2-indolinospirones or their salts, amorphous or crystalline forms

Abstract

The present application provides 2-indolinone spiroketone compounds or salts, amorphous forms or crystalline forms thereof as MDM2 inhibitors, and preparation methods and applications thereof. The amorphous forms or crystalline forms of the present application have good stability, and have very important values for drug development, preparation development and production.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202110090407.8, filed on January 22, 2021, entitled "Amorphous or crystalline form of 2-indolinespirocyclic ketone compounds or their salts or solvates". Technical Field

[0002] This invention belongs to the field of medicinal chemistry, and specifically relates to a 2-indolinespirocyclic ketone compound or its salts, solvates in amorphous or crystalline form as an MDM2 inhibitor, as well as its preparation method and application. Background Technology

[0003] p53, a tumor suppressor, plays a crucial role in controlling cell cycle progression, senescence, and apoptosis (Vogelstein et al., Nature 408:307 (2000); Goberdhan, Cancer Cell 7:505 (2005)). MDM2 and p53 are part of a self-regulating feedback loop (Wu et al., Genes Dev.7:1126 (1993)). MDM2 is transcribedly activated by p53 and MDM2, which in turn inhibits p53 activity through at least three mechanisms (Wu et al., Genes Dev.7:1126 (1993)). First, the MDM2 protein directly binds to the p53 transactivation domain, thus inhibiting p53-mediated transactivation. Second, the MDM2 protein contains a nuclear export signaling sequence, and upon binding to p53, it induces the nuclear export of p53, thereby preventing p53 from binding to the targeted DNA. Third, the MDM2 protein is an E3 ubiquitin ligase and, upon binding to p53, promotes p53 degradation.

[0004] WO2015 / 161032A1 discloses 2-indolinespirocyclic ketone compounds that inhibit MDM2-p53 interaction and thus activate the function of p53 and p53-related proteins for therapeutic applications. These compounds not only exhibit improved chemical solution stability but also unexpectedly enhanced antitumor activity, including achieving complete tumor regression in an animal model of human osteosarcoma. Specifically, compound number 8 described in the specification (referred to herein as compound 1) binds to the MDM2 protein, IC50... 50 The numerical and Ki values ​​were 3.8 nM and <1.0 nM, respectively. This compound can block the interaction between MDM2 and p53 and induce cell cycle arrest and apoptosis in a p53-dependent manner. Its structural formula is as follows:

[0005]

[0006] However, current literature, including this patent application, mainly reports the structure and pharmacological activity of this type of compound, without any research or reporting on its polymorphism, amorphous or other structural forms.

[0007] Solid substances, due to various factors such as molecular configuration, conformation, molecular arrangement, molecular forces, and eutectic substances, exhibit different molecular lattice spatial arrangements, forming two or more different crystal structures. This phenomenon is known as "polymorphism" or "isomorphism." Polymorphism is widespread in solid pharmaceuticals. Different crystal forms of the same drug may exhibit differences in physicochemical properties, such as appearance, density, hardness, melting point, solubility, stability, dissolution rate, and bioavailability. This phenomenon is particularly pronounced in oral solid dosage forms. Furthermore, the form and quantity of polymorphic compounds are unpredictable. Different crystalline forms of the same drug show significant differences in solubility, melting point, density, and stability, thus affecting the drug's homogeneity, bioavailability, efficacy, and safety to varying degrees.

[0008] Besides polymorphism, some solid compounds may also exist in amorphous forms. Amorphous refers to the structure of some non-perfectly crystalline amorphous regions (amorphous regions) or the composition of some amorphous solids (amorphous substances). For a specific solid drug, the existence and quantity of its amorphous forms are also unpredictable and may significantly affect the drug's solubility, melting point, density, stability, etc.

[0009] Therefore, in the process of new drug development, it is necessary to conduct comprehensive screening of drug compounds in both crystalline and amorphous forms, considering multiple factors. In particular, for the aforementioned compound of formula 1 used as an MDM2 inhibitor, developing amorphous or crystalline forms of the compound or its salts and solvates that may have pharmaceutical value, and improving the stability, solubility, and bioavailability of the compound, has potential pharmaceutical and clinical value. Summary of the Invention

[0010] This invention provides amorphous or crystalline forms of 2-indolinespirocyclic ketone compounds or their salts and solvates used as MDM2 inhibitors, along with their preparation methods and applications. The amorphous or crystalline forms of this invention exhibit good stability and are of significant value for drug development, formulation development, and manufacturing.

[0011] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, those skilled in the art will understand that the invention can be practiced without these details. The following description of several embodiments is given under the understanding that this disclosure is considered an example of the subject matter to be protected, and is not intended to limit the appended claims to the specific embodiments shown. The headings used throughout the invention are provided for convenience only and should not be construed as limiting the claims in any way. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

[0012] Furthermore, when referring to graphs such as XRPD graphs, DSC graphs, TGA graphs, etc., the term "substantially as shown" means that it is not necessarily the same as those described herein, but that, when considered by a person skilled in the art, falls within the limits of experimental error or deviation.

[0013] In one aspect, the present invention provides the following compounds of Formula 1 or their salts or solvates in amorphous or crystalline form:

[0014]

[0015] The chemical name of the compound is 4-[[[(3'R,4'S,5'R)-6”-chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2”-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3”-[3H]indole]-5'-yl]carbonyl]amino]bicyclo[2.2.2]octane-1-carboxylic acid, and the CAS number is 1818393-16-6.

[0016] Specifically, the form can take the following specific forms:

[0017] 1) Compound I, sulfate, amorphous form

[0018] In one embodiment, the form is an amorphous form I of the sulfate of Formula 1 compound. In one embodiment, it has:

[0019] 1) Basically as Figure 1 The X-ray diffraction (XRD) pattern shown;

[0020] 2) Basically as Figure 2 The thermogravimetric analysis (TGA) diagram shown;

[0021] 3) Basically as Figure 3 The differential scanning calorimetry (DSC) chart shown;

[0022] 4) Basically as Figure 4 The dynamic water adsorption-desorption (DVS) diagram shown; and / or

[0023] 5) Basically as Figure 5 The isothermal adsorption curve is shown.

[0024] 2) Compound II of Formula 1 hydrochloride amorphous form

[0025] In one embodiment, the form is the amorphous form II of the hydrochloride salt of Formula 1. In one embodiment, it has essentially the following characteristics: Figure 6 The XRD pattern shown.

[0026] 3) Crystalline form III of compound hydrochloride of formula 1

[0027] In one embodiment, the form is the crystalline form III of the hydrochloride salt of Formula 1 compound, which has:

[0028] 1) Basically as Figure 7 The X-ray powder diffraction (XRPD) pattern shown;

[0029] 2) Basically as Figure 8 The TGA diagram shown; and / or

[0030] 3) Basically as Figure 9 The DSC diagram shown.

[0031] 4) Crystallization form IV of compound hydrochloride of formula 1

[0032] In one embodiment, the form is the crystalline form IV of the hydrochloride salt of Formula 1 compound, which has substantially the following characteristics: Figure 10 The XRPD diagram shown.

[0033] 5) The crystalline form of maleate salt of compound 1 is V

[0034] In one embodiment, the form is the crystalline form V of maleate of Formula 1, which has characteristic peaks at the following positions in an XRPD plot expressed in 2θ angles: 8.159±0.2°, 10.519±0.2°, 15.078±0.2°, 15.839±0.2°, 16.959±0.2°, and 22.997±0.2°.

[0035] In one embodiment, the form is the maleate crystalline form V of compound of formula 1, which has:

[0036] 1) Basically as Figure 11 The XRPD diagram shown;

[0037] 2) Basically as Figure 12 The TGA diagram shown;

[0038] 3) Basically as Figure 13 The DSC diagram shown; and / or

[0039] 4) Basically as Figure 14 The DVS diagram shown.

[0040] 6) Crystallization form of hydrobromide of compound 1 (VI)

[0041] In one embodiment, the form is the crystalline form VI of the hydrobromide of Formula 1, which has:

[0042] 1) Basically as Figure 15 The XRPD diagram shown;

[0043] 2) Basically as Figure 16 The TGA diagram shown;

[0044] 3) Basically as Figure 17 The DSC diagram shown; and / or

[0045] 4) Basically as Figure 18 The DVS diagram shown.

[0046] 7) Compound 1, methanesulfonate, amorphous form VII

[0047] In one embodiment, the form is the amorphous form VII of the methanesulfonate compound of formula 1. In one embodiment, it has essentially the following characteristics: Figure 19 The XRD pattern shown.

[0048] 8) Sodium salt of Formula 1, amorphous form VIII

[0049] In one embodiment, the form is the amorphous form VIII of the sodium salt of Formula 1 compound. In one embodiment, it has:

[0050] 1) Basically as Figure 20 The XRD pattern shown;

[0051] 2) Basically as Figure 21 The TGA diagram shown;

[0052] 3) Basically as Figure 22 The DSC diagram shown; and / or

[0053] 4) Basically as Figure 23 The DVS diagram shown.

[0054] 9) Amorphous form of potassium salt of compound 1 (IX)

[0055] In one embodiment, the form is the amorphous form IX of the potassium salt of Formula 1 compound. In one embodiment, it has:

[0056] 1) Basically as Figure 24 The XRD pattern shown;

[0057] 2) Basically as Figure 25 The TGA diagram shown;

[0058] 3) Basically as Figure 26 The DSC diagram shown; and / or

[0059] 4) Basically as Figure 27 The DVS diagram shown.

[0060] 10) Crystallization form of compound X (Formula 1)

[0061] In one embodiment, the form is the crystalline form X of compound of formula 1, which has characteristic peaks at the following locations in an XRPD plot expressed in 2θ angles: 9.080±0.2°, 13.820±0.2°, 14.262±0.2°, 15.543±0.2° and 19.160±0.2°.

[0062] In a preferred embodiment, the crystalline form X of compound 1 has XRPD characteristic peaks at positions substantially as shown in Table 1 below and / or substantially as shown in Table 1 below. Figure 28 The XRPD diagram shown.

[0063] Table 1

[0064]

[0065]

[0066] In some preferred embodiments, the crystalline form X of compound 1 also has one or more of the following characteristics:

[0067] 1) In the TGA diagram, there is a weight loss of 2.5 ± 0.5% by weight between 10 and 150 °C, and the decomposition temperature is 260 ± 10 °C.

[0068] 2) In the DSC plot, there are two small absorption peaks near 193℃ and 211℃; and / or

[0069] 3) In the DVS chart, 2 ± 0.5% of the surface solvent is lost after DVS, the water absorption is <0.1% (almost no water absorption) from 0% RH to 60% RH, and the weight change is 1.6 ± 0.2% (slight hygroscopicity) from 60% RH to 80% RH.

[0070] In some preferred embodiments, the crystalline form X of compound 1 also has one or more of the following characteristics:

[0071] 1) Basically as Figure 29 The TGA diagram shown;

[0072] 2) Basically as Figure 30 The DSC diagram shown; and / or

[0073] 3) Basically as Figure 31 The DVS diagram shown.

[0074] 11) Crystallization form of compound XI monohydrate

[0075] In one embodiment, the form is the crystalline form XI of the monohydrate of compound 1, which has characteristic peaks at the following positions in an XRPD plot expressed in 2θ angles: 6.999±0.2°, 11.319±0.2°, 11.522±0.2° and 17.485±0.2°.

[0076] In a preferred embodiment, the crystalline form XI of the monohydrate of compound 1 has characteristic peaks at the following positions in the XRPD plot expressed in 2θ angles: 6.999±0.2°, 9.858±0.2°, 11.319±0.2°, 11.522±0.2°, 12.341±0.2°, 13.282±0.2°, 17.485±0.2°, 17.923±0.2°, 19.159±0.2°, and 28.644±0.2°.

[0077] In a preferred embodiment, the monohydrate crystalline form XI of compound 1 has XRPD characteristic peaks at positions substantially as shown in Table 2 below and / or substantially as shown in Table 2 below. Figure 32 The XRPD diagram shown.

[0078] Table 2

[0079]

[0080]

[0081] In some preferred embodiments, the monohydrate crystalline form XI of compound 1 further has one or more of the following characteristics:

[0082] 1) In the TGA diagram, there is a weight loss of 2.4 ± 0.5% before 100℃, which is equivalent to about one water molecule, and the decomposition temperature is 262 ± 2℃.

[0083] 2) The DSC chart shows a broad endothermic peak between 90℃ and 140℃. The sample's melting point is 243±3℃, and it decomposes upon melting; and / or

[0084] 3) In the DVS chart, the weight change from 0% RH to 80% RH is 0.17 ± 0.05% (non-hygroscopic).

[0085] In some preferred embodiments, the monohydrate crystalline form XI of compound 1 further has one or more of the following characteristics:

[0086] 1) Basically as Figure 33 The TGA diagram shown;

[0087] 2) Basically as Figure 34 The DSC diagram shown; and / or

[0088] 3) Basically as Figure 35 The DVS diagram shown.

[0089] 12) The crystalline form of the di-trifluoroethanol solvate of compound 1 is XII.

[0090] In one embodiment, the form is the crystalline form XII of the ditrifluoroethanol solvate of Formula 1, which has characteristic peaks at the following positions in an XRPD plot expressed in 2θ angles: 6.601±0.2°, 11.482±0.2°, 15.219±0.2°, 17.283±0.2°, 19.826±0.2°, and 22.862±0.2°.

[0091] In a preferred embodiment, the crystalline form XII of the ditrifluoroethanol solvate of Formula 1 has XRPD characteristic peaks at positions substantially as shown in Table 3 below and / or substantially as shown in Table 3 below. Figure 36 The XRPD diagram shown.

[0092] Table 3

[0093]

[0094]

[0095] In some preferred embodiments, the crystalline form XII of the di-trifluoroethanol solvate of Formula 1 also has one or more of the following characteristics:

[0096] 1) In the TGA plot, there is a weight loss of 27.7 ± 1.0 wt% before 150 °C, equivalent to approximately two trifluoroethanol molecules, and the decomposition temperature is 264 ± 2 °C; and / or

[0097] 2) In the DSC diagram, there is a broad endothermic peak in the range of 45℃-150℃, which is caused by the removal of trifluoroethanol molecules.

[0098] In some preferred embodiments, the crystalline form XII of the di-trifluoroethanol solvate of Formula 1 also has one or more of the following characteristics:

[0099] 1) Basically as Figure 37 The TGA diagram shown; and / or

[0100] 2) Basically as Figure 38 The DSC diagram shown.

[0101] 13) Compound of Formula 1, a semi-dimethyl sulfoxide solvent compound, crystal form XIII

[0102] In one embodiment, the form is the crystalline form XIII of the half-dimethyl sulfoxide solvent compound of Formula 1, which has characteristic peaks at the following positions in an XRPD plot expressed at 2θ angles: 6.737±0.2°, 9.302±0.2°, 9.494±0.2°, 15.957±0.2°, 17.240±0.2°, 17.683±0.2°, 18.520±0.2°, and 19.946±0.2°.

[0103] In a preferred embodiment, the crystalline form of the half-dimethyl sulfoxide solvent compound XIII of Formula 1 has XRPD characteristic peaks at positions substantially as shown in Table 4 below and / or substantially as shown in Table 4 below. Figure 39 The XRPD diagram shown.

[0104] Table 4

[0105]

[0106] In some preferred embodiments, the crystalline form of the dimethyl sulfoxide solvent compound XIII of Formula 1 also has one or more of the following characteristics:

[0107] 1) In the TGA plot, there is a weight loss of 11.2 ± 0.5 wt% before 80 °C, and a weight loss of 8.0 ± 0.5 wt% between 80 °C and 200 °C, equivalent to approximately half a dimethyl sulfoxide molecule, with a decomposition temperature of 266 ± 2 °C; and / or

[0108] 2) In the DSC diagram, there is a broad endothermic peak in the range of 80℃-160℃, which is caused by solvent removal. The melting point of the sample after solvent removal is 223±2℃.

[0109] In some preferred embodiments, the crystalline form of the dimethyl sulfoxide solvent compound XIII of Formula 1 also has one or more of the following characteristics:

[0110] 1) Basically as Figure 40 The TGA diagram shown; and / or

[0111] 2) Basically as Figure 41 The DSC diagram shown.

[0112] 14) Compound of Formula 1, hemimethylcyclohexane solvent compound, crystal form XIV

[0113] In one embodiment, the form is the crystalline form XIV of the hemimethylcyclohexane solvent compound of Formula 1, which has characteristic peaks at the following positions in an XRPD plot expressed in 2θ angles: 4.134±0.2°, 7.102±0.2°, 7.981±0.2°, 14.301±0.2°, and 16.701±0.2°.

[0114] In a preferred embodiment, the crystalline form of the hemimethylcyclohexane solvent compound XIV of Formula 1 has XRPD characteristic peaks at positions substantially as shown in Table 5 below and / or substantially as shown in Table 5 below. Figure 42 The XRPD diagram shown.

[0115] Table 5

[0116]

[0117]

[0118] In some preferred embodiments, the crystalline form XIV of the hemimethylcyclohexane solvent compound of Formula 1 also has one or more of the following characteristics:

[0119] 1) In the TGA plot, there is a weight loss of 8.62 ± 0.20 wt% before 150 °C, equivalent to about half a methylcyclohexane molecule, and the decomposition temperature is 263 ± 2 °C; and / or

[0120] 2) In the DSC diagram, there is a broad endothermic peak in the range of 45℃-120℃, which is suspected to be caused by the removal of methylcyclohexane molecules.

[0121] In some preferred embodiments, the crystalline form XIV of the hemimethylcyclohexane solvent compound of Formula 1 also has one or more of the following characteristics:

[0122] 1) Basically as Figure 43 The TGA diagram shown; and / or

[0123] 2) Basically as Figure 44 The DSC diagram shown.

[0124] 15) Compound of Formula 1, semi-tetrahydrofuran solvent compound, crystalline form XV

[0125] In one embodiment, the form is the crystalline form XV of the semi-tetrahydrofuran solvent compound of Formula 1, which has characteristic peaks at the following positions in an XRPD plot expressed in 2θ angles: 7.961±0.2°, 8.402±0.2°, 12.739±0.2°, 13.242±0.2°, 17.164±0.2°, 17.625±0.2°, and 19.540±0.2°.

[0126] In a preferred embodiment, the semi-tetrahydrofuran solvent compound XV of Formula 1 has XRPD characteristic peaks at positions substantially as shown in Table 6 below and / or substantially as shown in Table 6 below. Figure 45 The XRPD diagram shown.

[0127] Table 6

[0128]

[0129]

[0130] In some preferred embodiments, the semi-tetrahydrofuran solvent compound XV of Formula 1 also has one or more of the following characteristics:

[0131] 1) In the TGA plot, there is a weight loss of 6.8 ± 0.2 wt% before 150 °C, equivalent to about half a tetrahydrofuran molecule, and the decomposition temperature is 265 ± 2 °C; and / or

[0132] 2) In the DSC diagram, there is a broad endothermic peak in the range of 30℃-150℃, which is suspected to be caused by the removal of tetrahydrofuran molecules, and the melting point is 197℃±2℃.

[0133] In some preferred embodiments, the semi-tetrahydrofuran solvent compound XV of Formula 1 also has one or more of the following characteristics:

[0134] 1) Basically as Figure 46 The TGA diagram shown; and / or

[0135] 2) Basically as Figure 47 The DSC diagram shown.

[0136] 16) Compound XVI (amorphous form)

[0137] In one embodiment, the form is the amorphous form XVI of the compound of formula 1. In one embodiment, it has essentially the following characteristics: Figure 48 The XRPD diagram shown.

[0138] In a preferred embodiment, the amorphous form XVI of compound 1 further has one or more of the following characteristics:

[0139] 1) In the TGA plot, there is a slow weight loss of 2.9 ± 0.1 wt% before 150℃, and the decomposition temperature is 265 ± 2℃.

[0140] 2) No melting peaks are observed in the DSC chart; and / or

[0141] 3) In the DVS chart, the weight change is 2.5 ± 0.5% in the range of 0% RH to 80% RH (hygroscopic).

[0142] In a preferred embodiment, the amorphous form XVI of compound 1 further has one or more of the following characteristics:

[0143] 1) Basically as Figure 49 The TGA diagram shown;

[0144] 2) Basically as Figure 50 The DSC diagram shown; and / or

[0145] 3) Basically as Figure 51 The DVS diagram shown.

[0146] 17) Crystallization form of compound XVII of Formula 1

[0147] In one embodiment, the form is the crystalline form XVII of Formula 1, which has characteristic peaks at the following positions in an XRPD plot expressed at 2θ angles: 6.512±0.2°, 9.395±0.2°, 11.826±0.2°, 12.153±0.2°, 13.377±0.2°, 13.574±0.2°, 15.672±0.2°, and 20.999±0.2°.

[0148] In a preferred embodiment, the crystalline form of compound XVII of formula 1 has XRPD characteristic peaks at positions substantially as shown in Table 7 below and / or substantially as shown in Table 7 below. Figure 52 The XRPD diagram shown.

[0149] Table 7

[0150]

[0151]

[0152] In a preferred embodiment, the crystalline form XVII of Formula 1 compound also has one or more of the following characteristics:

[0153] 1) Basically as Figure 53 The TGA diagram shown;

[0154] 2) Basically as Figure 54 The DSC diagram shown; and / or

[0155] 3) Basically as Figure 55 The DVS diagram shown.

[0156] 18) The crystalline form of the hydrochloride salt of compound 1 is XVIII

[0157] In one embodiment, the form is the crystalline form of the hydrochloride salt of Formula 1, XVIII, which has characteristic peaks at the following locations in an XRPD plot expressed at 2θ angles: 6.677±0.2°, 11.138±0.2°, 16.060±0.2°, 20.062±0.2°, 20.637±0.2°, and 21.559±0.2°.

[0158] In a preferred embodiment, the hydrochloride crystalline form of compound XVIII of formula 1 has XRPD characteristic peaks at positions substantially as shown in Table 8 below and / or substantially as shown in Table 8 below. Figure 56 The XRPD diagram shown.

[0159] Table 8

[0160]

[0161]

[0162] In a preferred embodiment, the crystalline form of the hydrochloride salt of compound 1, XVIII, also has one or more of the following characteristics:

[0163] 1) Basically as Figure 57 The TGA diagram shown; and / or

[0164] 2) Basically as Figure 58 The DSC diagram shown;

[0165] 19) Compound 1, hydrobromide, amorphous form XIX

[0166] In one embodiment, the form is the amorphous form XIX of the hydrobromide of Formula 1. In one embodiment, it has essentially the following characteristics: Figure 59 The XRPD diagram shown.

[0167] In a preferred embodiment, the amorphous form XIX of the hydrobromide of Formula 1 further has one or more of the following characteristics:

[0168] 1) Basically as Figure 60 The TGA diagram shown; and / or

[0169] 2) Basically as Figure 61 The DSC diagram shown;

[0170] 20) The crystalline form of the hydrobromide of compound 1 is XX.

[0171] In one embodiment, the form is the hydrobromide crystalline form XX of Formula 1, which has characteristic peaks at the following positions in an XRPD plot expressed in 2θ angles: 5.074±0.2°, 11.757±0.2°, 13.838±0.2°, 16.901±0.2°, 20.602±0.2°, and 25.440±0.2°.

[0172] In a preferred embodiment, the hydrobromide crystalline form of compound XX of formula 1 has XRPD characteristic peaks at positions substantially as shown in Table 9 below and / or substantially as shown in Table 9 below. Figure 62 The XRPD diagram shown.

[0173] Table 9

[0174]

[0175]

[0176]

[0177] In a preferred embodiment, the hydrobromide crystalline form XX of Formula 1 further has one or more of the following characteristics:

[0178] 1) Basically as Figure 63 The TGA diagram shown; and / or

[0179] 2) Basically as Figure 64 The DSC diagram shown.

[0180] 21) The hydrobromide crystal form of compound 1 is XXI

[0181] In one embodiment, the form is the hydrobromide crystalline form XXI of Formula 1, which has characteristic peaks at the following positions in an XRPD plot expressed in 2θ angles: 8.141±0.2°, 8.695±0.2°, 12.157±0.2°, 12.805±0.2°, 13.860±0.2°, and 17.263±0.2°.

[0182] In a preferred embodiment, the hydrobromide crystalline form XXI of compound 1 has XRPD characteristic peaks at positions substantially as shown in Table 10 below and / or substantially as shown in Table 10 below. Figure 65 The XRPD diagram shown.

[0183] Table 10

[0184]

[0185]

[0186] In a preferred embodiment, the hydrobromide crystalline form XXI of Formula 1 further has one or more of the following characteristics:

[0187] 1) Basically as Figure 66 The TGA diagram shown; and / or

[0188] 2) Basically as Figure 67 The DSC diagram shown.

[0189] 22) The hydrobromide crystal form of compound XXII (Formula 1)

[0190] In one embodiment, the form is the hydrobromide crystalline form XXII of Formula 1, which has characteristic peaks at the following positions in an XRPD plot expressed in 2θ angles: 6.557±0.2°, 6.900±0.2°, 15.920±0.2°, 17.140±0.2°, 17.781±0.2°, and 19.860±0.2°.

[0191] In a preferred embodiment, the hydrobromide crystalline form XXII of compound 1 has XRPD characteristic peaks at positions substantially as shown in Table 11 below and / or substantially as shown in Table 11 below. Figure 68 The XRPD diagram shown.

[0192] Table 11

[0193]

[0194]

[0195] In a preferred embodiment, the hydrobromide crystalline form XXII of Formula 1 further has one or more of the following characteristics:

[0196] 1) Basically as Figure 69 The TGA diagram shown; and / or

[0197] 2) Basically as Figure 70 The DSC diagram shown.

[0198] 23) The crystalline form of the methanesulfonate of compound 1 is XXIII

[0199] In one embodiment, the form is the crystalline form XXIII of the methanesulfonate of Formula 1, which has characteristic peaks at the following locations in an XRPD plot expressed in 2θ angles: 5.203±0.2°, 9.640±0.2°, 13.970±0.2°, 16.731±0.2°, and 19.716±0.2°.

[0200] In a preferred embodiment, the crystalline form of the methanesulfonate of Formula 1, XXIII, has essentially the following characteristics:

[0201] The XRPD characteristic peaks and / or substantially similar at the locations shown in Table 12 are as follows: Figure 71 The XRPD diagram shown.

[0202]

[0203]

[0204] In a preferred embodiment, the crystalline form of the methanesulfonate of Formula 1, XXIII, also has one or more of the following characteristics:

[0205] 1) Basically as Figure 72 The TGA diagram shown; and / or

[0206] 2) Basically as Figure 73 The DSC diagram shown.

[0207] 24) The crystalline form of the methanesulfonate of compound 1 is XXIV.

[0208] In one embodiment, the form is the crystalline form XXIV of the methanesulfonate of Formula 1, which has characteristic peaks at the following locations in an XRPD plot expressed in 2θ angles: 12.235±0.2°, 17.980±0.2°, 18.584±0.2°, and 20.511±0.2°.

[0209] In a preferred embodiment, the methanesulfonate crystalline form of compound XXIV of formula 1 has XRPD characteristic peaks at positions substantially as shown in Table 13 below and / or substantially as shown in Table 13 below. Figure 74 The XRPD diagram shown.

[0210] Table 13

[0211]

[0212]

[0213] In a preferred embodiment, the crystalline form XXIV of the methanesulfonate of Formula 1 also has one or more of the following characteristics:

[0214] 1) Basically as Figure 75 The TGA diagram shown; and / or

[0215] 2) Basically as Figure 76 The DSC diagram shown.

[0216] 25) Formula 1 compound sulfate crystal form XXV

[0217] In one embodiment, the form is the sulfate crystalline form XXV of Formula 1 compound, which has characteristic peaks at the following locations in an XRPD plot expressed in 2θ angles: 4.054±0.2°, 11.785±0.2°, 13.286±0.2° and 15.680±0.2°.

[0218] In a preferred embodiment, the sulfate crystalline form of compound XXV of formula 1 has XRPD characteristic peaks at positions substantially as shown in Table 14 below and / or substantially as shown in Table 14 below. Figure 77 The XRPD diagram shown.

[0219] Table 14

[0220]

[0221]

[0222] In a preferred embodiment, the sulfate crystalline form XXV of Formula 1 compound also has one or more of the following characteristics:

[0223] 1) Basically as Figure 78 The TGA diagram shown; and / or

[0224] 2) Basically as Figure 79 The DSC diagram shown.

[0225] 26) Formula 1 compound sulfate crystal form XXVI

[0226] In one embodiment, the form is the sulfate crystalline form XXVI of Formula 1, which has characteristic peaks at the following positions in an XRPD plot expressed in 2θ angles: 7.266±0.2°, 9.275±0.2°, 10.713±0.2°, 14.219±0.2° and 18.583±0.2°.

[0227] In a preferred embodiment, the sulfate crystalline form of compound XXV of formula 1 has XRPD characteristic peaks at positions substantially as shown in Table 15 below and / or substantially as shown in Table 15 below. Figure 80 The XRPD diagram shown.

[0228] Table 15

[0229]

[0230] In a preferred embodiment, the sulfate crystalline form XXVI of Formula 1 compound also has one or more of the following characteristics:

[0231] 1) Basically as Figure 81 The TGA diagram shown; and / or

[0232] 2) Basically as Figure 82 The DSC diagram shown.

[0233] In a second aspect, the present invention provides a method for preparing amorphous or crystalline forms of compounds of Formula 1 or their salts or solvates.

[0234] In one embodiment, the present invention provides a method for preparing an amorphous or crystalline form of a salt of Formula 1 compound, comprising the following steps: reacting a compound of Formula 1 with an acid or base in an organic solvent, and then preparing the corresponding amorphous or crystalline form. The method for preparing the crystalline or amorphous form of the salt of Formula 1 compound can be a method well known in the art, such as suspension and stirring, stirring at room temperature, heating and cooling to crystallize, solvent evaporation, or antisolvent addition.

[0235] In the preparation method, the compound of Formula 1 can be obtained through various means, such as commercial purchase or laboratory synthesis. The acid can be a pharmaceutically acceptable acid or an acid commonly found in the art, and can be an inorganic or organic acid. The inorganic acid is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. The organic acid is preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, L-tartaric acid, fumaric acid, citric acid, malic acid, or succinic acid, more preferably hydrobromic acid, L-tartaric acid, fumaric acid, or maleic acid, and even more preferably hydrobromic acid or maleic acid. The molar ratio of the compound of Formula 1 to the acid is 1:(1-1.5), preferably 1:(1-1.2).

[0236] In the preparation method, the organic solvent can be one or more commonly used laboratory organic solvents, such as: alkane solvents, alcohol solvents, ketone solvents, ester solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, nitrile solvents, ether solvents, aliphatic hydrocarbon solvents, and polar aprotic solvents such as DMF and DMSO. Preferably, C1-C6 alcohols, ketone solvents, and ester solvents are preferred, and more preferably methanol, ethanol, isopropanol, acetone, 2-butanone, ethyl acetate, and isopropyl acetate. The mass-to-volume ratio of the compound of Formula 1 to the organic solvent is 100 mg:(0.1-1 mL), preferably 100 mg:(0.4-1 mL), and even more preferably 100 mg:0.6 mL or 100 mg:0.8 mL.

[0237] In the preparation method, the reaction temperature can be from room temperature to solvent reflux temperature.

[0238] In the preparation method, there is no special limitation on the crystallization time, as long as crystals can be precipitated, and the reaction time can be 1 hour to 36 hours.

[0239] In one embodiment, the present invention also provides a method for preparing an amorphous or crystalline form of a salt of compound of formula 1, which preferably includes the following steps: mixing a compound of formula 1 with an organic solvent, then adding a mixture of an acid and an organic solvent, stirring thoroughly, and filtering. The mixing before adding the acid is preferably carried out under stirring. After filtration, drying is preferably performed, preferably under vacuum drying, at a temperature preferably 40-60°C, for example, 50°C.

[0240] In one embodiment, the present invention also provides a method for preparing an amorphous or crystalline form of a salt of compound of formula 1, comprising the following steps: reacting a compound of formula 1 with a base in an organic solvent.

[0241] In the preparation method, the organic solvent can be a commonly used organic solvent in the laboratory, such as: alkane solvent, alcohol solvent, ketone solvent, preferably alcohol solvent, and more preferably methanol, ethanol, isopropanol, wherein the mass-volume ratio of the compound of formula 1 to the organic solvent is 100mg:(0.1-1mL), preferably 100mg:(0.4-1mL), and even more preferably 100mg:0.6mL, 100mg:0.8mL.

[0242] In the preparation method, the base is a commonly used alkali metal hydroxide in the art, such as LiOH, NaOH, KOH, and the molar ratio of the compound of Formula 1 to the base is 1:(1-1.5), preferably 1:(1-1.2).

[0243] In one embodiment, the present invention also provides a method for preparing an amorphous or crystalline form of a solvate of Formula 1, comprising the steps of contacting or reacting the Formula 1 compound with a solvent, and then preparing the corresponding amorphous or crystalline form. The method for preparing the amorphous or crystalline form of the solvate of Formula 1 can be a method well known in the art, such as suspension and stirring, stirring at room temperature, heating and cooling to crystallize, solvent evaporation, or crystallization with a mixed solvent.

[0244] In the preparation method, the solvent is preferably one or more selected from water, isopropyl ether, trifluoroethanol, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, toluene, and methylcyclohexane, wherein the mass-volume ratio of the compound of formula 1 to the solvent is 100 mg:(1-15 mL), preferably 100 mg:(2-12 mL).

[0245] In the preparation method, the crystallization temperature can be a temperature conventional in the art, such as 20-50°C.

[0246] In the preparation method, there is no special limitation on the crystallization time, as long as crystals can be precipitated, for example, 1-48 hours.

[0247] In one embodiment, the present invention also provides a method for preparing an amorphous or crystalline form of a compound of Formula 1, comprising the steps of contacting or reacting the compound of Formula 1 with a solvent, and then preparing the corresponding amorphous or crystalline form. The method for preparing the amorphous or crystalline form of the compound of Formula 1 may be a method well known in the art, such as suspension and stirring, stirring at room temperature, heating and cooling to crystallize, solvent evaporation, or antisolvent addition.

[0248] In the preparation method described above, the solvent can be water or an organic solvent commonly used in laboratories in the art, such as one or more of the following: alkane solvents, alcohol solvents, ketone solvents, ester solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, nitrile solvents, ether solvents, aliphatic hydrocarbon solvents, acetonitrile, DMF, and DMSO. Preferably, it is one or more of the following: alkane solvents, alcohol solvents, ketone solvents, ester solvents, halogenated hydrocarbon solvents, ether solvents, acetonitrile, nitromethane, and aromatic hydrocarbon solvents. More preferably, it is one or more of the following: n-heptane, methanol, ethanol, n-propanol, isopropanol, n-butanol, trifluoroethanol, acetone, 2-butanone, ethyl acetate, isopropyl acetate, isopropyl ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, acetonitrile, nitromethane, toluene, DMF, and DMSO. The mass-to-volume ratio of the compound of Formula 1 to the organic solvent is 100 mg:(0.1-3 mL).

[0249] In the preparation method, the crystallization temperature can be a temperature conventional in the art, such as 20-50°C.

[0250] In the preparation method, there is no special limitation on the crystallization time, as long as crystals can be precipitated, for example, 1-48 hours.

[0251] The solvent evaporation method described in this invention involves evaporating the clarified sample solution in an open container at different temperatures until the solvent evaporates completely.

[0252] The suspension stirring described in this invention involves stirring a supersaturated solution of a sample (containing insoluble solids) in different solvents for a period of time.

[0253] The heating and cooling crystallization method described in this invention involves dissolving the sample in a suitable solvent under high temperature conditions, filtering, and then stirring the filtrate at room temperature or low temperature to precipitate the crystals.

[0254] The mixed solvent crystallization method described in this invention involves dissolving a sample in a suitable solvent, adding another one or more solvents, stirring the precipitated solid system briefly, and then filtering it.

[0255] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula 1 above, or a salt thereof, a solvate thereof, in an amorphous or crystalline form, and pharmaceutically acceptable excipients.

[0256] The amorphous or crystalline form of the compound of Formula 1 or its salts or solvates may be a therapeutically effective amount. The pharmaceutically acceptable excipients may be excipients well known in the art, and in the case of solid dosage forms, include, but are not limited to: diluents, binders, disintegrants, lubricants, flow aids, release rate controllers, plasticizers, preservatives, antioxidants, etc.

[0257] The pharmaceutical composition may be selected in a dosage form suitable for human administration, such as tablets, capsules, granules, powders, or pills, preferably tablets, capsules, granules, disintegrating tablets, sustained-release or controlled-release tablets, etc.

[0258] The pharmaceutical composition of the present invention can be prepared by various methods known in the art, which can be prepared by mixing one or more of the amorphous or crystalline forms of the compound of Formula 1 or its salts or solvates in a therapeutically effective amount with one or more pharmaceutically acceptable excipients into a dosage form suitable for human administration, such as tablets, capsules, granules, etc.

[0259] "Therapeutic effective amount" means an amount of the compound form according to the invention that, when administered to a patient in need, is sufficient to achieve the treatment of a disease state, symptom, or disorder for which the compound is effective. Such an amount would be sufficient to elicit a biological or medical response in the tissue system or patient sought by the researcher or clinician.

[0260] In a fourth aspect, the present invention provides the use of the above-described compound of Formula 1 or its salts, solvates, in amorphous or crystalline form, or the above-described pharmaceutical composition, in the preparation of a medicament for the prevention and / or treatment of hyperproliferative diseases.

[0261] In one embodiment, the drug is preferably used for the prevention and / or treatment of cancer, including but not limited to adrenocortical carcinoma, advanced cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastases, adult brain / CNS tumors, pediatric brain / CNS tumors, breast cancer, male breast cancer, childhood cancer, unknown primary cancer, Castleman disease, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, Ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, and Hodgkin's disease. Diseases including: Kaposi's sarcoma, renal cell carcinoma, laryngeal and hypopharyngeal cancer, adult acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloid monocytic leukemia (CMML), childhood leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, lung carcinoid tumors, cutaneous lymphoma, malignant mesothelioma, multiple myeloma, and myelodysplastic syndrome. Nasal cavity and paranasal sinus carcinoma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, childhood non-Hodgkin lymphoma, oral and oropharyngeal carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary adenoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma-adult soft tissue cancer, basal skin cancer and squamous cell skin cancer, skin cancer-melanoma, small intestine cancer, gastric cancer, testicular cancer, thymic cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, or Wilms tumor.

[0262] The amorphous or crystalline forms of the compound of Formula 1 or its salts or solvates of the present invention have the following advantages:

[0263] 1. This invention is the first to discover a variety of previously unreported amorphous or crystalline forms of the compound of Formula 1 or its salts and solvates, which can serve as an important basis for subsequent drug development, formulation development and production.

[0264] 2. Through extensive experimentation and screening, this invention selected forms V, VI, XI, and XVI as candidate formulations. Forms V, VI, XI, and XVI exhibit good physical stability, are easy to store, and can avoid the risk of transcrystalline formation during drug development or production, thus preventing changes in bioavailability and efficacy. Therefore, they can be developed into dosage forms suitable for clinical use and commercial production. Furthermore, their preparation methods are simple, reproducible, and possess high development value. Attached Figure Description

[0265] Figure 1 The image shows the XRD pattern of the amorphous form I of the sulfate of compound formula 1.

[0266] Figure 2 The image shows the TGA diagram of the amorphous form I of the sulfate of compound formula 1.

[0267] Figure 3 The image shows the DSC diagram of the amorphous form I of the sulfate of compound formula 1.

[0268] Figure 4 The diagram shows the DVS diagram of the amorphous form I of the sulfate of compound formula 1.

[0269] Figure 5 The isothermal adsorption curves are for the amorphous form I of the sulfate of compound formula 1.

[0270] Figure 6 The image shows the XRD pattern of the amorphous form II of the hydrochloride salt of compound formula 1.

[0271] Figure 7 The image shows the XPRD diagram of the hydrochloride form III of compound formula 1.

[0272] Figure 8 The image shows the TGA diagram of the hydrochloride form III of compound formula 1.

[0273] Figure 9 This is the DSC diagram of the hydrochloride salt of compound formula 1 in crystalline form III.

[0274] Figure 10 The image shows the XPRD diagram of the hydrochloride form IV of compound formula 1.

[0275] Figure 11 The image shows the XPRD diagram of maleate salt V, a compound of formula 1.

[0276] Figure 12 The image shows the TGA diagram of maleate crystal form V of compound formula 1.

[0277] Figure 13 The image shows the DSC diagram of maleate salt V, a compound of formula 1.

[0278] Figure 14 The image shows the DVS diagram of maleate crystal form V of compound formula 1.

[0279] Figure 15 The image shows the XPRD diagram of the crystalline form VI of the hydrobromide of compound formula 1.

[0280] Figure 16 TGA diagram of the crystalline form VI of compound 1, hydrobromide.

[0281] Figure 17 The image shows the DSC diagram of the hydrobromide crystalline form VI of compound formula 1.

[0282] Figure 18 The image shows the DVS diagram of VI, the crystalline form of the hydrobromide of compound formula 1.

[0283] Figure 19 The image shows the XRD pattern of the amorphous form VII of the methanesulfonate compound of Formula 1.

[0284] Figure 20 The image shows the XRD pattern of the amorphous form VIII of the sodium salt of compound formula 1.

[0285] Figure 21 The TGA image is of the amorphous form VIII of the sodium salt of compound 1.

[0286] Figure 22 The image shows the DSC diagram of the amorphous form VIII of the sodium salt of compound 1.

[0287] Figure 23 The diagram shows the DVS diagram of the amorphous form VIII of the sodium salt of compound 1.

[0288] Figure 24 The image shows the XRD pattern of the amorphous form IX of the potassium salt of compound 1.

[0289] Figure 25 The image shows the TGA diagram of the amorphous form IX of the potassium salt of compound 1.

[0290] Figure 26 The image shows the DSC diagram of the amorphous form IX of the potassium salt of compound 1.

[0291] Figure 27 The diagram shows the DVS diagram of the amorphous form IX of the potassium salt of compound 1.

[0292] Figure 28 The image shows the XPRD diagram of the crystalline form X of compound 1.

[0293] Figure 29 The image shows the TGA diagram of the crystalline form X of compound 1.

[0294] Figure 30 The image shows the DSC diagram of crystalline form X of compound 1.

[0295] Figure 31 The image shows the DVS diagram of crystalline form X of compound 1.

[0296] Figure 32 The image shows the XPRD diagram of the monohydrate crystalline form XI of compound 1.

[0297] Figure 33 TGA diagram of the monohydrate crystalline form XI of compound 1.

[0298] Figure 34 The image shows the DSC diagram of the monohydrate crystalline form XI of compound 1.

[0299] Figure 35 The image shows the DVS diagram of the monohydrate crystalline form XI of compound 1.

[0300] Figure 36 The image shows the XPRD diagram of the crystalline form XII of the di-trifluoroethanol solvate of compound 1.

[0301] Figure 37 TGA image of the crystalline form XII of the di-trifluoroethanol solvate of compound 1.

[0302] Figure 38 The image shows the DSC diagram of the crystalline form XII of the di-trifluoroethanol solvate of compound 1.

[0303] Figure 39 The image shows the XPRD diagram of the crystalline form XIII of the dimethyl sulfoxide solvent compound of Formula 1.

[0304] Figure 40 TGA image of the crystalline form XIII of the dimethyl sulfoxide solvent compound of Formula 1.

[0305] Figure 41 The image shows the DSC diagram of the crystalline form XIII of the dimethyl sulfoxide solvent compound of Formula 1.

[0306] Figure 42 The image shows the XPRD diagram of the crystalline form XIV of the hemimethylcyclohexane solvent compound of Formula 1.

[0307] Figure 43 TGA image of compound XIV, a solvent compound of formula 1 in hemimethylcyclohexane.

[0308] Figure 44 The image shows the DSC diagram of compound XIV, a solvent compound of formula 1 in hemimethylcyclohexane, in its crystalline form.

[0309] Figure 45 The image shows the XPRD diagram of the crystalline form XV of the semi-tetrahydrofuran solvent compound of Formula 1.

[0310] Figure 46 TGA image of the crystalline form XV of the semi-tetrahydrofuran solvent compound of Formula 1.

[0311] Figure 47 The image shows the DSC diagram of the crystalline form XV of the semi-tetrahydrofuran solvent compound of Formula 1.

[0312] Figure 48 The image shows the XRD pattern of the amorphous form XVI of compound formula 1.

[0313] Figure 49 The image shows the TGA diagram of the amorphous form XVI of compound formula 1.

[0314] Figure 50 The image shows the DSC diagram of the amorphous form XVI of compound formula 1.

[0315] Figure 51 The image shows the DVS diagram of the amorphous form XVI of compound formula 1.

[0316] Figure 52 The image shows the XRD pattern of the crystalline form XVII of compound formula 1.

[0317] Figure 53 TGA diagram of the crystalline form XVII of compound 1.

[0318] Figure 54 The image shows the DSC diagram of the crystalline form XVII of compound 1.

[0319] Figure 55 The diagram shows the DVS diagram of the crystalline form XVII of compound 1.

[0320] Figure 56 The image shows the XRD pattern of the hydrochloride form XVIII of compound formula 1.

[0321] Figure 57 TGA image of the crystalline form XVIII of compound XVIII hydrochloride of Formula 1.

[0322] Figure 58 The image shows the DSC diagram of the crystalline form XVIII of the hydrochloride salt of compound formula 1.

[0323] Figure 59 The image shows the XRD pattern of the amorphous form XIX of the hydrobromide of compound 1.

[0324] Figure 60 TGA diagram of the amorphous form XIX of the hydrobromide of compound 1.

[0325] Figure 61 The image shows the DSC diagram of the amorphous form XIX of the hydrobromide of compound 1.

[0326] Figure 62 The image shows the XRD pattern of the hydrobromide crystalline form XX of compound 1.

[0327] Figure 63 The image shows the TGA diagram of the hydrobromide crystal form XX of compound 1.

[0328] Figure 64 The image shows the DSC diagram of the hydrobromide crystalline form XX of compound 1.

[0329] Figure 65 The image shows the XRD pattern of XXI, the crystalline form of the hydrobromide of compound formula 1.

[0330] Figure 66 The image shows the TGA graph of XXI, the crystalline form of the hydrobromide of compound 1.

[0331] Figure 67 The image shows the DSC diagram of XXI, the crystalline form of the hydrobromide of compound formula 1.

[0332] Figure 68 The image shows the XRD pattern of the hydrobromide crystalline form XXII of compound 1.

[0333] Figure 69 The image shows the TGA diagram of the crystalline form XXII of the hydrobromide salt of compound XXII (Formula 1).

[0334] Figure 70 The image shows the DSC diagram of the hydrobromide crystalline form XXII of compound 1.

[0335] Figure 71 The image shows the XRD pattern of the crystalline form XXIII of compound 1, methanesulfonate.

[0336] Figure 72 The image shows the TGA diagram of the crystalline form XXIII of compound 1, methanesulfonate.

[0337] Figure 73 The image shows the DSC diagram of the crystalline form XXIII of compound 1, methanesulfonate.

[0338] Figure 74 The image shows the XRD pattern of the crystalline form XXIV of compound 1, methanesulfonate.

[0339] Figure 75 The image shows the TGA diagram of the crystalline form XXIV of compound 1, methanesulfonate.

[0340] Figure 76 The image shows the DSC diagram of the crystalline form XXIV of compound 1, methanesulfonate.

[0341] Figure 77 The image shows the XRD pattern of the sulfate crystalline form XXV of compound 1.

[0342] Figure 78 The image shows the TGA graph of the sulfate form XXV of compound 1.

[0343] Figure 79 The image shows the DSC diagram of the sulfate crystalline form XXV of compound formula 1.

[0344] Figure 80 The image shows the XRD pattern of the sulfate form XXVI of compound 1.

[0345] Figure 81 The image shows the TGA diagram of the sulfate form XXVI of compound 1.

[0346] Figure 82 The image shows the DSC diagram of the sulfate crystalline form XXVI of compound formula 1. Detailed Implementation

[0347] Example

[0348] In the following examples, the experimental methods were performed under conventional conditions or conventional testing conditions, and the compounds used in the examples were obtained by commercially available or self-made methods.

[0349] Example 1: Preparation of amorphous form I of the sulfate of compound formula 1

[0350] Weigh 100 mg of compound 1 and add 0.4 mL of isopropanol to dissolve by sonication. Weigh 18 mg of concentrated sulfuric acid (approximately 1.2 equivalents) and dissolve it in 0.2 mL of isopropanol. Add the acid solution to the sample solution and stir overnight at room temperature. Then add 3.0 mL of isopropanol and continue stirring for 3 days. The system is an emulsion. The solid can be separated by centrifugation for more than 30 minutes. The solid is dried at 50 °C to obtain the amorphous form I of the sulfate of compound 1.

[0351] Example 2: Preparation of the amorphous form II of the hydrochloride salt of compound formula 1

[0352] Weigh 100 mg of compound 1 and dissolve it in 0.4 mL of acetone by sonication. Weigh 18 mg of concentrated hydrochloric acid (approximately 1.2 equivalents) and dissolve it in 0.2 mL of acetone. Add the acid solution to the sample solution and stir overnight at room temperature. The system becomes viscous. Add 3.0 mL of acetone and continue stirring overnight. Centrifuge and incubate the solid at 50 °C overnight to obtain the amorphous form II of the hydrochloride salt of compound 1.

[0353] Example 3: Preparation of the crystalline form III of the hydrochloride salt of compound formula 1

[0354] Weigh 100 mg of compound 1, add 1.6 mL of ethyl acetate and heat to 65 °C to dissolve. Weigh 19 mg of concentrated hydrochloric acid (approximately 1.2 equivalents) and dissolve in 0.2 mL of ethyl acetate. Add the acid solution to the sample solution, add 2.0 mL of ethyl acetate and keep stirring at 65 °C for 10 minutes. Then stop heating and let it cool naturally to room temperature and stir for 2 days. Centrifuge and dry the solid at 50 °C to obtain the crystalline form III of the hydrochloride salt of compound 1.

[0355] Example 4: Preparation of the crystalline form IV of the hydrochloride salt of compound formula 1

[0356] Weigh out the hydrochloride crystal form III of compound 1, heat it to 180℃ to remove the solvent, and obtain the anhydrous hydrochloride crystal form IV of compound 1, which has a poor crystal morphology.

[0357] Example 5: Preparation of maleate salt V of Formula 1

[0358] Weigh 100 mg of compound 1, add 0.8 mL of ethyl acetate and heat to 65 °C. Weigh 22 mg of maleic acid (approximately 1.2 equivalents), dissolve it in 0.2 mL of ethyl acetate at 65 °C, add the acid solution to the sample solution, keep warm and stir for 1 hour, then stop heating and let it cool naturally to room temperature and stir overnight. A large amount of solid precipitates out. Centrifuge and dry the solid at 50 °C to obtain the crystalline form V of maleate of compound 1.

[0359] Example 6: Preparation of the crystalline form VI of the hydrobromide of Formula 1

[0360] Weigh 100 mg of compound 1 and dissolve it in 0.4 mL of acetone by sonication. Weigh 38 mg of 40% hydrobromic acid (approximately 1.2 equivalents) and dissolve it in 0.2 mL of acetone. Add the acid solution to the sample solution and stir overnight at room temperature. After a large amount of turbidity is generated, add 0.4 mL of acetone and continue stirring for 5 hours. Centrifuge and dry the solid at 50 °C to obtain the crystalline form VI of hydrobromide of compound 1.

[0361] Example 7: Preparation of the amorphous form VII of the methanesulfonate of Formula 1

[0362] Weigh 100 mg of compound 1 and dissolve it in 0.4 mL of isopropanol by sonication. Weigh 22 mg of methanesulfonic acid (approximately 1.2 equivalents) and dissolve it in 0.2 mL of isopropanol. Add the acid solution to the sample solution and stir at 4 °C for 3 days. No solid precipitates. Add 1.0 mL of isopropyl ether and 0.4 mL of isopropanol. The system becomes heavily turbid. After stirring at room temperature for 6 hours, centrifuge. Dry the solid at 50 °C to obtain the amorphous form VII of methanesulfonate of compound 1.

[0363] Example 8: Preparation of the amorphous form VIII of the sodium salt of Formula 1

[0364] Weigh out 100 mg of compound 1, add 0.4 mL of ethanol and sonicate to dissolve. Add 7.5 mg of sodium hydroxide solid (approximately 1.2 equivalents), stir at room temperature to dissolve, and stir overnight without any solid precipitation. Add 2.0 mL of isopropyl ether, and a large amount of solid precipitates. Continue stirring overnight and then centrifuge. Dry the solid at 50 °C to obtain the amorphous form VIII of sodium salt of compound 1.

[0365] Example 9: Preparation of the amorphous form IX of the potassium salt of Formula 1

[0366] Weigh out 100 mg of compound 1, add 0.4 mL of ethanol and sonicate to dissolve. Add 13 mg of potassium hydroxide solid (approximately 1.2 equivalents), stir at room temperature to dissolve, and stir overnight without any solid precipitation. Add 2.0 mL of isopropyl ether, stir at room temperature overnight, and a solid precipitates. Add 2.0 mL of isopropyl ether and continue stirring for 3 hours. Centrifuge and dry the solid at 50 °C to obtain the amorphous form of potassium salt IX.

[0367] Example 10: Preparation of crystalline form X of compound of formula 1

[0368] Weigh out 100 mg of compound 1, add 2.0 mL of isopropyl acetate, stir at 4 °C for 4 days, and air dry at room temperature to obtain crystalline form X of compound 1.

[0369] Example 11: Preparation of the crystalline form XI of the monohydrate of compound 1

[0370] Weigh out 100 mg of compound 1, add 2.0 mL of isopropyl ether, stir at 4 °C for 4 days, and air dry at room temperature to obtain the monohydrate crystalline form XI of compound 1.

[0371] Example 12: Preparation of the crystalline form XII of compound 1, ditrifluoroethanol

[0372] Weigh 100 mg of compound 1 and place it in a bottle containing 5.0 mL of trifluoroethanol. Let it stand at room temperature for 7 days to obtain the crystalline form of compound 1, ditrifluoroethanol, XII.

[0373] Example 13: Preparation of the crystalline form XIII of the half-dimethyl sulfoxide solvent compound of Formula 1

[0374] Weigh out 100 mg of compound 1, add 0.6 mL of acetonitrile and 0.3 mL of dimethyl sulfoxide, place it at 40 °C for 1 day to form a crystallizing slurry, and take the solid and air dry at room temperature to obtain the crystalline form of the dimethyl sulfoxide solvent compound XIII of compound 1.

[0375] Example 14: Preparation of the crystalline form XIV of the hemimethylcyclohexane solvent compound of Formula 1

[0376] Weigh 100 mg of compound 1, add 1.0 mL of ethyl acetate and sonicate to dissolve. Add the supernatant dropwise to 10.0 mL of methylcyclohexane. The solid precipitates immediately. After stirring for 5 minutes, centrifuge to obtain the crystalline form of the hemimethylcyclohexane solvent compound XIV of compound 1.

[0377] Example 15: Preparation of the crystalline form XV of the semi-tetrahydrofuran solvent compound of Formula 1

[0378] Weigh out 50 mg of compound 1 and place it in a bottle containing 3.0 mL of tetrahydrofuran. Let it stand at room temperature for 3 days to obtain the semi-tetrahydrofuran solvent compound XV of compound 1.

[0379] Example 16: Preparation of the amorphous form XVI of compound 1

[0380] Weigh out 50 mg of compound 1, add 0.2 mL of methanol, and let stand at room temperature for 3 days to obtain the amorphous form XVI of compound 1.

[0381] Example 17: Preparation of the crystalline form XVII of compound 1

[0382] Weigh 100 mg of compound 1 into a 20 mL glass bottle, add 9.5 mL of pure acetonitrile, shake for 10 s, and the compound gradually dissolves. After standing for a period of time, a large amount of solid precipitates. Add a stir bar and stir overnight, then centrifuge and discard the supernatant to obtain the crystalline form of compound 1, XVII.

[0383] Example 18: Preparation of the crystalline form XVIII of the hydrochloride salt of compound 1

[0384] Weigh 40-50 mg of the amorphous form II of compound hydrochloride into a 4 mL glass bottle, add a stir bar, add 500 μl of tetrahydrofuran, stir the resulting suspension at 40 °C for 6 days, centrifuge rapidly, and dry the residual solid in a vacuum drying oven (-0.1 MPa, 25 °C) to obtain the crystalline form XVIII of compound hydrochloride of formula 1.

[0385] Example 19: Preparation of the amorphous form XIX of the hydrobromide of Formula 1

[0386] Weigh 1.0 g of compound 1 into a 40 mL glass bottle, add 10 mL of acetone to dissolve it, then add 230.6 mg of hydrobromic acid (diluted with 2 mL of acetone). After stirring overnight, no precipitation occurred. After adding 10 mL of the antisolvent ethyl acetate, a solid precipitated. The sample solution was stirred for another day and then rapidly centrifuged. The remaining solid was dried under vacuum (-0.1 MPa, 40 °C) to obtain the amorphous form of hydrobromide of compound 1, XIX.

[0387] Example 20: Preparation of the crystalline form XX of the hydrobromide of Formula 1

[0388] Weigh 40-50 mg of the amorphous form XIX of compound 1 hydrobromide into a 4 mL glass bottle, add a stir bar, add 500 μl of methanol, stir the resulting suspension at 40 °C for 6 days, centrifuge rapidly, and dry the residual solid in a vacuum drying oven (-0.1 MPa, 25 °C) to obtain the crystalline form XX of compound 1 hydrobromide.

[0389] Example 21: Preparation of the crystalline form XXI of the hydrobromide of Formula 1

[0390] Weigh 40-50 mg of the amorphous form XIX of the hydrobromide of Formula 1 into a 4 mL glass bottle, add a stir bar, add 500 μl of acetonitrile, stir the resulting suspension at 40 °C for 6 days, centrifuge rapidly, and dry the residual solid in a vacuum drying oven (-0.1 MPa, 25 °C) to obtain the crystalline form XXI of the hydrobromide of Formula 1.

[0391] Example 22: Preparation of the crystalline form XXII of the hydrobromide of Formula 1

[0392] Weigh 40-50 mg of the amorphous form XIX of the hydrobromide of Formula 1 into a 4 mL glass bottle, add a stir bar, and then add 500 μl of tetrahydrofuran. After stirring the resulting suspension at 40 °C for 6 days, centrifuge rapidly and take the residual solid to dry in a vacuum drying oven (-0.1 MPa, 25 °C) to obtain the crystalline form XXII of the hydrobromide of Formula 1.

[0393] Example 23: Preparation of the crystalline form XXIII of the methanesulfonate of Formula 1

[0394] Weigh 40-50 mg of the amorphous form VII of the methanesulfonate of Formula 1 into a 4 mL glass bottle, add a stir bar, and then add 500 μl of ethanol. After stirring the resulting suspension at 40 °C for 6 days, centrifuge quickly and take the residual solid to dry in a vacuum drying oven (-0.1 MPa, 25 °C) to obtain the crystalline form XXIII of the methanesulfonate of Formula 1.

[0395] Example 24: Preparation of the crystalline form XXIV of the methanesulfonate of Formula 1

[0396] Weigh 40-50 mg of the amorphous form VII of the methanesulfonate of Formula 1 into a 4 mL glass bottle, add a stir bar, and then add 500 μl of 1,4-dioxane. After stirring the resulting suspension at 40 °C for 6 days, centrifuge rapidly and take the residual solid to dry in a vacuum drying oven (-0.1 MPa, 25 °C) to obtain the crystalline form XXIV of the methanesulfonate of Formula 1.

[0397] Example 25: Preparation of the crystalline form XXV of the sulfate of compound 1

[0398] Weigh 40-50 mg of the amorphous form I of the sulfate of Formula 1 into a 4 mL glass bottle, add a stir bar, and then add 500 μl of methanol. After the resulting solution evaporates at room temperature, take the residual solid and dry it in a vacuum drying oven (-0.1 MPa, 25 °C) to obtain the crystalline form XXV of the sulfate of Formula 1.

[0399] Example 26: Preparation of the crystalline form XXVI of the sulfate of compound 1

[0400] Weigh 40-50 mg of the amorphous form I of the sulfate of Formula 1 into a 4 mL glass bottle, add a stir bar, and then add 500 μl of tetrahydrofuran. After stirring the resulting suspension at 40 °C for 3 days, centrifuge rapidly and take the residual solid to dry in a vacuum drying oven (-0.1 MPa, 25 °C) to obtain the crystalline form XXVI of the sulfate of Formula 1.

[0401] Example 27: Identification and characterization of compounds of formula 1 in forms I-XXVI

[0402] The instruments used and their parameters are as follows:

[0403] XPRD—X-ray powder diffraction—was used to characterize the solid using a Bruker D8 Advance Diffractometer. The copper target wavelength was [wavelength missing]. Kα radiation (40kV, 40mA), θ-2θ goniometer, Mo monochromator, Lynxeye detector, detection angle 3-40°2θ / 3-30°2θ, step size 0.02°2θ, speed 0.2s / step, sample amount >2mg.

[0404] TGA—Thermogravimetric analysis, using TA Instruments Q500 TGA, with sample amounts ranging from 1mg to 10mg. Commonly used detection methods are Hi-Res sensitivity 3.0, Ramp 10.00℃ / min, res 5.0 to 150.00℃, and Ramp 10.00℃ / min to 350℃.

[0405] DSC—Differential Scanning Calorimetry, using a TA Instruments Q200 DSC, with sample amounts ranging from 0.5 mg to 5 mg, and a gas flow rate of 40 mL / min. The commonly used detection method is Equilibrate at 20 °C, with a ramp of 10 °C / min up to 280 °C-300 °C.

[0406] DVS—Dynamic Moisture Adsorption-Desorption Analysis—is used for sample volumes of 1 mg to 10 mg and gas flow rates of 10 mL / min. A common testing method involves equilibration at 25°C and 0% humidity for 90 minutes. If the weight percentage is less than 0.0100%, the next isothermal test is stopped for 15 minutes, with a 10% step humidity increment every 90 minutes to 80.00%.

[0407] The characterization results of XPRD, TGA, DSC, and DVS mentioned above are attached. Figure 1-82 Table 1-15 and related textual descriptions.

[0408] Example 28: Competitive Experiment of Crystallization Forms X and XI

[0409] Equal amounts of samples in crystalline form X and crystalline form XI were taken, mixed thoroughly, and sampled for XRD analysis. The samples were then divided into three equal portions, and suspensions were formed by adding acetone / n-heptane (volume ratio 1 / 3 v:v), dichloromethane / n-heptane (volume ratio 1 / 3 v:v), and acetone / water (volume ratio 1 / 3 v:v) to the respective solutions. The suspensions were stirred at room temperature for 1-3 days, centrifuged, and sampled for XRD analysis. The results showed that the mixture of crystalline form X and crystalline form XI was converted to crystalline form XI upon stirring in all three systems. The most stable form at room temperature was crystalline form XI (testing environment humidity 46% RH-52% RH).

[0410] Example 29: Room Temperature Volatile Crystallization Experiment

[0411] Approximately 5 mg of compound of formula 1 was taken and added to the appropriate solvent to obtain a supernatant solution, which was then allowed to evaporate naturally at room temperature. The resulting solid was characterized by XPRD. Specific experiments and results are shown in Table 16 below.

[0412] Table 16

[0413] methanol 0.2 Form XVI ethanol 0.2 Form XVI acetone 0.2 Form XVI Ethyl acetate 0.2 Form XI Tetrahydrofuran 0.2 Form XVI Chloroform 0.2 Form XVI methanol water 1.4 / 0.2 Form XI ethanol water 1.0 / 0.1 Form XI Trifluoroethanol water 0.6 / 0.1 Form XI

[0414] Example 30: High-Temperature Volatilization Crystallization Experiment

[0415] Approximately 5 mg of compound I was taken and added to the appropriate solvent to obtain a clear solution, which was then evaporated to dryness at 40 °C. The resulting solid was characterized by XPRD. Specific experiments and results are shown in Table 17 below.

[0416] Table 17

[0417]

[0418]

[0419] Example 31: Crystallization Experiment with Mixed Solvents

[0420] Take approximately 15 mg of compound 1 and add solvent 1 to obtain a clear solution. Slowly add solvent 2 while stirring. After a solid precipitates, continue stirring for 5 minutes. Take a sample for XPRD characterization. If no solid precipitates, an oily substance is obtained, or the characterization result is an amorphous form, continue stirring overnight and repeat the XPRD characterization the next day. Specific experiments and results are shown in Table 18 below.

[0421] Table 18

[0422] methanol water 0.2 / 0.2 Form XI ethanol water 0.4 / 0.4 Form XI Trifluoroethanol water 0.4 / 0.2 Form XVI Isopropanol water 0.4 / 0.6 Form XI acetone water 0.3 / 0.4 Form XI Tetrahydrofuran water 0.2 / 0.4 Form XVI 1,4-Dioxane water 0.2 / 0.6 Form XI Acetonitrile water 1.5 / 1.0 Form XI dimethyl sulfoxide water 0.2 / 0.4 Form XVI acetone n-Heptane 0.2 / 2.0 Form XI

[0423] Example 32: Heating and Cooling Crystallization Experiment

[0424] Take about 15 mg of compound of formula 1, add solvent at 50℃-60℃ to obtain a clear solution, keep warm for 5 minutes, then place in an ice-salt bath and stir. After the solid precipitates, immediately centrifuge and take the solid sample for XRD characterization. The specific experiments and results are shown in Table 19 below.

[0425] Table 19

[0426]

[0427]

[0428] Example 33: Low-temperature crystallization of slurry

[0429] Take about 15 mg of compound of formula 1, add the corresponding solvent to obtain a suspension, stir at 4°C for 3 hours and 7 days, centrifuge the suspensions respectively, and take the solids for XRD characterization. The specific experiments and results are shown in Table 20 below.

[0430] Table 20

[0431]

[0432] Example 34: Room temperature slurry crystallization

[0433] Approximately 15 mg of compound of formula 1 was taken and added to the appropriate solvent to obtain a suspension. The suspension was stirred at room temperature for 3 hours and 7 days. The suspension after crystallization was centrifuged, and the solid was used for XRD characterization. Specific experiments and results are shown in Table 21 below.

[0434] Table 21

[0435]

[0436]

[0437] Example 35: High-Temperature Crystallization of Crystal Slurry

[0438] Approximately 15 mg of compound 1 was taken and added to the appropriate solvent to obtain a suspension. The suspension was stirred at high temperature for 3 hours and 7 days. The suspension after crystallization was centrifuged, and the solid was used for XRD characterization. Specific experiments and results are shown in Table 22 below.

[0439] Table 22

[0440]

[0441] Example 36: Hygroscopicity Study of Crystal Form XI

[0442] Approximately 10 mg of the crystalline XI sample was used for dynamic moisture adsorption (DVS) testing. The conclusions are shown in Table 23 below:

[0443] Table 23

[0444] Form XI 0.01％ No change

[0445] The above indicates that crystalline form XI does not easily absorb moisture during storage, is easy to preserve, and can extend its shelf life.

[0446] Example 37: Stability test of crystalline form XI (at different temperatures and humidity)

[0447] Sample XI was placed under high temperature and high humidity (75% RH) conditions, and samples were taken at 0 days, 5 days, 10 days, and 30 days to investigate its content, related substances, and crystal form. The results are shown in Table 24.

[0448] Table 24

[0449]

[0450]

[0451] The results showed that the content and purity of form XI remained almost unchanged when sampled at 5, 10 and 30 days under high temperature and high humidity conditions, demonstrating good stability.

[0452] Example 38: Hygroscopicity test of amorphous form XVI

[0453] Approximately 10 mg of amorphous XVI sample was used for dynamic moisture adsorption (DVS) testing. The conclusions are shown in Table 25 below:

[0454] Table 25

[0455] Form XVI 2.32％ No change

[0456] The above indicates that amorphous XVI samples do not easily absorb moisture during storage, are easy to preserve, and can have a long shelf life.

[0457] Example 39: Stability test of amorphous XVI

[0458] Amorphous XVI samples were placed at 60℃, high humidity (90% RH), and under illumination (4500 Lux). Samples were taken at 0, 5, and 10 days to investigate their content, related substances, and crystal form. The results are shown in Table 26.

[0459] Table 26

[0460] 0 days 99.4 0.38 amorphous 5 days - High humidity 102.1 0.40 - 5 days - sunlight 102.4 0.44 - 5 days -60℃ 101.7 0.48 - 10 days - High humidity 101.1 0.40 amorphous 10 days - sunlight 100.4 0.57 amorphous 10 days -60℃ 99.0 0.54 amorphous

[0461] Example 40: Hygroscopicity test of hydrobromide crystal form VI and maleate crystal form V

[0462] Dynamic moisture adsorption (DVS) tests were performed on hydrobromide and maleate crystal samples. The conclusions are shown in Table 27 below:

[0463] Table 27

[0464] Hydrobromide form VI 5.1% (hygroscopic) Not detected Maleate form V 1.2% (slightly hygroscopic) No change

[0465] Example 41: Polymorph Screening Test of Hydrochloride

[0466] Weigh 40-50 mg of Formula 1 compound into a 4 mL glass bottle, add a stir bar, and then add 500 μl of solvent (as shown in Table 28). After stirring the resulting suspension at 40 °C for 6 days, centrifuge quickly and take the residual solid to dry in a vacuum drying oven (-0.1 MPa, 25 °C).

[0467] Table 28

[0468] - initial form Amorphous Form II 1 methanol Amorphous Form II 2 ethanol Amorphous Form II 3 Isopropanol Amorphous Form II 4 Acetonitrile Amorphous Form II 5 acetone Hydrochloride crystal form III 6 Ethyl acetate Amorphous Form II 7 Acetonitrile - water = 1 - 1 Monohydrate crystal form XI 8 Tetrahydrofuran Crystallization form XVIII 9 Toluene Amorphous Form II 10 1,4-Dioxane Amorphous Form II

[0469] Example 42: Polymorphism Screening Test of Hydrobromide

[0470] Weigh 40-50 mg of the amorphous form XIX of the hydrobromide of compound 1 into a 4 mL glass bottle, add a stir bar, and then add 500 μl of solvent (as shown in Table 29 below). After stirring the resulting suspension at 40 °C for 6 days, centrifuge rapidly and take the residual solid to dry in a vacuum drying oven (-0.1 MPa, 25 °C).

[0471] Table 29

[0472] - initial form Amorphous XIX 1 methanol Crystal form XX 2 ethanol Crystallization form VI 3 Isopropanol Amorphous XIX 4 Acetonitrile Crystalline form XXI 5 acetone Amorphous XIX 6 Ethyl acetate Amorphous XIX 7 Acetonitrile - water = 1 - 1 Monohydrate crystal form XI 8 Tetrahydrofuran Crystallization form XXII 9 Toluene Amorphous XIX 10 1,4-Dioxane Amorphous XIX

[0473] Example 43: Polymorph screening of maleate

[0474] Weigh 40-50 mg of the maleate crystal form V of compound 1 into a 4 mL glass bottle, add a stir bar, and then add 500 μl of solvent (as shown in Table 30 below). After stirring the resulting suspension at 40 °C for 6 days, centrifuge rapidly and take the residual solid to dry in a vacuum drying oven (-0.1 MPa, 25 °C).

[0475] Table 30

[0476]

[0477]

[0478] Example 44: Polymorph screening of sodium salts

[0479] Weigh 40-50 mg of the sodium salt of compound 1 in amorphous form VIII into a 4 mL glass bottle, add a stir bar, and then add 500 μl of solvent (as shown in Table 31 below). After stirring the resulting suspension at 40 °C for 6 days, centrifuge rapidly and take the residual solid to dry in a vacuum drying oven (-0.1 MPa, 25 °C).

[0480] Table 31

[0481] - initial form Amorphous VIII 1 methanol Amorphous VIII 2 ethanol Amorphous VIII 3 Isopropanol Amorphous VIII 4 Acetonitrile Amorphous VIII 5 acetone Amorphous VIII 6 Ethyl acetate Amorphous VIII 7 Acetonitrile - water = 1 - 1 Monohydrate crystal form XI 8 Tetrahydrofuran Amorphous VIII 9 Toluene Amorphous VIII 10 1,4-Dioxane Amorphous VIII

[0482] Example 45: Polymorph screening of mesylates

[0483] Weigh 40-50 mg of the amorphous form VII of the methanesulfonate of compound 1 into a 4 mL glass bottle, add a stir bar, and then add 500 μl of solvent (as shown in Table 32 below). After stirring the resulting suspension at 40 °C for 6 days, centrifuge rapidly and take the residual solid to dry in a vacuum drying oven (-0.1 MPa, 25 °C).

[0484] Table 32

[0485]

[0486]

[0487] Example 46: Polymorphic Screening of Potassium Salts

[0488] Weigh 40-50 mg of the potassium salt amorphous form IX of compound 1 into a 4 mL glass bottle, add a stir bar, and then add 500 μl of solvent (as shown in Table 33 below). After stirring the resulting suspension at 40 °C for 3 days, centrifuge quickly and take the residual solid to dry in a vacuum drying oven (-0.1 MPa, 25 °C).

[0489] Table 33

[0490] - initial form Amorphous IX 1 methanol Amorphous IX 2 ethanol Amorphous IX 3 Isopropanol Amorphous IX 4 Acetonitrile Amorphous IX 5 acetone Amorphous IX 6 Ethyl acetate Amorphous IX 7 Tetrahydrofuran Amorphous IX 8 Toluene Amorphous IX 9 1,4-Dioxane Amorphous IX

[0491] Example 47: Polymorph Screening of Sulfates

[0492] Weigh 40-50 mg of the sulfate amorphous form I of compound formula 1 into a 4 mL glass bottle, add a stir bar, and then add 500 μl of solvent (as shown in Table 34 below). After stirring the resulting suspension at 40 °C for 3 days, centrifuge rapidly and take the residual solid to dry in a vacuum drying oven (-0.1 MPa, 25 °C).

[0493] Table 34

[0494] - initial form Amorphous I 1 methanol Crystallization form XXV 2 ethanol Amorphous I 3 Isopropanol Amorphous I 4 Acetonitrile Amorphous I 5 acetone Amorphous I 6 Ethyl acetate Amorphous I 7 Acetonitrile - water = 1 - 1 Amorphous I 8 Tetrahydrofuran Crystallization form XXVI 9 Toluene Amorphous I 10 1,4-Dioxane Crystallization form XXVI

[0495] Example 48: Stability test of salt type screening

[0496] Weigh 30 mg of the compound (maleate crystal form V) into an 8 mL glass bottle, then place it under high temperature (60°C, open), high humidity (room temperature / 75% RH, open), and light exposure (room temperature, white light: 6980 lux, UV 282 μW / cm²). 2 Under these conditions, samples were taken on days 5, 10, and 30 for analysis (HPLC, XRD).

[0497]

[0498] Stability results showed that the content and purity of the maleate crystal form V remained almost unchanged after 5, 10 and 30 days under high temperature, high humidity and light conditions, indicating good stability.

[0499] Every reference, including all patents, patent applications, and publications cited in this application, is incorporated herein by reference in its entirety as if each of them were individually incorporated. Furthermore, it will be understood that, given the foregoing teachings of this invention, those skilled in the art may make certain changes or modifications to the invention, and such equivalents will still be within the scope of the invention as defined by the appended claims.

Claims

1. The amorphous form XVI of the following compound of formula 1: Formula 1 The amorphous form XVI of the compound of Formula 1 has an XRPD diagram that is substantially as shown in Figure 48. It also has the following characteristics: 1) In the TGA plot, there is a slow weight loss of 2.9 ± 0.1 wt% before 150 °C, and the decomposition temperature is 265 ± 2 °C; and / or 2) No melting peaks are observed in the DSC chart.

2. The form described in claim 1, further comprising the following features: 1) Essentially, the TGA diagram is shown in Figure 49; and / or 2) Basically, the DSC diagram is shown in Figure 50.

3. The crystalline form of maleate salt of the following compound (Formula 1) is V: Formula 1 It has characteristic peaks at the following locations in the XRPD plot expressed in 2θ angles: 8.159±0.2°, 10.519±0.2°, 15.078±0.2°, 15.839±0.2°, 16.959±0.2° and 22.997±0.2°; Its features have: 1) Essentially, the TGA diagram is shown in Figure 12; and / or 2) Basically, the DSC diagram is shown in Figure 13.

4. The crystalline form V according to claim 3, having essentially the XRPD pattern shown in FIG11.

5. A method for preparing the crystalline form V according to any one of claims 3-4, comprising the following steps: reacting the compound of formula 1 with maleic acid in an organic solvent, and then preparing the corresponding crystalline form, wherein: The molar ratio of compound 1 to maleic acid is 1:(1-1.5); The organic solvent is ethyl acetate; The mass-to-volume ratio of compound 1 to organic solvent is 100 mg : (0.1-1 mL); The reaction temperature is from room temperature to the solvent reflux temperature; and The reaction time is 1h-36h.

6. A method for preparing the amorphous form XVI according to claim 1, comprising the following steps: contacting the compound of formula 1 with a solvent, and then preparing the corresponding amorphous form, wherein: The solvent is methanol, ethanol, or isopropanol; The mass-to-volume ratio of compound 1 to solvent is 100 mg : (0.1-3 mL); The crystallization temperature is 20-50℃; and Crystallization time is 1-48 hours.

7. A pharmaceutical composition comprising the form of any one of claims 1-4, and pharmaceutically acceptable excipients.

8. Use of the pharmaceutical composition of any one of claims 1-4 or claim 7 in the preparation of a medicament for the prevention and / or treatment of MDM2-related hyperproliferative diseases, wherein said disease is selected from the following cancers: adrenocortical carcinoma, anal cancer, bile duct cancer, bladder cancer, bone cancer, bone metastases, adult brain / CNS tumors, pediatric brain / CNS tumors, breast cancer, unknown primary cancer, giant lymphadenopathy, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, Ewing's tumor family, gallbladder cancer, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin's disease, Kaposi's sarcoma, renal cancer, laryngeal and hypopharyngeal cancer, adult acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CML). Cellular leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloid monocytic leukemia (CMML), childhood leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, cutaneous lymphoma, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal and paranasal sinus carcinoma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, oral and oropharyngeal carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary adenoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma-adult soft tissue cancer, basal skin cancer and squamous cell skin cancer, skin cancer-melanoma, small intestine cancer, gastric cancer, testicular cancer, thymic cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia or Welles' tumor.

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