WO2023185979A1 - 一种atx抑制剂或其盐的结晶形式及其制备方法与应用 - Google Patents

一种atx抑制剂或其盐的结晶形式及其制备方法与应用 Download PDF

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WO2023185979A1
WO2023185979A1 PCT/CN2023/084963 CN2023084963W WO2023185979A1 WO 2023185979 A1 WO2023185979 A1 WO 2023185979A1 CN 2023084963 W CN2023084963 W CN 2023084963W WO 2023185979 A1 WO2023185979 A1 WO 2023185979A1
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formula
compound represented
crystal form
solvent
salt
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PCT/CN2023/084963
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English (en)
French (fr)
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彭程
顾为凯
周春燕
李玉萍
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苏州爱科百发生物医药技术有限公司
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Publication of WO2023185979A1 publication Critical patent/WO2023185979A1/zh

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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and specifically relates to a crystalline form of an ATX inhibitor or a salt thereof and its preparation method and application.
  • Autotaxin is a secreted lysophospholipase D (lysoPLD) that converts lysophosphatidylcholine (LPC) into the bioactive phospholipid derivative lysophosphatidic acid (LPA).
  • LPA is the common name for acyl-hydroxy-glyceryl-3-phosphate, all consisting of a glycerol phosphate backbone esterified into a single fatty acid and signaling through specific G protein-coupled receptors (LPA1-6) to exert its biological activity .
  • LPA mediates multiple fundamental responses to tissue injury, including responses that may be aberrant or abnormally excessive, allowing tissue damage to lead to fibrosis rather than repair.
  • LPA signaling through LPA1 receptor specificity has profibrotic effects on epithelial cells, endothelial cells, and fibroblasts.
  • LPA signaling through LPA2 is a negative regulator of innate immune responses, such as those mediated by dendritic cells in allergic lung inflammation. Organisms may require this activity of LPA to prevent excessive inflammation after tissue injury.
  • the ATX/LPA axis is involved in many physiological and pathological processes and is related to a variety of diseases such as cancer, pain, cholestatic pruritus, fibrosis, inflammation, and cardiovascular diseases.
  • Interstitial lung disease encompasses a diverse group of diseases in which lung inflammation and fibrosis are ultimately common pathological pathways. More than 150 factors contribute to ILD, including sarcoidosis, silicosis, drug reactions, infections, and collagen vascular diseases.
  • Idiopathic pulmonary fibrosis IPF is the most common type of ILD. IPF is a special form of localized pulmonary fibrosis interstitial pneumonia. After surgical lung biopsy analysis, it has the appearance of ordinary interstitial pneumonia. Histopathological pattern of (UIP). Most IPF patients are over 50 years old and develop insidious progressive dyspnea and dry cough without sputum over months to years.
  • Pulmonary function assessment typically reveals reduced lung volume, limited physiological function, reduced respiratory diffusion, and post-exercise hypoxemia.
  • the progression of the disease is difficult to predict; patients' rates of respiratory decline and progression to death are variable, and progression may be rapid or slow, or there may be an acute decline during a stable phase.
  • the present invention provides a crystalline form of an ATX inhibitor or a salt thereof as shown in formula (I) and its preparation method and application.
  • the present invention provides a crystal form A of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 6.938, 7.606, 9.256, 12.359 and 15.793; preferably, there are characteristic peaks at 6.938, 7.606, 9.256, 9.912, 11.482, 12.359, 15.793 and 16.368 ;
  • the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is shown in Figure 1.
  • the present invention provides a B crystal form of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 7.593, 11.516, 13.092, 16.526 and 19.247; preferably at 7.593, 9.977, 11.516, 13.092, 15.380, 16.526, 19.247, 20.095, 23.854, 26 .355 There are characteristic peaks at , 27.639 and 29.809; the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is shown in Figure 3.
  • the present invention provides a C crystal form of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 10.463, 10.666, 18.572, 20.708, 22.028 and 23.848; preferably at 10.463, 10.666, 13.970, 14.482, 15.220, 15.519, 17.747, 18.572 ,20.708 There are characteristic peaks at , 22.028 and 23.848; more preferably at 10.463, 10.666, 12.408, 13.970, 14.482, 15.220, 15.519, 17.747, 18.572, 20.708, 21.384, 22.028, 22.851, 23.848 and 2 There is a characteristic peak at 5.788; the most preferred method is diffraction
  • the X-ray powder diffraction pattern expressed in angle 2 ⁇ is shown in Figure 5.
  • the present invention provides a D crystal form of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 9.922, 11.176, 15.797, 16.230, 18.691 and 19.404; preferably at 7.514, 9.922, 11.176, 12.937, 15.797, 16.230, 18.691, 19.404, 20 .310 There are characteristic peaks at and 21.224; more preferably, there are characteristic peaks at 7.514, 9.922, 11.176, 12.937, 15.797, 16.230, 17.219, 18.691, 19.404, 20.310, 21.224, 23.476, 24.003 and 24.627; most preferably at diffraction angle 2 ⁇ angle representation
  • the X-ray powder diffraction pattern is shown in Figure 7.
  • the present invention provides an E crystal form of the compound represented by formula (I),
  • the X-ray powder diffraction pattern expressed in terms of diffraction angle 2 ⁇ has characteristic peaks at 6.889, 9.043, 13.463, 15.828, 16.891 and 18.650; preferably at 5.164, 6.889, 8.818, 9.043, 13.463, 13.722, 15.828, 16.394, 16.89 1
  • the X-ray powder diffraction pattern expressed as the diffraction angle 2 ⁇ is shown in Figure 9.
  • the invention provides a pharmaceutically acceptable salt of the compound represented by formula (I), wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, and p-toluene. sulfonates,
  • the chemical ratio of the compound represented by formula (I) to acid molecules or anions is 1:0.5-1:3, and may be 1:0.5-1:2.5, 1:0.5-1:2 , 1:0.5 ⁇ 1:1.5, 1:0.5 ⁇ 1:1, preferably 1:0.5, 1:1, 1:2 or 1:3, most preferably 1:1 or 1:2.
  • the present invention provides a crystal form I of p-toluenesulfonate of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 3.733, 7.394, 16.080 and 19.153; preferably, there are characteristic peaks at 3.733, 7.394, 11.052, 14.739, 15.496, 16.080, 19.153, 22.059 and 28.088 ; More preferably, there are characteristic peaks at 3.733, 7.394, 9.755, 11.052, 11.438, 12.185, 12.726, 13.220, 14.739, 15.496, 16.080, 17.180, 18.240, 19.153, 22.059 and 28.088; Most preferably, derivatized with The angle of incidence 2 ⁇ represents X -The ray powder diffraction pattern is shown in Figure 11.
  • the present invention provides a crystal form II of p-toluenesulfonate of a compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 12.163, 14.065, 17.303, 19.416, 20.532 and 22.762; preferably at 3.780, 7.640, 10.191, 10.897, 12.163, 12.781, 14.065, 16.237, 1 7.303 There are characteristic peaks at , 19.416, 20.532 and 22.762; more preferably at 3.780, 7.640, 10.191, 10.897, 12.163, 12.781, 14.065, 15.837, 16.237, 16.954, 17.303, 19.000, 19.416, 20. 532, 20.906, 21.961, 22.286 and 22.762 There are characteristic peaks; the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is as shown in Figure 13.
  • the present invention provides a crystal form I of the hydrochloride of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 8.761, 9.480, 10.635 and 17.422; preferably, there are characteristic peaks at 8.761, 9.480, 10.635, 15.425, 16.788, 17.422 and 22.750; most preferably, The X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is shown in Figure 19.
  • the present invention provides a crystal form II of the hydrochloride of the compound represented by formula (I),
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ has characteristic peaks at 6.985, 11.691, 14.025, 16.680 and 17.536; preferably at 6.985, 11.691, 14.025, 16.680, 17.536, 18.259, 19.185, 21.121, 21.895 and 2 3.548 There are characteristic peaks at; the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is as shown in Figure 21.
  • the present invention provides a crystal form I of the sulfate of the compound represented by formula (I),
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ has characteristic peaks at 3.326, 6.485, 12.875, 13.879 and 19.273; preferably at 3.326, 6.485, 8.601, 12.875, 13.879, 16.915, 17.835, 19.273, 19.920 and 22.4 86 There are characteristic peaks at 3.326, 6.485, 8.601, 12.003, 12.875, 13.879, 14.315, 15.454, 16.087, 16.915, 17.835, 19.273, 19.920, 22.486, 23.727 and 25.010; Most preferably, the diffraction angle 2 ⁇
  • the X-ray powder diffraction pattern expressed in angle is shown in Figure 23.
  • the present invention provides a crystal form I of a phosphate salt of a compound represented by formula (I),
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ has characteristic peaks at 3.436, 6.784, 16.868, 18.478 and 20.264; preferably at 3.436, 6.028, 6.784, 13.507, 15.360, 16.868, 18.478, 20.264, 23.661 and 30.5 56 There are characteristic peaks at; the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is as shown in Figure 25.
  • the present invention provides a crystal form I of the methanesulfonate salt of the compound represented by formula (I),
  • the X-ray powder diffraction pattern expressed in terms of diffraction angle 2 ⁇ has characteristic peaks at 7.945, 8.540, 12.203, 13.820 and 20.863; preferably at 7.945, 8.540, 10.316, 10.621, 11.507, 12.203, 13.820, 14.579, 15.964 and 20. 863 There are characteristic peaks at 7.945, 8.540, 10.316, 10.621, 11.507, 12.203, 13.820, 14.579, 15.964, 17.640, 20.284, 20.863, 23.234, 23.888 and 26.418; most preferably at the diffraction angle 2 ⁇ angle representation
  • the X-ray powder diffraction pattern is shown in Figure 27.
  • the present invention provides a crystal form I of the benzenesulfonate salt of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 5.268, 6.306, 13.796, 15.768 and 18.673; preferably at 5.268, 6.306, 6.865, 13.796, 15.023, 15.768, 18.673, 21.035, 21.892 and 22.6 08 There are characteristic peaks at; more preferably, there are characteristic peaks at 5.268, 6.306, 6.865, 9.398, 11.030, 12.049, 13.796, 15.023, 15.768, 16.228, 17.946, 18.673, 20.835, 21.035, 21.892 and 22.608; the most Preferably at diffraction angle 2 ⁇
  • the X-ray powder diffraction pattern expressed in angle is shown in Figure 29.
  • the invention provides the A crystal form, B crystal form, C crystal form, D crystal form, E crystal form, p-toluenesulfonate, hydrochloride, sulfate, phosphate, methanesulfonate acid salt, benzenesulfonate, and the I crystalline form of p-toluenesulfonate, p-toluenesulfonate Form II of benzene sulfonate, Form I of hydrochloride, Form II of hydrochloride, Form I of sulfate, Form I of phosphate, Form I of mesylate, benzene sulfonate
  • the I crystal form of the acid salt has advantages in physical and chemical properties, preparation processing performance and bioavailability, such as melting point, solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, bulk There are advantages in at least one of the internal and external dissolution, bioavailability and other
  • the free base crystal form, salt form and salt form of the present invention have good physical and chemical stability, and the yield of the corresponding crystal form prepared from the same starting material is high, and it has good solubility, hygroscopicity and stability. , mechanical stability, fluidity, compressibility, adhesion, drug metabolism and other aspects have obvious advantages, providing new and better options for the development of ATX inhibitor drugs, which is of very important significance.
  • Figure 1 is the XRPD spectrum of crystal form A of the compound represented by formula (I).
  • Figure 2 is a TGA&DSC superimposed spectrum of crystal form A of the compound represented by formula (I).
  • Figure 3 is the XRPD spectrum of the B crystal form of the compound represented by formula (I).
  • Figure 4 is a TGA&DSC superimposed spectrum of the B crystal form of the compound represented by formula (I).
  • Figure 5 is the XRPD spectrum of the C crystal form of the compound represented by formula (I).
  • Figure 6 is a TGA&DSC superimposed spectrum of the C crystal form of the compound represented by formula (I).
  • Figure 7 is the XRPD spectrum of the D crystal form of the compound represented by formula (I).
  • Figure 8 is a DSC spectrum of the D crystal form of the compound represented by formula (I).
  • Figure 9 is the XRPD spectrum of the E crystal form of the compound represented by formula (I).
  • Figure 10 is a TGA&DSC superimposed spectrum of the E crystal form of the compound represented by formula (I).
  • Figure 11 is the XRPD spectrum of the p-toluenesulfonate crystal form I of the compound represented by formula (I).
  • Figure 12 is a TGA&DSC overlay spectrum of the p-toluenesulfonate crystal form I of the compound represented by formula (I).
  • Figure 13 is the XRPD spectrum of the p-toluenesulfonate salt form II of the compound represented by formula (I).
  • Figure 14 is a TGA&DSC overlay spectrum of the p-toluenesulfonate salt form II of the compound represented by formula (I).
  • Figure 15 is a DVS spectrum of the p-toluenesulfonate salt form II of the compound represented by formula (I).
  • Figure 16 shows the XRPD overlay before and after DVS test of the p-toluenesulfonate II crystal form of the compound represented by formula (I).
  • Figure 17 is an XRPD superimposed spectrum of the solid obtained by wet grinding of the B crystal form of the compound represented by formula (I).
  • Figure 18 is the XRPD spectrum of the solid obtained by pressing crystal form B of the compound represented by formula (I).
  • Figure 19 is the XRPD spectrum of the hydrochloride salt form I of the compound represented by formula (I).
  • FIG 20 is a TGA&DSC superimposed spectrum of the hydrochloride salt form I of the compound represented by formula (I).
  • Figure 21 is the XRPD spectrum of the hydrochloride salt form II of the compound represented by formula (I).
  • Figure 22 is a TGA&DSC superimposed spectrum of the hydrochloride salt form II of the compound represented by formula (I).
  • Figure 23 is the XRPD spectrum of the sulfate salt form I of the compound represented by formula (I).
  • Figure 24 is a TGA&DSC overlay spectrum of the sulfate salt form I of the compound represented by formula (I).
  • Figure 25 is an XRPD spectrum of the phosphate crystal form I of the compound represented by formula (I).
  • Figure 26 is a TGA&DSC overlay spectrum of the phosphate crystal form I of the compound represented by formula (I).
  • Figure 27 is the XRPD spectrum of the mesylate crystal form I of the compound represented by formula (I).
  • Figure 28 is a TGA&DSC overlay spectrum of the mesylate crystal form I of the compound represented by formula (I).
  • Figure 29 is the XRPD spectrum of the benzene sulfonate crystal form I of the compound represented by formula (I).
  • Figure 30 is a TGA&DSC overlay spectrum of the benzene sulfonate crystal form I of the compound represented by formula (I).
  • the present invention provides a crystal form A of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 6.938, 7.606, 9.256, 12.359 and 15.793; preferably, there are characteristic peaks at 6.938, 7.606, 9.256, 9.912, 11.482, 12.359, 15.793 and 16.368 ;
  • the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is shown in Figure 1.
  • the present invention further provides a method for preparing crystal form A of the compound represented by formula (I), which includes the steps of: mixing the compound represented by formula (I) with solvent 1, dissolving, adding solvent 2, and crystallizing.
  • the solvent 1 is selected from ether solvents.
  • the solvent 1 is selected from one or more of diethyl ether, propyl ether, butyl ether, anisole, petroleum ether, isopropyl ether and 1,4-dioxane.
  • the solvent 1 is selected from 1,4-dioxane.
  • the solvent 2 is selected from alcoholic solvents.
  • the solvent 2 is selected from C 1-4 alcohols.
  • the solvent 2 is selected from one or more of methanol, ethanol and isopropyl alcohol.
  • the solvent 2 is selected from isopropyl alcohol.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a B crystal form of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 7.593, 11.516, 13.092, 16.526 and 19.247; preferably at 7.593, 9.977, 11.516, 13.092, 15.380, 16.526, 19.247, 20.095, 23.854, There are characteristic peaks at 26.355, 27.639 and 29.809; the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is as shown in Figure 3.
  • the present invention further provides a method for preparing the B crystal form of the compound represented by formula (I), which includes the steps of: mixing the compound represented by formula (I) with solvent 3, dissolving, adding solvent 4, and crystallizing.
  • the solvent 3 is selected from ether solvents.
  • the solvent 3 is selected from one or more of diethyl ether, propyl ether, butyl ether, anisole, petroleum ether, isopropyl ether and 1,4-dioxane.
  • the solvent 3 is selected from 1,4-dioxane.
  • the solvent 4 is selected from nitrile solvents, preferably one or more of acetonitrile, propionitrile and valeronitrile, and more preferably acetonitrile.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a C crystal form of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 10.463, 10.666, 18.572, 20.708, 22.028 and 23.848; preferably at 10.463, 10.666, 13.970, 14.482, 15.220, 15.519, 17.747, 18.572 ,20.708 There are characteristic peaks at , 22.028 and 23.848; more preferably at 10.463, 10.666, 12.408, 13.970, 14.482, 15.220, 15.519, 17.747, 18.572, 20.708, 21.384, 22.028, 22.851, 23.848 and 2 There is a characteristic peak at 5.788; the most preferred method is diffraction
  • the X-ray powder diffraction pattern expressed in angle 2 ⁇ is shown in Figure 5.
  • the present invention further provides a method for preparing the C crystal form of the compound represented by formula (I), which includes the steps of: mixing the compound represented by formula (I) with solvent 5, suspending, stirring, and filtering to obtain a filter cake.
  • the solvent 5 is selected from ether solvents.
  • the solvent 5 is selected from one or more of diethyl ether, propyl ether, butyl ether, anisole, petroleum ether, isopropyl ether and methyl tert-butyl ether.
  • the solvent 5 is selected from methyl tert-butyl ether.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a D crystal form of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 9.922, 11.176, 15.797, 16.230, 18.691 and 19.404; preferably at 7.514, 9.922, 11.176, 12.937, 15.797, 16.230, 18.691, 19.404, 20 .310 There are characteristic peaks at and 21.224; more preferably, there are characteristic peaks at 7.514, 9.922, 11.176, 12.937, 15.797, 16.230, 17.219, 18.691, 19.404, 20.310, 21.224, 23.476, 24.003 and 24.627; most preferably at diffraction angle 2 ⁇ angle representation
  • the X-ray powder diffraction pattern is shown in Figure 7.
  • the present invention further provides a method for preparing the D crystal form of the compound represented by formula (I), which includes the steps of: mixing the compound represented by formula (I) with solvent 6, sealing, placing, and filtering to obtain a filter cake.
  • the solvent 6 is selected from ether solvents.
  • the solvent 6 is selected from one or more of diethyl ether, propyl ether, butyl ether, anisole, petroleum ether, isopropyl ether and 1,4-dioxane.
  • the solvent 6 is selected from 1,4-dioxane
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides an E crystal form of the compound represented by formula (I),
  • the X-ray powder diffraction pattern expressed in terms of diffraction angle 2 ⁇ has characteristic peaks at 6.889, 9.043, 13.463, 15.828, 16.891 and 18.650; preferably at 5.164, 6.889, 8.818, 9.043, 13.463, 13.722, 15.828, 16.394, 16.89 1
  • the X-ray powder diffraction pattern expressed as the diffraction angle 2 ⁇ is shown in Figure 9.
  • the present invention further provides a method for preparing the E crystal form of the compound represented by formula (I), which is characterized in that it includes the steps of: mixing the compound represented by formula (I) with solvent 7, dissolving, cooling, and crystallizing.
  • the solvent 7 is selected from ether solvents.
  • the solvent 7 is selected from one or more of diethyl ether, propyl ether, butyl ether, anisole, petroleum ether, isopropyl ether and 1,4-dioxane.
  • the solvent 7 is selected from 1,4-dioxane.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a pharmaceutically acceptable salt of the compound represented by formula (I), wherein the pharmaceutically acceptable salt is selected from p-toluenesulfonate, hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate,
  • the chemical ratio of the compound represented by formula (I) to acid molecules or anions is 1:0.5-1:3, such as 1:0.5-1:2.5, 1:0.5-1:2 , 1:0.5 ⁇ 1:1.5 or 1:0.5 ⁇ 1:1, preferably 1:0.5, 1:1, 1:2 or 1:3, most preferably 1:1 or 1:2.
  • the chemical ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:0.5-1:3, such as 1:0.5-1:2.5, 1:0.5-1:2 , 1:0.5 ⁇ 1:1.5 or 1:0.5 ⁇ 1:1, preferably 1:0.5, 1:1, 1:2 or 1:3, most preferably 1:1 or 1:2.
  • the chemical ratio of the compound represented by formula (I) to hydrochloric acid is 1:0.5 ⁇ 1:3, such as 1:0.5 ⁇ 1:2.5, 1:0.5 ⁇ 1:2, 1: 0.5 ⁇ 1:1.5 or 1:0.5 ⁇ 1:1, preferably 1:0.5, 1:1, 1:2 or 1:3, most preferably 1:1 or 1:2.
  • the chemical ratio of the compound represented by formula (I) to sulfuric acid is 1:0.5 ⁇ 1:3, such as 1:0.5 ⁇ 1:2.5, 1:0.5 ⁇ 1:2, 1: 0.5 ⁇ 1:1.5 or 1:0.5 ⁇ 1:1, preferably 1:0.5, 1:1, 1:2 or 1:3, most preferably 1:1 or 1:2.
  • the chemical ratio of the compound represented by formula (I) to phosphoric acid is 1:0.5 ⁇ 1:3, such as 1:0.5 ⁇ 1:2.5, 1:0.5 ⁇ 1:2, 1: 0.5 ⁇ 1:1.5 or 1:0.5 ⁇ 1:1, preferably 1:0.5, 1:1, 1:2 or 1:3, most preferably 1:1 or 1:2.
  • the chemical ratio of the compound represented by formula (I) to methanesulfonic acid is 1:0.5 ⁇ 1:3, such as 1:0.5 ⁇ 1:2.5, 1:0.5 ⁇ 1:2, 1:0.5 ⁇ 1:1.5 or 1:0.5 ⁇ 1:1, preferably 1:0.5, 1:1, 1:2 or 1:3, most preferably 1:1 or 1:2.
  • the chemical ratio of the compound represented by formula (I) to benzenesulfonic acid is 1:0.5 ⁇ 1:3, such as 1:0.5 ⁇ 1:2.5, 1:0.5 ⁇ 1:2, 1:0.5 ⁇ 1:1.5 or 1:0.5 ⁇ 1:1, preferably 1:0.5, 1:1, 1:2 or 1:3, most preferably 1:1 or 1:2.
  • the present invention further provides a method for preparing a pharmaceutically acceptable salt of the compound represented by formula (I), which includes the step of carrying out a salt-forming reaction between the compound represented by formula (I) and an acid.
  • the solvent used in the salt-forming reaction is selected from one or more of alcohols, ethers, esters, halogenated alkanes, ketones and water.
  • the solvent used in the salt-forming reaction is selected from one or more of tetrahydrofuran, methylene chloride, ethanol, ethyl acetate, acetone and water.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a crystal form I of p-toluenesulfonate of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 3.733, 7.394, 16.080 and 19.153; preferably, there are characteristic peaks at 3.733, 7.394, 11.052, 14.739, 15.496, 16.080, 19.153, 22.059 and 28.088 Characteristic peaks; more preferably, there are characteristic peaks at 3.733, 7.394, 9.755, 11.052, 11.438, 12.185, 12.726, 13.220, 14.739, 15.496, 16.080, 17.180, 18.240, 19.153, 22.059 and 28.088; most preferably Expressed in terms of diffraction angle 2 ⁇
  • the X-ray powder diffraction pattern is shown in Figure 11.
  • the present invention further provides a method for preparing the I crystal form of the p-toluenesulfonate salt of the compound represented by formula (I), which includes the steps of: mixing the compound represented by formula (I) with solvent 8, placing the system in dry ice, Add p-toluenesulfonic acid monohydrate, stir at room temperature, and crystallize.
  • the solvent 8 is selected from ester solvents.
  • the solvent 8 is selected from one or more of ethyl acetate, methyl acetate, butyl acetate and isobutyl acetate.
  • the solvent 8 is selected from ethyl acetate.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a crystal form II of p-toluenesulfonate of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 12.163, 14.065, 17.303, 19.416, 20.532 and 22.762; preferably at 3.780, 7.640, 10.191, 10.897, 12.163, 12.781, 14.065, 16.237, 1 7.303 There are characteristic peaks at , 19.416, 20.532 and 22.762; more preferably at 3.780, 7.640, 10.191, 10.897, 12.163, 12.781, 14.065, 15.837, 16.237, 16.954, 17.303, 19.000, 19.416, 20. 532, 20.906, 21.961, 22.286 and 22.762 There are characteristic peaks; the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is as shown in Figure 13.
  • the present invention further provides a method for preparing the II crystal form of p-toluenesulfonate of the compound represented by formula (I), which is characterized in that it includes the steps of: mixing the compound represented by formula (I) with solvent 9, placing the system Add p-toluenesulfonic acid monohydrate to ice-ethanol, stir overnight, and crystallize.
  • the solvent 9 is selected from ester solvents.
  • the solvent 9 is selected from one or more of ethyl acetate, methyl acetate, butyl acetate and isobutyl acetate.
  • the solvent 9 is selected from ethyl acetate.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a crystal form I of the hydrochloride of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 8.761, 9.480, 10.635 and 17.422; preferably, there are characteristic peaks at 8.761, 9.480, 10.635, 15.425, 16.788, 17.422 and 22.750; most preferably, The X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is shown in Figure 19.
  • the invention further provides a method for preparing crystal form I of the hydrochloride of the compound represented by formula (I), which includes the steps of: mixing the compound represented by formula (I) with solvent 10, placing the system in dry ice, and adding hydrochloric acid , stir at room temperature, crystals precipitate, stir overnight, and filter.
  • the solvent 10 is selected from ether solvents.
  • the solvent 10 is selected from one or more of diethyl ether, propyl ether, butyl ether, anisole, petroleum ether, isopropyl ether and tetrahydrofuran.
  • the solvent 10 is selected from tetrahydrofuran.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a crystal form II of the hydrochloride of the compound represented by formula (I),
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ has characteristic peaks at 6.985, 11.691, 14.025, 16.680 and 17.536; preferably at 6.985, 11.691, 14.025, 16.680, 17.536, 18.259, 19.185, 21.121, 21.895 and 2 3.548 There are characteristic peaks at; the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is as shown in Figure 21.
  • the invention further provides a method for preparing the II crystal form of the hydrochloride of the compound represented by formula (I), which includes the steps of: mixing the compound represented by formula (I) with solvent 11, placing the system in dry ice, and adding hydrochloric acid , stir at room temperature, expose the solvent to evaporate, stir and filter after solid precipitates.
  • the solvent 11 is selected from a mixed solvent of halogenated alkanes and alcohol solvents.
  • the solvent 11 is a haloalkane selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane and a solvent selected from the group consisting of methanol, ethanol and isopropyl alcohol.
  • a mixed solvent of alcoholic solvents is a haloalkane selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane and a solvent selected from the group consisting of methanol, ethanol and isopropyl alcohol.
  • the solvent 11 is selected from a mixed solvent of methylene chloride and ethanol.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a crystal form I of the sulfate of the compound represented by formula (I),
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ has characteristic peaks at 3.326, 6.485, 12.875, 13.879 and 19.273; preferably at 3.326, 6.485, 8.601, 12.875, 13.879, 16.915, 17.835, 19.273, 19.920 and 22.4 86 There are characteristic peaks at; more preferably at 3.326, 6.485, 8.601, 12.003, 12.875, 13.879, 14.315, 15.454, There are characteristic peaks at 16.087, 16.915, 17.835, 19.273, 19.920, 22.486, 23.727 and 25.010; the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is as shown in Figure 23.
  • the present invention further provides a method for preparing the I crystal form of the sulfate of the compound represented by formula (I), which includes the steps of: mixing the compound represented by formula (I) with solvent 12, placing the system in dry ice, and adding sulfuric acid; Stir at room temperature, raise the temperature to 50°C, stir overnight, cool to room temperature, and filter.
  • the solvent 12 is selected from ketone solvents.
  • the solvent 12 is selected from one or more of acetone, butanone, pentanone, hexanone and cyclohexanone.
  • the solvent 12 is selected from acetone.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a crystal form I of the phosphate of the compound represented by formula (I),
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ has characteristic peaks at 3.436, 6.784, 16.868, 18.478 and 20.264; preferably at 3.436, 6.028, 6.784, 13.507, 15.360, 16.868, 18.478, 20.264, 23.661 and 30.5 56 There are characteristic peaks at; the most preferred X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is as shown in Figure 25.
  • the present invention further provides a method for preparing the I crystal form of the phosphate of the compound represented by formula (I), which includes the steps of: mixing the compound represented by formula (I) with solvent 13, placing the system in dry ice, and adding phosphoric acid; Stir at room temperature, raise the temperature to 50°C and stir, crystals will precipitate, continue stirring, lower to room temperature, stir overnight, and filter.
  • the solvent 13 is selected from ester solvents.
  • the solvent 13 is selected from one or more of ethyl acetate, methyl acetate, butyl acetate and isobutyl acetate.
  • the solvent 13 is selected from ethyl acetate.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a crystal form I of the mesylate salt of the compound represented by formula (I),
  • the X-ray powder diffraction pattern expressed in terms of diffraction angle 2 ⁇ has characteristic peaks at 7.945, 8.540, 12.203, 13.820 and 20.863; preferably at 7.945, 8.540, 10.316, 10.621, 11.507, 12.203, 13.820, 14.579, 15.964 and 20. 863 There are characteristic peaks at 7.945, 8.540, 10.316, 10.621, 11.507, 12.203, 13.820, 14.579, 15.964, 17.640, 20.284, 20.863, 23.234, 23.888 and 26.418; most preferably at the diffraction angle 2 ⁇ angle representation
  • the X-ray powder diffraction pattern is shown in Figure 27.
  • the present invention further provides a method for preparing the crystal form I of the mesylate salt of the compound represented by formula (I), which includes the steps of: mixing the compound represented by formula (I) with solvent 14, placing the system in dry ice, and adding Methanesulfonic acid, stir at room temperature, raise the temperature to 50°C and stir, lower to room temperature and evaporate in the open, stir, crystallize and precipitate, stir, and filter.
  • the solvent 14 is selected from ether solvents.
  • the solvent 14 is selected from one or more of diethyl ether, propyl ether, butyl ether, anisole, petroleum ether, isopropyl ether and tetrahydrofuran.
  • the solvent 14 is selected from tetrahydrofuran.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a crystal form I of the benzenesulfonate salt of the compound represented by formula (I),
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 5.268, 6.306, 13.796, 15.768 and 18.673; preferably at 5.268, 6.306, 6.865, 13.796, 15.023, 15.768, 18.673, 21.035, 21.892 and 22.6 08 There are characteristic peaks at; more preferably, there are characteristic peaks at 5.268, 6.306, 6.865, 9.398, 11.030, 12.049, 13.796, 15.023, 15.768, 16.228, 17.946, 18.673, 20.835, 21.035, 21.892 and 22.608; the most Preferably at diffraction angle 2 ⁇
  • the X-ray powder diffraction pattern expressed in angle is shown in Figure 29.
  • the present invention further provides a method for preparing the I crystal form of the benzenesulfonate of the compound represented by formula (I), which includes the steps of: mixing the compound represented by formula (I) with solvent 15, placing the system in dry ice, and adding Stir benzene sulfonic acid at room temperature, raise the temperature to 50°C and stir, crystals will precipitate, continue stirring, lower to room temperature, stir overnight, and filter.
  • the solvent 15 is selected from ester solvents.
  • the solvent 15 is selected from one or more of ethyl acetate, methyl acetate, butyl acetate and isobutyl acetate.
  • the solvent 15 is selected from ethyl acetate.
  • the preparation method of the present invention further includes steps such as centrifugation, washing or drying.
  • the present invention further provides a crystal form A of the compound represented by formula (I) or the B crystal form of the compound represented by formula (I) or the C crystal form of the compound represented by formula (I) or the aforementioned
  • the crystal form II of the hydrochloride of the compound represented by formula (I) or the crystal form I of the sulfate of the compound represented by formula (I) or the crystal I of the phosphate of the compound represented by formula (I) A pharmaceutical
  • the present invention further provides a pharmaceutical composition, containing the A crystal form of the aforementioned compound represented by formula (I) or the aforementioned B crystal form of the compound represented by formula (I) or the aforementioned C crystal form of the compound represented by formula (I).
  • the I crystal form of the p-toluenesulfonate salt of the compound represented by I) or the II crystal form of the p-toluenesulfonate salt of the aforementioned compound represented by formula (I) or the hydrochloride salt of the aforementioned compound represented by formula (I) Form I or the form II of the hydrochloride of the compound represented by formula (I) or the form I of the sulfate of the compound represented by formula (I) or the phosphoric acid of
  • “Pharmaceutically acceptable excipient” refers to a pharmaceutically acceptable material, mixture or vehicle relevant to the consistency of the dosage form or pharmaceutical composition for administration. Suitable pharmaceutically acceptable excipients will vary depending on the dosage form selected. In addition, pharmaceutically acceptable excipients may be selected based on their specific function in the composition.
  • the pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, Coating agent, wetting agent, solvent, co-solvent, suspending agent, emulsifier, flavoring agent, taste masking agent, coloring agent, anti-caking agent, humectant, chelating agent, plasticizer, tackifier, Antioxidants, preservatives, stabilizers, surfactants and buffers.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, Coating agent, wetting agent, solvent, co-solvent, suspending agent, emulsifier, flavoring agent, taste masking agent, coloring agent, anti-caking agent, humectant, chelating agent, plasticizer, tackifier, Antioxidants, preservatives
  • the pharmaceutical composition is a solid dosage form.
  • the solid formulation is a capsule.
  • the capsule contains 25 mg to 200 mg of the compound represented by formula (I) or a salt thereof.
  • the present invention further provides a preparation method of a pharmaceutical composition, which includes preparing the A crystal form of the compound represented by the aforementioned formula (I) or the B crystal form of the aforementioned compound represented by the formula (I) or the aforementioned compound represented by the formula (I).
  • the present invention further provides a crystal form A of the compound represented by formula (I), a crystal form B of the compound represented by formula (I), a crystal form C of the compound represented by formula (I), or a crystal form C of the compound represented by formula (I).
  • the ATX-related disease is fibrotic disease, cancer, proliferative disease, inflammatory disease, autoimmune disease, respiratory disease, cardiovascular disease, neurodegenerative disease, dermatological disease, metabolic disease disease, myelodysplastic syndromes, disorders associated with abnormal angiogenesis, or pain.
  • the ATX-related disease is fibrotic disease, cancer, or dermatological disease.
  • the ATX-related disease is pulmonary fibrosis (eg, idiopathic pulmonary fibrosis), liver fibrosis, scleroderma, renal cancer, pancreatic cancer, or cholestatic pruritus.
  • pulmonary fibrosis eg, idiopathic pulmonary fibrosis
  • liver fibrosis e.g., scleroderma
  • renal cancer pancreatic cancer
  • cholestatic pruritus estatic pruritus
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present invention refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.2 (including numbers with more than 1 decimal place after rounding case), can be -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17 ,0.18,0.19,0.20.
  • the precipitation methods described in the present invention include but are not limited to stirring, cooling, volatilization, beating, and precipitation.
  • Being is a common term in the field of drug preparation. It usually refers to the mechanical or fluidization of solid drug raw materials to disperse or suspend the solid drug in a solvent.
  • the beating time is 5h-30h.
  • Deliquescence Absorbing enough water to form a liquid
  • the weight gain by attracting moisture is not less than 15%;
  • the weight gain by attracting moisture is less than 15% but not less than 2%;
  • weight gain due to moisture attraction is less than 2% but not less than 0.2%;
  • weight gain due to moisture absorption is less than 0.2%.
  • the “differential scanning calorimetry analysis or DSC” mentioned in the present invention refers to measuring the temperature difference and heat flow difference between the sample and the reference object during the heating or constant temperature process of the sample to characterize all physical changes related to thermal effects and Chemical changes to obtain phase change information of the sample.
  • the drying temperature in the present invention is generally 25°C to 100°C, preferably 40°C to 70°C. Drying can be done under normal pressure or under reduced pressure.
  • the crystal form of the sample was analyzed using a Bruker D8 ADVANCE X-powder diffractometer (using Cu-K ⁇ radiation).
  • the 2 ⁇ scanning angle of the sample is 3° to 42°, the scanning step is 0.02°, and the scanning time of each step is 0.05s/step.
  • the light tube voltage and current are 40kV and 40mA respectively.
  • Samples were analyzed using TA Instruments TGA Discovery 550. Put the sample into the aluminum pan with the tare removed, the system automatically weighs it, and then raises the sample to the specified temperature at a rate of 10°C/min under the protection of nitrogen.
  • Samples were analyzed using TA Instruments Discovery DSC 25. Weigh 2 to 10 mg of sample into a sample loading tray, and raise the sample to the specified temperature at a rate of 10°C/min under the protection of nitrogen (50 ml/min).
  • test sample was analyzed using Intrinsic DVS (System Measurement System UK). The amount of test sample is about 20 ⁇ 30mg. The temperature of the test room is controlled between 25 ⁇ 1°C, the relative humidity rises from 0% to 90% and then drops to 0% at a rate of 10%/h, and quality data is recorded every 20 seconds.
  • the compound represented by formula (I) of the present invention can be prepared according to the existing technology, for example, according to the method described in WO2022007882A1.
  • Table 1 XRPD diffraction peak data of crystal form A
  • the product is the p-toluenesulfonate II crystal form of the compound represented by formula (I).
  • the XRPD spectrum is shown in Figure 13, and its characteristic peak positions are shown in Table 7.
  • the DSC spectrum shows that the endothermic peak peak is 238.78°C.
  • Table 7 XRPD diffraction peak data of p-toluenesulfonate II crystal form of the compound represented by formula (I)
  • Table 11 XRPD diffraction peak data of the phosphate crystal form I of the compound represented by formula (I)
  • Table 13 XRPD diffraction peak data of benzene sulfonate crystal form I of the compound represented by formula (I)
  • Example 15 Suspension competition test of crystal form A, crystal form B and crystal form C of the compound represented by formula (I)
  • Example 19 Stability of phosphate crystal form I, benzenesulfonate crystal form I and p-toluenesulfonate crystal form II of the compound represented by formula (I)
  • Test conditions 25°C/60%RH, 40°C/75%RH-two weeks and four weeks; 60°C-one week and two weeks; 80°C-one day; light -1.2M lux. The results are shown in Table 17.
  • Table 17 Stability test results of phosphate crystal form I, benzenesulfonate crystal form I and p-toluenesulfonate crystal form II
  • Phosphate I crystal form and p-toluenesulfonate crystal form II are under the existing test conditions (25°C/60%RH, 40°C/75%RH-two weeks and four weeks; 60°C-one week and two weeks; 80°C - one day; illumination -1.2M lux), the crystalline form did not change, while the crystallinity of benzenesulfonate I crystalline form decreased under the conditions of 25°C/60%RH-two weeks and four weeks, and the crystalline form remained stable under other conditions. changes happened.
  • Example 20 Hygroscopicity of p-toluenesulfonate II crystal form of the compound represented by formula (I)
  • the hygroscopicity of p-toluenesulfonate II crystal form was evaluated through a dynamic moisture adsorption test between 0% RH and 90% RH at 25°C.
  • the DVS results are shown in Figure 15.
  • the hygroscopic weight gain of p-toluenesulfonate II crystal form when the humidity is 80% is 0.5731%, indicating that the product is slightly hygroscopic.
  • the crystal form of p-toluenesulfonate II did not change before and after the DVS test.
  • Example 21 Feasibility study on the preparation process of p-toluenesulfonate II crystal form of the compound represented by formula (I)
  • Example 22 Oral pharmacokinetic study in rats of free base B crystal form and p-toluenesulfonate salt form II of the compound represented by formula (I)
  • PK pharmacokinetics
  • the solvent is: 15% vitamin E TPGS+10% Transcutol HP+45% PEG 400+30% Water.
  • the pharmacokinetic parameters in rat plasma are shown in Tables 18 and 19.

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Abstract

提供一种式(I)所示ATX抑制剂及其盐的晶型的制备方法与应用。ATX抑制剂及其盐的晶型具备高的口服生物利用度且其引湿性低、稳定性好。ATX抑制剂及其盐的晶型的制备方法工艺简单，结晶过程易于控制，重现性好。

Description

一种ATX抑制剂或其盐的结晶形式及其制备方法与应用 技术领域
本发明属于医药化学技术领域，具体涉及一种ATX抑制剂或其盐的结晶形式及其制备方法与应用。
背景技术
Autotaxin(ATX)是一种将溶血磷脂酰胆碱(LPC)转化为生物活性磷脂衍生物溶血磷脂酸(LPA)的分泌型溶血磷脂酶D(lysoPLD)。LPA是酰基-羟基-甘油基-3-磷酸酯的通用名称，全部由酯化成单一脂肪酸的磷酸甘油骨架和通过特异性G蛋白偶联受体(LPA1-6)发出信号而发挥其生物学活性。LPA介导对组织损伤的多种基本反应，包括可能异常或异常过度的反应，使组织损伤导致纤维化而不是修复。通过LPA1受体特异性的LPA信号传导对上皮细胞、内皮细胞和成纤维细胞具有促纤维化作用。另一方面，通过LPA2的LPA信号传导是天然免疫应答的负调节因子，例如在过敏性肺部炎症中的树突状细胞介导的那些天然免疫应答。生物机体可能需要LPA的这种活性来防止组织损伤后的过度炎症。ATX/LPA轴参与了许多生理和病理过程，与多种疾病如癌症，疼痛，胆汁淤积性瘙痒症，纤维化，炎症，心血管疾病有关。
间质性肺疾病(ILD)包括多种不同的疾病，其中肺部炎症和纤维化是最终常见的病理学途径。有150多种因素导致ILD，包括肉样瘤病、矽肺、药物反应、感染和胶原血管疾病。特发性肺纤维化(idiopathic pulmonary fibrosis，IPF)是最常见的ILD类型，IPF是一种局限性肺纤维化性间质性肺炎的特殊形式，经外科肺活检分析，具有普通间质性肺炎(UIP)的组织病理学模式。多数IPF患者年龄超过50岁，并在数月至数年内出现隐匿性进行性呼吸困难和无痰干咳。肺功能评估通常显示肺容积减少，生理功能受限，呼吸弥散减弱，以及运动后的低氧血症。该疾病的进展难以预测，患者的呼吸功能下降率和发展到死亡是可变的，病情恶化进程可能迅速、也可能缓慢，或者在稳定期出现急性下降。
由于纤维化长期以来被认为是临床上不可逆的过程，因此传统治疗上侧重控制症状和并发症，几乎没有希望显著减缓病情的进展。多年来，IPF的主要治疗方法通常是使用抗炎药物，免疫抑制和抗氧化剂(如皮质类固醇，硫唑嘌呤，环磷酰胺)。
本申请人的PCT专利WO2022007882A1提供了一种如下式所示的化合物，已经发现该化合物对ATX具有很强的抑制活性。
发明内容
发明要解决的问题
基于多晶型化合物的存在形态和数量是无法预期的，本发明提供一种如式(I)所示的ATX抑制剂或其盐的结晶形式及其制备方法与应用。
用于解决问题的方案
本发明提供一种式(I)所示化合物的A晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在6.938、7.606、9.256、12.359和15.793处有特征峰；优选在6.938、7.606、9.256、9.912、11.482、12.359、15.793和16.368处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
本发明提供一种式(I)所示化合物的B晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在7.593、11.516、13.092、16.526和19.247处有特征峰；优选在7.593、9.977、11.516、13.092、15.380、16.526、19.247、20.095、23.854、26.355、27.639和29.809处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
本发明提供一种式(I)所示化合物的C晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在10.463、10.666、18.572、20.708、22.028和23.848处有特征峰；优选在10.463、10.666、13.970、14.482、15.220、15.519、17.747、18.572、20.708、22.028和23.848处有特征峰；更优选在10.463、10.666、12.408、13.970、14.482、15.220、15.519、17.747、18.572、20.708、21.384、22.028、22.851、23.848和25.788处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
本发明提供一种式(I)所示化合物的D晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在9.922、11.176、15.797、16.230、18.691和19.404处有特征峰；优选在7.514、9.922、11.176、12.937、15.797、16.230、18.691、19.404、20.310和21.224处有特征峰；更优选在7.514、9.922、11.176、12.937、15.797、16.230、17.219、18.691、19.404、20.310、21.224、23.476、24.003和24.627处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
本发明提供一种式(I)所示化合物的E晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在6.889、9.043、13.463、15.828、16.891和18.650处有特征峰；优选在5.164、6.889、8.818、9.043、13.463、13.722、15.828、16.394、16.891、18.650和20.464处有特征峰；更优选在5.164、6.889、8.818、9.043、10.541、13.463、13.722、15.828、16.394、16.891、18.083、18.650、20.464、22.201、22.871和23.627处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
本发明提供一种式(I)所示化合物的可药用盐，其中，所述可药用盐选自盐酸盐、硫酸盐、磷酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐，
在一些实施方式中，所述式(I)所示化合物与酸分子或阴离子的化学配比为1:0.5～1:3，可以为1:0.5～1:2.5、1:0.5～1:2、1:0.5～1:1.5、1:0.5～1:1，优选为1:0.5、1:1、1:2或1:3，最优选为1:1或1:2。
本发明提供一种式(I)所示化合物的对甲苯磺酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在3.733、7.394、16.080和19.153处有特征峰；优选在3.733、7.394、11.052、14.739、15.496、16.080、19.153、22.059和28.088处有特征峰；更优选在3.733、7.394、9.755、11.052、11.438、12.185、12.726、13.220、14.739、15.496、16.080、17.180、18.240、19.153、22.059和28.088处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
本发明提供一种式(I)所示化合物的对甲苯磺酸盐的II晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在12.163、14.065、17.303、19.416、20.532和22.762处有特征峰；优选在3.780、7.640、10.191、10.897、12.163、12.781、14.065、16.237、17.303、19.416、20.532和22.762处有特征峰；更优选在3.780、7.640、10.191、10.897、12.163、12.781、14.065、15.837、16.237、16.954、17.303、19.000、19.416、20.532、20.906、21.961、22.286和22.762处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
本发明提供一种式(I)所示化合物的盐酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在8.761、9.480、10.635和17.422处有特征峰；优选在8.761、9.480、10.635、15.425、16.788、17.422和22.750处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图19所示。
本发明提供一种式(I)所示化合物的盐酸盐的II晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在6.985、11.691、14.025、16.680和17.536处有特征峰；优选在6.985、11.691、14.025、16.680、17.536、18.259、19.185、21.121、21.895和23.548处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图21所示。
本发明提供一种式(I)所示化合物的硫酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在3.326、6.485、12.875、13.879和19.273处有特征峰；优选在3.326、6.485、8.601、12.875、13.879、16.915、17.835、19.273、19.920和22.486处有特征峰；更优选在3.326、6.485、8.601、12.003、12.875、13.879、14.315、15.454、16.087、16.915、17.835、19.273、19.920、22.486、23.727和25.010处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图23所示。
本发明提供一种式(I)所示化合物的磷酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在3.436、6.784、16.868、18.478和20.264处有特征峰；优选在3.436、6.028、6.784、13.507、15.360、16.868、18.478、20.264、23.661和30.556处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图25所示。
本发明提供一种式(I)所示化合物的甲磺酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在7.945、8.540、12.203、13.820和20.863处有特征峰；优选在7.945、8.540、10.316、10.621、11.507、12.203、13.820、14.579、15.964和20.863处有特征峰；更优选在7.945、8.540、10.316、10.621、11.507、12.203、13.820、14.579、15.964、17.640、20.284、20.863、23.234、23.888和26.418处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图27所示。
本发明提供一种式(I)所示化合物的苯磺酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在5.268、6.306、13.796、15.768和18.673处有特征峰；优选在5.268、6.306、6.865、13.796、15.023、15.768、18.673、21.035、21.892和22.608处有特征峰；更优选在5.268、6.306、6.865、9.398、11.030、12.049、13.796、15.023、15.768、16.228、17.946、18.673、20.835、21.035、21.892和22.608处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图29所示。
发明的效果
本发明提供的式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、对甲苯磺酸盐、盐酸盐、硫酸盐、磷酸盐、甲磺酸盐、苯磺酸盐，以及对甲苯磺酸盐的I晶型、对甲 苯磺酸盐的II晶型、盐酸盐的I晶型、盐酸盐的II晶型、硫酸盐的I晶型、磷酸盐的I晶型、甲磺酸盐的I晶型、苯磺酸盐的I晶型，其在理化性质，制剂加工性能及生物利用度等方面具有优势，例如在熔点，溶解度，引湿性，提纯作用，稳定性，黏附性，可压性，流动性，体内外溶出度，生物有效性等方面中的至少一方面存在优势。本发明所述的游离碱晶型、盐型以及盐型的晶型自身物理、化学稳定性好，以相同起始物制备得到相应晶型的收率高，且在溶解度、引湿性、稳定性、机械稳定性、流动性、可压性、黏附性、药物代谢性等方面具有明显优势，为ATX抑制剂药物开发提供了新的更好的选择，具有非常重要的意义。
附图说明
图1为式(I)所示化合物的A晶型的XRPD谱图。
图2为式(I)所示化合物的A晶型的TGA&DSC叠加谱图。
图3为式(I)所示化合物的B晶型的XRPD谱图。
图4为式(I)所示化合物的B晶型的TGA&DSC叠加谱图。
图5为式(I)所示化合物的C晶型的XRPD谱图。
图6为式(I)所示化合物的C晶型的TGA&DSC叠加谱图。
图7为式(I)所示化合物的D晶型的XRPD谱图。
图8为式(I)所示化合物的D晶型的DSC谱图。
图9为式(I)所示化合物的E晶型的XRPD谱图。
图10为式(I)所示化合物的E晶型的TGA&DSC叠加谱图。
图11为式(I)所示化合物的对甲苯磺酸盐I晶型的XRPD谱图。
图12为式(I)所示化合物的对甲苯磺酸盐I晶型的TGA&DSC叠加谱图。
图13为式(I)所示化合物的对甲苯磺酸盐II晶型的XRPD谱图。
图14为式(I)所示化合物的对甲苯磺酸盐II晶型的TGA&DSC叠加谱图。
图15为式(I)所示化合物的对甲苯磺酸盐II晶型的DVS谱图。
图16为式(I)所示化合物的对甲苯磺酸盐II晶型的DVS测试前后XRPD叠图。
图17为式(I)所示化合物的B晶型湿磨所得固体的XRPD叠加谱图。
图18为式(I)所示化合物的B晶型压片所得固体的XRPD谱图。
图19为式(I)所示化合物的盐酸盐I晶型的XRPD谱图。
图20为式(I)所示化合物的盐酸盐I晶型的TGA&DSC叠加谱图。
图21为式(I)所示化合物的盐酸盐II晶型的XRPD谱图。
图22为式(I)所示化合物的盐酸盐II晶型的TGA&DSC叠加谱图。
图23为式(I)所示化合物的硫酸盐I晶型的XRPD谱图。
图24为式(I)所示化合物的硫酸盐I晶型的TGA&DSC叠加谱图。
图25为式(I)所示化合物的磷酸盐I晶型的XRPD谱图。
图26为式(I)所示化合物的磷酸盐I晶型的TGA&DSC叠加谱图。
图27为式(I)所示化合物的甲磺酸盐I晶型的XRPD谱图。
图28为式(I)所示化合物的甲磺酸盐I晶型的TGA&DSC叠加谱图。
图29为式(I)所示化合物的苯磺酸盐I晶型的XRPD谱图。
图30为式(I)所示化合物的苯磺酸盐I晶型的TGA&DSC叠加谱图。
具体实施方式
为使本发明的技术方案和有益效果能够更加明显易懂，下面通过列举具体实施例的方式进行详细说明。其中，附图不一定是按比例绘制的，局部特征可以被放大或缩小，以更加清楚的显示局部特征的细节；除非另有定义，本文所使用的技术和科学术语与本申请所属的技术领域中的技术和科学术语的含义相同。
本发明提供一种式(I)所示化合物的A晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在6.938、7.606、9.256、12.359和15.793处有特征峰；优选在6.938、7.606、9.256、9.912、11.482、12.359、15.793和16.368处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
本发明进一步提供一种式(I)所示化合物的A晶型的制备方法，包括步骤：将式(I)所示化合物与溶剂1混合，溶清，加入溶剂2，结晶析出。
在某些实施方式中，所述溶剂1选自醚类溶剂。
在某些实施方式中，所述溶剂1选自乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和1,4-二氧六环中的一种或多种。
在某些实施方式中，所述溶剂1选自1,4-二氧六环。
在某些实施方式中，所述溶剂2选自醇类溶剂。
在某些实施方式中，所述溶剂2选自C1-4醇。
在某些实施方式中，所述溶剂2选自甲醇、乙醇和异丙醇中的一种或多种。
在某些实施方式中，所述溶剂2选自异丙醇。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的B晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在7.593、11.516、13.092、16.526和19.247处有特征峰；优选在7.593、9.977、11.516、13.092、15.380、16.526、19.247、20.095、23.854、 26.355、27.639和29.809处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
本发明进一步提供一种式(I)所示化合物的B晶型的制备方法，包括步骤：将式(I)所示化合物与溶剂3混合，溶清，加入溶剂4，结晶析出。
在某些实施方式中，所述溶剂3选自醚类溶剂。
在某些实施方式中，所述溶剂3选自乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和1,4-二氧六环中的一种或多种。
在某些实施方式中，所述溶剂3选自1,4-二氧六环。
在某些实施方式中，所述溶剂4选自腈类溶剂，优选为乙腈、丙腈和戊腈中的一种或多种，更优选为乙腈。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的C晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在10.463、10.666、18.572、20.708、22.028和23.848处有特征峰；优选在10.463、10.666、13.970、14.482、15.220、15.519、17.747、18.572、20.708、22.028和23.848处有特征峰；更优选在10.463、10.666、12.408、13.970、14.482、15.220、15.519、17.747、18.572、20.708、21.384、22.028、22.851、23.848和25.788处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
本发明进一步提供一种式(I)所示化合物的C晶型的制备方法，包括步骤：将式(I)所示化合物与溶剂5混合，混悬，搅拌，过滤得滤饼。
在某些实施方式中，所述溶剂5选自醚类溶剂。
在某些实施方式中，所述溶剂5选自乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和甲基叔丁基醚中的一种或多种。
在某些实施方式中，所述溶剂5选自甲基叔丁基醚。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的D晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在9.922、11.176、15.797、16.230、18.691和19.404处有特征峰；优选在7.514、9.922、11.176、12.937、15.797、16.230、18.691、19.404、20.310和21.224处有特征峰；更优选在7.514、9.922、11.176、12.937、15.797、16.230、17.219、18.691、19.404、20.310、21.224、23.476、24.003和24.627处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
本发明进一步提供一种式(I)所示化合物的D晶型的制备方法，包括步骤：将式(I)所示化合物与溶剂6混合，密封，放置，过滤得滤饼。
在某些实施方式中，所述溶剂6选自醚类溶剂。
在某些实施方式中，所述溶剂6选自乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和1,4-二氧六环中的一种或多种。
在某些实施方式中，所述溶剂6选自1,4-二氧六环
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的E晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在6.889、9.043、13.463、15.828、16.891和18.650处有特征峰；优选在5.164、6.889、8.818、9.043、13.463、13.722、15.828、16.394、16.891、18.650和20.464处有特征峰；更优选在5.164、6.889、8.818、9.043、10.541、13.463、13.722、15.828、16.394、16.891、18.083、18.650、20.464、22.201、22.871和23.627处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
本发明进一步提供一种式(I)所示化合物的E晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂7混合，溶清，降温，结晶析出。
在某些实施方式中，所述溶剂7选自醚类溶剂。
在某些实施方式中，所述溶剂7选自乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和1,4-二氧六环中的一种或多种。
在某些实施方式中，所述溶剂7选自1,4-二氧六环。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的可药用盐，其中，所述可药用盐选自对甲苯磺酸盐、盐酸盐、硫酸盐、磷酸盐、甲磺酸盐、苯磺酸盐，
在某些实施方式中，所述式(I)所示化合物与酸分子或阴离子的化学配比为1:0.5～1:3，例如1:0.5～1:2.5、1:0.5～1:2、1:0.5～1:1.5或1:0.5～1:1，优选1:0.5、1:1、1:2或1:3，最优选为1:1或1:2。
在某些实施方式中，所述式(I)所示化合物与对甲苯磺酸的化学配比为1:0.5～1:3，例如1:0.5～1:2.5、1:0.5～1:2、1:0.5～1:1.5或1:0.5～1:1，优选1:0.5、1:1、1:2或1:3，最优选1:1或1:2。
在某些实施方式中，所述式(I)所示化合物与盐酸的化学配比为1:0.5～1:3，例如1:0.5～1:2.5、1:0.5～1:2、1:0.5～1:1.5或1:0.5～1:1，优选1:0.5、1:1、1:2或1:3，最优选1:1或1:2。
在某些实施方式中，所述式(I)所示化合物与硫酸的化学配比为1:0.5～1:3，例如1:0.5～1:2.5、1:0.5～1:2、1:0.5～1:1.5或1:0.5～1:1，优选1:0.5、1:1、1:2或1:3，最优选1:1或1:2。
在某些实施方式中，所述式(I)所示化合物与磷酸的化学配比为1:0.5～1:3，例如1:0.5～1:2.5、1:0.5～1:2、1:0.5～1:1.5或1:0.5～1:1，优选1:0.5、1:1、1:2或1:3，最优选1:1或1:2。
在某些实施方式中，所述式(I)所示化合物与甲磺酸的化学配比为1:0.5～1:3，例如1:0.5～1:2.5、1:0.5～1:2、1:0.5～1:1.5或1:0.5～1:1，优选1:0.5、1:1、1:2或1:3，最优选1:1或1:2。
在某些实施方式中，所述式(I)所示化合物与苯磺酸的化学配比为1:0.5～1:3，例如1:0.5～1:2.5、1:0.5～1:2、1:0.5～1:1.5或1:0.5～1:1，优选1:0.5、1:1、1:2或1:3，最优选1:1或1:2。
本发明进一步提供一种式(I)所示化合物的可药用盐的制备方法，包括步骤：式(I)所述化合物与酸进行成盐反应的步骤。
在某些实施方式中，所述成盐反应所用的溶剂选自醇、醚、酯、卤代烷烃、酮和水中的一种或多种。
在某些实施方式中，所述成盐反应所用的溶剂选自四氢呋喃、二氯甲烷、乙醇、乙酸乙酯、丙酮和水中的一种或多种。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的对甲苯磺酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在3.733、7.394、16.080和19.153处有特征峰；优选在3.733、7.394、11.052、14.739、15.496、16.080、19.153、22.059和28.088处有特 征峰；更优选在3.733、7.394、9.755、11.052、11.438、12.185、12.726、13.220、14.739、15.496、16.080、17.180、18.240、19.153、22.059和28.088处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
本发明进一步提供一种式(I)所示化合物的对甲苯磺酸盐的I晶型的制备方法，包括步骤：将式(I)所示化合物与溶剂8混合，将体系置于干冰中，加入一水对甲苯磺酸，室温搅拌，结晶析出。
在某些实施方式中，所述溶剂8选自酯类溶剂。
在某些实施方式中，所述溶剂8选自乙酸乙酯、乙酸甲酯、乙酸丁酯和乙酸异丁酯中的一种或多种。
在某些实施方式中，所述溶剂8选自乙酸乙酯。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的对甲苯磺酸盐的II晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在12.163、14.065、17.303、19.416、20.532和22.762处有特征峰；优选在3.780、7.640、10.191、10.897、12.163、12.781、14.065、16.237、17.303、19.416、20.532和22.762处有特征峰；更优选在3.780、7.640、10.191、10.897、12.163、12.781、14.065、15.837、16.237、16.954、17.303、19.000、19.416、20.532、20.906、21.961、22.286和22.762处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
本发明进一步提供一种式(I)所示化合物的对甲苯磺酸盐的II晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂9混合，将体系置于冰-乙醇中，加入一水对甲苯磺酸，搅拌过夜，结晶析出。
在某些实施方式中，所述溶剂9选自酯类溶剂。
在某些实施方式中，所述溶剂9选自乙酸乙酯、乙酸甲酯、乙酸丁酯和乙酸异丁酯中的一种或多种。
在某些实施方式中，所述溶剂9选自乙酸乙酯。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的盐酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在8.761、9.480、10.635和17.422处有特征峰；优选在8.761、9.480、10.635、15.425、16.788、17.422和22.750处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图19所示。
本发明进一步提供一种式(I)所示化合物的盐酸盐的I晶型的制备方法，包括步骤：将式(I)所示化合物与溶剂10混合，将体系置于干冰中，加入盐酸，室温搅拌，结晶析出，搅拌过夜，过滤。
在某些实施方式中，所述溶剂10选自醚类溶剂。
在某些实施方式中，所述溶剂10选自乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和四氢呋喃中的一种或多种。
在某些实施方式中，所述溶剂10选自四氢呋喃。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的盐酸盐的II晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在6.985、11.691、14.025、16.680和17.536处有特征峰；优选在6.985、11.691、14.025、16.680、17.536、18.259、19.185、21.121、21.895和23.548处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图21所示。
本发明进一步提供一种式(I)所示化合物的盐酸盐的II晶型的制备方法，包括步骤：将式(I)所示化合物与溶剂11混合，将体系置于干冰中，加入盐酸，室温搅拌，敞口挥发溶剂，析出固体后搅拌，过滤。
在某些实施方式中，所述溶剂11选自卤代烷烃类和醇类溶剂的混合溶剂。
在某些实施方式中，所述溶剂11为选自二氯甲烷、三氯甲烷、四氯化碳和1,2-二氯乙烷的卤代烷烃类和选自甲醇、乙醇和异丙醇的醇类溶剂的混合溶剂。
在某些实施方式中，所述溶剂11选自二氯甲烷和乙醇的混合溶剂。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的硫酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在3.326、6.485、12.875、13.879和19.273处有特征峰；优选在3.326、6.485、8.601、12.875、13.879、16.915、17.835、19.273、19.920和22.486处有特征峰；更优选在3.326、6.485、8.601、12.003、12.875、13.879、14.315、15.454、 16.087、16.915、17.835、19.273、19.920、22.486、23.727和25.010处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图23所示。
本发明进一步提供一种式(I)所示化合物的硫酸盐的I晶型的制备方法，包括步骤：将式(I)所示化合物与溶剂12混合，将体系置于干冰中，加入硫酸，室温搅拌，升温至50℃搅拌过夜，降至室温，过滤。
在某些实施方式中，所述溶剂12选自酮类溶剂。
在某些实施方式中，所述溶剂12选自丙酮、丁酮、戊酮、己酮和环己酮中的一种或多种。
在某些实施方式中，所述溶剂12选自丙酮。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的磷酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在3.436、6.784、16.868、18.478和20.264处有特征峰；优选在3.436、6.028、6.784、13.507、15.360、16.868、18.478、20.264、23.661和30.556处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图25所示。
本发明进一步提供一种式(I)所示化合物的磷酸盐的I晶型的制备方法，包括步骤：将式(I)所示化合物与溶剂13混合，将体系置于干冰中，加入磷酸，室温搅拌，升温至50℃搅拌，结晶析出，继续搅拌，降至室温搅拌过夜，过滤。
在某些实施方式中，所述溶剂13选自酯类溶剂。
在某些实施方式中，所述溶剂13选自乙酸乙酯、乙酸甲酯、乙酸丁酯和乙酸异丁酯中的一种或多种。
在某些实施方式中，所述溶剂13选自乙酸乙酯。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的甲磺酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在7.945、8.540、12.203、13.820和20.863处有特征峰；优选在7.945、8.540、10.316、10.621、11.507、12.203、13.820、14.579、15.964和20.863处有特征峰；更优选在7.945、8.540、10.316、10.621、11.507、12.203、13.820、14.579、15.964、17.640、20.284、20.863、23.234、23.888和26.418处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图27所示。
本发明进一步提供一种式(I)所示化合物的甲磺酸盐的I晶型的制备方法，包括步骤：将式(I)所示化合物与溶剂14混合，将体系置于干冰中，加入甲磺酸，室温搅拌，升温至50℃搅拌，降至室温敞口挥发搅拌，结晶析出，搅拌，过滤。
在某些实施方式中，所述溶剂14选自醚类溶剂。
在某些实施方式中，所述溶剂14选自乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和四氢呋喃中的一种或多种。
在某些实施方式中，所述溶剂14选自四氢呋喃。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种式(I)所示化合物的苯磺酸盐的I晶型，
以衍射角2θ角度表示的X-射线粉末衍射图，在5.268、6.306、13.796、15.768和18.673处有特征峰；优选在5.268、6.306、6.865、13.796、15.023、15.768、18.673、21.035、21.892和22.608处有特征峰；更优选在5.268、6.306、6.865、9.398、11.030、12.049、13.796、15.023、15.768、16.228、17.946、18.673、20.835、21.035、21.892和22.608处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图29所示。
本发明进一步提供一种式(I)所示化合物的苯磺酸盐的I晶型的制备方法，包括步骤：将式(I)所示化合物与溶剂15混合，将体系置于干冰中，加入苯磺酸，室温搅拌，升温至50℃搅拌，结晶析出，继续搅拌，降至室温搅拌过夜，过滤。
在某些实施方式中，所述溶剂15选自酯类溶剂。
在某些实施方式中，所述溶剂15选自乙酸乙酯、乙酸甲酯、乙酸丁酯和乙酸异丁酯中的一种或多种。
在某些实施方式中，所述溶剂15选自乙酸乙酯。
在某些实施方式中，本发明所述的制备方法还包括离心、洗涤或干燥等步骤。
本发明进一步提供一种由前述的式(I)所示化合物的A晶型或前述的式(I)所示化合物的B晶型或前述的式(I)所示化合物的C晶型或前述的式(I)所示化合物的D晶型或前述的式(I)所示化合物的E晶型或前述的式(I)所示化合物的可药用盐或前述的式(I)所示化合物的对甲苯磺酸盐的I晶型或前述的式(I)所示化合物的对甲苯磺酸盐的II晶型或前述的式(I)所示化合物的盐酸盐的I晶型或前述的式(I)所示化合物的盐酸盐的II晶型或前述的式(I)所示化合物的硫酸盐的I晶型或前述的式(I)所示化合物的磷酸盐的I晶型或前述的式(I)所示化合物的甲磺酸盐的I晶型或前述的式(I)所示化合物的苯磺酸盐的I晶型制备得到的药物组合物。
本发明进一步提供一种药物组合物，含有前述的式(I)所示化合物的A晶型或前述的式(I)所示化合物的B晶型或前述的式(I)所示化合物的C晶型或前述的式(I)所示化合物的D晶型或前述的式(I)所示化合物的E晶型或前述的式(I)所示化合物的可药用盐或前述的式(I)所示化合物的对甲苯磺酸盐的I晶型或前述的式(I)所示化合物的对甲苯磺酸盐的II晶型或前述的式(I)所示化合物的盐酸盐的I晶型或前述的式(I)所示化合物的盐酸盐的II晶型或前述的式(I)所示化合物的硫酸盐的I晶型或前述的式(I)所示化合物的磷酸盐 的I晶型或前述的式(I)所示化合物的甲磺酸盐的I晶型或前述的式(I)所示化合物的苯磺酸盐的I晶型和至少一种药学上可接受的赋形剂。
“药学上可接受的赋形剂”是指与给药剂型或药物组合物一致性相关的药学上可接受的材料、混合物或溶媒。合适的药学上可接受的赋形剂会依据所选剂型而不同。此外，可根据他们在组合物中的特定功能来选择药学上可接受的赋形剂。
在某些实施方式中，所述药学上可接受的赋形剂包括以下类型的赋形剂：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、矫味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、塑化剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。
在某些实施方式中，所述药物组合物为固体制剂。
在某些实施方式中，所述固体制剂为胶囊剂。
在某些实施方式中，所述胶囊剂中含有的式(I)所示化合物或其盐为25mg～200mg。
本发明进一步提供一种药物组合物的制备方法，包括将前述的式(I)所示化合物的A晶型或前述的式(I)所示化合物的B晶型或前述的式(I)所示化合物的C晶型或前述的式(I)所示化合物的D晶型或前述的式(I)所示化合物的E晶型或前述的式(I)所示化合物的可药用盐或前述的式(I)所示化合物的对甲苯磺酸盐的I晶型或前述的式(I)所示化合物的对甲苯磺酸盐的II晶型或前述的式(I)所示化合物的盐酸盐的I晶型或前述的式(I)所示化合物的盐酸盐的II晶型或前述的式(I)所示化合物的硫酸盐的I晶型或前述的式(I)所示化合物的磷酸盐的I晶型或前述的式(I)所示化合物的甲磺酸盐的I晶型或前述的式(I)所示化合物的苯磺酸盐的I晶型与至少一种药学上可接受的赋形剂混合的步骤。
本发明进一步提供一种前述的式(I)所示化合物的A晶型或前述的式(I)所示化合物的B晶型或前述的式(I)所示化合物的C晶型或前述的式(I)所示化合物的D晶型或前述的式(I)所示化合物的E晶型或前述的式(I)所示化合物的可药用盐或前述的式(I)所示化合物的对甲苯磺酸盐的I晶型或前述的式(I)所示化合物的对甲苯磺酸盐的II晶型或前述的式(I)所示化合物的盐酸盐的I晶型或前述的式(I)所示化合物的盐酸盐的II晶型或前述的式(I)所示化合物的硫酸盐的I晶型或前述的式(I)所示化合物的磷酸盐的I晶型或前述的式(I)所示化合物的甲磺酸盐的I晶型或前述的式(I)所示化合物的苯磺酸盐的I晶型，或前述药物组合物，或由前述方法制备得到的药物组合物在制备用于治疗和/或预防ATX(自分泌运动因子)相关的疾病的药物中的应用。
在某些实施方式中，所述ATX相关的疾病为纤维变性疾病、癌症、增殖性疾病、炎症性疾病、自身免疫性疾病、呼吸系统疾病、心血管疾病、神经变性疾病、皮肤学疾病、代谢疾病、骨髓增生异常综合症、异常血管生成相关疾病或疼痛。
在某些实施方式中，所述ATX相关的疾病为纤维变性疾病、癌症、皮肤学疾病。
在某些实施方式中，所述ATX相关的疾病为肺纤维化(例如特发性肺纤维化)、肝纤维化、硬皮病、肾癌、胰腺癌或胆汁淤积性瘙痒症。
本发明所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.2(包括超过1位小数的数字经过四舍五入后的情况)，可以为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
本发明所述的析出方式包括但不限于搅拌、降温、挥发、打浆、沉淀。
“打浆”是药物制备领域的常用名词，通常是指将固体药物原料进行机械化或流体化处理，使得固体药物分散或混悬于溶剂中。
在一些实施方式中，所述打浆的时间为5h-30h。
依据《中国药典》2015年版四部中“9103药物引湿性指导原则”中引湿性特征描述与引湿性增重的界定，
潮解：吸收足量水分形成液体；
极具引湿性：引湿增重不小于15％；
有引湿性：引湿增重小于15％但不小于2％；
略有引湿性：引湿增重小于2％但不小于0.2％；
无或几乎无引湿性：引湿增重小于0.2％。
本发明中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本发明中所述干燥温度一般为25℃～100℃，优选40℃～70℃，可以常压干燥，也可以减压干燥。
下面通过具体实施例对本发明的方法进行说明，应理解，这些实施例是用于说明本发明的基本原理、主要特征和优点，而本发明不受以下实施例的范围限制；实施例中采用的实施条件可以根据具体要求做进一步调整，未注明的实施条件通常为常规实验中的条件。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热
TGA：热重分析
DVS：动态水分吸附
HPLC：高效液相色谱
检测仪器及方法
X-射线粉末衍射(XRPD)
利用Bruker D8 ADVANCE X-粉末衍射仪(采用Cu-Kα辐射)对样品进行晶型分析。样品2θ扫描角度为3°～42°，扫描步长为0.02°，每步扫描时间为0.05s/步。光管电压和电流分别为40kV、40mA。制样时将适量样品放到载样盘上，用玻璃片等工具压平，确保其表面光滑平整。
热重分析(TGA)
采用TA Instruments TGA Discovery 550对样品进行分析。将样品放入去掉皮重的铝盘中，系统自动称重，然后在氮气的保护下将样品以10℃/min的速率升高到指定温度。
差示扫描量热分析(DSC)
采用TA Instruments Discovery DSC 25对样品进行分析。称量2～10mg样品放入载样盘中，在氮气(50ml/min)的保护下将样品以10℃/min的速率升高到指定温度。
动态水分吸附分析(DVS)
利用Intrinsic DVS(System Measurement System UK)对样品进行分析。测试样品量约为20～30mg。测试室的温度控制在25±1℃之间，相对湿度以10％/h的速率从0％升至90％再降至0％，每20s记录一次质量数据。
高效液相色谱(HPLC)
利用Agilent 1260 HPLC进行溶解度及稳定性测试。
本发明所述式(I)所示化合物可根据现有技术制备得到，例如根据WO2022007882A1文献记载的方法制备获得。
实施例1：式(I)所示化合物的A晶型的制备
称取约500mg式(I)所示化合物于100ml圆底烧瓶中，加入4ml 1,4-二氧六环使其溶解，然后快速加入反溶剂异丙醇36ml，在磁力作用下搅拌5小时后干冰降温，过滤，所得固体50℃烘干过夜得到产物。经X-射线粉末衍射检测，该产物为A晶型，XRPD谱图如图1所示，其特征峰位置如表1所示。DSC谱图显示，吸热峰峰值182.72℃。
表1：A晶型的XRPD衍射峰数据
实施例2：式(I)所示化合物的B晶型的制备
称取约500mg式(I)所示化合物于100ml圆底烧瓶中，加入4ml 1,4-二氧六环使其溶解，然后快速加入反溶剂乙腈36ml，在磁力作用下搅拌5小时后干冰降温，过滤，所得固体50℃烘干过夜得到产物。经X-射线粉末衍射检测，该产物为B晶型，XRPD谱图如图3所示，其特征峰位置如表2所示。DSC谱图显示，吸热峰峰值184.17℃。
表2：B晶型的XRPD衍射峰数据
实施例3：式(I)所示化合物的C晶型的制备
称取约500mg式(I)所示化合物于8ml玻璃瓶中，加入4ml甲基叔丁基醚，制成悬浮液，放在50℃下悬浮搅拌2天，所得固体50℃烘干过夜得到产物。经X-射线粉末衍射检测，该产物为C晶型，XRPD谱图如图5所示，其特征峰位置如表3所示。DSC谱图显示，吸热 峰峰值188.83℃。
表3：C晶型的XRPD衍射峰数据
实施例4：式(I)所示化合物的D晶型的制备
称取约100mg式(I)所示化合物于液相小瓶中，敞口置于装有30mL 1,4-二氧六环的大瓶中，大瓶封口密封，室温条件放置7天后取出固体。经X-射线粉末衍射检测，该产物为D晶型，XRPD谱图如图7所示，其特征峰位置如表4所示。DSC谱图显示，吸热峰峰值182.91℃。
表4：D晶型的XRPD衍射峰数据

实施例5：式(I)所示化合物的E晶型的制备
称取约200mg式(I)所示化合物于4ml玻璃瓶中，加入1.5ml 1,4-二氧六环使其溶解，置于冰水混合物中搅拌5h后过滤，所得固体50℃烘干过夜得到产物。经X-射线粉末衍射检测，该产物为E晶型，XRPD谱图如图9所示，其特征峰位置如表5所示。DSC谱图显示，吸热峰峰值98.11℃。
表5：E晶型的XRPD衍射峰数据
实施例6：式(I)所示化合物的对甲苯磺酸盐I晶型的制备
称量约50mg式(I)所示化合物于4mL小瓶中，加入2mL乙酸乙酯，溶液浑浊，将小 瓶转移至干冰中加入1.2eq的一水对甲苯磺酸，室温搅拌30min后，溶液澄清，但壁上附有粘性物质，继续搅拌2h后，析出白色固体，搅拌过夜后过滤烘干得到产物。经X-射线粉末衍射检测，该产物为式(I)所示化合物的对甲苯磺酸盐I晶型，XRPD谱图如图11所示，其特征峰位置如表6所示。DSC谱图显示，吸热峰峰值198.08℃。
表6：式(I)所示化合物的对甲苯磺酸盐I晶型的XRPD衍射峰数据
实施例7：式(I)所示化合物的对甲苯磺酸盐II晶型的制备
称量约4000mg式(I)所示化合物于200mL圆底烧瓶中，加入160mL乙酸乙酯，溶液浑浊，体系为白色。将圆底烧瓶转移至冰-乙醇中分多次加入1.2eq的一水对甲苯磺酸，体系有白色变为黄色。使其在冰-乙醇体系中搅拌，使温度自然升至室温，此过程中底部粘有黄色粘性物质，虽搅拌时间加长，黄色粘性物质逐渐消失，体系慢慢转变为白色。搅拌过夜后过滤，并用冰EA淋洗，然后50℃烘干过夜得到产物。经X-射线粉末衍射检测，该产物为式(I)所示化合物的对甲苯磺酸盐II晶型，XRPD谱图如图13所示，其特征峰位置如表7所示。DSC谱图显示，吸热峰峰值238.78℃。
表7：式(I)所示化合物的对甲苯磺酸盐II晶型的XRPD衍射峰数据

实施例8：式(I)所示化合物的盐酸盐I晶型的制备
称量约50mg式(I)所示化合物于4mL小瓶中，加入1mL四氢呋喃，溶液澄清，将小瓶转移至干冰中加入2.2eq的盐酸，室温搅拌2h后析出固体，搅拌过夜后过滤烘干得到产物。经X-射线粉末衍射检测，该产物为式(I)所示化合物的盐酸盐I晶型，XRPD谱图如图19所示，其特征峰位置如表8所示。DSC谱图显示，吸热峰峰值147.18℃、181.01℃。
表8：式(I)所示化合物的盐酸盐I晶型的XRPD衍射峰数据

实施例9：式(I)所示化合物的盐酸盐II晶型的制备
称量约50mg式(I)所示化合物于4mL小瓶中，加入1mL二氯甲烷:乙醇1:1，溶液澄清，将小瓶转移至干冰中加入2.2eq的盐酸，室温搅拌过夜后，敞口挥发搅拌，析出固体后约搅拌4h，过滤烘干得到产物。经X-射线粉末衍射检测，该产物为式(I)所示化合物的盐酸盐II晶型，XRPD谱图如图21所示，其特征峰位置如表9所示。DSC谱图显示，吸热峰峰值188.19℃、221.47℃。
表9：式(I)所示化合物的盐酸盐II晶型的XRPD衍射峰数据
实施例10：式(I)所示化合物的硫酸盐I晶型的制备
称量约25mg式(I)所示化合物于4mL小瓶中，加入1mL丙酮，将小瓶转移至干冰中加入1.2eq的硫酸，室温搅拌2h，升温至50度搅拌过夜，降温至室温，过滤烘干得到产物。经X-射线粉末衍射检测，该产物为式(I)所示化合物的硫酸盐I晶型，XRPD谱图如图23所示，其特征峰位置如表10所示。DSC谱图显示，吸热峰峰值197.63℃。
表10：式(I)所示化合物的硫酸盐I晶型的XRPD衍射峰数据

实施例11：式(I)所示化合物的磷酸盐I晶型的制备
称量约500mg式(I)所示化合物于50mL圆底烧瓶中，加入20mL乙酸乙酯，溶液浑浊，将小瓶转移至干冰中加入1.2eq的磷酸，室温搅拌1h后，转移至50℃下搅拌，约5min后溶液澄清，但底部有一团粘性固体，30min后析出白色固体，继续搅拌4h后，自然降至室温后搅拌过夜，过滤烘干得到产物。经X-射线粉末衍射检测，该产物为式(I)所示化合物的磷酸盐I晶型，XRPD谱图如图25所示，其特征峰位置如表11所示。DSC谱图显示，吸热峰峰值193.16℃。
表11：式(I)所示化合物的磷酸盐I晶型的XRPD衍射峰数据
实施例12：式(I)所示化合物的甲磺酸盐I晶型的制备
称量约50mg式(I)所示化合物于4mL小瓶中，加入1mL四氢呋喃，溶液浑澄清，将小瓶转移至干冰中加入2.2eq的甲磺酸，室温搅拌4h后，转移至50℃下搅拌，自然降至室温后敞口挥发搅拌，析出固体后搅拌4h，过滤烘干得到产物。经X-射线粉末衍射检测，该产物为式(I)所示化合物的甲磺酸盐I晶型，XRPD谱图如图27所示，其特征峰位置如表12所示。DSC谱图显示，吸热峰峰值132.42℃。
表12：式(I)所示化合物的甲磺酸盐I晶型的XRPD衍射峰数据

实施例13：式(I)所示化合物的苯磺酸盐I晶型的制备
称量约500mg式(I)所示化合物于50mL圆底烧瓶中，加入20mL乙酸乙酯，溶液浑浊，将小瓶转移至干冰中加入1.2eq的苯磺酸，室温搅拌30分钟后，溶液溶清。转移至50℃下搅拌，约20min后溶液澄清后析出白色固体，继续搅拌4h后，自然降至室温后搅拌过夜，过滤烘干得到产物。经X-射线粉末衍射检测，该产物为式(I)所示化合物的苯磺酸盐I晶型，XRPD谱图如图29所示，其特征峰位置如表13所示。DSC谱图显示，吸热峰峰值128.60℃。
表13：式(I)所示化合物的苯磺酸盐I晶型的XRPD衍射峰数据

实施例14：式(I)所示化合物的B和C晶型的稳定性
分别称取一定量的式(I)所示化合物的B晶型和C晶型于液相小瓶中，各制备9份。分别放入60℃、80℃、25℃，60％RH和40℃,75％RH以及光照稳定性箱中，测定60℃1周、2周稳定性，80℃一天，光照10天的稳定性以及25℃，60％RH和40℃,75％RH条件下2周和4周的稳定性，并且测定固体的晶型和纯度，结果如表14所示。
表14：式(I)所示化合物的B晶型和C晶型的稳定性试验结果

从稳定性试验结果可以看出，物理稳定性方面，B和C晶型在各种测试条件下晶型均没有发生改变。化学稳定性方面，B晶型除了在光照10天后，降解了0.51％，其他条件几乎无降解。稳定性实验过程中B晶型、C晶型在光照条件下样品颜色由类白色变为淡黄色，其他条件下的样品颜色无明显变化。
实施例15：式(I)所示化合物的A晶型、B晶型和C晶型的混悬竞争试验
称取适量活性药物成分(Active pharmaceutical ingredient，API),A晶型、B晶型和C晶型，置于1mL相应溶剂中，在25℃或50℃搅拌3天或7天，评估其晶型稳定性，结果如表15所示。
表15：A晶型、B晶型和C晶型的混悬竞争试验结果
通过晶型A、B、C混悬竞争打浆实验得出，在乙醇、乙腈和异丙醇中均转化成B晶型,在水和甲基叔丁基醚中大部分转化成B晶型。表明B晶型在25℃至50℃范围内比A和C晶型更稳定。
实施例16、式(I)所示化合物的B晶型研磨试验评价
取一定量的式(I)所示化合物的B晶型于研钵中，加入1～2滴溶剂(H2O或EtOH)，研磨5min后进行XRPD测试。如图17，所得固体均与B晶型一致，只是结晶度有所下降。
实施例17、式(I)所示化合物的B晶型压片试验评价
取一定量的式(I)所示化合物的B晶型进行压片实验。取适量B晶型粉末在10MPa压 力下压制三分钟后进行XRPD检测。如图18，所得固体与B晶型一致，只是结晶度有所下降。
实施例18、式(I)所示化合物的B晶型高聚物诱导试验评价
称取约10mg式(I)所示化合物的B晶型于1mL的溶剂中，加入约10％(质量比)的高聚物，室温下搅拌24h后过滤，所得固体进行XRPD测试，表16显示高聚物诱导所得固体均为B晶型，说明B晶型具有较好的物理稳定性。
表16：B晶型高聚物诱导实验条件及结果
实施例19：式(I)所示化合物的磷酸盐I晶型、苯磺酸盐I晶型和对甲苯磺酸盐II晶型的稳定性
将一定量的式(I)所示化合物的磷酸盐I晶型，苯磺酸盐I晶型和对甲苯磺酸盐II晶型样品放入稳定性试验箱中，一定时间后取出检测HPLC、XRPD。
测试条件：25℃/60％RH、40℃/75％RH-二周、四周；60℃-一周、二周；80℃-一天；光照-1.2M lux。结果如表17所示。
表17：磷酸盐I晶型、苯磺酸盐I晶型和对甲苯磺酸盐II晶型的稳定性试验结果

结果可以看出，磷酸盐I晶型、苯磺酸盐I晶型在光照-1.2M lux条件下分别降解了1.06％、3.11％，而对甲苯磺酸盐II晶型只降解了0.06％；苯磺酸盐在60℃-一周、二周，80℃-1天分别降解0.31％、0.34％、0.3％，磷酸盐I晶型和对甲苯磺酸盐II晶型无明显降解。在其他条件(25℃/60％RH、40℃/75％RH-二周、四周)下，磷酸盐I晶型、苯磺酸盐I晶型、对甲苯磺酸盐II晶型几乎无降解。磷酸盐I晶型、对甲苯磺酸盐II晶型在现有的测试条件(25℃/60％RH、40℃/75％RH-二周、四周；60℃-一周、二周；80℃-一天；光照-1.2M lux)下晶型均未改变，而苯磺酸盐I晶型在25℃/60％RH-二周、四周条件下结晶度有所下降，在其他条件晶型均发生改变。
实施例20：式(I)所示化合物的对甲苯磺酸盐II晶型的引湿性
通过25℃下0％RH～90％RH之间的动态水分吸附试验对对甲苯磺酸盐II晶型的引湿性进行了评估。DVS结果参见图15，对甲苯磺酸盐II晶型在湿度为80％时的吸湿增重为0.5731％，表明产物略有吸湿性。对甲苯磺酸盐II晶型在DVS测试前后晶型未发生改变。
实施例21：式(I)所示化合物的对甲苯磺酸盐II晶型的制剂工艺可行性研究
取一定量的对甲苯磺酸盐II晶型进行加热(225℃)、研磨(2min)、避光研磨及压片处理后测定其XRPD，晶型均未发生改变。
实施例22：式(I)所示化合物的游离碱B晶型和对甲苯磺酸盐II晶型的大鼠中口服药代动力学研究
在SD大鼠中，分别评价了游离碱B晶型和对甲苯磺酸盐II晶型经口灌胃(300mg/kg、1000mg/kg)后的药代动力学(PK)。溶媒为：15％vitamin E TPGS+10％Transcutol HP+45％PEG 400+30％Water。采血点：给药前，给药后30min，1h，2h，4h，6h，8h，12h，24h，32和48h。在大鼠血浆中药代动力学参数如表18和表19所示。
表18：式(I)所示化合物的游离碱B晶型的大鼠口服药代动力学研究结果

表19：式(I)所示化合物的对甲苯磺酸盐II晶型的大鼠口服药代动力学研究结果
应当理解，以上实施例均为示例性的，不用于包含权利要求所包含的所有可能的实施方式。在不脱离本发明的范围的情况下，还可以在以上实施例的基础上做出各种变形和改变。同样的，也可以对以上实施例的各个技术特征进行任意组合，以形成可能没有被明确描述的本发明的另外的实施例。因此，上述实施例仅表达了本发明的几种实施方式，不对本发明专利的保护范围进行限制。

Claims (37)

  1. 式(I)所示化合物的A晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在6.938、7.606、9.256、12.359和15.793处有特征峰；优选在6.938、7.606、9.256、9.912、11.482、12.359、15.793和16.368处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
  2. 式(I)所示化合物的B晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在7.593、11.516、13.092、16.526和19.247处有特征峰；优选在7.593、9.977、11.516、13.092、15.380、16.526、19.247、20.095、23.854、26.355、27.639和29.809处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
  3. 式(I)所示化合物的C晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在10.463、10.666、18.572、20.708、22.028和23.848处有特征峰；优选在10.463、10.666、13.970、14.482、15.220、15.519、17.747、18.572、20.708、22.028和23.848处有特征峰；更优选在10.463、10.666、12.408、13.970、14.482、15.220、15.519、17.747、18.572、20.708、21.384、22.028、22.851、23.848和25.788处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
  4. 式(I)所示化合物的D晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在9.922、11.176、15.797、16.230、18.691和19.404处有特征峰；优选在7.514、9.922、11.176、12.937、15.797、16.230、18.691、19.404、20.310和21.224处有特征峰；更优选在7.514、9.922、11.176、12.937、15.797、16.230、17.219、18.691、19.404、20.310、21.224、23.476、24.003和24.627处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
  5. 式(I)所示化合物的E晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在6.889、9.043、13.463、15.828、16.891和18.650处有特征峰；优选在5.164、6.889、8.818、9.043、13.463、13.722、15.828、16.394、16.891、18.650和20.464处有特征峰；更优选在5.164、6.889、8.818、9.043、10.541、13.463、13.722、15.828、16.394、16.891、18.083、18.650、20.464、22.201、22.871和23.627处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
  6. 式(I)所示化合物的可药用盐，其特征在于，所述可药用盐选自盐酸盐、硫酸盐、磷酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐，
  7. 根据权利要求6所述的可药用盐，其特征在于，所述式(I)所示化合物与酸分子或阴离子的化学配比为1:0.5～1:3，优选1:0.5、1:1、1:2或1:3，最优选1:1或1:2。
  8. 根据权利要求6或7所述的可药用盐，其特征在于，所述可药用盐为对甲苯磺酸盐。
  9. 式(I)所示化合物的对甲苯磺酸盐的I晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在3.733、7.394、16.080和19.153处有特征峰；优选在3.733、7.394、11.052、14.739、15.496、16.080、19.153、22.059和28.088处有特征峰；更优选在3.733、7.394、9.755、11.052、11.438、12.185、12.726、13.220、14.739、15.496、16.080、17.180、18.240、19.153、22.059和28.088处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
  10. 式(I)所示化合物的对甲苯磺酸盐的II晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在12.163、14.065、17.303、19.416、20.532和22.762处有特征峰；优选在3.780、7.640、10.191、10.897、12.163、12.781、14.065、16.237、17.303、19.416、20.532和22.762处有特征峰；更优选在3.780、7.640、10.191、10.897、12.163、12.781、14.065、15.837、16.237、16.954、17.303、19.000、19.416、20.532、20.906、21.961、22.286和22.762处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
  11. 式(I)所示化合物的盐酸盐的I晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在8.761、9.480、10.635和17.422处有特征峰；优选在8.761、9.480、10.635、15.425、16.788、17.422和22.750处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图19所示。
  12. 式(I)所示化合物的盐酸盐的II晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在6.985、11.691、14.025、16.680和17.536处有特征峰；优选在6.985、11.691、14.025、16.680、17.536、18.259、19.185、21.121、21.895和23.548处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图21所示。
  13. 式(I)所示化合物的硫酸盐的I晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在3.326、6.485、12.875、13.879和19.273处有特征峰；优选在3.326、6.485、8.601、12.875、13.879、16.915、17.835、19.273、19.920和22.486处有特征峰；更优选在3.326、6.485、8.601、12.003、12.875、13.879、14.315、15.454、16.087、16.915、17.835、19.273、19.920、22.486、23.727和25.010处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图23所示。
  14. 式(I)所示化合物的磷酸盐的I晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在3.436、6.784、16.868、18.478和20.264处有特征峰；优选在3.436、6.028、6.784、13.507、15.360、16.868、18.478、20.264、23.661和30.556处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图25所示。
  15. 式(I)所示化合物的甲磺酸盐的I晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在7.945、8.540、12.203、13.820和20.863处有特征峰；优选在7.945、8.540、10.316、10.621、11.507、12.203、13.820、14.579、15.964和20.863处有特征峰；更优选在7.945、8.540、10.316、10.621、11.507、12.203、13.820、14.579、15.964、17.640、20.284、20.863、23.234、23.888和26.418处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图27所示。
  16. 式(I)所示化合物的苯磺酸盐的I晶型，
    其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在5.268、6.306、13.796、15.768和18.673处有特征峰；优选在5.268、6.306、6.865、13.796、15.023、15.768、18.673、21.035、21.892和22.608处有特征峰；更优选在5.268、6.306、6.865、9.398、11.030、12.049、13.796、15.023、15.768、16.228、17.946、18.673、20.835、21.035、21.892和22.608处有特征峰；最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图29所示。
  17. 根据权利要求1-5和9-16中任意一项所述的晶型，其特征在于，所述2θ角误差范围为±0.20。
  18. 权利要求1所述的式(I)所示化合物的A晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂1混合，溶清，加入溶剂2，结晶析出；
    优选地，所述溶剂1选自醚类溶剂，优选为乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和1,4-二氧六环中的一种或多种，更优选为1,4-二氧六环；
    优选地，所述溶剂2选自醇类溶剂，优选为C1-4醇，更优选为甲醇、乙醇和异丙醇中的一种或多种，最优选为异丙醇。
  19. 权利要求2所述的式(I)所示化合物的B晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂3混合，溶清，加入溶剂4，结晶析出；
    优选地，所述溶剂3选自醚类溶剂，优选为乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和1,4-二氧六环中的一种或多种，更优选为1,4-二氧六环；
    优选地，所述溶剂4选自腈类溶剂，优选为乙腈、丙腈和戊腈中的一种或多种，更优选为乙腈。
  20. 权利要求3所述的式(I)所示化合物的C晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂5混合，混悬，搅拌，过滤得滤饼；
    优选地，所述溶剂5选自醚类溶剂，优选为乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和甲基叔丁基醚中的一种或多种，更优选为甲基叔丁基醚。
  21. 权利要求4所述的式(I)所示化合物的D晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂6混合，密封，放置，过滤得滤饼；
    优选地，所述溶剂6选自醚类溶剂，优选为乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和1,4-二氧六环中的一种或多种，更优选为1,4-二氧六环。
  22. 权利要求5所述的式(I)所示化合物的E晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂7混合，溶清，降温至室温，结晶析出；
    优选地，所述溶剂7选自醚类溶剂，优选为乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和1,4-二氧六环中的一种或多种，更优选为1,4-二氧六环。
  23. 权利要求6-8中任意一项所述的可药用盐的制备方法，其特征在于，包括步骤：式(I)所述化合物与酸进行成盐反应的步骤。
  24. 根据权利要求23所述的方法，其特征在于，所述成盐反应所用的溶剂选自醇、醚、酯、卤代烷烃、酮和水中的一种或多种，优选为四氢呋喃、二氯甲烷、乙醇、乙酸乙酯、丙酮和水中的一种或多种。
  25. 权利要求9所述的式(I)所示化合物的对甲苯磺酸盐的I晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂8混合，将体系置于干冰中，加入一水对甲苯磺酸，室温搅拌，结晶析出；
    优选地，所述溶剂8选自酯类溶剂，优选为乙酸乙酯、乙酸甲酯、乙酸丁酯和乙酸异丁酯中的一种或多种，更优选为乙酸乙酯。
  26. 权利要求10所述的式(I)所示化合物的对甲苯磺酸盐的II晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂9混合，将体系置于冰-乙醇中，加入一水对甲苯磺酸，搅拌过夜，结晶析出；
    优选地，所述溶剂9选自酯类溶剂，优选为乙酸乙酯、乙酸甲酯、乙酸丁酯和乙酸异丁酯中的一种或多种，更优选为乙酸乙酯。
  27. 权利要求11所述的式(I)所示化合物的盐酸盐的I晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂10混合，将体系置于干冰中，加入盐酸，室温搅拌，结晶析出，搅拌过夜，过滤；
    优选地，所述溶剂10选自醚类溶剂，优选为乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和四氢呋喃中的一种或多种，更优选为四氢呋喃。
  28. 权利要求12所述的式(I)所示化合物的盐酸盐的II晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂11混合，将体系置于干冰中，加入盐酸，室温搅拌，敞口挥发溶剂，析出固体后搅拌，过滤；
    优选地，所述溶剂11选自卤代烷烃类和醇类溶剂的混合溶剂，优选为选自二氯甲烷、三氯甲烷、四氯化碳和1,2-二氯乙烷的卤代烷烃类和选自甲醇、乙醇和异丙醇的醇类溶剂的混合溶剂，更优选为二氯甲烷和乙醇的混合溶剂。
  29. 权利要求13所述的式(I)所示化合物的硫酸盐的I晶型的制备方法，其特征在于， 包括步骤：将式(I)所示化合物与溶剂12混合，将体系置于干冰中，加入硫酸，室温搅拌，升温至50℃搅拌过夜，降至室温，过滤；
    优选地，所述溶剂12选自酮类溶剂，优选为丙酮、丁酮、戊酮、己酮和环己酮中的一种或多种，更优选为丙酮。
  30. 权利要求14所述的式(I)所示化合物的磷酸盐的I晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂13混合，将体系置于干冰中，加入磷酸，室温搅拌，升温至50℃搅拌，结晶析出，继续搅拌，降至室温搅拌过夜，过滤；
    优选地，所述溶剂13选自酯类溶剂，优选为乙酸乙酯、乙酸甲酯、乙酸丁酯和乙酸异丁酯中的一种或多种，更优选为乙酸乙酯。
  31. 权利要求15所述的式(I)所示化合物的甲磺酸盐的I晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂14混合，将体系置于干冰中，加入甲磺酸，室温搅拌，升温至50℃搅拌，降至室温敞口挥发搅拌，结晶析出，搅拌，过滤；
    优选地，所述溶剂14选自醚类溶剂，优选为乙醚、丙醚、丁醚、苯甲醚、石油醚、异丙醚和四氢呋喃中的一种或多种，更优选为四氢呋喃。
  32. 权利要求16所述的式(I)所示化合物的苯磺酸盐的I晶型的制备方法，其特征在于，包括步骤：将式(I)所示化合物与溶剂15混合，将体系置于干冰中，加入苯磺酸，室温搅拌，升温至50℃搅拌，结晶析出，继续搅拌，降至室温搅拌过夜，过滤；
    优选地，所述溶剂15选自酯类溶剂，优选为乙酸乙酯、乙酸甲酯、乙酸丁酯和乙酸异丁酯中的一种或多种，更优选为乙酸乙酯。
  33. 一种由根据权利要求1所述的式(I)所示化合物的A晶型或权利要求2所述的式(I)所示化合物的B晶型或权利要求3所述的式(I)所示化合物的C晶型或权利要求4所述的式(I)所示化合物的D晶型或权利要求5所述的式(I)所示化合物的E晶型或权利要求6-8中的任一项所述的式(I)所示化合物的可药用盐或权利要求9所述的式(I)所示化合物的对甲苯磺酸盐的I晶型或权利要求10所述的式(I)所示化合物的对甲苯磺酸盐的II晶型或权利要求11所述的式(I)所示化合物的盐酸盐的I晶型或权利要求12所述的式(I)所示化合物的盐酸盐的II晶型或权利要求13所述的式(I)所示化合物的硫酸盐的I晶型或权利要求14所述的式(I)所示化合物的磷酸盐的I晶型或权利要求15所述的式(I)所示化合物的甲磺酸盐的I晶型或权利要求16所述的式(I)所示化合物的苯磺酸盐的I晶型制备得到的药物组合物。
  34. 一种药物组合物，含有根据权利要求1所述的式(I)所示化合物的A晶型或权利要求2所述的式(I)所示化合物的B晶型或权利要求3所述的式(I)所示化合物的C晶型或权利要求4所述的式(I)所示化合物的D晶型或权利要求5所述的式(I)所示化合物的E晶型或权利要求6-8中的任一项所述的式(I)所示化合物的可药用盐或权利要求9所述的式(I)所示化合物的对甲苯磺酸盐的I晶型或权利要求10所述的式(I)所示化合物的对甲苯磺酸盐的II晶型或权利要求11所述的式(I)所示化合物的盐酸盐的I晶型或权利要求12所述的式(I)所示化合物的盐酸盐的II晶型或权利要求13所述的式(I)所示化合物的硫酸盐的I晶型或权利要求14所述的式(I)所示化合物的磷酸盐的I晶型或权利要求15所述的式(I)所示化合物的甲磺酸盐的I晶型或权利要求16所述的式(I)所示化合物的苯磺酸盐的I晶型和至少一种药学上可接受的赋形剂。
  35. 一种药物组合物的制备方法，包括将根据权利要求1所述的式(I)所示化合物的A晶型或权利要求2所述的式(I)所示化合物的B晶型或权利要求3所述的式(I)所示化合物的C晶型或权利要求4所述的式(I)所示化合物的D晶型或权利要求5所述的式(I)所示化合物的E晶型或权利要求6-8中的任一项所述的式(I)所示化合物的可药用盐或权利要求9所述的式(I)所示化合物的对甲苯磺酸盐的I晶型或权利要求10所述的式(I)所示化合物的对甲苯磺酸盐的II晶型或权利要求11所述的式(I)所示化合物的盐酸盐的I晶型或权利要求12所述的式(I)所示化合物的盐酸盐的II晶型或权利要求13所述的式(I)所示化合物的硫酸盐的I晶型或权利要求14所述的式(I)所示化合物的磷酸盐的I晶型或权利要求15所述的式(I)所示化合物的甲磺酸盐的I晶型或权利要求16所述的式(I)所示化合物的苯磺酸盐的I晶型与至少一种药学上可接受的赋形剂混合的步骤。
  36. 权利要求1所述的式(I)所示化合物的A晶型或权利要求2所述的式(I)所示化合物的B晶型或权利要求3所述的式(I)所示化合物的C晶型或权利要求4所述的式(I)所示化合物的D晶型或权利要求5所述的式(I)所示化合物的E晶型或权利要求6-8中的任一项所述的式(I)所示化合物的可药用盐或权利要求9所述的式(I)所示化合物的对甲苯磺酸盐的I晶型或权利要求10所述的式(I)所示化合物的对甲苯磺酸盐的II晶型或权利要求11所述的式(I)所示化合物的盐酸盐的I晶型或权利要求12所述的式(I)所示化合物的盐酸盐的II晶型或权利要求13所述的式(I)所示化合物的硫酸盐的I晶型或权利要求14所述的式(I)所示化合物的磷酸盐的I晶型或权利要求15所述的式(I)所示化合物的甲磺酸盐的I晶型或权利要求16所述的式(I)所示化合物的苯磺酸盐的I晶型，或权利要求33或34所述的药物组合物，或由根据权利要求35所述的方法制备得到的药物组合物在制备用于治疗和/或预防ATX(自分泌运动因子)相关的疾病的药物中的应用。
  37. 根据权利要求36所述的应用，所述ATX相关的疾病为纤维变性疾病、癌症、增殖性疾病、炎症性疾病、自身免疫性疾病、呼吸系统疾病、心血管疾病、神经变性疾病、皮肤学疾病、代谢疾病、骨髓增生异常综合症、异常血管生成相关疾病或疼痛，优选为纤维变性疾病、癌症、皮肤学疾病，优选为肺纤维化(例如特发性肺纤维化)、肝纤维化、硬皮病、肾癌、胰腺癌或胆汁淤积性瘙痒症。
PCT/CN2023/084963 2022-03-31 2023-03-30 一种atx抑制剂或其盐的结晶形式及其制备方法与应用 WO2023185979A1 (zh)

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Citations (3)

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US20190194199A1 (en) * 2017-06-02 2019-06-27 Wuxi Shuangliang Biotechnology Co., Ltd. Pharmaceutically Acceptable Salt of EGFR Inhibitor, Crystal Form Thereof, Preparation Method Therefor and Application Thereof
WO2019228403A1 (en) * 2018-05-29 2019-12-05 Fronthera U.S. Pharmaceuticals Llc Autotaxin inhibitors and uses thereof
WO2022007882A1 (zh) * 2020-07-09 2022-01-13 苏州爱科百发生物医药技术有限公司 一种atx抑制剂及其制备方法和应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190194199A1 (en) * 2017-06-02 2019-06-27 Wuxi Shuangliang Biotechnology Co., Ltd. Pharmaceutically Acceptable Salt of EGFR Inhibitor, Crystal Form Thereof, Preparation Method Therefor and Application Thereof
WO2019228403A1 (en) * 2018-05-29 2019-12-05 Fronthera U.S. Pharmaceuticals Llc Autotaxin inhibitors and uses thereof
WO2022007882A1 (zh) * 2020-07-09 2022-01-13 苏州爱科百发生物医药技术有限公司 一种atx抑制剂及其制备方法和应用

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