Salt and crystal form of protein arginine methyltransferase inhibitor, and pharmaceutical use thereof

Abstract

Provided in the present invention are a crystal form of L-malate of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpent-4-en-2-amine (a compound of formula (I)) and a preparation method therefor, and the use thereof in a pharmaceutical composition and in medicine.

Description

A salt, a crystal form of a protein arginine methyltransferase inhibitor and its medical use TECHNICAL FIELD

[0001] The present application relates to a salt form, a crystal form of a compound and its preparation method and application, in particular to a L-malate salt of a protein arginine methyltransferase inhibitor compound, a crystal form thereof and its preparation method and application, and belongs to the field of medicinal chemistry. BACKGROUND

[0002] Adaptor protein-associated kinase 1 (AAK1) is a member of the Ark1 / Prk1 family of serine / threonine kinases. AAK1 mRNA exists in two splice forms, referred to as short and long forms. The long form predominates and is highly expressed in brain and heart. AAK1 is enriched in synaptosomal preparations and colocalizes with endocytic structures in cultured cells. AAK1 regulates clatherin-coated endocytosis, an important process in synaptic vesicle recycling and receptor-mediated endocytosis. AAK1 binds to the AP2 complex, a heterotetramer that links receptor cargo to clatherin coats. Binding of clatherin to AAK1 stimulates AAK1 kinase activity. AAK1 phosphorylates the mu-2 subunit of AP-2, which promotes the binding of mu-2 to tyrosine-containing sorting motifs on cargo receptors. Mu2 phosphorylation is not essential for receptor uptake, but phosphorylation increases the efficiency of internalization.

[0003] AAK1 has been identified as an inhibitor of neuregulin-1 / ErbB4 signaling in PC12 cells. Loss of AAK1 expression via RNA interference-mediated gene silencing or treatment with the kinase inhibitor K252a, which inhibits AAK1 kinase activity, resulted in an enhancement of neuregulin-1-induced neurite outgrowth. These treatments resulted in increased expression of ErbB4 and increased accumulation of ErbB4 in or near the plasma membrane. NRGl and ErbB4 are putative schizophrenia susceptibility genes. SNPs in both genes are associated with multiple schizophrenia endophenotypes. Neuregulin 1 and ErbB4 KO mouse models have shown schizophrenia-related morphological changes and behavioral phenotypes. In addition, a single nucleotide polymorphism in an intron of the AAK1 gene is associated with age of onset of Parkinson’s disease. These results suggest that inhibition of AAK1 activity can be useful in the treatment of schizophrenia, cognitive deficit in schizophrenia, Parkinson’s disease, neuropathic pain, bipolar disorder, and Alzheimer’s disease.

[0004] An AAK1 inhibitor and its use are disclosed in WO2023284838A1, wherein the following compound of formula (I) is involved:

[0005] When used as a therapeutic agent for treating humans, the administration of a therapeutically effective dose is a problem and can result in toxic side effects or ineffective treatment. Therefore, it is important to select a salt, a crystalline form, which is stable, reproducible, and has physicochemical properties that are advantageous for its use as a therapeutic agent. SUMMARY

[0006] The present application provides a pharmaceutically acceptable L-malate salt of a compound of formula (I):

[0007] The present application also provides a crystalline form of the L-malate salt of the compound of formula (I).

[0008] The present application provides a crystalline form 1 of the L-malate salt of the compound of formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ positions using Cu-Ka radiation: 4.96°±0.2°, 19.71°±0.2°, 21.73°±0.2°, 22.65°±0.2°, 26.25°±0.2°.

[0009] In some embodiments, Form 1 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially as shown in FIG. 1 using Cu-Ka radiation;

[0010] In some embodiments, Form 1 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially as shown in FIG. 1 using Cu-Ka radiation;

[0011] In some embodiments, Form 1 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially as shown in FIG. 1 using Cu-Ka radiation;

[0012] In some embodiments, Form 1 of the L-malate salt of the compound of Formula (I) as described above has a thermogravimetric analysis profile, a differential scanning calorimetry profile and an isothermic adsorption profile substantially as shown in FIG. 2, FIG. 3 and FIG. 4, respectively.

[0013] Form 2 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially as shown in FIG. 5 using Cu-Ka radiation;

[0014] In some embodiments, Form 2 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially as shown in FIG. 5 using Cu-Ka radiation;

[0015] In some embodiments, Form 2 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially as shown in FIG. 5 using Cu-Ka radiation;

[0016] In some embodiments, Form 2 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially as shown in FIG. 5 using Cu-Ka radiation;

[0017] In some embodiments, Form 2 of the L-malate salt of the compound of Formula (I) as described above has a thermogravimetric analysis profile, a differential scanning calorimetry profile and an isothermic adsorption profile substantially as shown in FIG. 6, FIG. 7 and FIG. 8, respectively.

[0018] The present application provides Form 3 of the L-malate salt of the compound of Formula (I), which has an X-ray powder diffraction pattern substantially as shown in FIG. 9 using Cu-Ka radiation;

[0019] In some embodiments, Form 3 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially as shown in FIG. 9 using Cu-Ka radiation;

[0020] In some embodiments, Form 3 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially as shown in FIG. 9 using Cu-Ka radiation;

[0021] In some embodiments, Form 3 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially as shown in FIG. 9 using Cu-Ka radiation;

[0022] In some embodiments, Form 3 of the L-malate salt of the compound of Formula (I) as described above has a thermogravimetric analysis profile and a differential scanning calorimetry profile substantially as shown in FIGS. 10 and 11, respectively.

[0023] The present application provides Form 4 of the L-malate salt of the compound of Formula (I), which has an X-ray powder diffraction pattern substantially as shown in FIG. 12 using Cu-Ka radiation;

[0024] In some embodiments, Form 4 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially as shown in FIG. 12 using Cu-Ka radiation;

[0025] In some embodiments, Form 4 of the L-malate salt of the compound of Formula (I) as set forth above, has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ positions: 8.93°±0.2°, 10.76°±0.2°, 11.44°±0.2°, 12.47°±0.2°, 15.94°±0.2°, 18.85°±0.2°, 20.74°±0.2°, 21.20°±0.2°, 22.13°±0.2°, 22.91°±0.2°, 23.88°±0.2°, 24.28°±0.2°, 25.10°±0.2°, 25.80°±0.2°;

[0026] In some embodiments, Form 4 of the L-malate salt of the compound of Formula (I) as set forth above, has an X-ray powder diffraction pattern substantially as shown in FIG. 12 using Cu-Ka radiation;

[0027] In some embodiments, Form 4 of the L-malate salt of the compound of Formula (I) as set forth above, has a thermogravimetric analysis profile, a differential scanning calorimetry profile and an isothermic adsorption profile substantially as shown in FIG. 13, FIG. 14, FIG. 15, respectively.

[0028] The present application provides Form 5 of the L-malate salt of the compound of Formula (I), which has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ positions: 6.03°±0.2°, 6.24°±0.2°, 18.03°±0.2°, 18.57°±0.2°, 24.95°±0.2°;

[0029] In some embodiments, Form 5 of the L-malate salt of the compound of Formula (I) as set forth above, has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ positions: 6.03°±0.2°, 6.24°±0.2°, 9.28°±0.2°, 18.03°±0.2°, 18.57°±0.2°, 20.57°±0.2°, 21.50°±0.2°, 24.95°±0.2°;

[0030] In some embodiments, Form 5 of the L-malate salt of the compound of Formula (I) as set forth above has an X-ray powder diffraction pattern substantially as set forth in FIG. 16 using Cu-Ka radiation;

[0031] In some embodiments, Form 5 of the L-malate salt of the compound of Formula (I) as set forth above has an X-ray powder diffraction pattern substantially as set forth in FIG. 16 using Cu-Ka radiation;

[0032] The present application provides Form 6 of the L-malate salt of the compound of Formula (I) having an X-ray powder diffraction pattern substantially as set forth in FIG. 17 using Cu-Ka radiation;

[0033] In some embodiments, Form 6 of the L-malate salt of the compound of Formula (I) as set forth above has an X-ray powder diffraction pattern substantially as set forth in FIG. 17 using Cu-Ka radiation;

[0034] In some embodiments, Form 6 of the L-malate salt of the compound of Formula (I) as set forth above has an X-ray powder diffraction pattern substantially as set forth in FIG. 17 using Cu-Ka radiation;

[0035] In some embodiments, Form 6 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 17 using Cu-Ka radiation;

[0036] In some embodiments, Form 6 of the L-malate salt of the compound of Formula (I) as described above has a thermogravimetric analysis profile, a differential scanning calorimetry profile and an isothermic adsorption profile substantially as shown in FIG. 18, FIG. 19, FIG. 20, respectively.

[0037] The present application provides Form 7 of the L-malate salt of the compound of Formula (I), which has an X-ray powder diffraction pattern with characteristic peaks at the following 2-theta positions: 11.78°±0.2°, 19.34°±0.2°, 21.30°±0.2°, 23.33°±0.2°, 24.31°±0.2° using Cu-Ka radiation;

[0038] In some embodiments, Form 7 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern with characteristic peaks at the following 2-theta positions: 11.78°±0.2°, 12.72°±0.2°, 18.00°±0.2°, 18.21°±0.2°, 19.34°±0.2°, 21.30°±0.2°, 23.33°±0.2°, 24.31°±0.2° using Cu-Ka radiation;

[0039] In some embodiments, Form 7 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern with characteristic peaks at the following 2-theta positions: 11.78°±0.2°, 12.72°±0.2°, 13.79°±0.2°, 16.39°±0.2°, 17.18°±0.2°, 18.00°±0.2°, 18.21°±0.2°, 19.34°±0.2°, 21.30°±0.2°, 21.53°±0.2°, 22.51°±0.2°, 23.33°±0.2°, 24.31°±0.2°, 25.43°±0.2°, 26.05°±0.2° using Cu-Ka radiation;

[0040] In some embodiments, Form 7 of the L-malate salt of the compound of Formula (I) as described above has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 21 using Cu-Ka radiation;

[0041] In some embodiments, Form 7 of the L-malate salt of the compound of Formula (I) as described above has a thermogravimetric analysis profile, a differential scanning calorimetry profile and an isothermic adsorption profile substantially as shown in FIG. 22, FIG. 23, FIG. 24, respectively.

[0042] The present application provides Form 8 of L-malate salt of the compound shown in formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 6.26°±0.2°, 11.58°±0.2°, 16.12°±0.2°, 18.61°±0.2°, 25.01°±0.2°;

[0043] In some embodiments, the aforementioned Form 8 of L-malate salt of the compound shown in formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 4.55°±0.2°, 6.26°±0.2°, 11.58°±0.2°, 16.12°±0.2°, 16.43°±0.2°, 18.61°±0.2°, 19.12°±0.2°, 25.01°±0.2°;

[0044] In some embodiments, the aforementioned Form 8 of L-malate salt of the compound shown in formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 4.55°±0.2°, 6.26°±0.2°, 9.32°±0.2°, 11.58°±0.2°, 12.47°±0.2°, 13.52°±0.2°, 16.12°±0.2°, 16.43°±0.2°, 18.06°±0.2°, 18.61°±0.2°, 19.12°±0.2°, 20.59°±0.2°, 21.52°±0.2°, 23.07°±0.2°, 25.01°±0.2°;

[0045] In some embodiments, the aforementioned Form 8 of L-malate salt of the compound shown in formula (I), which has an X-ray powder diffraction pattern substantially as shown in FIG. 25 using Cu-Kα radiation;

[0046] In some embodiments, the aforementioned Form 8 of L-malate salt of the compound shown in formula (I), which has a thermogravimetric analysis curve, a differential scanning calorimetry curve and an isothermal adsorption curve substantially as shown in FIGS. 26-28, respectively.

[0047] The present application provides an amorphous form of L-malate salt of the compound shown in formula (I), which has an X-ray powder diffraction pattern substantially as shown in FIG. 29 using Cu-Kα radiation.

[0048] In some embodiments, the aforementioned amorphous form of L-malate salt of the compound shown in formula (I), which has a thermogravimetric analysis curve and a differential scanning calorimetry curve substantially as shown in FIGS. 30, 31, respectively.

[0049] In some embodiments, the L-malate salt of the compound of formula (I) has a crystal structure successfully determined by single crystal diffraction method, and the cell parameters are shown in Table 1. The crystal structure belongs to triclinic system, has no helical axis, P1 space group, and the cell constants are α = 92.3960(10)°, β = 99.6040(10)°, γ = 92.7970(10)°, and the cell volume is The Z' of the system is 2; in some embodiments, one cell of the crystal form 1 contains 2 free state molecules, 2 L-malic acid molecules, and 2 water molecules, and the molar ratio of the free state, L-malic acid, and water is 1:1:1; in some embodiments, the asymmetric unit in the cell is shown in Figure 32.

[0050] The present application provides a preparation method of the L-malate salt of the compound of formula (I), which comprises the step of salifying the compound of formula (I) with malic acid,

[0051] The present application provides a preparation method of the crystal form of the L-malate salt of the compound of formula (I), wherein the method comprises: subjecting the L-malate salt of the compound of formula (I) to crystallization from a mother liquor, volatilization crystallization, anti-solvent crystallization, cooling crystallization, water vapor stress crystallization, or diffusion crystallization; in some embodiments, the solvent used is selected from one or more of C1-6haloalkane solvents, C2-6ester solvents, C2-6ether solvents, C1-6alcohol solvents, or water; in some embodiments, the solvent used is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, propanol, diethyl ether, tetrahydrofuran, and water.

[0052] In one aspect, the present application also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of the L-malate salt, crystal form, or amorphous form of the compound of formula (I) described above, and a pharmaceutically acceptable carrier or excipient.

[0053] The present application also relates to the use of the L-malate salt, crystal form, amorphous form, pharmaceutical composition, or pharmaceutical preparation described in any of the technical solutions described above in the preparation of a medicament for treating AAK1-mediated diseases; the AAK1-mediated diseases are neuropathic pain, such as diabetic neuropathic pain and post-herpetic pain.

[0054] The present application also provides a method for treating a disease in a mammal, comprising administering to the subject a therapeutically effective amount of the L-malate salt, crystalline form, amorphous form, pharmaceutical composition or pharmaceutical preparation of any one of the preceding technical solutions, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount preferably being 1-1500 mg; the disease preferably being neuropathic pain; the disease more preferably being diabetic neuropathic pain, post-herpetic pain.

[0055] The present application also provides a method for treating a disease in a mammal, comprising administering to the subject a therapeutically effective amount of the L-malate salt, crystalline form, amorphous form, pharmaceutical composition or pharmaceutical preparation of any one of the preceding technical solutions, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount preferably being 1-1500 mg; the disease preferably being neuropathic pain; the disease more preferably being diabetic neuropathic pain, post-herpetic pain.

[0056] An "effective amount" or "therapeutically effective amount" as described herein refers to an amount of a compound disclosed herein that, when administered, will relieve to some extent one or more of the symptoms of the disease or condition being treated. In some embodiments, the result is a decrease and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound disclosed herein that is needed to provide a clinically significant decrease in disease symptoms. Examples of a therapeutically effective amount include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-90 mg, 5-70 mg, 5-80 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-1500 mg, 10-1000 mg, 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 10-450 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-125 mg, 10-100 mg, 10-90 mg, 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg; 20-1500 mg, 20-1000 mg, 20-900 mg, 20-800 mg, 20-700 mg, 20-600 mg, 20-500 mg, 20-400 mg, 20-350 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-125 mg, 20-100 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg;50-1500 mg, 50-1000 mg, 50-900 mg, 50-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-125 mg, 50-100 mg; 100-1500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, 100-200 mg.

[0057] The present application relates to a pharmaceutical composition or a pharmaceutical formulation comprising a therapeutically effective amount of the L-malate salt, crystalline form, amorphous form, pharmaceutical composition or pharmaceutical formulation of the present application and a carrier and / or excipient. The pharmaceutical composition can be in the form of a unit formulation (the amount of the main drug in the unit formulation is also referred to as "formulation specification"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of the compound of the present application or a stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt or co-crystal thereof.

[0058] A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of the L-malate salt, crystalline form, amorphous form, pharmaceutical composition or pharmaceutical preparation of the present application, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount preferably being 1-1500 mg; the disease preferably being neuropathic pain; the disease more preferably being diabetic neuropathic pain, post-herpetic pain.

[0059] A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of the L-malate salt, crystalline form, amorphous form, pharmaceutical composition or pharmaceutical preparation of the present application, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount preferably being 1-1500 mg; the disease preferably being neuropathic pain; the disease more preferably being diabetic neuropathic pain, post-herpetic pain.

[0060] The present application relates to a kit which can comprise a composition in single or multiple dose form, the kit comprising the L-malate salt, crystalline form or amorphous form of the present application, the amount of the L-malate salt, crystalline form or amorphous form of the present application being the same as its amount in the above pharmaceutical composition.

[0061] In the present application, the amount of the L-malate salt, crystalline form or amorphous form of the present application is converted into the form of free base in each case.

[0062] "Formulation strength" refers to the weight of the main drug contained in each bottle, tablet or other unit formulation.

[0063] In still another aspect, the present application also provides the use of the aforementioned compound of formula (I) or its solvate or the L-malate salt of the compound of formula (I) or its crystalline form or amorphous form or the aforementioned pharmaceutical composition in the preparation of a medicament for the treatment of neuropathic pain; more preferably, the aforementioned disease is diabetic neuropathic pain, post-herpetic neuralgia.

[0064] It is understood that the expression "preferably, the X-ray powder diffraction pattern further comprises characteristic peaks at the following 2-theta positions", or "more preferably, the X-ray powder diffraction pattern further comprises characteristic peaks at the following 2-theta positions", and the like, means that the X-ray powder diffraction pattern further comprises characteristic peaks at the "following 2-theta positions" in addition to the characteristic peaks at the aforementioned 2-theta positions.

[0065] The X-ray powder diffraction or DSC pattern, TGA pattern disclosed in the present application, and those substantially identical thereto, also fall within the scope of the present application.

[0066] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0067] As used herein, "crystal of the present application", "crystalline form of the present application", "polymorph of the present application", and the like, are used interchangeably.

[0068] The "room temperature" as used herein generally refers to 4-30°C, preferably 20±5°C.

[0069] The crystal form structure of the present application can be analyzed using various analytical techniques known to those of ordinary skill in the art, including but not limited to, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and / or Thermogravimetric Analysis (TGA), also known as Thermogravimetry (TG).

[0070] The "2-theta" or "2-theta angle" as used herein refers to the diffraction angle, theta (θ) is the Bragg angle, and the unit is ° or degree. The error range of 2-theta can be ±0.3, ±0.2, or ±0.1.

[0071] It is understood that the numerical values described and claimed in the present application are approximate values. Variations within the numerical values can be attributed to the calibration of the equipment, equipment errors, the purity of the crystal, the size of the crystal, the size of the sample, and other factors.

[0072] It is understood that the crystal form of the present application is not limited to the characteristic pattern, such as XRD, DSC, TGA, which is exactly the same as the characteristic pattern described in the figures disclosed in the present application. Any crystal form having a characteristic pattern substantially the same as or essentially the same as the characteristic pattern described in the figures disclosed in the present application falls within the scope of the present application.

[0073] It is appreciated that, as is well known in the art of differential scanning calorimetry (DSC), the height of the melting peak of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the position of the peak is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline compounds of the application are characterized by a DSC pattern having a characteristic peak position, with a margin of error of ± 3 °C, substantially the same as the DSC patterns provided in the figures of the present application.

[0074] The crystalline forms disclosed in the present application can be prepared by common methods for preparing crystalline forms, as follows:

[0075] 1. Volatilization experiment is to volatilize the sample clear solution at different temperatures to solvent dry.

[0076] 2. Crystal slurry experiment is to stir the sample supersaturated solution (with insoluble solid) at a certain temperature in different solvent systems.

[0077] 3. Anti-solvent experiment is to dissolve the sample in a good solvent, add anti-solvent, precipitate the solid after short stirring, and then filter.

[0078] 4. Cooling crystallization experiment is to dissolve a certain amount of sample in the corresponding solvent at high temperature, and then directly crystallize at room temperature or low temperature.

[0079] 5. High polymer template experiment is to add different types of high polymer materials to the sample clear solution, and volatilize to solvent dry at room temperature.

[0080] 6. Thermal method experiment is to treat the sample according to certain thermal method crystallization conditions and cool to room temperature.

[0081] 7. Water vapor diffusion experiment is to place the sample in a certain humidity environment at room temperature. BRIEF DESCRIPTION OF DRAWINGS

[0082] Figure 1 is an X-ray powder diffraction pattern of crystalline Form 1 of the L-malate salt of the compound of formula (I).

[0083] Figure 2 is a thermogravimetric analysis pattern of crystalline Form 1 of the L-malate salt of the compound of formula (I).

[0084] Figure 3 is a differential scanning calorimetry analysis curve pattern of crystalline Form 1 of the L-malate salt of the compound of formula (I).

[0085] Figure 4 is an isothermal adsorption curve of crystalline Form 1 of the L-malate salt of the compound of formula (I).

[0086] Figure 5 is an X-ray powder diffraction pattern of crystalline Form 2 of the L-malate salt of the compound of formula (I).

[0087] FIG. 6 is a thermogravimetric analysis profile of crystalline Form 2 of the L-malate salt of the compound of formula (I).

[0088] FIG. 7 is a differential scanning calorimetry profile of crystalline Form 2 of the L-malate salt of the compound of formula (I).

[0089] FIG. 8 is an isotherm adsorption curve of crystalline Form 2 of the L-malate salt of the compound of formula (I).

[0090] FIG. 9 is an X-ray powder diffraction profile of crystalline Form 3 of the L-malate salt of the compound of formula (I).

[0091] FIG. 10 is a thermogravimetric analysis profile of crystalline Form 3 of the L-malate salt of the compound of formula (I).

[0092] FIG. 11 is a differential scanning calorimetry profile of crystalline Form 3 of the L-malate salt of the compound of formula (I).

[0093] FIG. 12 is an X-ray powder diffraction profile of crystalline Form 4 of the L-malate salt of the compound of formula (I).

[0094] FIG. 13 is a thermogravimetric analysis profile of crystalline Form 4 of the L-malate salt of the compound of formula (I).

[0095] FIG. 14 is a differential scanning calorimetry profile of crystalline Form 4 of the L-malate salt of the compound of formula (I).

[0096] FIG. 15 is an isotherm adsorption curve of crystalline Form 4 of the L-malate salt of the compound of formula (I).

[0097] FIG. 16 is an X-ray powder diffraction profile of crystalline Form 5 of the L-malate salt of the compound of formula (I).

[0098] FIG. 17 is an X-ray powder diffraction profile of crystalline Form 6 of the L-malate salt of the compound of formula (I).

[0099] FIG. 18 is a thermogravimetric analysis profile of crystalline Form 6 of the L-malate salt of the compound of formula (I).

[0100] FIG. 19 is a differential scanning calorimetry profile of crystalline Form 6 of the L-malate salt of the compound of formula (I).

[0101] FIG. 20 is an isotherm adsorption curve of crystalline Form 6 of the L-malate salt of the compound of formula (I).

[0102] FIG. 21 is an X-ray powder diffraction profile of crystalline Form 7 of the L-malate salt of the compound of formula (I).

[0103] FIG. 22 is a thermogravimetric analysis profile of crystalline Form 7 of the L-malate salt of the compound of formula (I).

[0104] FIG. 23 is a differential scanning calorimetry profile of crystalline Form 7 of the L-malate salt of the compound of Formula (I).

[0105] FIG. 24 is an isotherm adsorption curve of crystalline Form 7 of the L-malate salt of the compound of Formula (I).

[0106] FIG. 25 is an X-ray powder diffraction pattern of crystalline Form 8 of the L-malate salt of the compound of Formula (I).

[0107] FIG. 26 is a thermogravimetric analysis profile of crystalline Form 8 of the L-malate salt of the compound of Formula (I).

[0108] FIG. 27 is a differential scanning calorimetry profile of crystalline Form 8 of the L-malate salt of the compound of Formula (I).

[0109] FIG. 28 is an isotherm adsorption curve of crystalline Form 8 of the L-malate salt of the compound of Formula (I).

[0110] FIG. 29 is an X-ray powder diffraction pattern of the amorphous form of the L-malate salt of the compound of Formula (I).

[0111] FIG. 30 is a thermogravimetric analysis profile of the amorphous form of the L-malate salt of the compound of Formula (I).

[0112] FIG. 31 is a differential scanning calorimetry profile of the amorphous form of the L-malate salt of the compound of Formula (I).

[0113] FIG. 32 is a single crystal structure of the compound of Formula (I). DETAILED DESCRIPTION

[0114] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR is measured by a (Bruker Ascend 500) nuclear magnetic instrument, and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCI3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0115] XRD is measured by using an X-ray powder diffractometer (Bruker D8 Advance Diffractometer). The 2θ scan angle is from 3-40° 2θ, and the scan step is 0.02°. When testing the sample, the light tube voltage and current are 40 kV and 40 mA, respectively, and the sample disc is a zero background sample disc.

[0116] TGA test conditions: The TGA instrument model is TA Instruments Q500 TGA. 1-10 mg of sample was placed in a pre-weighed sample pan and automatically weighed in the TGA furnace. The sample was heated at a rate of 10 °C / min to the final temperature with a nitrogen purge rate of 40 mL / min in the furnace.

[0117] DSC test conditions: The DSC instrument model is TA Instruments Q200 DSC. 0.5-5 mg of sample was accurately weighed into a standard pan or crimped aluminum crucible sample pan and heated at a rate of 10 °C / min to the final temperature with a nitrogen purge rate of 50 mL / min in the furnace.

[0118] The known starting materials of the present application can be synthesized using or according to methods known in the art,

[0119] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0120] In the examples, unless otherwise specified, room temperature refers to 20-30 °C.

[0121] The following detailed description of the implementation process and beneficial effects of the present application through specific examples is intended to help the reader better understand the essence and characteristics of the present application and is not intended to limit the scope of the present application.

[0122] Example 1: Preparation of the compound of formula (I)

[0123] The compound of formula (I) was prepared according to the method described in WO2023284838A1.

[0124] Example 2: Preparation of crystalline form 1 of L-malate salt of the compound of formula (I)

[0125] About 200 mg of the compound of formula (I) was dissolved in 1 mL of isopropyl alcohol to obtain solution 1; about 79 mg of L-malic acid was dissolved in 0.2 mL of isopropyl alcohol to obtain solution 2; solution 2 was added dropwise to solution 1 to obtain solution 3; solution 3 was stirred for 10 minutes to obtain a suspension; the suspension was stirred for 2 days and centrifuged, and the solid was dried at 40 °C under vacuum overnight to obtain crystalline form 1 of the L-malate salt of the compound of formula (I).

[0126] 1H NMR (400 MHz, CD3OD) δ 8.63-8.61 (d, J = 8.0 Hz, 1H), 8.26 (s, 1H), 8.18-8.16 (d, J = 8.0 Hz, 1H), 8.10-8.09 (d, J = 4.0 Hz, 1H), 7.71-7.68 (d, J = 12.0 Hz, 1H), 7.21-6.94 (t, J = 56.0 Hz, 1H), 6.84-6.56 (t, J = 56.0 Hz, 1H), 5.00-4.99 (t, J = 1.6 Hz, 1H), 4.83 (s, 1H), 4.20-4.16 (m, 3H), 2.69-2.64 (dd, J = 4 Hz, 16 Hz, 1H), 2.59-2.56 (d, J = 12.0 Hz, 1H), 2.45-2.39 (m, 2H), 1.76 (s, 3H), 1.42 (s, 3H)

[0127] Karl-Fischer determination showed a water content of 3.61%.

[0128] Example 3: Preparation of Form 2 of L-malate salt of the compound of formula (I)

[0129] About 200 mg of the compound of formula (I) was dissolved in 1 mL of ethyl acetate to give solution 1; about 79 mg of L-malic acid was dissolved in 0.2 mL of methanol to give solution 2; solution 2 was added dropwise to solution 1 to give solution 3; solution 3 was stirred for 2 days to give a suspension; the suspension was centrifuged and the solid was dried at 40 °C under vacuum overnight to give Form 2 of L-malate salt of the compound of formula (I).

[0130] Example 4: Preparation of Form 3 of L-malate salt of the compound of formula (I)

[0131] About 50 mg of the compound of formula (I) was dissolved in 0.5 mL of isopropanol to give solution 1; about 20 mg of L-malic acid was dissolved in 0.1 mL of isopropanol to give solution 2; solution 2 was added dropwise to solution 1 to give a suspension immediately; the suspension was stirred overnight, centrifuged and the solid was dried at 40 °C under vacuum overnight to give Form 3 of L-malate salt of the compound of formula (I).

[0132] Example 5: Preparation of Form 4 of L-malate salt of the compound of formula (I)

[0133] About 300 mg of Form 3 of L-malate salt of the compound of formula (I) was taken and added to 6 mL of dichloromethane and 0.3 mL of ethanol; the slurry was left to crystallize at room temperature for 3 days, centrifuged and dried at 40 °C under vacuum overnight to give Form 4 of L-malate salt.

[0134] Example 6: Preparation of Form 5 of L-malate salt of the compound of formula (I)

[0135] About 300 mg of the compound of formula (I) L-malate Form 3 was taken, 10 mL of isopropyl ether and 0.2 mL of dimethyl sulfoxide were added, and the solution was evaporated to dryness at 40 °C to obtain an oil, which was solidified to obtain L-malate Form 5.

[0136] Example 7: Preparation of Form 6 of L-malate of the compound of formula (I)

[0137] About 300 mg of the compound of formula (I) L-malate Form 3 was taken, 14 mL of water and 0.5 mL of acetonitrile were added, and the solution was filtered at 60 °C, the filtrate was stirred at 4 °C overnight, centrifuged, and dried under vacuum at 40 °C overnight to obtain L-malate Form 6.

[0138] Example 8: Preparation of Form 7 of L-malate of the compound of formula (I)

[0139] About 300 mg of the compound of formula (I) L-malate Form 3 was taken, heated to 100 °C to obtain L-malate Form 7.

[0140] Example 9: Preparation of Form 8 of L-malate of the compound of formula (I)

[0141] About 300 mg of the compound of formula (I) L-malate Form 6 was taken, heated to 100 °C to obtain L-malate Form 8.

[0142] Example 10: Preparation of amorphous form of L-malate of the compound of formula (I)

[0143] About 30 mg of the compound of formula (I) L-malate was taken, 2 mL of ethanol was added, the solution was filtered, and then concentrated to dryness under reduced pressure at 50 °C to obtain the amorphous form of L-malate.

[0144] Test Example

[0145] 1. Crystal Form Test Example

[0146] Table 1. Table of instrument information and detection method parameters

[0147] 2. Specific peak characterization results of XRD test of the compound

[0148] The X-ray powder diffraction pattern (XRD) of the L-malate Form 1 of the compound I prepared in Example 2 is shown in Figure 1. The specific peaks are shown in Table 2.

[0149] Table 2

[0150] The X-ray powder diffraction pattern (XRD) of the L-malate salt Form 2 of Compound I prepared in Example 3 is shown in Figure 5. Specific peak values are shown in Table 3.

[0151] Table 3

[0152] The X-ray powder diffraction pattern (XRD) of the L-malate salt Form 3 of Compound I prepared in Example 4 is shown in Figure 9. Specific peak values are shown in Table 4.

[0153] Table 4

[0154] The X-ray powder diffraction pattern (XRD) of the L-malate salt Form 4 of Compound I prepared in Example 5 is shown in Figure 12. Specific peak values are shown in Table 5.

[0155] Table 5

[0156] The X-ray powder diffraction pattern (XRD) of the L-malate salt Form 5 of Compound I prepared in Example 6 is shown in Figure 16. Specific peak values are shown in Table 6.

[0157] Table 6

[0158] The X-ray powder diffraction pattern (XRD) of the L-malate salt Form 6 of Compound I prepared in Example 7 is shown in Figure 17. Specific peak values are shown in Table 7.

[0159] Table 7

[0160] The X-ray powder diffraction pattern (XRD) of the L-malate salt Form 7 of Compound I prepared in Example 8 is shown in Figure 21. Specific peak values are shown in Table 8.

[0161] Table 8

[0162] The X-ray powder diffraction pattern (XRD) of the L-malate salt Form 8 of Compound I prepared in Example 9 is shown in Figure 25. Specific peak values are shown in Table 9.

[0163] Table 9

[0164] 3. DSC (Differential Scanning Calorimetry) test results for each Form

[0165] The differential scanning calorimetry (DSC) curve of the L-malate of the compound of formula (I) obtained in Example 2 is shown in Figure 3. The DSC curve shows three endothermic peaks: Tstart = 39.97℃, Tpeak = 66.48℃, ΔH = 22.04 J / g; Tstart = 97.73℃, Tpeak = 109.37℃, ΔH = 80.34 J / g; and Tstart = 136.92℃, Tpeak = 142.50℃, ΔH = 41.61 J / g.

[0166] The differential scanning calorimetry (DSC) curve of crystal form 2 of the L-malate of compound (I) obtained in Example 3 is shown in Figure 7. The DSC curve shows an endothermic peak, which is T 开始 =149.70℃, T 峰 =150.91℃, △H=93.33J / g.

[0167] The differential scanning calorimetry (DSC) curve of crystal form 3 of the L-malate of compound (I) obtained in Example 4 is shown in Figure 11. The DSC curve shows three endothermic peaks, namely T... 开始 =85.68℃, T 峰 =91.34℃, △H=141.5J / g, T 开始 =137.62℃, T 峰 =142.05℃, △H=31.42J / g, T 开始 =148.31℃, T 峰 =150.25℃, △H=2.221J / g.

[0168] The differential scanning calorimetry (DSC) curve of crystal form 4 of the L-malate of compound (I) obtained in Example 5 is shown in Figure 14. The DSC curve shows one endothermic peak and one exothermic peak, corresponding to T0 and T1, respectively. 开始 =149.45℃, T 峰 =150.63℃, △H=90.00J / g, T 开始 =100.07℃, T 峰 =108.87℃, △H=4.346J / g.

[0169] The differential scanning calorimetry (DSC) curve of the L-malate crystal form 6 of the compound of formula (I) obtained in Example 7 is shown in Figure 19. The DSC curve shows two endothermic peaks: Tstart = 85.83℃, Tpeak = 95.75℃, ΔH = 38.76 J / g, and Tstart = 143.47℃, Tpeak = 144.80℃, ΔH = 113.1 J / g.

[0170] The differential scanning calorimetry profile of the crystalline Form 7 of L-malate salt of the compound of formula (I) prepared in Example 8 is shown in Figure 23. The differential scanning calorimetry curve (DSC) shows two endothermic peaks at T 开始 = 140.79 °C, T 峰 = 144.39 °C, ΔH = 40.04 J / g, T 开始 = 148.42 °C, T 峰 = 150.29 °C, ΔH = 19.24 J / g.

[0171] The differential scanning calorimetry profile of the crystalline Form 8 of L-malate salt of the compound of formula (I) prepared in Example 9 is shown in Figure 27. The differential scanning calorimetry curve (DSC) shows one endothermic peak at T 开始 = 142.79 °C, T 峰 = 144.69 °C, ΔH = 109.3 J / g.

[0172] The differential scanning calorimetry profile of the amorphous form of L-malate salt of the compound of formula (I) prepared in Example 10 is shown in Figure 31. The differential scanning calorimetry curve (DSC) shows one broad endothermic peak and one sharp endothermic peak at T 开始 = 147.49 °C, T 峰 = 150.66 °C, ΔH = 70.14 J / g.

[0173] 4. TGA (Thermogravimetric Analysis) test results of each crystalline form

[0174] The thermogravimetric profile of the crystalline Form 1 of L-malate salt of the compound of formula (I) prepared in Example 2 is shown in Figure 2. The thermogravimetric curve (TGA) shows 1.451% weight loss up to 50 °C and 1.181% weight loss between 100-150 °C.

[0175] The thermogravimetric profile of the crystalline Form 2 of L-malate salt of the compound of formula (I) prepared in Example 3 is shown in Figure 6. The thermogravimetric curve (TGA) shows 0.3411% weight loss up to 150 °C.

[0176] The thermogravimetric profile of the crystalline Form 3 of L-malate salt of the compound of formula (I) prepared in Example 4 is shown in Figure 10. The thermogravimetric curve (TGA) shows 6.396% weight loss up to 80 °C and 2.801% weight loss between 80-110 °C.

[0177] The thermogravimetric profile of the crystalline Form 4 of L-malate salt of the compound of formula (I) prepared in Example 5 is shown in Figure 13. The thermogravimetric curve (TGA) shows 0.1627% weight loss up to 150 °C.

[0178] The thermogravimetric analysis profile of the Form 6 of L-malate salt of the compound of formula (I) prepared in Example 7 is shown in Figure 18, which shows a thermogravimetric analysis curve (TGA) showing 1.835% weight loss up to 100°C.

[0179] The thermogravimetric analysis profile of the Form 7 of L-malate salt of the compound of formula (I) prepared in Example 8 is shown in Figure 22, which shows a thermogravimetric analysis curve (TGA) showing 0.373% weight loss up to 100°C, 0.982% weight loss up to 100-150°C.

[0180] The thermogravimetric analysis profile of the Form 8 of L-malate salt of the compound of formula (I) prepared in Example 9 is shown in Figure 26, which shows a thermogravimetric analysis curve (TGA) showing 0.3095% weight loss up to 150°C.

[0181] The thermogravimetric analysis profile of the amorphous Form of L-malate salt of the compound of formula (I) prepared in Example 10 is shown in Figure 30, which shows a thermogravimetric analysis curve (TGA) showing 1.687% weight loss up to 80°C, 3.002% weight loss up to 80-150°C.

[0182] 5. Results of isotheral sorption curve test of each Form

[0183] The isotheral sorption curve of Form 1 of L-malate salt of the compound of formula (I) prepared in Example 2 is shown in Figure 4, which shows isotheral sorption curve (DVS) showing 1.423% moisture uptake in the range of 0-20% RH, 0.1859% moisture uptake in the range of 20-80% RH.

[0184] The isotheral sorption curve of Form 2 of L-malate salt of the compound of formula (I) prepared in Example 3 is shown in Figure 8, which shows isotheral sorption curve (DVS) showing 0.03992% moisture uptake in the range of 0-80% RH.

[0185] The isotheral sorption curve of Form 4 of L-malate salt of the compound of formula (I) prepared in Example 5 is shown in Figure 15, which shows isotheral sorption curve (DVS) showing 0.2576% moisture uptake in the range of 0-70% RH, 0.8362% moisture uptake in the range of 70-80% RH.

[0186] The isotheral sorption curve of Form 6 of L-malate salt of the compound of formula (I) prepared in Example 7 is shown in Figure 20, which shows isotheral sorption curve (DVS) showing 0.4664% moisture uptake in the range of 0-70% RH, 1.596% moisture uptake in the range of 70-80% RH.

[0187] The isothermal adsorption curve of crystal form 7 of the L-malate of compound (I) obtained in Example 8 is shown in Figure 24. The isothermal adsorption curve (DVS) shows that there is 1.167% moisture absorption in the 0-80%RH range.

[0188] The isothermal adsorption curve of crystal form 8 of the L-malate of compound (I) obtained in Example 9 is shown in Figure 28. The isothermal adsorption curve (DVS) shows that there is 0.8529% moisture absorption in the 0-80%RH range.

[0189] 6. Studies on transformations in solution

[0190] Table 10. Information on the transformation experiments in solutions of crystal form 1 and crystal form 2

[0191] 7. Solid-state transformation research

[0192] Table 11. Experimental Information on Dynamic Humidity Transformation of Crystal Form 1

[0193] 8. Studies on transformations in solution

[0194] Table 12 Experimental relationship between hydrates and anhydrous substances

[0195] 9. Solid-state stability study

[0196] The solid-state stability of crystal form 1 was investigated under accelerated test (40℃±2℃ / 75%RH±5%RH), long-term test (5℃±3℃), long-term test (25℃±2℃ / 60%±5%RH), and intermediate condition test (30℃±2℃ / 65%±5%RH).

[0197] Table 13. Summary of accelerated test results for L-malate crystal form 1 (40℃±2℃ 75%RH±5%RH)

[0198] Conclusion: L-malate crystal form 1 exhibits good solid-state stability under the above conditions.

[0199] Table 14. Summary of Long-Term Test Results (5℃±3℃) for L-Malate Crystal Form 1

[0200] Conclusion: L-malate crystal form 1 exhibits good solid-state stability under the above conditions.

[0201] Table 15. Summary of Long-Term Test Results for L-Malate Crystal Form 1 (25℃±2℃ / 60%±5%RH)

[0202] Conclusion: L-malate crystal form 1 exhibits good solid-state stability under the above conditions.

[0203] Table 16. Summary of results of intermediate condition test for L-malate crystal form 1 (30℃±2℃ / 65%±5%RH)

[0204] Conclusion: L-malate crystal form 1 exhibits good solid-state stability under the above conditions.

[0205] 10. Equilibrium solubility study

[0206] Table 17. Experimental Information on the Equilibrium Solubility of L-Malate Crystal Form 1

[0207] Table 18. Equilibrium solubility test results of L-malate crystal form 1

[0208] Conclusion: L-malate crystal form 1 has good solubility in water, simulated gastric juice, simulated intestinal juice after fasting, and simulated intestinal juice after saturation.

[0209] 11. Single Crystal Data

[0210] L-malate crystal form 1 belongs to the triclinic crystal system, space group P1, and does not contain a helical axis. Each unit cell of the single crystal contains 2 free molecules, 2 L-malic acid molecules, and 2 water molecules. The molar ratio of free molecules, L-malic acid, and water is 1:1:1, therefore L-malate crystal form 1 is a monohydrate.

[0211] Table 19 Single Crystal Structure Information Table

[0212] 12. Comparison of Crystal Form Data

[0213] Table 20 Crystallinity and Hygroscopicity Data for Other Crystal Forms

Claims

1. An L-malate salt of a compound of Formula (I), 2. The L-malate salt of the compound of formula (I) according to claim 1, wherein, The L-malate salt of the compound of formula (I) is in crystalline Form 1 having an X-ray powder diffraction pattern with characteristic diffraction peaks at 4.96° ± 0.2°, 19.71° ± 0.2°, 21.73° ± 0.2°, 22.65° ± 0.2°, 26.25° ± 0.2°; further having an X-ray powder diffraction pattern with characteristic diffraction peaks at 4.96° ± 0.2°, 14.76° ± 0.2°, 19.71° ± 0.2°, 21.73° ± 0.2°, 22.65° ± 0.2°, 24.67° ± 0.2°, 26.25° ± 0.2°, 27.11° ± 0.2°; further, the X-ray powder diffraction pattern is substantially as shown in Figure 1 using Cu-Ka radiation.

3. The L-malate salt of the compound of formula (I) according to claim 1, wherein, The L-malate salt of the compound of formula (I) is in crystalline Form 2 having an X-ray powder diffraction pattern with characteristic diffraction peaks at 10.58° ± 0.2°, 18.34° ± 0.2°, 20.57° ± 0.2°, 22.99° ± 0.2°, 25.71° ± 0.2°; or with characteristic diffraction peaks at 10.58° ± 0.2°, 11.99° ± 0.2°, 16.45° ± 0.2°, 18.34° ± 0.2°, 20.57° ± 0.2°, 22.99° ± 0.2°, 25.46° ± 0.2°, 25.71° ± 0.2°; or the X-ray powder diffraction pattern is substantially as shown in Figure 5; or is in crystalline Form 3 of the L-malate salt of the compound of formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 4.28° ± 0.2°, 8.52° ± 0.2°, 12.77° ± 0.2°, 23.33° ± 0.2°, 24.05° ± 0.2°; or with characteristic diffraction peaks at 4.28° ± 0.2°, 8.52° ± 0.2°, 12.77° ± 0.2°, 17.04° ± 0.2°, 20.47° ± 0.2°, 21.33° ± 0.2°, 23.33° ± 0.2°, 24.05° ± 0.2°; or the X-ray powder diffraction pattern is substantially as shown in Figure 9; or it is Form 4 of the L-malate salt of the compound of Formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 10.76°±0.2°, 12.47°±0.2°, 20.74°±0.2°, 22.91°±0.2°, 23.88°±0.2°; or characteristic diffraction peaks at 10.76°±0.2°, 11.44°±0.2°, 12.47°±0.2°, 20.74°±0.2°, 21.20°±0.2°, 22.91°±0.2°, 23.88°±0.2°, 25.10°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 12; using Cu-Ka radiation; or it is Form 5 of the L-malate salt of the compound of Formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 6.03°±0.2°, 6.24°±0.2°, 18.03°±0.2°, 18.57°±0.2°, 24.95°±0.2°; or characteristic diffraction peaks at 6.03°±0.2°, 6.24°±0.2°, 9.28°±0.2°, 18.03°±0.2°, 18.57°±0.2°, 20.57°±0.2°, 21.50°±0.2°, 24.95°±0.2°; an X-ray powder diffraction pattern substantially as shown in Figure 16; using Cu-Ka radiation; or it is Form 6 of the L-malate salt of the compound of Formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 4.62°±0.2°, 6.66°±0.2°, 9.13°±0.2°, 18.24°±0.2°, 21.47°±0.2°; or characteristic diffraction peaks at 4.62°±0.2°, 6.66°±0.2°, 9.13°±0.2°, 15.41°±0.2°, 17.83°±0.2°, 18.24°±0.2°, 21.47°±0.2°, 25.87°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 17; using Cu-Ka radiation; or it is Form 7 of the L-malate salt of the compound of Formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 11.78°±0.2°, 19.34°±0.2°, 21.30°±0.2°, 23.33°±0.2°, 24.31°±0.2°; or characteristic diffraction peaks at 11.78°±0.2°, 12.72°±0.2°, 18.00°±0.2°, 18.21°±0.2°, 19.34°±0.2°, 21.30°±0.2°, 23.33°±0.2°, 24.31°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 21; using Cu-Ka radiation; or it is Form 8 of the L-malate salt of the compound of Formula (I), having an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at 6.26°±0.2°, 11.58°±0.2°, 16.12°±0.2°, 18.61°±0.2°, 25.01°±0.2°; or having characteristic diffraction peaks at 4.55°±0.2°, 6.26°±0.2°, 11.58°±0.2°, 16.12°±0.2°, 16.43°±0.2°, 18.61°±0.2°, 19.12°±0.2°, 25.01°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 25.

4. The L-malate salt of the compound of Formula (I) according to claim 1, which is amorphous, having an X-ray powder diffraction pattern substantially as shown in Figure 29 using Cu-Ka radiation.

5. A process for the preparation of the L-malate salt of the compound of formula (I) according to claim 1, comprising the step of salification of the compound of formula (I) with malic acid, 6. A method of preparing the crystalline form of any one of claims 2-4, comprising: crystallization, evaporative crystallization, anti-solvent crystallization, cooling crystallization, water vapor stress crystallization or diffusion crystallization of the L-malate salt of the compound of Formula (I); further, the solvent used in the crystallization is selected from one or more of C1-6haloalkane solvents, C2-6ester solvents, C2-6ether solvents, C1-6alcohol solvents or water; further, the solvent used in the crystallization is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, propanol, diethyl ether, tetrahydrofuran or water.

7. A pharmaceutical composition comprising the L-malate salt, crystalline form or amorphous form of any one of claims 1-5, and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition or a pharmaceutical formulation comprising 1-1500 mg of the L-malate salt, crystalline form or amorphous form of any one of claims 1-5 per unit dose.

9. Use of the L-malate salt, crystalline form or amorphous form of any one of claims 1-5, or the pharmaceutical composition or pharmaceutical formulation of claim 6 or 7, in the manufacture of a medicament for treating a disease mediated by AAK1.

10. The use according to claim 9, wherein the disease is selected from diabetic neuropathic pain, post-herpetic pain.

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