.2°、18.11±0.2°、18.26±0.2°、18.98±0.2°、19.94±0.2°、20.74±0.2°、21.12±0.2°、22.23±0.2°、23.16±0.2°、23.52±0.2°、24.98±0.2°、26.25±0.2°、27.75±0.2°、28.22±0.2°、29.07±0.2°、32.14±0.2°、32.90±0.2°、34.40±0.2°、35.82±0.2°、38.54±0.2°处有衍射峰。
在一些实施方案中，所述的式III所示水合物的晶型C，其以2θ角表示的X-射线粉末衍射图中具有如下表4所示的衍射峰：
表4
Figure PCTCN2022101986-appb-000011
Figure PCTCN2022101986-appb-000012
在一些实施方案中，所述的式III所示水合物的晶型C，其X射线粉末衍射(XRPD)图谱如图5所示。
在一些实施方案中，所述的式III所示水合物的晶型C，其差示扫描量热(DSC)曲线在85.8℃、99.2℃、169.5℃和192.9℃处有吸热峰。
在一些实施方案中，所述的式III所示水合物的晶型C，其差示扫描量热曲线如图6所示。
在一些实施方案中，所述的式III所示水合物的晶型C，其热重分析曲线(TGA)显示在21.3℃至150℃温度范围失重9.2％。
在一些实施方案中，所述的式III所示水合物的晶型C，其热重分析曲线如图6所示。
在一些实施方案中，所述的式III所示水合物的晶型C，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式III所示水合物的晶型C的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式III所示水合物的晶型C的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式IV所示水合物：
Figure PCTCN2022101986-appb-000013
本发明还提供了一种式IV所示水合物的晶型D，其以2θ角表示的X射线粉末衍射图在6.62±0.2°、7.64±0.2°处有衍射峰。
在一些实施方案中，所述的式IV所示水合物的晶型D，其以2θ角表示的X-射线粉末衍射图在6.62±0.2°、7.64±0.2°、13.22±0.2°、13.79±0.2°处有衍射峰。
在一些实施方案中，所述的式IV所示水合物的晶型D，其以2θ角表示的X-射线粉末衍射图在6.62±0.2°、7.64±0.2°、11.43±0.2°、13.22±0.2°、13.79±0.2°处有衍射峰。
在一些实施方案中，所述的式IV所示水合物的晶型D，其以2θ角表示的X-射线粉末衍射图具有如下表5所示的衍射峰：
表5
Figure PCTCN2022101986-appb-000014
Figure PCTCN2022101986-appb-000015
在一些实施方案中，所述的式IV所示水合物的晶型D，其X射线粉末衍射(XRPD)图谱如图7所示。
在一些实施方案中，所述的式IV所示水合物的晶型D，其差示扫描量热(DSC)曲线在106.9℃和200.3℃处具有吸热峰。
在一些实施方案中，所述的式IV所示水合物的晶型D，其差示扫描量热曲线如图8中所示。
在一些实施方案中，所述的式IV所示水合物的晶型D，其热重分析曲线(TGA)显示在17.5℃至150℃温度范围失重7.8％。
在一些实施方案中，所述的式IV所示水合物的晶型D，其热重分析曲线如图8中所示。
在一些实施方案中，所述的式IV所示水合物的晶型D，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式IV所示水合物的晶型D的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式IV所示水合物的晶型D的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式V所示水合物：
Figure PCTCN2022101986-appb-000016
本发明还提供了一种式V所示水合物的晶型E，其以2θ角表示的X射线粉末衍射图在6.49±0.2°、7.20±0.2°、8.42±0.2°、10.41±0.2°、11.56±0.2°、16.87±0.2°、19.11±0.2°处有衍射峰。
在一些实施方案中，所述的式V所示水合物的晶型E，其以2θ角表示的X-射线粉末衍射图在6.49±0.2°、7.20±0.2°、8.42±0.2°、10.41±0.2°、11.56±0.2°、16.87±0.2°、19.11±0.2°、19.56±0.2°处有衍射峰。
在一些实施方案中，所述的式V所示水合物的晶型E，其以2θ角表示的X-射线粉末衍射图在6.49±0.2°、7.20±0.2°、7.61±0.2°、8.42±0.2°、10.41±0.2°、11.56±0.2°、12.78±0.2°、14.34±0.2°、16.10±0.2°、16.56±0.2°、16.87±0.2°、19.11±0.2°、19.56±0.2°、21.11±0.2°、22.71±0.2°、23.19±0.2°、25.15±0.2°处有衍射峰。
在一些实施方案中，所述的式V所示水合物的晶型E，其以2θ角表示的X-射线粉末衍射图具有 如下表6所示的衍射峰：
表6
Figure PCTCN2022101986-appb-000017
在一些实施方案中，所述的式V所示水合物的晶型E，其X射线粉末衍射(XRPD)图谱如图9所示。
在一些实施方案中，所述的式V所示水合物的晶型E，其差示扫描量热(DSC)曲线在70.4℃、114.8℃和218.9℃处具有吸热峰。
在一些实施方案中，所述的式V所示水合物的晶型E，其差示扫描量热曲线如图10中所示。
在一些实施方案中，所述的式V所示水合物的晶型E，其热重分析曲线(TGA)显示在28.5℃至150℃温度范围失重7.0％。
在一些实施方案中，所述的式V所示水合物的晶型E，其热重分析曲线如图10中所示。
在一些实施方案中，所述的式V所示水合物的晶型E，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式V所示水合物的晶型E的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式V所示水合物的晶型E的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式VI所示水合物：
Figure PCTCN2022101986-appb-000018
本发明还提供了一种式VI所示水合物的晶型I，其以2θ角表示的X射线粉末衍射图在6.72±0.2°、7.97±0.2°、10.46±0.2°、13.65±0.2°、17.22±0.2°、20.22±0.2°处有衍射峰。
在一些实施方案中，所述的式VI所示水合物的晶型I，其以2θ角表示的X-射线粉末衍射图在6.72±0.2°、7.97±0.2°、10.46±0.2°、12.39±0.2°、13.65±0.2°、17.22±0.2°、20.22±0.2°处有衍射峰。
在一些实施方案中，所述的式VI所示水合物的晶型I，其以2θ角表示的X-射线粉末衍射图在6.72±0.2°、7.97±0.2°、10.46±0.2°、12.39±0.2°、13.65±0.2°、17.22±0.2°、20.22±0.2°、24.20±0.2°处有衍射峰。
在一些实施方案中，所述的式VI所示水合物的晶型I，其以2θ角表示的X-射线粉末衍射图具有如下表7所示的衍射峰:
表7
Figure PCTCN2022101986-appb-000019
在一些实施方案中，所述的式VI所示水合物的晶型I，其X射线粉末衍射(XRPD)图谱如图11所示。
在一些实施方案中，所述的式VI所示水合物的晶型I，其差示扫描量热(DSC)曲线在94.6℃和213.2℃处具有吸热峰。
在一些实施方案中，所述的式VI所示水合物的晶型I，其差示扫描量热曲线如图12中所示。
在一些实施方案中，所述的式VI所示水合物的晶型I，其热重分析曲线(TGA)显示在29.4℃至 150℃温度范围失重5.2％。
在一些实施方案中，所述的式VI所示水合物的晶型I，其热重分析曲线如图12中所示。
在一些实施方案中，所述的式VI所示水合物的晶型I，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式VI所示水合物的晶型I的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式VI所示水合物的晶型I的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式VII所示水合物：
Figure PCTCN2022101986-appb-000020
本发明还提供了一种式VII所示水合物的晶型J，其以2θ角表示的X射线粉末衍射图在6.55±0.2°、12.42±0.2°、13.13±0.2°、16.82±0.2°、17.73±0.2°、19.66±0.2°处有衍射峰。
在一些实施方案中，所述的式VII所示水合物的晶型J，其以2θ角表示的X-射线粉末衍射图在5.14±0.2°、6.55±0.2°、12.07±0.2°、12.42±0.2°、13.13±0.2°、16.82±0.2°、17.73±0.2°、19.66±0.2°处有衍射峰。
在一些实施方案中，所述的式VII所示水合物的晶型J，其以2θ角表示的X-射线粉末衍射图在5.14±0.2°、6.55±0.2°、9.84±0.2°、12.07±0.2°、12.42±0.2°、13.13±0.2°、13.70±0.2°、14.87±0.2°、16.82±0.2°、17.73±0.2°、19.66±0.2°、20.53±0.2°、21.44±0.2°、23.21±0.2°处有衍射峰。
在一些实施方案中，所述的式VII所示水合物的晶型J，其以2θ角表示的X-射线粉末衍射图具有如下表8所示的衍射峰：
表8
Figure PCTCN2022101986-appb-000021
Figure PCTCN2022101986-appb-000022
在一些实施方案中，所述的式VII所示水合物的晶型J，X射线粉末衍射(XRPD)图谱如图13所示。
在一些实施方案中，所述的式VII所示水合物的晶型J，其差示扫描量热(DSC)曲线在102.2℃和247.6℃处具有吸热峰。
在一些实施方案中，所述的式VII所示水合物的晶型J，其差示扫描量热曲线如图14中所示。
在一些实施方案中，所述的式VII所示水合物的晶型J，其热重分析曲线(TGA)显示在19.6℃至150℃温度范围失重3.9％。
在一些实施方案中，所述的式VII所示水合物的晶型J，其热重分析曲线如图14中所示。
在一些实施方案中，所述的式VII所示水合物的晶型J，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式VII所示水合物的晶型J的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的VII所示水合物的晶型J的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式VIII所示化合物(即式I所示化合物的马来酸盐)、其晶型或水合物：
Figure PCTCN2022101986-appb-000023
本发明还提供一种式VIII所示化合物的晶型A，其以2θ角表示的X射线粉末衍射图在6.33±0.2°、11.56±0.2°、14.41±0.2°、16.64±0.2°、17.45±0.2°、18.21±0.2°、18.45±0.2°、21.19±0.2°、23.46±0.2°、24.20±0.2°处有衍射峰。
在一些实施方案中，所述的式VIII所示化合物的晶型A，其以2θ角表示的X-射线粉末衍射图在6.33±0.2°、11.56±0.2°、14.41±0.2°、16.64±0.2°、17.45±0.2°、18.21±0.2°、18.45±0.2°、20.22±0.2°、21.19±0.2°、23.46±0.2°、24.20±0.2°、25.04±0.2°处有衍射峰。
在一些实施方案中，所述的式VIII所示化合物的晶型A，其以2θ角表示的X-射线粉末衍射图在6.33±0.2°、11.15±0.2°、11.56±0.2°、12.71±0.2°、14.41±0.2°、14.60±0.2°、16.64±0.2°、16.81±0.2°、17.45±0.2°、18.21±0.2°、18.45±0.2°、18.79±0.2°、19.18±0.2°、20.22±0.2°、21.19±0.2°、21.58±0.2°、22.45±0.2°、23.46±0.2°、24.20±0.2°、24.52±0.2°、25.04±0.2°、26.68±0.2°、27.88±0.2°、28.08±0.2°、28.82±0.2°、29.88±0.2°、31.01±0.2°、35.20±0.2°处有衍射峰。
在一些实施方案中，所述的式VIII所示化合物的晶型A，其以2θ角表示的X-射线粉末衍射图具有如下表9所示的衍射峰：
表9
Figure PCTCN2022101986-appb-000024
Figure PCTCN2022101986-appb-000025
在一些实施方案中，所述的式VIII所示化合物的晶型A，其X射线粉末衍射(XRPD)图谱如图17所示。
在一些实施方案中，所述的式VIII所示化合物的晶型A，其差示扫描量热(DSC)曲线在45.8℃、204.0℃和206.1℃处具有吸热峰。
在一些实施方案中，所述的式VIII所示化合物的晶型A，其差示扫描量热曲线如图18所示。
在一些实施方案中，所述的式VIII所示化合物的晶型A，其热重分析曲线(TGA)在28.8℃至150℃温度范围失重6.9％。
在一些实施方案中，所述的式VIII所示化合物的晶型A，其热重分析曲线如图18所示。
在一些实施方案中，所述的式VIII所示化合物的晶型A，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式VIII所示化合物的晶型A的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的VIII所示化合物的晶型A的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式VIII所示化合物的晶型B，其以2θ角表示的X射线粉末衍射图在11.59±0.2°、16.89±0.2°、17.37±0.2°、18.24±0.2°、22.60±0.2°、23.66±0.2°、23.89±0.2°处有衍射峰。
在一些实施方案中，所述的式VIII所示化合物的晶型B，其以2θ角表示的X射线粉末衍射图在11.59±0.2°、11.79±0.2°、14.39±0.2°、16.89±0.2°、17.37±0.2°、18.24±0.2°、21.30±0.2°、22.60±0.2°、23.66±0.2°、23.89±0.2°处有衍射峰。
在一些实施方案中，所述的式VIII所示化合物的晶型B，其以2θ角表示的X射线粉末衍射图在6.28±0.2°、10.96±0.2°、11.59±0.2°、11.79±0.2°、14.39±0.2°、16.53±0.2°、16.89±0.2°、17.37±0.2°、17.93±0.2°、18.24±0.2°、18.66±0.2°、19.04±0.2°、19.38±0.2°、19.94±0.2°、21.30±0.2°、21.70±0.2°、22.60±0.2°、23.25±0.2°、23.66±0.2°、23.89±0.2°、24.33±0.2°、25.03±0.2°、25.43±0.2°、26.83±0.2°、27.62±0.2°、27.92±0.2°、28.76±0.2°、29.72±0.2°处有衍射峰。
在一些实施方案中，所述的式VIII所示化合物的晶型B，其以2θ角表示的X-射线粉末衍射图具有如下表10所示的衍射峰：
表10
Figure PCTCN2022101986-appb-000026
Figure PCTCN2022101986-appb-000027
在一些实施方案中，所述的式VIII所示化合物的晶型B，其X射线粉末衍射(XRPD)图谱如图19所示。
在一些实施方案中，所述的式VIII所示化合物的晶型B，其差示扫描量热(DSC)曲线在142.9℃和204.1℃处具有吸热峰。
在一些实施方案中，所述的式VIII所示化合物的晶型B，其差示扫描量热曲线如图20中所示。
在一些实施方案中，所述的式VIII所示化合物的晶型B，其热重分析曲线(TGA)显示在29.1℃ 至170℃温度范围失重4.0％。
在一些实施方案中，所述的式VIII所示化合物的晶型B，其热重分析曲线如图20中所示。
在一些实施方案中，所述的式VIII所示化合物的晶型B，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式VIII所示化合物的晶型B的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的VIII所示化合物的晶型B的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟,温度范围为室温～350℃。
本发明还提供了一种式IX化合物(即式I所示化合物的柠檬酸盐)、其晶型或水合物：
Figure PCTCN2022101986-appb-000028
本发明还提供了一种式IX化合物的晶型A，其以2θ角表示的X射线粉末衍射图在5.09±0.2°、8.16±0.2°、10.13±0.2°、15.22±0.2°、18.27±0.2°、21.05±0.2°处有衍射峰。
在一些实施方案中，所述的式IX化合物的晶型A，其以2θ角表示的X射线粉末衍射图在5.09±0.2°、8.16±0.2°、9.11±0.2°、10.13±0.2°、15.22±0.2°、18.27±0.2°、18.75±0.2°、21.05±0.2°处有衍射峰。
在一些实施方案中，所述的式IX化合物的晶型A，其以2θ角表示的X射线粉末衍射图在4.57±0.2°、5.09±0.2°、8.16±0.2°、9.11±0.2°、10.13±0.2°、12.25±0.2°、12.85±0.2°、13.65±0.2°、15.22±0.2°、16.35±0.2°、16.59±0.2°、18.27±0.2°、18.75±0.2°、19.76±0.2°、20.47±0.2°、21.05±0.2°、21.50±0.2°、22.43±0.2°、24.27±0.2°、25.49±0.2°处有衍射峰。
在一些实施方案中，所述的式IX化合物的晶型A，其以2θ角表示的X-射线粉末衍射图具有如下表11所示的衍射峰：
表11
Figure PCTCN2022101986-appb-000029
Figure PCTCN2022101986-appb-000030
在一些实施方案中，所述的式IX化合物的晶型A，其X射线粉末衍射(XRPD)图谱如图21所示。
在一些实施方案中，所述的式IX化合物的晶型A，其差示扫描量热(DSC)曲线在189.5℃处具有吸热峰。
在一些实施方案中，所述的式IX化合物的晶型A，其差示扫描量热曲线如图22中所示。
在一些实施方案中，所述的式IX化合物的晶型A，其热重分析曲线(TGA)显示在27.3℃至150℃温度范围失重1.6％。
在一些实施方案中，所述的式IX化合物的晶型A，其热重分析曲线如图22中所示。
在一些实施方案中，所述的式IX化合物的晶型A，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式IX化合物的晶型A的热重分析(TGA)方法如下：升温速率为10℃/分钟温度范围为室温～350℃。
在一些实施方案中，所述的式IX化合物的晶型A的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式I所示化合物的晶型I，其以2θ角表示的X射线粉末衍射图在15.03±0.2°、18.91±0.2°、19.83±0.2°、20.40±0.2°、21.11±0.2°处有衍射峰；
Figure PCTCN2022101986-appb-000031
在一些实施方案中，所述的式I所示化合物的晶型I，其以2θ角表示的X射线粉末衍射图在9.64±0.2°、11.16±0.2°、12.53±0.2°、15.03±0.2°、18.91±0.2°、19.83±0.2°、20.40±0.2°、21.11±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示化合物的晶型I，其以2θ角表示的X射线粉末衍射图在7.94±0.2°、9.64±0.2°、11.16±0.2°、11.92±0.2°、12.53±0.2°、14.26±0.2°、15.03±0.2°、16.48±0.2°、16.79±0.2°、17.51±0.2°、18.91±0.2°、19.33±0.2°、19.83±0.2°、20.40±0.2°、21.11±0.2°、22.56±0.2°、23.43±0.2°、23.93±0.2°、24.17±0.2°、25.16±0.2°、26.68±0.2°、28.60±0.2°、29.63±0.2°、30.57±0.2°、31.62±0.2°、32.71±0.2°、33.66±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示化合物的晶型I，其以2θ角表示的X-射线粉末衍射图具有如下表12所示的衍射峰：
表12
Figure PCTCN2022101986-appb-000032
Figure PCTCN2022101986-appb-000033
在一些实施方案中，所述的式I所示化合物的晶型I，其X射线粉末衍射(XRPD)图谱如图23所示。
在一些实施方案中，所述的式I所示化合物的晶型I，其差示扫描量热(DSC)曲线在244.0℃处具有吸热峰。
在一些实施方案中，所述的式I所示化合物的晶型I，其差示扫描量热曲线如图24中所示。
在一些实施方案中，所述的式I所示化合物的晶型I，其热重分析曲线(TGA)显示在29.8℃至200℃温度范围失重1.9％。
在一些实施方案中，所述的式I所示化合物的晶型I，其热重分析曲线如图24中所示。
在一些实施方案中，所述的式I所示化合物的晶型I，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式I所示化合物的晶型I的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式I所示化合物的晶型I的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式I所示化合物的晶型II，其以2θ角表示的X射线粉末衍射图在7.83±0.2°、9.79±0.2°、18.19±0.2°、19.90±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示化合物的晶型II，其以2θ角表示的X-射线粉末衍射图在7.83±0.2°、9.09±0.2°、9.79±0.2°、17.99±0.2°、18.19±0.2°、19.59±0.2°、19.90±0.2°、23.55±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示化合物的晶型II，其以2θ角表示的X-射线粉末衍射图在7.83±0.2°、8.56±0.2°、9.09±0.2°、9.79±0.2°、11.07±0.2°、11.74±0.2°、13.86±0.2°、15.18±0.2°、15.65±0.2°、17.15±0.2°、17.99±0.2°、18.19±0.2°、19.59±0.2°、19.90±0.2°、20.62±0.2°、23.55±0.2°、24.31±0.2°、27.41±0.2°、29.02±0.2°、31.17±0.2°、31.57±0.2°、35.74±0.2°、36.79±0.2°、38.38±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示化合物的晶型II，其以2θ角表示的X-射线粉末衍射图具有如下表13所示的衍射峰：
表13
Figure PCTCN2022101986-appb-000034
在一些实施方案中，所述的式I所示化合物的晶型II，其X射线粉末衍射(XRPD)图谱如图25中所示。
在一些实施方案中，所述的式I所示化合物的晶型II，其差示扫描量热(DSC)曲线在244.9℃处具有吸热峰。
在一些实施方案中，所述的式I所示化合物的晶型II，其差示扫描量热曲线如图26中所示。
在一些实施方案中，所述的式I所示化合物的晶型II，其热重分析曲线(TGA)显示在25.1℃至150℃温度范围失重1.1％。
在一些实施方案中，所述的式I所示化合物的晶型II，其热重分析曲线如图26中所示。
在一些实施方案中，所述的式I所示化合物的晶型II，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式I所示化合物的晶型II的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式I所示化合物的晶型II的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式I所示化合物的晶型III，其以2θ角表示的X射线粉末衍射图在4.50±0.2°、6.89±0.2°、7.24±0.2°、13.42±0.2°、14.46±0.2°、20.72±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示的化合物的晶型III，其以2θ角表示的X-射线粉末衍射图在4.50±0.2°、6.89±0.2°、7.24±0.2°、13.42±0.2°、14.46±0.2°、15.47±0.2°、20.72±0.2°、21.92±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示的化合物的晶型III，其以2θ角表示的X-射线粉末衍射图在4.50±0.2°、6.89±0.2°、7.24±0.2°、9.88±0.2°、12.56±0.2°、13.42±0.2°、14.46±0.2°、15.47±0.2°、16.73±0.2°、17.58±0.2°、19.25±0.2°、19.81±0.2°、20.72±0.2°、21.45±0.2°、21.92±0.2°、23.34±0.2°、26.25±0.2°、27.65±0.2°、30.69±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示的化合物的晶型III，其以2θ角表示的X-射线粉末衍射图具有如下表14所示的衍射峰：
表14
Figure PCTCN2022101986-appb-000035
Figure PCTCN2022101986-appb-000036
在一些实施方案中，所述的式I所示化合物的晶型III，其X射线粉末衍射(XRPD)图谱如图27所示。
在一些实施方案中，所述的式I所示化合物的晶型III，其差示扫描量热(DSC)曲线在135.1℃和244.1℃处具有吸热峰。
在一些实施方案中，所述的式I所示化合物的晶型III，其差示扫描量热曲线如图28中所示。
在一些实施方案中，所述的式I所示化合物的晶型III，其热重分析曲线(TGA)显示在26.5℃至150℃温度范围失重4.3％。
在一些实施方案中，所述的式I所示化合物的晶型III，其热重分析曲线如图28中所示。
在一些实施方案中，所述的式I所示化合物的晶型III，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式I所示化合物的晶型III的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式I所示化合物的晶型III的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式I所示化合物的晶型V，其以2θ角表示的X射线粉末衍射图在4.19±0.2°、7.47±0.2°、12.44±0.2°、14.35±0.2°、16.60±0.2°、20.79±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示化合物的晶型V，其以2θ角表示的X-射线粉末衍射图在4.19±0.2°、7.47±0.2°、12.44±0.2°、14.35±0.2°、15.17±0.2°、16.60±0.2°、20.79±0.2°、26.86±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示化合物的晶型V，其以2θ角表示的X-射线粉末衍射图在4.19±0.2°、7.47±0.2°、12.44±0.2°、14.35±0.2°、15.17±0.2°、16.60±0.2°、17.29±0.2°、18.99±0.2°、19.93±0.2°、20.79±0.2°、21.55±0.2°、25.29±0.2°、26.23±0.2°、26.86±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示化合物的晶型V，其以2θ角表示的X-射线粉末衍射图具有如下表15所示的衍射峰：
表15
Figure PCTCN2022101986-appb-000037
在一些实施方案中，所述的式I所示化合物的晶型V，其X射线粉末衍射(XRPD)图谱如图29所示。
在一些实施方案中，所述的式I所示化合物的晶型V，其差示扫描量热(DSC)曲线在132.3℃和242.9℃处具有吸热峰。
在一些实施方案中，所述的式I所示化合物的晶型V，其差示扫描量热曲线如图30中所示。
在一些实施方案中，所述的式I所示化合物的晶型V，其热重分析曲线(TGA)显示在22.0℃至150℃温度范围失重5.9％。
在一些实施方案中，所述的式I所示化合物的晶型V，其热重分析曲线如图30中所示。
在一些实施方案中，所述的式I所示化合物的晶型V，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式I所示化合物的晶型V的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式I所示化合物的晶型V的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供了一种式I所示化合物的晶型VI，其以2θ角表示的X射线粉末衍射图在4.36±0.2°、8.49±0.2°、14.64±0.2°、15.34±0.2°、18.94±0.2°、19.74±0.2°、20.13±0.2°、21.08±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示化合物的晶型VI，其以2θ角表示的X-射线粉末衍射图在4.36±0.2°、8.49±0.2°、13.03±0.2°、14.64±0.2°、15.34±0.2°、18.94±0.2°、19.74±0.2°、20.13±0.2°、21.08±0.2°、21.81±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示化合物的晶型VI，其以2θ角表示的X-射线粉末衍射图在4.36±0.2°、6.96±0.2°、8.49±0.2°、12.23±0.2°、13.03±0.2°、14.64±0.2°、15.34±0.2°、16.16±0.2°、17.91±0.2°、18.94±0.2°、19.74±0.2°、20.13±0.2°、21.08±0.2°、21.81±0.2°、25.07±0.2°、26.01±0.2°处有衍射峰。
在一些实施方案中，所述的式I所示化合物的晶型VI，其以2θ角表示的X-射线粉末衍射图具有如下表16所示的衍射峰：
表16
Figure PCTCN2022101986-appb-000038
在一些实施方案中，所述的式I所示化合物的晶型VI，其X射线粉末衍射(XRPD)图谱如图31所示。
在一些实施方案中，所述的式I所示化合物的晶型VI，其差示扫描量热(DSC)曲线在134.3℃、140.9℃和240.8℃处具有吸热峰。
在一些实施方案中，所述的式I所示化合物的晶型VI，其差示扫描量热曲线如图32中所示。
在一些实施方案中，所述的式I所示化合物的晶型VI，其热重分析曲线(TGA)在28.5℃至150℃温度范围失重7.0％。
在一些实施方案中，所述的式I所示化合物的晶型VI，其热重分析曲线如图32中所示。
在一些实施方案中，所述的式I所示化合物的晶型VI，其XRPD使用Cu,Kα辐射。
在一些实施方案中，所述的式I所示化合物的晶型VI的热重分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
在一些实施方案中，所述的式I所示化合物的晶型VI的差示扫描量热分析(TGA)方法如下：升温速率为10℃/分钟，温度范围为室温～350℃。
本发明还提供一种式I所示化合物的盐的制备方法，所述的式I所示化合物的盐为如前所述的式II所示化合物(即式I所示化合物的盐酸盐)、式VIII所示化合物(即式I所示化合物的马来酸盐)或式IX化合物(即式I所示化合物的柠檬酸盐)，其包括如下步骤：将式I所示化合物和酸在溶剂中进行成盐反应即可；所述的酸为HCl、马来酸或柠檬酸。
在一些实施方案中，所述的式I所示化合物的盐的制备方法中，所述的溶剂可以选自甲醇、乙醇、异丙醇、正丁醇、乙腈、水、二氯甲烷、甲基叔丁基醚、二甲基亚砜、三氯甲烷、四氢呋喃、2-甲基呋喃、乙酸乙酯、乙酸异丙酯、1,4-二氧六环、N,N-二甲基甲酰胺、水、环己烷、丙酮、N-甲基吡咯烷酮、丁酮、甲基异丁酮、甲苯和苯甲醚中的一种或多种。
在一些实施方案中，所述的式I所示化合物的盐的制备方法中，所述的溶剂可以选自甲醇、乙醇、异丙醇、乙腈、水、二氯甲烷、甲基叔丁基醚、二甲基亚砜、三氯甲烷、四氢呋喃、2-甲基呋喃、乙酸乙酯、乙酸异丙酯、1,4-二氧六环、N,N-二甲基甲酰胺、水和丙酮中的一种或多种。
在一些实施方案中，所述的式I所示化合物的盐的制备方法中，所述的溶剂可以选自甲醇、丙酮、乙酸乙酯、二甲基亚砜、四氢呋喃、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺、异丙醇、乙腈/乙酸乙酯溶液、乙腈水溶液、丙酮/水溶液、二氯甲烷/甲基叔丁基醚溶液和三氯甲烷/乙醇溶液中的一种或多种。
本发明还提供了一种如前所述的式II所示化合物的晶型A的制备方法，其包括如下步骤：将式I所示化合物与HCl在溶剂中反应析晶，得到式II所示化合物的晶型A；所述溶剂为有机溶剂或者有机溶剂与水的混合溶剂；所述有机溶剂为二氯甲烷、甲醇、乙醇和异丙醇中的一种或多种。
在一些实施方案中，所述的式II所示化合物的晶型A的制备方法中，式I所示化合物与HCl的摩尔比可以为1:(1-2.5)，例如1:1或1:2.5。
在一些实施方案中，所述的式II所示化合物的晶型A的制备方法中，所述式I所示化合物与溶剂的质量体积比可以为10-50mg/mL；例如10、15、20、30或40mg/mL。
在一些实施方案中，所述的式II所示化合物的晶型A的制备方法中，所述有机溶剂与水的混合溶剂中，所述有机溶剂为甲醇、乙醇和异丙醇中的一种或多种，例如甲醇和水的混合溶剂。
在一些实施方案中，所述的式II所示化合物的晶型A的制备方法中，所述溶剂为甲醇和水的混合溶剂或二氯甲烷和乙醇的混合溶剂，优选为二氯甲烷和乙醇的混合溶剂。所述甲醇和水的混合溶剂中，甲醇和水的体积比可以为(100-110):1。所述二氯甲烷和乙醇的混合溶剂中，二氯甲烷和乙醇的体积比可以为(5-7):1，例如6:1。
在一些实施方案中，所述的式II所示化合物的晶型A的制备方法中，反应析晶的操作可以包括以下步骤：将式I所示化合物、HCl、甲醇和水的混合溶液反应(例如先在室温下反应，然后在50℃下反应；例如，在室温下反应3天，后转移至50℃反应3小时)后体系中的固体分离出来得到所述式II所示化合物的晶型A。优选地，固体分离出来后进一步进行干燥，例如：先在25℃下真空干燥(例如干燥2小时)，然后在50℃下真空干燥(例如干燥2小时)。
在一些实施方案中，所述的式II所示化合物的晶型A的制备方法中，反应析晶的操作可以包括以下步骤：将式I所示化合物、HCl、二氯甲烷和乙醇的混合溶液反应(例如在20～30℃下反应；例如在20～30℃下反应24小时)后体系中的固体分离出来得到所述式II所示化合物的晶型A。优选地，固体分离出来后进一步进行干燥，例如：在50℃下真空干燥(例如干燥2小时)。
本发明还提供了一种如前所述的式II所示化合物的晶型B的制备方法，其包括如下步骤：将式I所示化合物与HCl在丙酮和水的混合溶剂中反应析晶，得到式II所示化合物的晶型B。
在一些实施方案中，所述的式II所示化合物的晶型B的制备方法中，式I所示化合物与HCl的摩尔比可以为1:(1-1.05)，优选为1:1。
在一些实施方案中，所述的式II所示化合物的晶型B的制备方法中，所述式I所示化合物与丙酮的质量体积比可以为20-60mg/mL，优选为50mg/mL。
在一些实施方案中，所述的式II所示化合物的晶型B的制备方法中，所述丙酮和水的混合溶剂中，丙酮和水的体积比可以为(100-120):1。
在一些实施方案中，所述的式II所示化合物的晶型B的制备方法中，反应析晶的操作可以包括以下步骤：将式I所示化合物、HCl、丙酮和水的混合溶液在室温下反应(例如先在室温下反应，然后在50℃下反应；例如，在室温下反应3天，后转移至50℃反应2小时)后体系中的固体分离出来得到所述式II所示化合物的晶型B。优选地，固体分离出来后进一步进行干燥，例如：在25℃下真空干燥(例如干燥12小时)。
本发明还提供了一种如前所述的式II所示化合物的晶型K的制备方法，其包括如下步骤：将式VII所示水合物的晶型J在N 2条件下吹扫20min，升温至120℃，降温至30℃，得到式II所示化合物的晶型K。
本发明还提供了一种如前所述的式III所示水合物的晶型C的制备方法，其包括如下步骤：将式II所示化合物(例如式II所示化合物晶型A)在乙腈和乙酸乙酯的混合溶剂中搅拌(例如在5-50℃搅拌24小时)，得到式III所示水合物的晶型C。
在一些实施方案中，所述的式III所示水合物的晶型C的制备方法中，所述式II所示化合物的晶型A与乙腈和乙酸乙酯的混合溶剂的质量体积比为20-200mg/mL；优选为100mg/mL。
在一些实施方案中，所述的式III所示水合物的晶型C的制备方法中，所述乙腈和乙酸乙酯的混合溶剂中，所述乙腈与乙酸乙酯的体积比可以为(2-5):1；优选为3:1。
在一些实施方案中，所述的式III所示水合物的晶型C的制备方法中，在搅拌后还可以包括以下步骤：将混合溶液中的固体分离出来得到所述式III所示水合物的晶型C。优选地，固体分离出来后 进一步进行干燥，例如：在50℃下真空干燥(例如干燥2小时)。
本发明还提供了一种如前所述的式IV所示水合物的晶型D的制备方法，其包括如下步骤：将式II所示化合物(例如式II所示化合物的晶型A)在乙腈和水的混合溶剂中搅拌(例如在25℃搅拌24小时)，得到式IV所示水合物的晶型D。
在一些实施方案中，所述的式IV所示水合物的晶型D的制备方法中，所述式II所示化合物的晶型A与乙腈和水的混合溶剂的质量体积比为20-200mg/mL；优选为100mg/mL。
在一些实施方案中，所述的式IV所示水合物的晶型D的制备方法中，所述乙腈和水的混合溶剂中，乙腈与水的体积比为(5-20):1；优选为12:1。
在一些实施方案中，所述的式IV所示水合物的晶型D的制备方法中，在搅拌后还可以包括以下步骤：将混合溶液中的固体分离出来得到所述式IV所示水合物的晶型D。优选地，固体分离出来后进一步进行干燥，例如：在50℃下真空干燥(例如干燥2小时)。
本发明还提供了一种如前所述的式V所示水合物的晶型E的制备方法，其包括如下步骤：将式II所示化合物(例如式II所示化合物的晶型A)在丙酮和水的混合溶剂中搅拌挥发(例如在25℃搅拌挥发24小时)，得到式V所示水合物的晶型E。
在一些实施方案中，所述的式V所示水合物的晶型E的制备方法中，所述式II所示化合物的晶型A与丙酮和水的混合溶剂的质量体积比为20-200mg/mL；优选为100mg/mL。
在一些实施方案中，所述的式V所示水合物的晶型E的制备方法中，所述丙酮和水的混合溶剂中，丙酮与水的体积比为(5-12):1，优选为9:1。
在一些实施方案中，所述的式V所示水合物的晶型E的制备方法中，在搅拌挥发后还可以包括以下步骤：将混合溶液中的固体分离出来得到所述式V所示水合物的晶型E。优选地，固体分离出来后进一步进行干燥，例如：在50℃下真空干燥(例如干燥2小时)。
本发明还提供了一种如前所述的式VI所示水合物的晶型I的制备方法，其包括如下步骤：将式V所示水合物的晶型E在N 2条件下吹扫，升温至80℃-150℃，降温至30℃，暴露在空气中，得到式VI所示水合物的晶型I。
本发明还提供了一种如前所述的式VII所示水合物的晶型J的制备方法，其包括如下步骤：将式II所示化合物的晶型A在二氯甲烷和甲基叔丁基醚的混合溶剂中搅拌(例如在25℃搅拌24小时)，得到式VII所示水合物的晶型J。
在一些实施方案中，所述的式VII所示水合物的晶型J的制备方法中，所述式II所示化合物的晶型A与二氯甲烷和甲基叔丁基醚的混合溶剂的质量体积比为20-200mg/mL；优选为100mg/mL。
在一些实施方案中，所述的式VII所示水合物的晶型J的制备方法中，所述二氯甲烷和甲基叔丁基醚的混合溶剂中，二氯甲烷与甲基叔丁基醚的体积比为(1-10):1；优选为5:1。
在一些实施方案中，所述的式VII所示水合物的晶型J的制备方法中，在搅拌后还可以包括以下步骤：将混合溶液中的固体分离出来得到所述式VII所示水合物的晶型J。优选地，固体分离出来后进一步进行干燥，例如：在50℃下真空干燥(例如干燥2小时)。
本发明还提供了一种如前所述的式VIII所示化合物的晶型A的制备方法，其包括如下步骤：将式I所示化合物与马来酸在甲醇中反应析晶，得到式VIII所示化合物的晶型A。
在一些实施方案中，所述的式VIII所示化合物的晶型A的制备方法中，式I所示化合物与马来酸的摩尔比可以为1:(1-1.1)，优选为1:1。
在一些实施方案中，所述的式VIII所示化合物的晶型A的制备方法中，所述式I所示化合物与甲醇的质量体积比可以为20-60mg/mL，优选为50mg/mL。
在一些实施方案中，所述的式VIII所示化合物的晶型A的制备方法中，反应析晶的操作可以包括以下步骤：将式I所示化合物、马来酸和甲醇的混合溶液反应(例如先在室温下反应，然后在50℃下反应；例如，在室温下反应3天，后转移至50℃反应2小时)后体系中的固体分离出来得到所述式VIII所示化合物的晶型A。优选地，固体分离出来后进一步进行干燥，例如：在25℃下真空干燥(例如干燥12小时)。
本发明还提供了一种如前所述的式VIII所示化合物的晶型B的制备方法，其包括如下步骤：将式I所示化合物与马来酸在丙酮中反应析晶，得到式VIII所示化合物的晶型B。
在一些实施方案中，所述的式VIII所示化合物的晶型B的制备方法中，式I所示化合物与马来酸的摩尔比可以为1:(1-1.1)，优选为1:1。
在一些实施方案中，所述的式VIII所示化合物的晶型B的制备方法中，所述式I所示化合物与甲醇的质量体积比可以为20-60mg/mL，优选为50mg/mL。
在一些实施方案中，所述的式VIII所示化合物的晶型B的制备方法中，反应析晶的操作可以包括以下步骤：将式I所示化合物、马来酸和丙酮的混合溶液反应(例如先在室温下反应，然后在50℃下反应；例如，在室温下反应3天，后转移至50℃反应2小时)后体系中的固体分离出来得到所述式VIII所示化合物的晶型B。优选地，固体分离出来后进一步进行干燥，例如：在25℃下真空干燥(例如干燥12小时)。
本发明还提供了一种如前所述的式IX化合物的晶型A的制备方法，其包括如下步骤：将式I所示化合物与柠檬酸在乙酸乙酯中反应析晶，得到式IX化合物的晶型A。
在一些实施方案中，所述的式IX化合物的晶型A的制备方法中，式I所示化合物与马来酸的摩尔比可以为1:(1-1.1)，优选为1:1。
在一些实施方案中，所述的式IX化合物的晶型A的制备方法中，所述式I所示化合物与甲醇的质量体积比可以为20-60mg/mL，优选为50mg/mL。
在一些实施方案中，所述的式IX化合物的晶型A的制备方法中，反应析晶的操作可以包括以下步骤：将式I所示化合物、马来酸和甲醇的混合溶液反应(例如先在室温下反应，然后在50℃下反应；例如，在室温下反应3天，后转移至50℃反应2小时)后体系中的固体分离出来得到所述式IX化合物的晶型A。优选地，固体分离出来后进一步进行干燥，例如：在25℃下真空干燥(例如干燥12小时)。
本发明还提供了一种如前所述的式I所示化合物的晶型I的制备方法，其包括如下步骤：将式I 所示化合物通过反溶剂结晶法得到式I所示化合物的晶型I，其中反溶剂结晶法中的正溶剂为DMSO，反溶剂为甲醇。
在一些实施方案中，所述式I所示化合物的晶型I的制备方法中，反溶剂结晶法的操作可以包括以下步骤：向式I所示化合物于正溶剂的溶液中加入反溶剂，将体系中的固体分离出来得到式I所示化合物的晶型I。优选地，固体分离出来后进一步进行干燥，例如：在25℃下真空干燥(例如干燥12小时)。
在一些实施方案中，所述式I所示化合物的晶型I的制备方法中，所述的正溶剂与反溶剂的体积比可以为(1.5-2):1，例如8:5。
在一些实施方案中，所述式I所示化合物的晶型I的制备方法中，所述式I所示化合物与所述正溶剂的质量体积比可以为10-100mg/mL，所述式I所示化合物与反溶剂的质量体积比为90-120mg/mL。优选地，所述式I所示化合物与正溶剂的质量体积比为62.5mg/mL，所述式I所示化合物与反溶剂的质量体积比为100:1mg/mL。
本发明还提供了一种如前所述的式I所示化合物的晶型II的制备方法，其包括如下步骤：将式I所示化合物(例如式I所示化合物的晶型I)在三氯甲烷和乙醇的混合溶剂中进行挥发结晶，得到式I所示化合物的晶型II。
在一些实施方案中，所述式I所示化合物的晶型II的制备方法中，所述式I所示化合物的晶型I与三氯甲烷和乙醇的混合溶剂的质量体积比为20-50mg/mL；优选为50mg/mL。
在一些实施方案中，所述式I所示化合物的晶型II的制备方法中，所述的三氯甲烷和乙醇的混合溶剂中，三氯甲烷与乙醇的体积比为(1-5):1；优选为1:1。
在一些实施方案中，所述式I所示化合物的晶型II的制备方法中，挥发结晶的操作可以包括以下步骤：将式I所示化合物的晶型I在三氯甲烷和乙醇的混合溶剂中挥发(例如50℃下挥发)至无溶剂，得到式I所示化合物的晶型II。
本发明还提供了一种如前所述的式I所示化合物的晶型III的制备方法，其包括如下步骤：将式I所示化合物(例如式I所示化合物的晶型I)的四氢呋喃溶液在乙酸异丙酯气氛中气液扩散，得到式I所示化合物的晶型III。
在一些实施方案中，所述式I所示化合物的晶型III的制备方法中，所述式I所示化合物与四氢呋喃的质量体积比为20-60mg/mL；优选为50mg/mL。
本发明还提供了一种如前所述的式I所示化合物的晶型V的制备方法，其包括如下步骤：将式I所示化合物(例如式I所示化合物的晶型I)于1,4-二氧六环和乙腈的混合溶剂中进行挥发结晶，得到式I所示化合物的晶型V。
在一些实施方案中，所述式I所示化合物的晶型V的制备方法包括如下步骤：将式I所示化合物于1,4-二氧六环和乙腈的混合溶剂中在室温下(例如25℃)下进行挥发结晶得到式I所示化合物的晶型V。
在一些实施方案中，所述式I所示化合物的晶型V的制备方法包括如下步骤：将式I所示化合物 于1,4-二氧六环和乙腈的混合溶剂中在5℃条件下搅拌(例如搅拌12小时)，然后在室温下(例如25℃)下进行挥发结晶得到式I所示化合物的晶型V。
在一些实施方案中，所述式I所示化合物的晶型V的制备方法中，所述的1,4-二氧六环和乙腈的混合溶剂中，1,4-二氧六环和乙腈的体积比为(1.5-2):1，例如8:5。
在一些实施方案中，所述式I所示化合物的晶型V的制备方法中，所述式I所示化合物与1,4-二氧六环的质量体积比为20-50mg/mL，所述式I所示化合物与乙腈的质量体积比为10-30mg/mL。优选地，所述式I所示化合物与1,4-二氧六环的质量体积比为40mg/mL，所述式I所示化合物与乙腈的质量体积比为20mg/mL。
本发明还提供了一种如前所述的式I所示化合物的晶型VI的制备方法，其包括如下步骤：将式I所示化合物(例如式I所示化合物的晶型I)于N,N-二甲基甲酰胺和异丙醇的混合溶剂中进行冷却结晶，得到式I所示化合物的晶型VI。
在一些实施方案中，所述式I所示化合物的晶型VI的制备方法包括如下步骤：将式I所示化合物于N,N-二甲基甲酰胺和异丙醇的混合溶剂中在-20℃下(任选地，在-20℃搅拌下)进行冷却结晶得到式I所示化合物的晶型VI。任选地，在-20℃下冷却前，将式I所示化合物于N,N-二甲基甲酰胺和异丙醇的混合溶剂中在5℃下搅拌(例如搅拌12小时)。
在一些实施方案中，所述式I所示化合物的晶型VI的制备方法中，所述N,N-二甲基甲酰胺和异丙醇的混合溶剂中，N,N-二甲基甲酰胺和异丙醇的体积比为(1.5-2):1，例如8:5。
在一些实施方案中，所述式I所示化合物的晶型VI的制备方法中，所述式I所示化合物与N,N-二甲基甲酰胺的质量体积比为20-50mg/mL，所述式I所示化合物与反溶剂异丙醇的质量体积比为10-30mg/mL。优选地，所述式I所示化合物与N,N-二甲基甲酰胺的质量体积比为40mg/mL，所述式I所示化合物与反溶剂异丙醇的质量体积比为20mg/mL。
本发明还提供一种如上所述的化合物、水合物或晶型在制备用于治疗与前蛋白转化酶枯草杆菌蛋白酶Kexin-9型(PCSK9)相关的疾病的药物的应用。
在一些实施方案中，所述应用中，所述的与前蛋白转化酶枯草杆菌蛋白酶Kexin-9型(PCSK9)相关的疾病为代谢性疾病，例如高脂血症、高胆固醇血症、高甘油三酯血症、脂肪肝变形、动脉粥样硬化、肥胖等。
定义和说明：
本发明的晶型可以通过一种或几种固态分析方法进行鉴定。如X射线粉末衍射、单晶X-射线衍射、差示扫描量热、热重曲线等。本领域技术人员应当理解，X射线粉末衍射的峰强度和/或峰情况可能会因为实验条件不同而不同。同时由于仪器不同的精确度，测得的2θ值会有约±0.2°的误差。而峰的相对强度值比峰的位置更依赖于所测定样品的某些性质，如晶体的尺寸大小，纯度高低，因此测得的峰强度可能出现约±20％的偏差。尽管存在试验误差、仪器误差和取向优先等，本领域技术人员还是可以从本申请提供的X射线粉末衍射数据获得足够的鉴别各个晶型的信息。而在DSC测量中，根据加热速率、晶体形状和纯度和其它测量参数，实测获得的吸热峰的初始温度、最高温度和熔化热数据 均具有一定程度的可变性。
除非另有说明，本文所用的下列术语或短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。本发明中未指明反应温度的，其反应温度为室温，室温一般为20-35℃。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本发明中，所述的X-射线粉末衍射图均使用Cu靶的Kα谱线测得的。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：发明提供的式I所示的化合物的盐酸盐晶型A、盐酸盐晶型B、盐酸盐晶型K、盐酸盐水合物晶型C、盐酸盐水合物晶型D、盐酸盐水合物晶型E、盐酸盐水合物晶型I、盐酸盐水合物晶型J、马来酸盐晶型A、马来酸盐晶型B、柠檬酸盐晶型A、游离态晶型I、游离态晶型II、游离态晶型III、游离态晶型V、游离态晶型VI具有以下一个或多个优点：(1)性质稳定；(2)引湿性好；(3)生物利用度好(4)具有良好的成药前景(5)游离态晶型及盐型相对于无定形具有更好的稳定性。
附图说明
图1为式Ⅰ化合物的盐酸盐的晶型A的Cu-Kα辐射的XRPD谱图。
图2为式Ⅰ化合物的盐酸盐的晶型A的TGA/DSC谱图。
图3为式Ⅰ化合物的盐酸盐的晶型B的Cu-Kα辐射的XRPD谱图。
图4为式Ⅰ化合物的盐酸盐的晶型B的TGA/DSC谱图。
图5为式Ⅰ化合物的盐酸盐的晶型C的Cu-Kα辐射的XRPD谱图。
图6为式Ⅰ化合物的盐酸盐的晶型C的TGA/DSC谱图。
图7为式Ⅰ化合物的盐酸盐的晶型D的Cu-Kα辐射的XRPD谱图。
图8为式Ⅰ化合物的盐酸盐的晶型D的TGA/DSC谱图。
图9为式Ⅰ化合物的盐酸盐的晶型E的Cu-Kα辐射的XRPD谱图。
图10为式Ⅰ化合物的盐酸盐的晶型E的TGA/DSC谱图。
图11为式Ⅰ化合物的盐酸盐的晶型I的Cu-Kα辐射的XRPD谱图。
图12为式Ⅰ化合物的盐酸盐的晶型I的TGA/DSC谱图。
图13为式Ⅰ化合物的盐酸盐的晶型J的Cu-Kα辐射的XRPD谱图。
图14为式Ⅰ化合物的盐酸盐的晶型J的TGA/DSC谱图。
图15为式Ⅰ化合物的盐酸盐的晶型K的Cu-Kα辐射的XRPD谱图。
图16为式Ⅰ化合物的盐酸盐的晶型K的TGA/DSC谱图。
图17为式Ⅰ化合物的马来酸盐的晶型A的Cu-Kα辐射的XRPD谱图。
图18为式Ⅰ化合物的马来酸盐的晶型A的TGA/DSC谱图。
图19为式Ⅰ化合物的马来酸盐的晶型B的Cu-Kα辐射的XRPD谱图。
图20为式Ⅰ化合物的马来酸盐的晶型B的TGA/DSC谱图。
图21为式Ⅰ化合物的柠檬酸盐的晶型A的Cu-Kα辐射的XRPD谱图。
图22为式Ⅰ化合物的柠檬酸盐的晶型A的TGA/DSC谱图。
图23为式Ⅰ化合物的游离态晶型I的Cu-Kα辐射的XRPD谱图。
图24为式Ⅰ化合物的游离态晶型I的TGA/DSC谱图。
图25为式Ⅰ化合物的游离态晶型II的Cu-Kα辐射的XRPD谱图。
图26为式Ⅰ化合物的游离态晶型II的TGA/DSC谱图。
图27为式Ⅰ化合物的游离态晶型III的Cu-Kα辐射的XRPD谱图。
图28为式Ⅰ化合物的游离态晶型III的TGA/DSC谱图。
图29为式Ⅰ化合物的游离态晶型V的Cu-Kα辐射的XRPD谱图。
图30为式Ⅰ化合物的游离态晶型V的TGA/DSC谱图。
图31为式Ⅰ化合物的游离态晶型VI的Cu-Kα辐射的XRPD谱图。
图32为式Ⅰ化合物的游离态晶型VI的TGA/DSC谱图。
图33为式Ⅰ化合物的游离态无定形的Cu-Kα辐射的XRPD谱图。
图34为式Ⅰ化合物的L-苹果酸盐的晶型A的Cu-Kα辐射的XRPD谱图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。本发明中纯度测试、动态溶解度和稳定性测试是由安捷伦1260高效液相色谱仪测试；样品中离子含量由ThermoFisher ICS-1100离子色谱测试；如表17，X射线粉末衍射(XRPD)图在PANalytacal生产的X射线粉末衍射分析仪X’Pert 3(反射)上采集；热重分析曲线(TGA)和差示扫描量热(DSC)图分别在TA Q5000/Discovery 5500热重分析仪和TA Q2000/Discovery 2500差示扫描量热仪上采集；动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。
表17
Figure PCTCN2022101986-appb-000039
如表18所示，离子色谱测试条件：
表18
离子色谱仪 ThermoFisher ICS-1100
色谱柱 IonPac AS18 Analytical Column,250*4mm
流动相 25mM NaOH
进样体积 25μL
流速 1.0mL/min
温度 35℃
柱温 35℃
电流 80mA
运行时间 Cl -:7.0min；SO 4 2-:13.0min；PO 4 3-:40.0min
如表19，热重分析(TGA)测试条件和差示扫描量热(DSC)分析条件：
表19
参数 热重分析(TGA) 差示扫描量热(DSC)
方法 线性升温 线性升温
样品盘 铝盘，敞开 铝盘，压盖/不压盖
温度范围 室温-350℃ 室温-350℃
扫描速率(℃/min) 10 10
保护气体 氮气 氮气
如表20，纯度测试、动态溶解度和稳定性测试的HPLC测试条件：
表20
Figure PCTCN2022101986-appb-000040
本发明中选用溶剂的中英文名称对照表如表21所示：
表21 本发明中选用溶剂的中英文名称对照表
英文 中文 英文 中文
MeOH 甲醇 1,4-dioxane 1,4-二氧六环
EtOH 乙醇 ACN 乙腈
IPA 异丙醇 DCM 二氯甲烷
Acetone 丙酮 CHCl 3 三氯甲烷
MIBK 甲基异丁基酮 toluene 甲苯
EtOAc 乙酸乙酯 n-heptane 正庚烷
IPAc 乙酸异丙酯 DMSO 二甲基亚砜
MTBE 甲基叔丁基醚 DMAc N,N-二甲基乙酰胺
THF 四氢呋喃 NMP N-甲基吡咯烷酮
2-MeTHF 2-甲基四氢呋喃 H 2O 水
化合物经手工或者软件命名，市售化合物采用供应商目录名称。
本发明中式Ⅰ所示的化合物由广州嘉越医药科技有限公司提供，按照专利PCT/CN2017/078616记载的制备方法制备得到
Figure PCTCN2022101986-appb-000041
实施例1
所述的式I所示化合物的盐酸盐的晶型A(也即式II所示化合物的晶型A)的制备方法为：将浓盐酸(110mg,12mol/L)的甲醇(6.5mL)溶液加入到式I所示化合物(500mg)的甲醇(4mL)溶液中，室温搅拌3天后转移至50℃搅拌3小时，过滤，50℃真空干燥2h，得到A晶型387.4mg。
XRPD图如图1所示，TGA及DSC结果如图2所示，TGA结果显示，从室温升温至150℃，样品失重为1.2％；DSC曲线于235.4℃及249.3℃(峰值温度)观察到吸热峰。IC/HPLC结果显示酸碱摩尔比为1:1。
实施例2
所述的式I所示化合物的盐酸盐的晶型A(也即式II所示化合物的晶型A)的制备方法为：将式I所示化合物(10g，1.0eq)用混合溶剂(150g，二氯甲烷:乙醇＝6:1)溶解，控温20～30℃，向其中滴加氯化氢乙醇溶液(浓度为29.7％，2.5eq)，反应24h，过滤，50℃真空干燥2h，得到盐酸盐的A晶型9.69g，纯度99.96％。
实施例3
所述的式I所示化合物的盐酸盐的晶型B(也即式II所示化合物的晶型B)的制备方法为：将浓盐酸(99.8mg,12mol/L)的丙酮(5mL)溶液加入到式I所示化合物(505mg)的丙酮(5mL)溶液中，室温搅拌3天后转移至50℃搅拌2小时，过滤，25℃真空干燥12h,得到盐酸盐的B晶型417.5mg。
XRPD图如图3所示，TGA及DSC结果如图4所示，TGA结果显示，从室温升温至150℃，样品失重为1.4％；DSC曲线于211.4℃，223.4℃和253.7℃(峰值温度)共观察到吸热峰。IC/HPLC结果显示酸碱摩尔比为1:0.9。
实施例4
所述的式I所示化合物的盐酸盐的晶型C(也即式III所示水合物的晶型C)的制备方法为：将式I所示化合物盐酸盐晶型A(500mg)溶解在乙腈/乙酸乙酯(5mL，乙腈/乙酸乙酯的体积比为3:1)溶液中，5-50℃循环悬浮搅拌24h，过滤，50℃真空干燥2h，得到盐酸盐的C晶型419.8mg。
XRPD图如图5所示，TGA及DSC结果如图6所示，TGA结果显示，从室温升温至150℃，样品失重为9.2％；DSC曲线于85.8℃，99.2℃，169.5℃和192.9℃(峰值温度)共观察到吸热峰。IC/HPLC结果显示酸碱摩尔比为1:1。盐酸盐的C晶型为水合物晶型，具体为3个水。
实施例5
所述的式I所示化合物的盐酸盐的晶型D(也即式IV水合物的晶型D)的制备方法为：将式I所 示化合物盐酸盐晶型A(500mg)溶解在乙腈/水(5mL，乙腈/水的体积比为92:8)溶液中，25℃悬浮搅拌24h，过滤，50℃真空干燥2h，得到盐酸盐的D晶型413.5mg。
XRPD图如图7所示，TGA及DSC结果如图8所示，TGA结果显示，从室温升温至150℃，样品失重为7.8％；DSC曲线于106.9℃和200.3℃(峰值温度)处观察到吸热峰。IC/HPLC结果显示酸碱摩尔比为1:1。盐酸盐的D晶型为水合物晶型，具体为2.5个水。
实施例6
所述的式I所示化合物的盐酸盐的晶型E(也即式V水合物的晶型E)的制备方法为：将式I所示化合物盐酸盐晶型A(500mg)溶解在丙酮/水(5mL，丙酮/水的体积比为9:1)溶液中，25℃搅拌挥发24h，过滤，50℃真空干燥2h，得到盐酸盐的E晶型417.7mg。
XRPD图如图9所示，TGA及DSC结果如图10所示，TGA结果显示，从室温升温至150℃，样品失重为7.0％；DSC曲线于70.4℃、114.8℃和218.9℃(峰值温度)处观察到吸热峰。IC/HPLC结果显示酸碱摩尔比为1:1。盐酸盐的E晶型为水合物晶型，具体为2.3个水。
实施例7
所述的式I所示化合物的盐酸盐的晶型I(也即式VI所示水合物的晶型I)的制备方法为：将盐酸盐晶型E样品在N 2条件下吹扫、升温至80℃-150℃，降温至30℃，暴露在空气中，得到盐酸盐的晶型I。
XRPD图如图11所示，TGA及DSC结果如图12所示，TGA结果显示，从室温升温至150℃，样品失重为5.2％；DSC曲线于94.6℃和213.2℃(峰值温度)处观察到吸热峰。IC/HPLC结果显示酸碱摩尔比为1:1。盐酸盐的I晶型为水合物晶型，具体为1.7个水。
实施例8
所述的式I所示化合物的盐酸盐的晶型J(也即式VII所示水合物的晶型J)的制备方法为：将式I所示化合物盐酸盐晶型A(500mg)溶解在二氯甲烷/甲基叔丁基醚(5mL，二氯甲烷/甲基叔丁基醚的体积比为5:1)溶液中，25℃悬浮搅拌24h，过滤，50℃真空干燥2h，得到盐酸盐的J晶型415.1mg。
XRPD图如图13所示，TGA及DSC结果如图14所示，TGA结果显示，从室温升温至150℃，样品失重为3.9％；DSC曲线于102.2℃和247.6℃(峰值温度)处观察到吸热峰。IC/HPLC结果显示酸碱摩尔比为1:1。盐酸盐的J晶型为水合物晶型，具体为1.2个水。
实施例9
所述的式I所示化合物的盐酸盐的晶型K(也即式II所示化合物的晶型K)的制备方法为：将盐酸盐晶型J在N 2条件下吹扫20min、升温至120℃、降温至30℃，得到盐酸盐晶型K。
XRPD图如图15所示，TGA及DSC结果如图16所示，TGA结果显示，从室温升温至150℃，样品失重为3.7％；DSC曲线于83.8℃和247.0℃(峰值温度)处观察到吸热峰。IC/HPLC结果显示酸碱摩尔比为1:1。
实施例10
所述的式I所示化合物的马来酸盐的晶型A(也即式VIII所示化合物的晶型A)的制备方法为： 将马来酸(116mg)的甲醇(5mL)溶液加入到式I所示化合物(503mg)的甲醇(5mL)溶液中，室温搅拌三天后转移至50℃搅拌2小时，过滤，25℃真空干燥12h,得到马来酸盐的A晶型526mg。
XRPD图如图17所示，TGA及DSC结果如图18所示，TGA结果显示，从室温升温至150℃，样品失重为6.9％；DSC曲线于45.8℃、204.0℃和206.1℃(峰值温度)观察到吸热信号。IC/HPLC结果显示酸碱摩尔比为1:1。
实施例11
所述的式I所示化合物的马来酸盐的晶型B(也即式VIII所示化合物的晶型B)的制备方法为：将马来酸(113mg)的丙酮(5mL)溶液加入到式I所示化合物(500mg)的丙酮(5mL)溶液中，室温搅拌三天后转移至50℃搅拌2小时，过滤，25℃真空干燥12h,得到马来酸盐的B晶型521mg。
XRPD图如图19所示，TGA及DSC结果如图20所示，TGA结果显示，从室温升温至170℃，样品失重为4.0％；DSC曲线于142.9℃和204.1℃(峰值温度)观察到吸热信号。IC/HPLC结果显示酸碱摩尔比为1:1。
实施例12
所述的式I所示化合物的柠檬酸盐的晶型A(也即式IX化合物的晶型A)的制备方法为：将柠檬酸(210mg)的乙酸乙酯(5mL)溶液加入到式I所示化合物(504mg)的乙酸乙酯(5mL)溶液中，室温搅拌三天后转移至50℃搅拌2小时，过滤，25℃真空干燥12h,得到柠檬酸盐的A晶型620mg。
XRPD图如图21所示，TGA及DSC结果如图22所示，TGA结果显示，从室温升温至150℃，样品失重为1.6％；DSC曲线于189.5℃(峰值温度)处观察到吸热峰。IC/HPLC结果显示酸碱摩尔比为1:1。
实施例13
所述的式I所示化合物的游离态晶型I(也即式I所示化合物的晶型I)的制备方法为：25℃氮气保护条件下，将式I所示化合物(500mg)加至DMSO(8mL)中溶解后，加入甲醇(5mL)，降温至10℃搅拌20小时，过滤，25℃真空干燥12h,得到游离态晶型I 473mg。
XRPD图如图23所示，TGA及DSC结果如图24所示，TGA结果显示，从室温升温至200℃，样品失重为1.9％；DSC曲线于243.0℃(起始温度)有一个吸热峰。
实施例14
所述的式I所示化合物的游离态晶型II(也即式I所示化合物的晶型II)的制备方法为：将游离态晶型I(500mg)在三氯甲烷/乙醇(10mL,三氯甲烷/乙醇的体积比为1:1)中，在50℃条件下缓慢挥发至无溶剂，得到游离态晶型II 491mg。
XRPD图如图25所示，TGA及DSC结果如图26所示，TGA结果显示，从室温升温至200℃，样品失重为1.1％；DSC曲线于244.9℃观察到吸热峰(峰值温度)。
实施例15
所述的式I所示化合物的游离态晶型III(也即式I所示化合物的晶型III)的制备方法为：将游离态晶型I(500mg)在四氢呋喃(10mL)中溶清后在乙酸异丙酯气氛中气液扩散获得，得到游离态晶 型III 471.4mg。
XRPD图如图27所示，TGA及DSC结果如图28所示，TGA结果显示，从室温升温至200℃，样品失重为4.3％；DSC曲线于135.1℃和244.1℃观察到吸热峰(峰值温度)。
实施例16
所述的式I所示化合物的游离态晶型V(也即式I所示化合物的晶型V)的制备方法为：将游离态晶型I(500mg)溶解在1,4-二氧六环(8mL)后进行反溶剂(5mL,ACN作为反溶剂)添加，所得澄清溶液转移至5℃条件下搅拌12h后，置于室温(25℃)下挥发获得的，得到游离态晶型V 480.6mg。
XRPD图如图29所示，TGA及DSC结果如图30所示，TGA结果显示，从室温升温至200℃，样品失重为5.9％；DSC曲线于132.3℃和242.9℃观察到吸热峰(峰值温度)。
实施例17
所述的式I所示化合物的游离态晶型VI(也即式I所示化合物的晶型VI)的制备方法为：将游离态晶型I(500mg)溶解在N,N-二甲基甲酰胺(8mL)后进行反溶剂(5mL,异丙醇作为反溶剂)添加，澄清液转移至5℃条件下搅拌12h后，置于-20℃条件下搅拌12h，过滤，50℃真空干燥12h，得到游离态晶型VI 482.2mg。
XRPD图如图31所示，TGA及DSC结果如图32所示，TGA结果显示，从室温升温至200℃，样品失重为7.0％；DSC曲线于134.3℃、140.9℃和240.8℃观察到吸热峰(峰值温度)。
实施例18动态溶解度评估
对盐酸盐晶型A/B、马来酸盐晶型A及柠檬酸盐晶型A在水和三种生物溶媒中的动态溶解度进行了评估。
以10mg/mL的固体投料浓度(40mg固体投入4mL溶剂中)在37℃下旋转混合，并在不同时间点(1、2、4和24小时)测定各样品在水、SGF、FaSSIF和FeSSIF四种体系中的溶解度。
1.模拟胃液的配制(SGF)
称取201.2mg氯化钠和102.2mg曲纳通X-100(购于北京索莱宝科技有限公司)至100mL容量瓶中，加纯水溶解，超声至固体完全溶解后加约1.632mL盐酸(1M)，加入纯化水至接近目标体积，用1M盐酸或1M氢氧化钠调节pH至1.8，最后使用纯化水定容。
2.模拟禁食状态肠液的配制(FaSSIF)
配制FaSSIF储备缓冲液：称取340.9mg磷酸二氢钠，41.7mg氢氧化钠及620.5mg氯化钠于100-mL容量瓶中。加入适量纯化水并超声溶解固体。加入纯化水至接近目标体积，调节pH至6.5后，纯化水定容混匀。
称取220.7mg SIF粉末(购于Biorelevant)于100-mL容量瓶中。加入适量FaSSIF储备缓冲液溶解固体。继续加入FaSSIF储备缓冲液定容混匀。FaSSIF溶液可在4℃保存7天，使用前需在室温平衡2小时。
3.模拟喂食状态肠液的配制(FeSSIF)
配制FeSSIF储备缓冲液：取0.820mL冰醋酸，404.2mg氢氧化钠及1187.9mg氯化钠于100-mL 容量瓶中。加入适量纯化水溶解固体。之后加入纯化水至接近目标体积，调节pH至5.0后，定容混匀。
称取1119.7mg SIF粉末于100-mL容量瓶中。加入适量FeSSIF储备缓冲液溶解固体。继续加入FeSSIF储备缓冲液定容混匀。FeSSIF溶液可在4℃保存7天，使用前需在室温平衡2小时。
表22 动态溶解度测试结果总结
Figure PCTCN2022101986-appb-000042
备注：S：游离态浓度(mg/mL)
结论：如表22所示，柠檬酸盐在水中的溶解度优于其它盐型(24小时溶解度～0.04mg/mL)，马来酸盐在SGF中的溶解度优于其它盐型(24小时溶解度～0.07mg/mL)，在FaSSIF中观察到盐酸盐晶型A/B动态溶解度在1小时或2小时内明显高于其他盐型，在24小时后四种盐型溶解度相近，在FeSSIF中观察到马来酸盐样品在2小时内溶解度(～0.9mg/mL)高于其他盐型，在24小时后柠檬酸盐溶解度略高于其他盐型(～0.2mg/mL)。
实施例19引湿性评估
通过DVS对盐酸盐晶型A进行了引湿性评估。样品在25℃/80％RH时的水分吸附量为0.08％，表明其几乎无引湿性，且DVS测试后样品晶型未发生变化。
实施例20固态稳定性
1)盐酸盐晶型A/B、马来酸盐晶型A及柠檬酸盐晶型A样品的固态稳定性
对盐酸盐晶型A样品的固态稳定性进行了进一步评估，包括在25℃/60％RH和40℃/75％RH条件下放置时间延长至12周，同时增加了在80℃/闭口条件下放置48小时的试验。试验中，称取～10mg固体加入HPLC小瓶中，瓶口用封口膜封口，膜上扎5个小孔，将小瓶置于25℃/60％RH和40℃/75％RH环境中1周/9周/12周后，及80℃/闭口条件下放置24小时/48小时后进行XRPD和HPLC纯度测试。
对盐酸盐晶型B、马来酸盐晶型A及柠檬酸盐晶型A样品的固态稳定性进行了进一步评估，包括在25℃/60％RH和40℃/75％RH条件下放置时间延长至1周。试验中，称取～10mg固体加入HPLC小瓶中，瓶口用封口膜封口，膜上扎5个小孔，将小瓶置于25℃/60％RH和40℃/75％RH环境中1周后进行XRPD和HPLC纯度测试。
表23
Figure PCTCN2022101986-appb-000043
如表23所示，在25℃/60％RH和40℃/75％RH条件下敞口放置1周/9周/12周后，盐酸盐晶型A样品HPLC纯度变化≤0.15area％，且晶型未发生变化。在80℃/闭口放置48小时后，盐酸盐晶型A的HPLC纯度为99.92area％(杂质峰从0.04area％增长至0.08area％)，晶型未发生变化。
在盐酸盐晶型B、马来酸盐晶型A及柠檬酸盐晶型A样品分别在25℃/60％RH和40℃/75％RH 条件下敞口放置一周后，结果显示三种盐型在对应条件下放置一周后晶型均未发生改变，盐酸盐晶型B和马来酸盐晶型A的纯度略有下降(<0.05area％)，柠檬酸盐晶型A的纯度降低约0.2area％。
3)游离态晶型I样品的固态稳定性
对游离态晶型I样品的固态稳定性进行了进一步评估，包括在25℃/60％RH条件下放置时间延长至24个月和40℃/75％RH条件下放置时间延长至6个月。试验中，称取～10mg固体加入HPLC小瓶中，瓶口用封口膜封口，膜上扎5个小孔，将小瓶置于25℃/60％RH环境中3月/6月/9月和40℃/75％RH环境中1月/2月/3月/6月后进行XRPD和HPLC纯度测试。
表24
Figure PCTCN2022101986-appb-000044
如表24所示，25℃/60％RH环境中3月/6月/9月和40℃/75％RH环境中1月/2月/3月/6月后，游离态晶型I样品HPLC纯度变化≤0.21area％，且晶型未发生变化。
实施例21药物代谢动力学
实验方法：
1)大鼠共设1组，每组6只，雌雄各半。给药前禁食不少于12h，自由饮水，给药后4h，统一进食，静脉给予式I所示化合物盐酸盐晶型A 20mg/kg，给药体积10ml/kg；于给药前及给药后5min(静脉组)、15min(静脉组)、0.5、1.0、2.0、4.0、6.0、10、24和48h取血0.2ml，置EDTA-K2抗凝试管中，11000rpm离心5min(4℃)，分离血浆，-70℃保存待测。
2)样品前处理式I所示化合物取血浆样品15μL于96孔板中，加入300μL乙腈，密封孔板，涡旋混匀，在4℃，3600rpm的条件下离心10min。取离心后的上清液100μL至96孔板中，加入300μL乙腈:水(1:1,v/v)，密封孔板，低速涡旋混匀，进样分析。式I所示化合物的线性范围为：2-2000ng/mL。
实验结果如表25：
表25
Figure PCTCN2022101986-appb-000045
Figure PCTCN2022101986-appb-000046
从上述的实验结果可以看出，式I所示化合物盐酸盐晶型A的溶解性好，生物利用度高。
对比例1
按照专利PCT/CN2017/078616记载的制备方法制备得到式I所示化合物，其为游离态无定形，XRPD图如图33所示。
对比例2
本发明还做了关于D-葡萄糖醛酸和L-苹果酸的成盐筛选。以游离态晶型I为原料，根据化合物的碱性pKa(pKa1＝5.8±0.3)及起始物料在室温条件下不同溶剂中的粗略溶解度，选择了D-葡萄糖醛酸和L-苹果酸为酸性配体(游离态/酸性配体的摩尔投料比为1:1)和如表26中的5种溶剂体系，筛选试验。筛选试验具体步骤如下：称取约20mg游离态晶型I和等摩尔量的不同配体至HPLC小瓶中，加入0.5mL溶剂混合得到悬浊液，液体酸首先用相应溶剂稀释后再与起始样品混合。室温悬浮搅拌约4天后，离心分离固体并在室温下真空干燥约4小时，结果如表26所示。
表26
Figure PCTCN2022101986-appb-000047
从表26可以看出，当酸为D-葡萄糖醛酸时使用上述的五种溶剂成盐，其中在溶剂EtOAc、MeOH、Acetone、DCM中都不能与游离态晶型I成盐；图34为式Ⅰ化合物的L-苹果酸盐的晶型A的Cu-Kα辐射的XRPD谱图。当酸为L-苹果酸时使用上述的五种溶剂成盐，其中在溶剂MeOH、ACN/H 2O中不能与游离态晶型I成盐。游离态晶型及盐型相对于无定形具有稳定性强的优势。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (14)

  1. 一种化合物、其晶型或其水合物，所述化合物如II、VIII或IX所示；
    Figure PCTCN2022101986-appb-100001
  2. 一种晶型，其为式II所示化合物的晶型A、B或K，式VIII所示化合物的晶型A或B，或式IX化合物的晶型A；
    Figure PCTCN2022101986-appb-100002
    其中，式II所示化合物的晶型A以2θ角表示的X射线粉末衍射图在5.78±0.2°、11.51±0.2°、16.97±0.2°、17.77±0.2°处有衍射峰；
    式II所示化合物的晶型B以2θ角表示的X射线粉末衍射图在6.54±0.2°、16.60±0.2°和25.35±0.2°处有衍射峰；
    式II所示化合物的晶型K以2θ角表示的X射线粉末衍射图在6.59±0.2°、13.16±0.2°、15.06±0.2°、16.10±0.2°、16.86±0.2°、17.36±0.2°、18.15±0.2°、20.50±0.2°、21.53±0.2°、24.84±0.2°、26.85±0.2°处有衍射峰；
    式VIII所示化合物的晶型A以2θ角表示的X射线粉末衍射图在6.33±0.2°、11.56±0.2°、14.41±0.2°、16.64±0.2°、17.45±0.2°、18.21±0.2°、18.45±0.2°、21.19±0.2°、23.46±0.2°、24.20±0.2°处有衍射峰；
    式VIII所示化合物的晶型B以2θ角表示的X射线粉末衍射图在11.59±0.2°、16.89±0.2°、17.37±0.2°、18.24±0.2°、22.60±0.2°、23.66±0.2°、23.89±0.2°处有衍射峰；
    式IX化合物的晶型A以2θ角表示的X射线粉末衍射图在5.09±0.2°、8.16±0.2°、10.13±0.2°、15.22±0.2°、18.27±0.2°、21.05±0.2°处有衍射峰。
  3. 如权利要求2所述的晶型，其特征在于，所述式II所示化合物的晶型A以2θ角表示的X-射线粉末衍射图在5.78±0.2°、10.11±0.2°、11.51±0.2°、13.73±0.2°、16.97±0.2°、17.77±0.2°处有衍射峰；优选地，所述式II所示化合物的晶型A以2θ角表示的X-射线粉末衍射图在5.78±0.2°、7.12±0.2°、8.29±0.2°、10.11±0.2°、11.51±0.2°、12.21±0.2°、13.73±0.2°、14.19±0.2°、14.85±0.2°、16.97±0.2°、17.28±0.2°、17.77±0.2°、18.53±0.2°、19.19±0.2°、19.88±0.2°、20.25±0.2°、20.76±0.2°、21.34±0.2°、23.09±0.2°、23.47±0.2°、24.68±0.2°、25.89±0.2°、26.51±0.2°、27.16±0.2°、28.52±0.2°、29.26±0.2°、31.27±0.2°、 31.62±0.2°、33.52±0.2°、35.05±0.2°、38.78±0.2°处有衍射峰；
    和/或，所述式II所示化合物的晶型A的差示扫描量热曲线在235.4℃及249.3℃处具有吸热峰；
    和/或，所述式II所示化合物的晶型A的热重分析曲线显示从27.7℃至150℃温度范围失重1.2％；
    和/或，所述式II所示化合物的晶型B以2θ角表示的X射线粉末衍射图在6.54±0.2°、15.34±0.2°、16.60±0.2°、20.40±0.2°、25.35±0.2°处有衍射峰；优选地，所述的式II所示化合物的晶型B以2θ角表示的X射线粉末衍射图在6.54±0.2°、10.57±0.2°、12.60±0.2°、13.10±0.2°、14.04±0.2°、15.34±0.2°、16.60±0.2°、18.61±0.2°、18.92±0.2°、20.40±0.2°、21.21±0.2°、23.11±0.2°、23.52±0.2°、25.35±0.2°、26.53±0.2°处有衍射峰；
    和/或，所述式II所示化合物的晶型B的差示扫描量热曲线在211.4℃、223.4℃和253.7℃处具有吸热峰；
    和/或，所述式II所示化合物的晶型B的热重分析曲线显示在29.1℃至150℃温度范围失重1.4％；
    和/或，所述式II所示化合物的晶型K以2θ角表示的X射线粉末衍射图在6.59±0.2°、13.16±0.2°、15.06±0.2°、16.10±0.2°、16.86±0.2°、17.36±0.2°、18.15±0.2°、20.50±0.2°、21.53±0.2°、22.39±0.2°、24.84±0.2°、26.85±0.2°处有衍射峰；优选地，所述式II所示化合物的晶型K以2θ角表示的X射线粉末衍射图在5.01±0.2°、6.59±0.2°、7.57±0.2°、9.06±0.2°、10.50±0.2°、11.52±0.2°、12.74±0.2°、13.16±0.2°、13.78±0.2°、15.06±0.2°、16.10±0.2°、16.86±0.2°、17.36±0.2°、18.15±0.2°、20.50±0.2°、21.53±0.2°、22.39±0.2°、24.07±0.2°、24.84±0.2°、25.50±0.2°、26.09±0.2°、26.85±0.2°、27.68±0.2°、29.46±0.2°、34.15±0.2°处有衍射峰；
    和/或，所述式II所示化合物的晶型K的差示扫描量热曲线在83.8℃和247.0℃处具有吸热峰；
    和/或，所述式II所示化合物的晶型K的热重分析曲线显示在19.9℃至150℃温度范围失重3.7％；
    和/或，所述式VIII所示化合物的晶型A以2θ角表示的X-射线粉末衍射图在6.33±0.2°、11.56±0.2°、14.41±0.2°、16.64±0.2°、17.45±0.2°、18.21±0.2°、18.45±0.2°、20.22±0.2°、21.19±0.2°、23.46±0.2°、24.20±0.2°、25.04±0.2°处有衍射峰；优选地，所述式VIII所示化合物的晶型A以2θ角表示的X-射线粉末衍射图在6.33±0.2°、11.15±0.2°、11.56±0.2°、12.71±0.2°、14.41±0.2°、14.60±0.2°、16.64±0.2°、16.81±0.2°、17.45±0.2°、18.21±0.2°、18.45±0.2°、18.79±0.2°、19.18±0.2°、20.22±0.2°、21.19±0.2°、21.58±0.2°、22.45±0.2°、23.46±0.2°、24.20±0.2°、24.52±0.2°、25.04±0.2°、26.68±0.2°、27.88±0.2°、28.08±0.2°、28.82±0.2°、29.88±0.2°、31.01±0.2°、35.20±0.2°处有衍射峰；
    和/或，所述式VIII所示化合物的晶型A的差示扫描量热曲线在45.8℃、204.0℃和206.1℃处具有吸热峰；
    和/或，所述式VIII所示化合物的晶型A的热重分析曲线在28.8℃至150℃温度范围失重6.9％；
    和/或，所述式VIII所示化合物的晶型B以2θ角表示的X射线粉末衍射图在11.59±0.2°、11.79±0.2°、14.39±0.2°、16.89±0.2°、17.37±0.2°、18.24±0.2°、21.30±0.2°、22.60±0.2°、23.66±0.2°、23.89±0.2°处有衍射峰；
    和/或，所述的式VIII所示化合物的晶型B以2θ角表示的X射线粉末衍射图在6.28±0.2°、 10.96±0.2°、11.59±0.2°、11.79±0.2°、14.39±0.2°、16.53±0.2°、16.89±0.2°、17.37±0.2°、17.93±0.2°、18.24±0.2°、18.66±0.2°、19.04±0.2°、19.38±0.2°、19.94±0.2°、21.30±0.2°、21.70±0.2°、22.60±0.2°、23.25±0.2°、23.66±0.2°、23.89±0.2°、24.33±0.2°、25.03±0.2°、25.43±0.2°、26.83±0.2°、27.62±0.2°、27.92±0.2°、28.76±0.2°、29.72±0.2°处有衍射峰；
    和/或，所述的式VIII所示化合物的晶型B的差示扫描量热曲线在142.9℃和204.1℃处具有吸热峰；
    和/或，所述式VIII所示化合物的晶型B的热重分析曲线显示在29.1℃至170℃温度范围失重4.0％；
    和/或，所述式IX化合物的晶型A以2θ角表示的X射线粉末衍射图在5.09±0.2°、8.16±0.2°、9.11±0.2°、10.13±0.2°、15.22±0.2°、18.27±0.2°、18.75±0.2°、21.05±0.2°处有衍射峰；优选地，所述式IX化合物的晶型A以2θ角表示的X射线粉末衍射图在4.57±0.2°、5.09±0.2°、8.16±0.2°、9.11±0.2°、10.13±0.2°、12.25±0.2°、12.85±0.2°、13.65±0.2°、15.22±0.2°、16.35±0.2°、16.59±0.2°、18.27±0.2°、18.75±0.2°、19.76±0.2°、20.47±0.2°、21.05±0.2°、21.50±0.2°、22.43±0.2°、24.27±0.2°、25.49±0.2°处有衍射峰；
    和/或，所述式IX化合物的晶型A的差示扫描量热曲线在189.5℃处具有吸热峰；
    和/或，所述式IX化合物的晶型A的热重分析曲线显示在27.3℃至150℃温度范围失重1.6％。
  4. 如权利要求3所述的晶型，其特征在于，所述式II所示化合物的晶型A以2θ角表示的X-射线粉末衍射图具有如下表1所示的衍射峰：优选地，所述式II所示化合物的晶型A的X射线粉末衍射图谱如图1所示；
    表1
    Figure PCTCN2022101986-appb-100003
    Figure PCTCN2022101986-appb-100004
    和/或，所述式II所示化合物的晶型A的差示扫描量热曲线如图2中所示；
    和/或，所述式II所示化合物的晶型A的热重分析曲线如图2中所示；
    和/或，所述式II所示化合物的晶型B以2θ角表示的X-射线粉末衍射图具有如下表2所示的衍射峰，优选地，所述式II所示化合物的晶型B的X射线粉末衍射如图3所示；
    表2
    Figure PCTCN2022101986-appb-100005
    Figure PCTCN2022101986-appb-100006
    和/或，所述式II所示化合物的晶型B的差示扫描量热曲线如图4中所示；
    和/或，所述式II所示化合物的晶型B的热重分析曲线如图4中所示；
    和/或，所述式II所示化合物的晶型K以2θ角表示的X-射线粉末衍射图具有如下表3所示的衍射峰；优选地，所述式II所示化合物的晶型K的X射线粉末衍射图谱如图15所示；
    表3
    Figure PCTCN2022101986-appb-100007
    Figure PCTCN2022101986-appb-100008
    和/或，所述式II所示化合物的晶型K的差示扫描量热曲线如图16中所示；
    和/或，所述式II所示化合物的晶型K的热重分析曲线如图16中所示；
    和/或，所述的式VIII所示化合物的晶型A以2θ角表示的X-射线粉末衍射图具有如下表9所示的衍射峰；优选地，所述式VIII所示化合物的晶型A的X射线粉末衍射图谱如图17所示；
    表9
    Figure PCTCN2022101986-appb-100009
    Figure PCTCN2022101986-appb-100010
    和/或，所述式VIII所示化合物的晶型A的差示扫描量热曲线如图18所示；
    和/或，所述式VIII所示化合物的晶型A的热重分析曲线如图18所示；
    和/或，所述的式VIII所示化合物的晶型B以2θ角表示的X-射线粉末衍射图具有如下表10所示的衍射峰；优选地，所述的式VIII所示化合物的晶型B的X射线粉末衍射(XRPD)图谱如图19所示；
    表10
    Figure PCTCN2022101986-appb-100011
    Figure PCTCN2022101986-appb-100012
    和/或，所述式VIII所示化合物的晶型B的差示扫描量热曲线如图20中所示；
    和/或，所述式VIII所示化合物的晶型B的热重分析曲线如图20中所示；
    和/或，所述式IX化合物的晶型A以2θ角表示的X-射线粉末衍射图具有如下表11所示的衍射峰；优选地，所述式IX化合物的晶型A的X射线粉末衍射图谱如图21所示；
    表11
    Figure PCTCN2022101986-appb-100013
    Figure PCTCN2022101986-appb-100014
    和/或，所述式IX化合物的晶型A的差示扫描量热曲线如图22中所示；
    和/或，所述式IX化合物的晶型A的热重分析曲线如图22中所示。
  5. 一种式XX所示水合物，其中n为1-3；
    Figure PCTCN2022101986-appb-100015
    例如，所述式XX所示水合物为式III、IV、V、VI或VII所示水合物：
    Figure PCTCN2022101986-appb-100016
    Figure PCTCN2022101986-appb-100017
  6. 一种如权利要求5所述水合物的晶型，其为式III所示水合物的晶型C、式IV所示水合物的晶型D、式V所示水合物的晶型E、式VI所示水合物的晶型I或式VII所示水合物的晶型J；
    其中，式III所示水合物的晶型C以2θ角表示的X射线粉末衍射图在6.90±0.2°、10.53±0.2°、13.79±0.2°、21.12±0.2°处有衍射峰；
    式IV所示水合物的晶型D以2θ角表示的X射线粉末衍射图在6.62±0.2°、7.64±0.2°处有衍射峰；
    式V所示水合物的晶型E以2θ角表示的X射线粉末衍射图在6.49±0.2°、7.20±0.2°、8.42±0.2°、10.41±0.2°、11.56±0.2°、16.87±0.2°、19.11±0.2°处有衍射峰；
    式VI所示水合物的晶型I以2θ角表示的X射线粉末衍射图在6.72±0.2°、7.97±0.2°、10.46±0.2°、13.65±0.2°、17.22±0.2°、20.22±0.2°处有衍射峰；
    式VII所示水合物的晶型J以2θ角表示的X射线粉末衍射图在6.55±0.2°、12.42±0.2°、13.13±0.2°、16.82±0.2°、17.73±0.2°、19.66±0.2°处有衍射峰。
  7. 如权利要求6所述的晶型，其特征在于，所述式III所示水合物的晶型C以2θ角表示的X-射线粉末衍射图在6.90±0.2°、10.53±0.2°、13.79±0.2°、19.94±0.2°、20.74±0.2°、21.12±0.2°、26.25±0.2°处有衍射峰；优选地，所述式III所示水合物的晶型C以2θ角表示的X-射线粉末衍射图在6.90±0.2°、7.97±0.2°、10.53±0.2°、12.98±0.2°、13.79±0.2°、14.15±0.2°、15.23±0.2°、17.37±0.2°、18.11±0.2°、18.26±0.2°、18.98±0.2°、19.94±0.2°、20.74±0.2°、21.12±0.2°、22.23±0.2°、23.16±0.2°、23.52±0.2°、24.98±0.2°、26.25±0.2°、27.75±0.2°、28.22±0.2°、29.07±0.2°、32.14±0.2°、32.90±0.2°、34.40±0.2°、35.82±0.2°、38.54±0.2°处有衍射峰；
    和/或，所述式III所示水合物的晶型C的差示扫描量热曲线在85.8℃、99.2℃、169.5℃和192.9℃处有吸热峰；
    和/或，所述式III所示水合物的晶型C的热重分析曲线显示在21.3℃至150℃温度范围失重9.2％；
    和/或，所述式IV所示水合物的晶型D以2θ角表示的X-射线粉末衍射图在6.62±0.2°、7.64±0.2°、13.22±0.2°、13.79±0.2°处有衍射峰；优选地，所述式IV所示水合物的晶型D以2θ角表示的X-射线粉末衍射图在6.62±0.2°、7.64±0.2°、11.43±0.2°、13.22±0.2°、13.79±0.2°处有衍射峰；
    和/或，所述式IV所示水合物的晶型D的差示扫描量热曲线在106.9℃和200.3℃处具有吸热峰；
    和/或，所述式IV所示水合物的晶型D的热重分析曲线显示在17.5℃至150℃温度范围失重7.8％；
    和/或，所述式V所示水合物的晶型E以2θ角表示的X-射线粉末衍射图在6.49±0.2°、7.20±0.2°、8.42±0.2°、10.41±0.2°、11.56±0.2°、16.87±0.2°、19.11±0.2°、19.56±0.2°处有衍射峰；优选地，所述式 V所示水合物的晶型E以2θ角表示的X-射线粉末衍射图在6.49±0.2°、7.20±0.2°、7.61±0.2°、8.42±0.2°、10.41±0.2°、11.56±0.2°、12.78±0.2°、14.34±0.2°、16.10±0.2°、16.56±0.2°、16.87±0.2°、19.11±0.2°、19.56±0.2°、21.11±0.2°、22.71±0.2°、23.19±0.2°、25.15±0.2°处有衍射峰；
    和/或，所述式V所示水合物的晶型E的差示扫描量热曲线在70.4℃、114.8℃和218.9℃处具有吸热峰；
    和/或，所述式V所示水合物的晶型E的热重分析曲线显示在28.5℃至150℃温度范围失重7.0％；
    和/或，所述式VI所示水合物的晶型I以2θ角表示的X-射线粉末衍射图在6.72±0.2°、7.97±0.2°、10.46±0.2°、12.39±0.2°、13.65±0.2°、17.22±0.2°、20.22±0.2°处有衍射峰；优选地，
    和/或，所述式VI所示水合物的晶型I以2θ角表示的X-射线粉末衍射图在6.72±0.2°、7.97±0.2°、10.46±0.2°、12.39±0.2°、13.65±0.2°、17.22±0.2°、20.22±0.2°、24.20±0.2°处有衍射峰；
    和/或，所述的式VI所示水合物的晶型I的差示扫描量热曲线在94.6℃和213.2℃处具有吸热峰；
    和/或，所述式VI所示水合物的晶型I的热重分析曲线显示在29.4℃至150℃温度范围失重5.2％；
    和/或，所述式VII所示水合物的晶型J以2θ角表示的X-射线粉末衍射图在5.14±0.2°、6.55±0.2°、12.07±0.2°、12.42±0.2°、13.13±0.2°、16.82±0.2°、17.73±0.2°、19.66±0.2°处有衍射峰；优选地，所述式VII所示水合物的晶型J以2θ角表示的X-射线粉末衍射图在5.14±0.2°、6.55±0.2°、9.84±0.2°、12.07±0.2°、12.42±0.2°、13.13±0.2°、13.70±0.2°、14.87±0.2°、16.82±0.2°、17.73±0.2°、19.66±0.2°、20.53±0.2°、21.44±0.2°、23.21±0.2°处有衍射峰；
    和/或，所述式VII所示水合物的晶型J的差示扫描量热曲线在102.2℃和247.6℃处具有吸热峰；
    和/或，所述式VII所示水合物的晶型J的热重分析曲线显示在19.6℃至150℃温度范围失重3.9％。
  8. 如权利要求7所述的晶型，其特征在于，所述式III所示水合物的晶型C以2θ角表示的X-射线粉末衍射图中具有如下表4所示的衍射峰；优选地，所述式III所示水合物的晶型C的X射线粉末衍射图谱如图5所示；
    表4
    Figure PCTCN2022101986-appb-100018
    Figure PCTCN2022101986-appb-100019
    和/或，所述式III所示水合物的晶型C的差示扫描量热曲线如图6所示；
    和/或，所述式III所示水合物的晶型C的热重分析曲线如图6所示；
    和/或，所述式IV所示水合物的晶型D以2θ角表示的X-射线粉末衍射图具有如下表5所示的衍射峰；优选地，所述式IV所示水合物的晶型D的X射线粉末衍射图谱如图7所示；
    表5
    Figure PCTCN2022101986-appb-100020
    和/或，所述式IV所示水合物的晶型D的差示扫描量热曲线如图8中所示；
    和/或，所述式IV所示水合物的晶型D的热重分析曲线如图8中所示；
    和/或，所述式V所示水合物的晶型E以2θ角表示的X-射线粉末衍射图具有如下表6所示的衍射峰；优选地，所述式V所示水合物的晶型E的X射线粉末衍射图谱如图9所示；
    表6
    Figure PCTCN2022101986-appb-100021
    和/或，所述式V所示水合物的晶型E的差示扫描量热曲线如图10中所示；
    和/或，所述式V所示水合物的晶型E的热重分析曲线如图10中所示；
    和/或，所述式VI所示水合物的晶型I以2θ角表示的X-射线粉末衍射图具有如下表7所示的衍射峰；优选地，所述式VI所示水合物的晶型I的X射线粉末衍射图谱如图11所示；
    表7
    Figure PCTCN2022101986-appb-100022
    Figure PCTCN2022101986-appb-100023
    和/或，所述式VI所示水合物的晶型I的差示扫描量热曲线如图12中所示；
    和/或，所述式VI所示水合物的晶型I的热重分析曲线如图12中所示；
    和/或，所述式VII所示水合物的晶型J以2θ角表示的X-射线粉末衍射图具有如下表8所示的衍射峰；优选地，所述式VII所示水合物的晶型J的X射线粉末衍射图谱如图13所示；
    表8
    Figure PCTCN2022101986-appb-100024
    和/或，所述式VII所示水合物的晶型J的差示扫描量热曲线如图14中所示；
    和/或，所述式VII所示水合物的晶型J的热重分析曲线如图14中所示。
  9. 一种式I所示化合物的晶型，其为晶型I、II、III、V或VI；
    Figure PCTCN2022101986-appb-100025
    其中，式I所示化合物的晶型I以2θ角表示的X射线粉末衍射图在15.03±0.2°、18.91±0.2°、19.83±0.2°、20.40±0.2°、21.11±0.2°处有衍射峰；
    式I所示化合物的晶型II以2θ角表示的X射线粉末衍射图在7.83±0.2°、9.79±0.2°、18.19±0.2°、19.90±0.2°处有衍射峰；
    式I所示化合物的晶型III以2θ角表示的X射线粉末衍射图在4.50±0.2°、6.89±0.2°、7.24±0.2°、13.42±0.2°、14.46±0.2°、20.72±0.2°处有衍射峰；
    式I所示化合物的晶型V以2θ角表示的X射线粉末衍射图在4.19±0.2°、7.47±0.2°、12.44±0.2°、14.35±0.2°、16.60±0.2°、20.79±0.2°处有衍射峰；
    式I所示化合物的晶型VI以2θ角表示的X射线粉末衍射图在4.36±0.2°、8.49±0.2°、14.64±0.2°、15.34±0.2°、18.94±0.2°、19.74±0.2°、20.13±0.2°、21.08±0.2°处有衍射峰。
  10. 如权利要求9所述的晶型，其特征在于，所述式I所示化合物的晶型I以2θ角表示的X射线粉末衍射图在9.64±0.2°、11.16±0.2°、12.53±0.2°、15.03±0.2°、18.91±0.2°、19.83±0.2°、20.40±0.2°、21.11±0.2°处有衍射峰；优选地，所述式I所示化合物的晶型I以2θ角表示的X射线粉末衍射图在7.94±0.2°、9.64±0.2°、11.16±0.2°、11.92±0.2°、12.53±0.2°、14.26±0.2°、15.03±0.2°、16.48±0.2°、16.79±0.2°、17.51±0.2°、18.91±0.2°、19.33±0.2°、19.83±0.2°、20.40±0.2°、21.11±0.2°、22.56±0.2°、23.43±0.2°、23.93±0.2°、24.17±0.2°、25.16±0.2°、26.68±0.2°、28.60±0.2°、29.63±0.2°、30.57±0.2°、31.62±0.2°、32.71±0.2°、33.66±0.2°处有衍射峰；
    和/或，所述式I所示化合物的晶型I的差示扫描量热曲线在244.0℃处具有吸热峰；
    和/或，所述式I所示化合物的晶型I的热重分析曲线显示在29.8℃至200℃温度范围失重1.9％；
    和/或，所述式I所示化合物的晶型II以2θ角表示的X-射线粉末衍射图在7.83±0.2°、9.09±0.2°、9.79±0.2°、17.99±0.2°、18.19±0.2°、19.59±0.2°、19.90±0.2°、23.55±0.2°处有衍射峰；优选地，所述式I所示化合物的晶型II以2θ角表示的X-射线粉末衍射图在7.83±0.2°、8.56±0.2°、9.09±0.2°、9.79±0.2°、11.07±0.2°、11.74±0.2°、13.86±0.2°、15.18±0.2°、15.65±0.2°、17.15±0.2°、17.99±0.2°、18.19±0.2°、19.59±0.2°、19.90±0.2°、20.62±0.2°、23.55±0.2°、24.31±0.2°、27.41±0.2°、29.02±0.2°、31.17±0.2°、31.57±0.2°、35.74±0.2°、36.79±0.2°、38.38±0.2°处有衍射峰；
    和/或，所述式I所示化合物的晶型II的差示扫描量热曲线在244.9℃处具有吸热峰；
    和/或，所述式I所示化合物的晶型II的热重分析曲线显示在25.1℃至150℃温度范围失重1.1％；
    和/或，所述式I所示的化合物的晶型III以2θ角表示的X-射线粉末衍射图在4.50±0.2°、6.89±0.2°、7.24±0.2°、13.42±0.2°、14.46±0.2°、15.47±0.2°、20.72±0.2°、21.92±0.2°处有衍射峰；优选地，所述式I所示的化合物的晶型III以2θ角表示的X-射线粉末衍射图在4.50±0.2°、6.89±0.2°、7.24±0.2°、9.88±0.2°、12.56±0.2°、13.42±0.2°、14.46±0.2°、15.47±0.2°、16.73±0.2°、17.58±0.2°、19.25±0.2°、19.81±0.2°、20.72±0.2°、21.45±0.2°、21.92±0.2°、23.34±0.2°、26.25±0.2°、27.65±0.2°、30.69±0.2°处有衍射峰；
    和/或，所述式I所示化合物的晶型III的差示扫描量热曲线在135.1℃和244.1℃处具有吸热峰；
    和/或，所述式I所示化合物的晶型III的热重分析曲线显示在26.5℃至150℃温度范围失重4.3％；
    和/或，所述式I所示化合物的晶型V以2θ角表示的X-射线粉末衍射图在4.19±0.2°、7.47±0.2°、12.44±0.2°、14.35±0.2°、15.17±0.2°、16.60±0.2°、20.79±0.2°、26.86±0.2°处有衍射峰；优选地，所述式I所示化合物的晶型V以2θ角表示的X-射线粉末衍射图在4.19±0.2°、7.47±0.2°、12.44±0.2°、14.35±0.2°、15.17±0.2°、16.60±0.2°、17.29±0.2°、18.99±0.2°、19.93±0.2°、20.79±0.2°、21.55±0.2°、25.29±0.2°、26.23±0.2°、26.86±0.2°处有衍射峰；
    和/或，所述式I所示化合物的晶型V的差示扫描量热曲线在132.3℃和242.9℃处具有吸热峰；
    和/或，所述式I所示化合物的晶型V的热重分析曲线显示在22.0℃至150℃温度范围失重5.9％；
    和/或，所述式I所示化合物的晶型VI以2θ角表示的X-射线粉末衍射图在4.36±0.2°、8.49±0.2°、13.03±0.2°、14.64±0.2°、15.34±0.2°、18.94±0.2°、19.74±0.2°、20.13±0.2°、21.08±0.2°、21.81±0.2°处有衍射峰；优选地，所述式I所示化合物的晶型VI以2θ角表示的X-射线粉末衍射图在4.36±0.2°、6.96±0.2°、8.49±0.2°、12.23±0.2°、13.03±0.2°、14.64±0.2°、15.34±0.2°、16.16±0.2°、17.91±0.2°、18.94±0.2°、19.74±0.2°、20.13±0.2°、21.08±0.2°、21.81±0.2°、25.07±0.2°、26.01±0.2°处有衍射峰；
    和/或，所述式I所示化合物晶型VI的差示扫描量热曲线在134.3℃、140.9℃和240.8℃处具有吸热峰；
    和/或，所述式I所示化合物的晶型VI的热重分析曲线在28.5℃至150℃温度范围失重7.0％。
  11. 如权利要求10所述的晶型，其特征在于，所述式I所示化合物的晶型I以2θ角表示的X-射线粉末衍射图具有如下表12所示的衍射峰；优选地，所述式I所示化合物的晶型I的X射线粉末衍射图谱如图23所示；
    表12
    Figure PCTCN2022101986-appb-100026
    Figure PCTCN2022101986-appb-100027
    和/或，所述式I所示化合物的晶型I的差示扫描量热曲线如图24中所示；
    和/或，所述式I所示化合物的晶型I的热重分析曲线如图24中所示；
    和/或，所述的式I所示化合物的晶型II以2θ角表示的X-射线粉末衍射图具有如下表13所示的衍射峰；优选地，所述式I所示化合物的晶型II的X射线粉末衍射图谱如图25中所示；
    表13
    Figure PCTCN2022101986-appb-100028
    Figure PCTCN2022101986-appb-100029
    和/或，所述式I所示化合物的晶型II的差示扫描量热曲线如图26中所示；
    和/或，所述式I所示化合物的晶型II的热重分析曲线如图26中所示；
    和/或，所述的式I所示的化合物的晶型III以2θ角表示的X-射线粉末衍射图具有如下表14所示的衍射峰；优选地，所述式I所示化合物的晶型III的X射线粉末衍射图谱如图27所示；
    表14
    Figure PCTCN2022101986-appb-100030
    Figure PCTCN2022101986-appb-100031
    和/或，所述式I所示化合物的晶型III的差示扫描量热曲线如图28中所示；
    和/或，所述式I所示化合物的晶型III的热重分析曲线如图28中所示；
    和/或，所述式I所示化合物的晶型V以2θ角表示的X-射线粉末衍射图具有如下表15所示的衍射峰；优选地，所述式I所示化合物的晶型V的X射线粉末衍射图谱如图29所示；
    表15
    Figure PCTCN2022101986-appb-100032
    和/或，所述式I所示化合物的晶型V的差示扫描量热曲线如图30中所示；
    和/或，所述式I所示化合物的晶型V的热重分析曲线如图30中所示；
    和/或，所述式I所示化合物的晶型VI以2θ角表示的X-射线粉末衍射图具有如下表16所示的衍射峰；优选地，所述式I所示化合物的晶型VI的X射线粉末衍射图谱如图31所示；
    表16
    Figure PCTCN2022101986-appb-100033
    和/或，所述式I所示化合物的晶型VI的差示扫描量热曲线如图32中所示；
    和/或，所述式I所示化合物的晶型VI的热重分析曲线如图32中所示。
  12. 一种如权利要求1所述的化合物、如权利要求2所述的晶型、如权利要求5所述的水合物、如权利要求6所述的晶型、或如权利要求9所述的晶型的制备方法，其特征在于：
    如II、VIII或IX所示化合物的制备方法包括如下步骤：将式I所示化合物和酸在溶剂中进行成盐反应，得到如II、VIII或IX所示的化合物；所述的酸为HCl、马来酸或柠檬酸；
    式II所示化合物的晶型A的制备方法包括如下步骤：将式I所示化合物与HCl在溶剂中反应析晶，得到式II所示化合物的晶型A；所述溶剂为有机溶剂或者有机溶剂与水的混合溶剂；所述有机溶剂为二氯甲烷、甲醇、乙醇和异丙醇中的一种或多种；
    式II所示化合物的晶型B的制备方法包括如下步骤：将式I所示化合物与HCl在丙酮和水的混合溶剂中反应析晶，得到式II所示化合物的晶型B；
    式II所示化合物的晶型B的制备方法包括如下步骤：将式I所示化合物与HCl在丙酮和水的混合溶剂中反应析晶，得到式II所示化合物的晶型B；
    式II所示化合物的晶型K的制备方法，其包括如下步骤：将如权利要求6所述的式VII所示水合物的晶型J在N 2条件下吹扫20min，升温至120℃，降温至30℃，得到式II所示化合物的晶型K；
    式III所示水合物的晶型C的制备方法，其包括如下步骤：将式II所示化合物在乙腈和乙酸乙酯 的混合溶剂中搅拌，得到式III所示水合物的晶型C；
    式IV所示水合物的晶型D的制备方法包括如下步骤：将式II所示化合物在乙腈和水的混合溶剂中搅拌，得到式IV所示水合物的晶型D；
    式V所示水合物的晶型E的制备方法包括如下步骤：将式II所示化合物在丙酮和水的混合溶剂中搅拌挥发，得到式V所示水合物的晶型E；
    式VI所示水合物的晶型I的制备方法包括如下步骤：将如权利要求6所述的式V所示水合物的晶型E在N 2条件下吹扫，升温至80℃-150℃，降温至30℃，暴露在空气中，得到式IV所示水合物的晶型I；
    式VII所示水合物的晶型J的制备方法包括如下步骤：将如权利要求2所述的式II所示化合物的晶型A在二氯甲烷和甲基叔丁基醚的混合溶剂中搅拌，得到式VII所示水合物的晶型J；
    式VIII所示化合物的晶型A的制备方法包括如下步骤：将式I所示化合物与马来酸在甲醇中反应析晶，得到式VIII所示化合物的晶型A；
    式VIII所示化合物的晶型B的制备方法包括如下步骤：将式I所示化合物与马来酸在丙酮中反应析晶，得到式VIII所示化合物的晶型B；
    式IX化合物的晶型A的制备方法包括如下步骤：将式I所示化合物与柠檬酸在乙酸乙酯中反应析晶，得到式IX化合物的晶型A；
    式I所示化合物的晶型I的制备方法包括如下步骤：将式I所示化合物通过反溶剂结晶法得到式I所示化合物的晶型I，其中反溶剂结晶法中的正溶剂为DMSO，反溶剂为甲醇；
    式I所示化合物的晶型II的制备方法包括如下步骤：将式I所示化合物在三氯甲烷和乙醇的混合溶剂中进行挥发结晶，得到式I所示化合物的晶型II；
    式I所示化合物的晶型III的制备方法包括如下步骤：将式I所示化合物的四氢呋喃溶液在乙酸异丙酯气氛中气液扩散，得到式I所示化合物的晶型III；
    式I所示化合物的晶型V的制备方法包括如下步骤：将式I所示化合物于1,4-二氧六环和乙腈的混合溶剂中进行挥发结晶，得到式I所示化合物的晶型V；
    式I所示化合物的晶型VI的制备方法包括如下步骤：将式I所示化合物于N,N-二甲基甲酰胺和异丙醇的混合溶剂中进行冷却结晶，得到式I所示化合物的晶型VI。
  13. 如权利要求12所述的制备方法，其特征在于，如II、VIII或IX所示的化合物的制备方法中，所述的溶剂选自甲醇、乙醇、异丙醇、正丁醇、乙腈、水、二氯甲烷、甲基叔丁基醚、二甲基亚砜、三氯甲烷、四氢呋喃、2-甲基呋喃、乙酸乙酯、乙酸异丙酯、1,4-二氧六环、N,N-二甲基甲酰胺、水、环己烷、丙酮、N-甲基吡咯烷酮、丁酮、甲基异丁酮、甲苯和苯甲醚中的一种或多种；
    和/或，所述的式II所示化合物的晶型A的制备方法中，所述式I所示化合物与HCl的摩尔比为1:(1-2.5)，例如1:1或1:2.5；
    和/或，所述的式II所示化合物的晶型A的制备方法中，所述式I所示化合物与溶剂的质量体积比为10-50mg/mL，例如10、15、20、30或40mg/mL；
    和/或，所述的式II所示化合物的晶型A的制备方法中，所述溶剂为甲醇和水的混合溶剂或二氯甲烷和乙醇的混合溶剂，优选为二氯甲烷和乙醇的混合溶剂；所述甲醇和水的混合溶剂中，甲醇和水的体积比可以为(100-110):1；所述二氯甲烷和乙醇的混合溶剂中，二氯甲烷和乙醇的体积比可以为(5-7):1，例如6:1；
    和/或所述的式II所示化合物的晶型B的制备方法中，所述式I所示化合物与HCl的摩尔比为1:(1-1.05)，优选为1:1；
    和/或，所述的式II所示化合物的晶型B的制备方法中，所述式I所示化合物与丙酮的质量体积比为20-60mg/mL，优选为50mg/mL；
    和/或，所述的式II所示化合物的晶型B的制备方法中，所述丙酮和水的混合溶剂中，丙酮和水的体积比为(100-120):1；
    和/或，所述的式III所示水合物的晶型C的制备方法中，所述式II所示化合物的晶型A与乙腈和乙酸乙酯的混合溶剂的质量体积比为20-200mg/mL；优选为100mg/mL；
    和/或，所述的式III所示水合物的晶型C的制备方法中，所述乙腈和乙酸乙酯的混合溶剂中，所述乙腈与乙酸乙酯的体积比为(2-5):1；优选为3:1；
    和/或，所述的式IV所示水合物的晶型D的制备方法中，所述式II所示化合物的晶型A与乙腈和水的混合溶剂的质量体积比为20-200mg/mL；优选为100mg/mL；
    和/或，所述的式IV所示水合物的晶型D的制备方法中，所述乙腈和水的混合溶剂中，乙腈与水的体积比为(5-20):1；优选为12:1；
    和/或，所述的式V所示水合物的晶型E的制备方法中，所述式II所示化合物的晶型A与丙酮和水的混合溶剂的质量体积比为20-200mg/mL；优选为100mg/mL；
    和/或，所述的式V所示水合物的晶型E的制备方法中，所述丙酮和水的混合溶剂中，丙酮与水的体积比为(5-12):1，优选为9:1；
    和/或，所述的式VII所示水合物的晶型J的制备方法中，所述式II所示化合物的晶型A与二氯甲烷和甲基叔丁基醚的混合溶剂的质量体积比为20-200mg/mL；优选为100mg/mL；
    和/或，所述的式VII所示水合物的晶型J的制备方法中，所述二氯甲烷和甲基叔丁基醚的混合溶剂中，二氯甲烷与甲基叔丁基醚的体积比为(1-10):1；优选为5:1；
    和/或，所述的式VIII所示化合物的晶型A的制备方法中，式I所示化合物与马来酸的摩尔比为1:(1-1.1)，优选为1:1；
    和/或，所述的式VIII所示化合物的晶型A的制备方法中，所述式I所示化合物与甲醇的质量体积比为20-60mg/mL，优选为50mg/mL；
    和/或，所述的式VIII所示化合物的晶型B的制备方法中，所述式I所示化合物与马来酸的摩尔比为1:(1-1.1)，优选为1:1；
    和/或，所述的式VIII所示化合物的晶型B的制备方法中，所述式I所示化合物与甲醇的质量体积比为20-60mg/mL，优选为50mg/mL；
    和/或，所述的式IX化合物的晶型A的制备方法中，式I所示化合物与马来酸的摩尔比为1:(1-1.1)，优选为1:1；
    和/或，所述的式IX化合物的晶型A的制备方法中，所述式I所示化合物与甲醇的质量体积比为20-60mg/mL，优选为50mg/mL；
    和/或，所述式I所示化合物的晶型I的制备方法中，所述的正溶剂与反溶剂的体积比为(1.5-2):1，例如8:5；
    和/或，所述式I所示化合物与所述正溶剂的质量体积比为10-100mg/mL，所述式I所示化合物与反溶剂的质量体积比为90-120mg/mL；
    和/或，所述式I所示化合物的晶型II的制备方法中，所述式I所示化合物的晶型I与三氯甲烷和乙醇的混合溶剂的质量体积比为20-50mg/mL；优选为50mg/mL；
    和/或，所述式I所示化合物的晶型II的制备方法中，所述的三氯甲烷和乙醇的混合溶剂中，三氯甲烷与乙醇的体积比为(1-5):1；优选为1:1；
    和/或，所述式I所示化合物的晶型III的制备方法中，所述式I所示化合物与四氢呋喃的质量体积比为20-60mg/mL；优选为50mg/mL；
    和/或，所述式I所示化合物的晶型V的制备方法中，所述的1,4-二氧六环和乙腈的混合溶剂中，1,4-二氧六环和乙腈的体积比为(1.5-2):1，例如8:5；
    和/或，所述式I所示化合物的晶型V的制备方法中，所述式I所示化合物与1,4-二氧六环的质量体积比为20-50mg/mL，所述式I所示化合物与乙腈的质量体积比为10-30mg/mL；
    和/或，所述式I所示化合物的晶型VI的制备方法中，所述的N,N-二甲基甲酰胺和异丙醇的混合溶剂中，N,N-二甲基甲酰胺和异丙醇的体积比为(1.5-2):1，例如8:5；
    和/或，所述式I所示化合物的晶型VI的制备方法中，所述N,N-二甲基甲酰胺和异丙醇的混合溶剂中，N,N-二甲基甲酰胺和异丙醇的体积比为(1.5-2):1，例如8:5；
    和/或，所述式I所示化合物的晶型VI的制备方法中，所述式I所示化合物与N,N-二甲基甲酰胺的质量体积比为20-50mg/mL，所述式I所示化合物与反溶剂异丙醇的质量体积比为10-30mg/mL。
  14. 一种如权利要求1所述的化合物、其晶型或其水合物，如权利要求2-4中至少一项所述的晶型、如权利要求5所述的水合物、如权利要求6-8中至少一项所述的晶型、或如权利要求9-11中至少一项所述的晶型在制备用于治疗与前蛋白转化酶枯草杆菌蛋白酶Kexin-9型相关的疾病的药物的应用；所述的与前蛋白转化酶枯草杆菌蛋白酶Kexin-9型相关的疾病可以为代谢性疾病，例如高脂血症、高胆固醇血症、高甘油三酯血症、脂肪肝变形、动脉粥样硬化或肥胖。
PCT/CN2022/101986 2021-06-28 2022-06-28 苯基[a]吲哚[2,3-g]并喹嗪类化合物的晶型、其盐和盐的晶型及其制备方法和应用 WO2023274242A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664974A (zh) * 2012-09-17 2014-03-26 中国科学院上海药物研究所 芳基[a]吲哚[2,3-g]并喹嗪类化合物、其制备方法、药物组合物及其应用
WO2017167202A1 (zh) * 2016-03-30 2017-10-05 中国科学院上海药物研究所 苯基[a]吲哚[2,3-g]并喹嗪类化合物、其制备方法、药物组合物及其应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664974A (zh) * 2012-09-17 2014-03-26 中国科学院上海药物研究所 芳基[a]吲哚[2,3-g]并喹嗪类化合物、其制备方法、药物组合物及其应用
WO2017167202A1 (zh) * 2016-03-30 2017-10-05 中国科学院上海药物研究所 苯基[a]吲哚[2,3-g]并喹嗪类化合物、其制备方法、药物组合物及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GUO, DILIANG ET AL.: "Design, Synthesis, and Biological Evaluation of Novel Tetrahydroprotoberberine Derivatives (THPBs) as Selective α1A-Adrenoceptor Antagonists", J. MED. CHEM., vol. 59, 6 October 2016 (2016-10-06), XP055427275, DOI: 10.1021/acs.jmedchem.6b01217 *

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