A benzofuranone compound salt type and / or crystal form and a preparation method and application thereof

Abstract

The application relates to a benzofuranone compound salt type and / or crystal type with a structure of formula I and a preparation method and application thereof. The application provides a pharmaceutically acceptable salt of a benzofuranone compound shown in formula I, wherein the pharmaceutically acceptable salt is one of hydrochloride, sulfate, phosphate, hydrobromide, maleate, tartrate, fumarate, citrate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, succinate, acetate and lactate; the salt formed by the compound of formula I has a structure as shown in formula II, and n is selected from 1 or 2. The dynamic solubility is better, the stability is better, the drug absorption is facilitated, the drug efficacy is stable, the storage stability is good, and the application prospect is better.

Description

Technical Field

[0001] This invention belongs to the technical field of medicinal chemistry, specifically relating to a benzofuranone compound salt form and / or crystal form, its preparation method, and its application. Background Technology

[0002] Acute kidney injury (AKI) has numerous etiologies and complex, incompletely understood mechanisms, characterized by high morbidity, high mortality, and significant harm. AKI is typically caused by factors affecting renal perfusion (primarily leading to renal hypoxia) and harmful substances, including surgery, malignant tumors, cardiopulmonary dysfunction, hepatorenal syndrome, sepsis, and nephrotoxic drugs. Serum creatinine (Cre) and blood urea nitrogen (BUN) levels are key indicators for assessing the occurrence and severity of kidney injury. Currently, commonly used symptomatic medications for AKI, such as vasodilators or diuretics, lack specific therapeutic agents. Acetylcysteine ​​(NAC) has regulatory effects on cellular metabolic activity, anti-oxidative stress, and anti-toxic damage capabilities, and has been used clinically for the intervention of AKI induced by contrast agents, showing some therapeutic effect. Flavonoids, such as flavonoids, possess anti-inflammatory, antioxidant, and free radical scavenging properties, and can be used to prevent and treat AKI. There are also literature reports that atorvastatin has a protective effect against gentamicin-induced acute kidney injury (Lee MC, Cheng K.J., Chen SM, et al . A novel preventive mechanism of gentamicin-inducednephrotoxicity by atorvastatin. Biomed Chromatogr . 2019, 33(11): e4639.). However, NAC, rosin, and atorvastatin have limited effects on improving kidney damage.

[0003] Compound I has shown good therapeutic effects on cisplatin-induced acute kidney injury, ischemia-reperfusion-induced kidney injury, and gentamicin-induced acute kidney injury, which are superior to known clinically used drugs and other positive control drugs. However, when compound I is in its free base form, its solubility and stability are poor, which is not conducive to drug preservation, drug absorption, and efficacy stability.

[0004]

[0005] It is well known that the salt form and crystal form of a drug have a significant impact on its physicochemical properties, quality, and stability, thereby affecting its absorption, bioavailability, efficacy, and safety. Therefore, it is necessary to study the salt form and crystal form of compound I to develop a stable, easily absorbed solid form that meets the requirements of formulation characteristics. Summary of the Invention

[0006] The present invention aims to provide a salt form and / or crystal form of a benzofuranone compound, its preparation method, and its application. The salt form and crystal form of this benzofuranone compound can be used as protective drugs against acute kidney injury, addressing technical issues such as improving the solubility and stability of benzofuranone compounds, facilitating drug absorption and storage, or combinations thereof.

[0007] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0008] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0009] Definitions of standard chemical terms can be found in the references “Pharmacopoeia of the People’s Republic of China (2020 Edition)”, China Medical Science and Technology Press, May 2020: 1st Edition, and “Basic Organic Chemistry (Volumes 1 & 2)”, Xing Qiyi, Higher Education Press, June 2005, 3rd Edition.

[0010] Unless otherwise specified, conventional methods within the scope of the art, such as solubility detection, HPLC detection, XRPD detection, etc., shall be used.

[0011] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0012] In a first aspect, the present invention provides: a pharmaceutically acceptable salt of a benzofuranone compound of Formula I; said pharmaceutically acceptable salt being an acid salt formed with an inorganic and / or organic acid.

[0013] The pharmaceutically acceptable salt is one of the following: hydrochloride, sulfate, phosphate, hydrobromide, maleate, tartrate, fumarate, citrate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, succinate, acetate, and lactate. The salt formed by the compound of Formula I has the structure shown in Formula II.

[0014] Where n is selected from 1 or 2.

[0015] Secondly, the present invention provides: the crystal form of the above-mentioned pharmaceutically acceptable salt.

[0016] Among them, the crystal form of the hydrochloride is selected from one of the following: hydrochloride crystal form A and hydrochloride crystal form B.

[0017] Among them, the technical characteristics of hydrochloride crystal form A are as follows: the X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 4.3±0.2°, 11.7±0.2°, 14.4±0.2°, 17.4±0.2°, 19.9±0.2°, and 20.8±0.2°.

[0018] Among them, the preferred crystal form A of the hydrochloride with technical characteristics is that the X-ray powder diffraction pattern also has characteristic peaks at 2θ angles of 23.4±0.2°, 24.6±0.2°, 26.1±0.2°, and 30.6±0.2°.

[0019] Among them, the hydrochloride crystal form A with the technical characteristics is further preferably: having Figure 4 The XPRD spectral features are shown.

[0020] Among them, the technical characteristic of hydrochloride crystal form B is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.1±0.2°, 13.8±0.2°, 15.5±0.2°, 18.3±0.2°, 21.7±0.2°, and 22.9±0.2°.

[0021] Among them, the technical feature of sulfate crystal form includes one of sulfate crystal form A and sulfate crystal form B.

[0022] Among them, the technical characteristics of sulfate crystal form A are as follows: its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 8.5±0.2°, 11.7±0.2°, 11.9±0.2°, 12.7±0.2°, 15.3±0.2°, 16.1±0.2°, 19.2±0.2°, and 21.1±0.2°.

[0023] Among them, the technical characteristic of sulfate crystal form B is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 10.7±0.2°, 14.7±0.2°, 11.9±0.2°, 17.8±0.2°, 18.5±0.2°, and 19.2±0.2°.

[0024] Among them, the technical characteristic of maleate crystal form A is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 12.0±0.2°, 12.6±0.2°, 13.3±0.2°, 16.3±0.2°, 17.2±0.2°, 20.5±0.2°, and 21.1±0.2°.

[0025] Among them, the crystal forms of phosphates include one of the following: phosphate crystal form A, phosphate crystal form B, phosphate crystal form C, and phosphate crystal form D.

[0026] Among them, the technical characteristic of phosphate crystal form A is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 8.1±0.2°, 9.4±0.2°, 10.8±0.2°, 12.1±0.2°, and 16.7±0.2°.

[0027] Among them, the technical characteristic of phosphate crystal form B is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 12.3±0.2°, 16.1±0.2°, 22.5±0.2°, 22.8±0.2°, and 24.8±0.2°.

[0028] Among them, the technical characteristic phosphate crystal form C is: its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 8.2±0.2°, 12.3±0.2°, 15.2±0.2°, 16.3±0.2°, and 19.0±0.2°.

[0029] Among them, the technical characteristic phosphate crystal form D is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 9.6±0.2°, 11.0±0.2°, 12.3±0.2°, 14.3±0.2°, 16.5±0.2°, and 19.2±0.2°.

[0030] Among them, the crystal forms of tartrates include one of tartrate crystal form A and tartrate crystal form B.

[0031] Among them, the technical characteristics of tartrate crystal form A are as follows: its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 5.8±0.2°, 11.6±0.2°, 13.2±0.2°, 13.9±0.2°, 16.3±0.2°, 17.4±0.2°, and 20.6±0.2°.

[0032] Among them, the technical characteristic of tartrate crystal form B is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.1±0.2°, 7.1±0.2°, 14.7±0.2°, 17.0±0.2°, 19.8±0.2°, and 21.6±0.2°.

[0033] Among them, the technical characteristics of fumarate crystal forms include: fumarate crystal form A, whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 10.9±0.2°, 11.7±0.2°, 14.1±0.2°, 16.7±0.2°, 18.7±0.2°, 20.7±0.2°, and 22.5±0.2°.

[0034] Among them, the preferred technical feature of fumarate crystal form A is that its X-ray powder diffraction pattern also has characteristic peaks at 8.6±0.2°, 16.2±0.2°, 20.2±0.2°, 21.5±0.2°, 22.0±0.2°, 23.9±0.2°, 24.6±0.2°, and 25.2±0.2°.

[0035] Among them, the preferred technical feature of fumarate crystal form A is: having Figure 37 The XPRD spectral features are shown.

[0036] Among them, the crystal forms of citrate include one of citrate crystal form A, citrate crystal form B, citrate crystal form C and citrate crystal form D.

[0037] Among them, the technical characteristics of citrate crystal form A are as follows: its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 5.4±0.2°, 6.0±0.2°, 11.1±0.2°, 14.8±0.2°, 15.4±0.2°, 16.5±0.2°, and 20.3±0.2°.

[0038] Among them, the technical characteristics of citrate crystal form B are as follows: its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 4.7±0.2°, 7.9±0.2°, 11.2±0.2°, 12.9±0.2°, 14.1±0.2°, 15.4±0.2°, 19.9±0.2°, and 26.6±0.2°.

[0039] Among them, the technical characteristics of citrate crystal form C are as follows: its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 9.9±0.2°, 10.4±0.2°, 12.5±0.2°, 14.5±0.2°, 15.7±0.2°, 16.1±0.2°, 16.9±0.2°, 19.2±0.2°, and 22.0±0.2°.

[0040] Among them, the technical characteristic of citrate crystal form D is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 8.3±0.2°, 11.1±0.2°, 12.0±0.2°, 13.2±0.2°, 14.5±0.2°, 16.6±0.2°, 17.2±0.2°, and 20.0±0.2°.

[0041] Among them, the technical characteristics of the crystal form of p-toluenesulfonate are as follows: p-toluenesulfonate crystal form A, whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 11.1±0.2°, 12.0±0.2°, 12.9±0.2°, 15.4±0.2°, 16.6±0.2°, 17.0±0.2°, 18.1±0.2°, 18.7±0.2°, and 20.3±0.2°.

[0042] Among them, the crystal forms of methanesulfonates include one of methanesulfonate crystal form A and methanesulfonate crystal form B.

[0043] Among them, the technical characteristic of methanesulfonate crystal form A is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 11.3±0.2°, 12.8±0.2°, 15.7±0.2°, 19.1±0.2°, and 20.2±0.2°.

[0044] Among them, the technical characteristic of methanesulfonate crystal form B is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.7±0.2°, 10.1±0.2°, 11.0±0.2°, 12.5±0.2°, 13.3±0.2°, 17.1±0.2°, and 21.0±0.2°.

[0045] Among them, the crystal forms of succinate include one of the following: succinate crystal form A, succinate crystal form B, and succinate crystal form C.

[0046] Among them, the technical characteristic of succinate crystal form A is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 12.0±0.2°, 12.9±0.2°, 13.4±0.2°, 16.3±0.2°, 17.3±0.2°, 18.8±0.2°, and 21.6±0.2°.

[0047] Among them, the technical characteristics of succinate crystal form B are as follows: its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 10.9±0.2°, 11.7±0.2°, 13.8±0.2°, 16.9±0.2°, 18.5±0.2°, 20.3±0.2°, and 22.3±0.2°.

[0048] Among them, the preferred technical feature of succinate crystal form B is that the X-ray powder diffraction pattern also has characteristic peaks at 2θ angles of 8.5±0.2°, 21.5±0.2°, 21.8±0.2°, 24.1±0.2°, and 24.8±0.2°.

[0049] Among them, the preferred technical feature of succinate crystal form B is: it also has Figure 64 The XRPD spectral features are shown.

[0050] Among them, the technical characteristic of succinate crystal form C is that its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 7.9±0.2°, 11.9±0.2°, 14.1±0.2°, 17.3±0.2°, and 19.6±0.2°.

[0051] Among them, the preferred technical feature of succinate crystal form C is that the X-ray powder diffraction pattern also has characteristic peaks at 2θ angles of 13.4±0.2°, 14.7±0.2°, 20.4±0.2°, 22.9±0.2°, and 24.3±0.2°.

[0052] Among them, the preferred technical feature of succinate crystal form C is: it also has Figure 67 The XRPD spectral features are shown.

[0053] Thirdly, the present invention provides a method for preparing the crystal form of the above-mentioned pharmaceutically acceptable salt, comprising the following steps: mixing, stirring, and separating the solid and liquid components of the compound of formula 1.

[0054] The technical feature ligand acid is selected from one of the following: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, maleic acid, tartaric acid, fumaric acid, citric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, succinic acid, acetic acid, and lactic acid.

[0055] The technical feature solvent is selected from at least one of the following: water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, acetone, N-methylpyrrolidone, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dioxane, dimethyl sulfoxide, n-hexane, and n-heptane.

[0056] The preferred solvent for the technical feature is acetonitrile when the ligand acid is maleic acid, and at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, tartaric acid, fumaric acid, citric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, succinic acid, acetic acid, or lactic acid when the ligand acid is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, or n-heptane mixture, acetonitrile, acetone, or tetrahydrofuran.

[0057] The preferred technical feature of the ethanol / n-heptane mixture is that the volume ratio of ethanol to n-heptane is (1-3):(1-3).

[0058] The technical characteristics of the stirring are: stirring time is 60-80 hours, and temperature is 20-30℃.

[0059] Fourthly, the present invention provides a pharmaceutical composition comprising at least one of the above-described crystal forms.

[0060] Fifthly, the present invention provides: a medicament comprising the above-described pharmaceutical composition and pharmaceutically acceptable excipients.

[0061] The technical feature excipients are selected from at least one of the following: carrier and excipient.

[0062] In a sixth aspect, the present invention provides the use of the above-described crystal form in the preparation of a medicament for the prevention or treatment of acute kidney injury.

[0063] The technical feature of acute kidney injury is selected from at least one of the following: ischemic acute kidney injury, acute kidney injury caused by systemic infection, drug-induced acute kidney injury, surgery-related acute kidney injury, acute kidney injury caused by crush syndrome, acute kidney injury caused by cardiorenal syndrome, and acute kidney injury caused by hepatorenal syndrome.

[0064] Among them, the preferred technical feature of drug-induced acute kidney injury is acute kidney injury induced by cisplatin or gentamicin.

[0065] Compared with the free base A of compound I, the present invention has at least the following beneficial effects: 1. This invention provides crystal forms of salts of compounds of formula I. The corresponding crystal forms of the salts (such as hydrochloride crystal form A, fumarate crystal form A, and succinate crystal form B) have significantly better dynamic solubility in pure water than free base A, which is more conducive to the absorption of the compound. 2. The free base A of Formula I will transform into a new crystal form when placed in pure water, and the solubility of the new crystal form in water will be greatly reduced, causing the drug to precipitate. As an oral preparation, this will affect the absorption of the drug. However, the crystal forms of the corresponding salts provided by this invention (such as hydrochloride crystal form A, fumarate crystal form A, and succinate crystal form B) are completely soluble in pure water, and will not cause the problem of transformation and precipitation that affects drug absorption or causes unstable efficacy.

[0066] 3. The chemical purity of the free base of Formula I decreased by about 6.3% after being placed under accelerated test conditions for 1 week. However, the chemical purity of the corresponding salt crystal forms (such as hydrochloride crystal form A, fumarate crystal form A, and succinate crystal form B) provided by this invention remained basically unchanged after being placed under accelerated test conditions for 1 week. It has better stability, is easier to preserve, and is more suitable for development as a pharmaceutical solid form.

[0067] 4. The chemical purity of the physiological saline solution of the free base of Formula I decreased by 29% after 48 hours of light exposure, while the crystal forms of the corresponding salts provided by this invention (such as hydrochloride crystal form A, fumarate crystal form A, and succinate crystal form B) decreased by less than 3.04%. This may be due to the blocking and delaying effect of the salt-type acid anion on the oxidation reaction of the amino group of the compound, resulting in an unexpected technical effect. Attached Figure Description

[0068] Figure 1 This is the XRPD image of free alkali crystal form A.

[0069] Figure 2 This is the TGA image of free alkali crystal form A.

[0070] Figure 3 This is the DSC diagram of free alkali crystal form A.

[0071] Figure 4 This is the XRPD image of hydrochloride crystal form A in Example 2.

[0072] Figure 5 This is a TGA image of hydrochloride crystal form A in Example 2.

[0073] Figure 6 This is the DSC diagram of hydrochloride crystal form A in Example 2.

[0074] Figure 7 This is the XRPD image of hydrochloride crystal form B in Example 3.

[0075] Figure 8 This is a TGA image of hydrochloride crystal form B in Example 3.

[0076] Figure 9 This is the DSC diagram of hydrochloride crystal form B in Example 3.

[0077] Figure 10 This is the XRPD diagram of sulfate crystal form A in Example 6.

[0078] Figure 11 This is a TGA image of sulfate crystal form A in Example 6.

[0079] Figure 12 This is the DSC diagram of sulfate crystal form A in Example 6.

[0080] Figure 13This is the XRPD diagram of sulfate crystal form B in Example 7.

[0081] Figure 14 This is a TGA image of sulfate crystal form B in Example 7.

[0082] Figure 15 This is the DSC diagram of sulfate crystal form B in Example 7.

[0083] Figure 16 This is the XRPD image of maleate crystal form A in Example 13.

[0084] Figure 17 This is a TGA image of maleate crystal form A in Example 13.

[0085] Figure 18 This is the DSC diagram of maleate crystal form A in Example 13.

[0086] Figure 19 This is the XRPD diagram of phosphate crystal form A in Example 14.

[0087] Figure 20 This is a TGA image of phosphate crystal form A in Example 14.

[0088] Figure 21 This is the DSC diagram of phosphate crystal form A in Example 14.

[0089] Figure 22 This is the XRPD diagram of phosphate crystal form B in Example 15.

[0090] Figure 23 This is a TGA image of phosphate crystal form B in Example 15.

[0091] Figure 24 This is the DSC diagram of phosphate crystal form B in Example 15.

[0092] Figure 25 This is the XRPD diagram of phosphate crystal form C in Example 16.

[0093] Figure 26 This is a TGA image of phosphate crystal form C in Example 16.

[0094] Figure 27 This is the DSC diagram of phosphate crystal form C in Example 16.

[0095] Figure 28 This is the XRPD diagram of phosphate crystal form D in Example 17.

[0096] Figure 29 This is a TGA image of phosphate crystal form D in Example 17.

[0097] Figure 30 This is the DSC diagram of phosphate crystal form D in Example 17.

[0098] Figure 31 This is the XRPD image of tartrate crystal form A in Example 18.

[0099] Figure 32 This is a TGA image of chalcopyrite crystal form A in Example 18.

[0100] Figure 33 This is the DSC diagram of tartrate crystal form A in Example 18.

[0101] Figure 34 This is the XRPD diagram of tartrate crystal form B in Example 19.

[0102] Figure 35 This is a TGA image of tartrate crystal form B from Example 19.

[0103] Figure 36 This is the DSC diagram of tartrate crystal form B in Example 19.

[0104] Figure 37 This is the XRPD image of fumarate crystal form A in Example 25.

[0105] Figure 38 This is a TGA image of fumarate crystal form A from Example 25.

[0106] Figure 39 This is the DSC diagram of fumarate crystal form A in Example 25.

[0107] Figure 40 This is the XRPD diagram of citrate crystal form A in Example 26.

[0108] Figure 41 This is a TGA image of citrate crystal form A in Example 26.

[0109] Figure 42 This is the DSC diagram of citrate crystal form A in Example 26.

[0110] Figure 43 This is the XRPD diagram of citrate crystal form B in Example 27.

[0111] Figure 44 This is a TGA image of citrate crystal form B from Example 27.

[0112] Figure 45 This is the DSC diagram of citrate crystal form B in Example 27.

[0113] Figure 46 This is an XRPD image of citrate crystal form C in Example 28.

[0114] Figure 47 This is a TGA image of citrate crystal form C in Example 28.

[0115] Figure 48 This is the DSC diagram of citrate crystal form C in Example 28.

[0116] Figure 49 This is the XRPD diagram of citrate crystal form D in Example 29.

[0117] Figure 50 This is a TGA diagram of citrate crystal form D in Example 29.

[0118] Figure 51 This is the DSC diagram of citrate crystal form D in Example 29.

[0119] Figure 52 The image shown is the XRPD diagram of toluenesulfonate crystal form A in Example 31.

[0120] Figure 53 The image shown is a TGA image of toluenesulfonate crystal form A from Example 31.

[0121] Figure 54 This is the DSC diagram of p-toluenesulfonate crystal form A in Example 31.

[0122] Figure 55 This is the XRPD diagram of methanesulfonate crystal form A in Example 35.

[0123] Figure 56 This is a TGA image of methanesulfonate crystal form A from Example 35.

[0124] Figure 57 This is the DSC diagram of methanesulfonate crystal form A in Example 35.

[0125] Figure 58 This is the XRPD diagram of methanesulfonate crystal form B in Example 36.

[0126] Figure 59 This is a TGA image of methanesulfonate crystal form B from Example 36.

[0127] Figure 60 This is the DSC diagram of methanesulfonate crystal form B in Example 36.

[0128] Figure 61 This is the XRPD diagram of succinate crystal form A in Example 39.

[0129] Figure 62 This is the TGA image of succinate crystal form A in Example 39.

[0130] Figure 63 This is the DSC diagram of succinate crystal form A in Example 39.

[0131] Figure 64 This is the XRPD image of succinate crystal form B in Example 40.

[0132] Figure 65 This is a TGA image of succinate crystal form B from Example 40.

[0133] Figure 66 This is the DSC diagram of succinate crystal form B in Example 40.

[0134] Figure 67 This is the XRPD diagram of succinate crystal form C in Example 45.

[0135] Figure 68 This is a TGA image of succinate crystal form C in Example 45.

[0136] Figure 69 This is the DSC diagram of succinate crystal form C in Example 45.

[0137] Figure 70 The image shows the XRPD plot of succinate crystal form D in Comparative Example 1.

[0138] Figure 71 The image shows the TGA plot of succinate crystal form D in Comparative Example 1.

[0139] Figure 72 The image shows the DSC diagram of succinate crystal form D in Comparative Example 1.

[0140] Figure 73 The image shows the XRPD plot of succinate crystal form E in Comparative Example 2.

[0141] Figure 74 This is a DVS diagram of hydrochloride crystal form A in Example 2.

[0142] Figure 75 This is an XRPD overlay image of hydrochloride crystal form A before and after DVS testing in Example 2.

[0143] Figure 76 This is the DVS diagram of fumarate crystal form A in Example 25.

[0144] Figure 77 This is an XRPD overlay image of fumarate crystal form A before and after DVS testing in Example 25.

[0145] Figure 78 This is the DVS diagram of succinate crystal form B in Example 40.

[0146] Figure 79 This is an XRPD overlay image of succinate crystal form B before and after DVS testing in Example 40.

[0147] Figure 80 This is the DVS diagram of free alkali salt crystal form A in Example 1.

[0148] Figure 81This is an XRPD overlay image of the free alkali salt crystal form A before and after the DVS test in Example 1.

[0149] Figure 82 The results of the dynamic solubility test of free alkali salt crystal form A at different time points are shown in Example 1.

[0150] Figure 83 This is a dynamic solubility curve.

[0151] Figure 84 For example 1, free alkali salt crystal form A 1 H NMR spectrum. Detailed Implementation

[0152] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0153] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0154] The detection method parameters used in this invention are as follows: X-ray powder diffraction (XRPD) The X-ray powder diffraction (XRPD) measurements described in this invention were collected using an X-ray powder diffraction analyzer manufactured by PANalytical, and the specific parameters are shown in Table 1.

[0155] Table 1 XRPD detection parameters

[0156] Thermogravimetric analysis (TGA) The TGA measurements described in this invention were performed using a Discovery TA5500 / TA550 thermogravimetric analyzer with a heating rate of 10℃ / min, a temperature range of room temperature to 300℃, and a nitrogen gas flow rate of 25 ml / min as the protective gas.

[0157] Differential scanning calorimetry (DSC) The DSC measurements described in this invention were performed using a Discovery TA2500 / TA250 thermogravimetric analyzer with a heating rate of 10℃ / min and a temperature range of 25℃-300℃. The protective gas was nitrogen at a flow rate of 50 ml / min.

[0158] Dynamic moisture adsorption (DVS) The DVS curves described in this invention were collected using a DVS Intrinsic or Intrinsic Plus. Relative humidity at 25°C was corrected using the deliquescence points of LiCl, Mg(NO3)2, and KCl; specific parameters are shown in Table 2.

[0159] Table 2 Dynamic Moisture Adsorption Detection Parameters

[0160] Liquid NMR The liquid NMR spectrum described in this invention was acquired on a Bruker 400M NMR spectrometer, using DMSO-d6 as the solvent. High-performance liquid chromatography (HPLC) The purity and solid stability results of the samples described in this invention were tested using an Agilent high-performance liquid chromatograph. The specific high-performance liquid chromatography test conditions are shown in Table 3.

[0161] Table 3 High-performance liquid chromatography detection parameters

[0162] Ion chromatography (IC) The salt molar ratio of the samples described in this invention was determined using a Thermo AQ RFIC ion chromatograph. Specific ion chromatography test conditions are shown in Table 4.

[0163] Table 4 Ion Chromatography Test Conditions

[0164] Example 1: Synthesis method of free base of compound I:

[0165] Add 2 kg of intermediate 19-1 and 2.2 kg of 5-methoxybenzofuran-3(2) to the reactor. H )-ketone, 20 L of anhydrous ethanol, heated to 50 °C, stirred and dissolved. Then add 1.9 kg of piperazine, purge three times with nitrogen for protection, heat the reaction solution to reflux, and reflux for 16 hours. After the reaction is complete, concentrate the solvent to dryness under reduced pressure to obtain a solid; add ethyl acetate, heat to 50 °C, stir and beat for 5 hours, then cool to room temperature, filter, and dry to obtain 3.6 kg of intermediate 78-1.

[0166] 2.5 kg of intermediate 78-1 and 25 L of dichloromethane were added to the reactor and stirred to dissolve. After dissolution, 7.9 kg of DIPEA was added; the temperature was lowered to 0 °C; then 1.6 kg of HOBT and 2.2 kg of EDCI were added sequentially, and the mixture was stirred at 0 °C for 10 minutes; then 2.9 kg of N-2-azaspiro[3.3]hept-6-ylcarbamate tert-butyl ester was added, and the mixture was protected with nitrogen purging three times and stirred at room temperature for 16 hours. After the reaction was complete, water was added and stirred, and the mixture was allowed to stand to separate into layers; the aqueous layer was extracted three times with dichloromethane; the organic phases were combined, concentrated under reduced pressure to obtain a solid, which was then dried to obtain 4.1 kg of intermediate 78-2.

[0167] Dichloromethane and intermediate 78-2 were added to the reaction vessel and stirred until dissolved. Then, 12 L of concentrated hydrochloric acid was slowly added dropwise at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was complete, water was added and stirred, followed by the slow addition of sodium hydroxide aqueous solution to adjust the pH to 13. The mixture was allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The filtrate was concentrated under reduced pressure and dried under vacuum to obtain 2.05 kg of compound I.

[0168] ESI-MS: m / z = 422.2[M+H] + ; 1 H NMR (400 MHz, DMSO- D 6) δ 7.38 (d, J = 9.0 Hz, 1H), 7.29 (dd, J = 9.0, 2.7 Hz, 1H), 7.19 (d, J = 2.8 Hz, 1H), 6.82 (s, 1H), 3.78(s, 7H), 3.53 (s, 3H), 3.19 (d, J = 48.5 Hz, 3H), 2.33 (s, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 1.77 (s, 2H). The crystal form of the obtained Formula I compound was confirmed. The X-ray diffraction pattern showed characteristic diffraction peaks at angles of 2θ at 8.2°, 10.2°, 14.3°, 14.7°, 15.1°, 17.8°, 19.4°, 20.6°, and 25.2° (see...). Figure 1 (Table 1); TGA results show that the weight loss before 150℃ is approximately 1.43%, and DSC results show an endothermic peak at 162.9℃ (see Table 1). Figure 2 , Figure 3 The solid obtained by the above preparation method is the free alkali crystal form A of compound of formula 1.

[0169] In the following examples, the preparation of salts of compounds of Formula I all used the above-mentioned free base as a raw material.

[0170] Example 2: Preparation of the hydrochloride salt of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of solvent (ethanol / n-heptane = 1:1), stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is hydrochloride crystal form A.

[0171] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 4.3°, 11.7°, 14.4°, 17.4°, 19.9°, and 20.8° (see...). Figure 4 (Table 12); TGA results show that the weight loss before 150℃ is approximately 9.29%, and DSC results show endothermic peaks at 120.2℃ and 221.6℃ (see Table 12). Figures 5-6 HPLC / IC results showed that the acid-base molar ratio of the sample was 1:1. The solid obtained by the above preparation method was the hydrochloride crystal form A of compound of formula 1.

[0172] Example 3: Preparation of the hydrochloride salt of compound 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetone, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is hydrochloride crystal form B.

[0173] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 6.1°, 13.8°, 15.5°, 18.3°, 21.7°, and 22.9° (see...). Figure 7 (Table 13); TGA results show that the weight loss before 100℃ is approximately 4.19%, and DSC results show endothermic peaks at 70.8℃, 167.2℃, and 217.6℃ (see Table 13). Figures 8-9 The solid obtained by the above preparation method is the hydrochloride crystal form B of compound of formula 1.

[0174] Example 4: Preparation of the hydrochloride salt of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of tetrahydrofuran, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is hydrochloride crystal form B.

[0175] Example 5: Preparation of the hydrochloride salt of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetonitrile, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is hydrochloride crystal form B.

[0176] Example 6: Preparation of sulfate of Formula 1 compound Weigh approximately 20 mg of compound 1 and equimolar amounts of sulfuric acid, add them to 0.5 ml of solvent (ethanol / n-heptane = 1:1), stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is sulfate crystal form A.

[0177] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 8.5°, 11.7°, 11.9°, 12.7°, 15.3°, 16.1°, 19.2°, and 21.1° (see...). Figure 10 (Table 14); TGA results show that the weight loss before 150℃ is approximately 4.68%, and DSC results show endothermic peaks at 97.2℃, 200.4℃, and 208.7℃ (see Table 14). Figures 11-12 HPLC / IC results showed that the acid-base molar ratio of the sample was 1:1. The solid obtained by the above preparation method was the sulfate crystal form A of compound of formula 1.

[0178] Example 7: Preparation of sulfate of Formula 1 compound Weigh approximately 20 mg of compound 1 and an equimolar amount of sulfuric acid, add them to 0.5 ml of acetone, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is sulfate crystal form B.

[0179] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 10.7°, 14.7°, 11.9°, 17.8°, 18.5°, and 19.2° (see...). Figure 13 (Table 15); TGA results show that the weight loss before 150℃ is approximately 6.74%, and DSC results show endothermic peaks at 87.0℃ and 183.9℃ (see Table 15). Figures 14-15 The solid obtained by the above preparation method is the sulfate crystal form B of compound of formula 1.

[0180] Example 8: Preparation of sulfate of Formula 1 compound Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of tetrahydrofuran, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is sulfate crystal form A.

[0181] Example 9: Preparation of sulfate of Formula 1 compound Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetonitrile, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is sulfate crystal form B.

[0182] Example 10: Preparation of maleate salt of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of solvent (ethanol / n-heptane = 1:1), stir at room temperature for about 3 days, centrifuge to separate the solid and test the 1H NMR spectrum; no salt formation was observed.

[0183] Example 11: Preparation of maleate salt of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetone, stir at room temperature for about 3 days, add n-heptane as solvent, and form a gel.

[0184] Example 12: Preparation of maleate salt of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of tetrahydrofuran, stir at room temperature for about 3 days, centrifuge to separate the solid and test the 1H NMR spectrum; no salt formation was observed.

[0185] Example 13: Preparation of maleate salt of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetonitrile, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is maleate crystal form A.

[0186] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 12.0°, 12.6°, 13.3°, 16.3°, 17.2°, 20.5°, and 21.1° (see...). Figure 16 (Table 16); TGA results show that the weight loss before 150℃ is approximately 4.73%, and DSC results show endothermic peaks at 162.3℃ and 180.3℃ (see Table 16). Figures 17-18 ). 1 ¹H NMR results showed that the acid-base molar ratio of the sample was 1:1. The solid obtained by the above preparation method was maleate salt of compound 1, crystal form A.

[0187] Example 14: Preparation of phosphate of Formula 1 compound Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of solvent (ethanol / n-heptane = 1:1), stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is phosphate crystal form A.

[0188] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 8.1°, 9.4°, 10.8°, 12.1°, and 16.7° (see...). Figure 19 (Table 17); TGA results show that the weight loss before 150℃ is approximately 1.82%, and DSC results show endothermic peaks at 61.3℃, 238.1℃, and 249℃ (see Table 17). Figures 20-21HPLC / IC results showed that the acid-base molar ratio of the sample was 1:1. The solid obtained by the above preparation method was phosphate crystal form A of compound of formula 1.

[0189] Example 15: Preparation of phosphate of Formula 1 compound Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetone, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is phosphate crystal form B.

[0190] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 12.3°, 16.1°, 22.5°, 22.8°, and 24.8° (see...). Figure 22 (Table 18); TGA results show that the weight loss before 150℃ is approximately 4.83%, and DSC results show endothermic peaks at 71.7℃, 229.9℃, and 240.5℃ (see Table 18). Figures 23-24 HPLC / IC results showed that the acid-base molar ratio of the sample was 1.2:1. The solid obtained by the above preparation method was phosphate crystal form B of compound of formula 1.

[0191] Example 16: Preparation of phosphate of Formula 1 compound Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of tetrahydrofuran, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is phosphate crystal form C.

[0192] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 8.2°, 12.3°, 15.2°, 16.3°, and 19.0° (see...). Figure 25 (Table 19); TGA results show that the weight loss before 150℃ is approximately 2.33%, and DSC results show endothermic peaks at 68.3℃, 233.7℃, and 242.6℃ (see Table 19). Figures 26-27 HPLC / IC results showed that the acid-base molar ratio of the sample was 1.1:1. The solid obtained by the above preparation method was the phosphate crystal form C of compound of formula 1.

[0193] Example 17: Preparation of phosphate of Formula 1 compound Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetonitrile, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is phosphate crystal form D.

[0194] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 9.6°, 11.0°, 12.3°, 14.3°, 16.5°, and 19.2° (see...). Figure 28(Table 20); TGA results show that the weight loss before 150℃ is approximately 0.79%, and DSC results show endothermic peaks at 76.4℃, 161.4℃, and 233.3℃ (see Table 20). Figures 29-30 HPLC / IC results showed that the acid-base molar ratio of the sample was 1.2:1. The solid obtained by the above preparation method was the phosphate crystal form D of compound of formula 1.

[0195] Example 18: Preparation of tartrate salt of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of solvent (ethanol / n-heptane = 1:1), stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is tartrate crystal form A.

[0196] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 5.8°, 11.6°, 13.2°, 13.9°, 16.3°, 17.4°, and 20.6° (see...). Figure 31 (Table 21); TGA results show that the weight loss before 150℃ is approximately 4.6%, and DSC results show endothermic peaks at 82.5℃ and 206.4℃ (see Table 21). Figures 32-33 ). 1 ¹H NMR results showed that the acid-base molar ratio of the sample was 1:1. The solid obtained by the above preparation method was tartrate salt of Formula 1, crystal form A.

[0197] Example 19: Preparation of tartrate salt of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetone, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is tartaric acid crystal form B.

[0198] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 6.1°, 7.1°, 14.7°, 17.0°, 19.8°, and 21.6° (see...). Figure 34 (Table 22); TGA results show that the weight loss before 150℃ is approximately 4.01%, and DSC results show endothermic peaks at 75.9℃ and 207.8℃ (see Table 22). Figures 35-36 ). 1 ¹H NMR results showed that the acid-base molar ratio of the sample was 1.1:1. The solid obtained by the above preparation method was tartrate salt of Formula 1, crystal form B.

[0199] Example 20: Preparation of tartrate salt of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of tetrahydrofuran, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is tartrate crystal form B.

[0200] Example 21: Preparation of tartrate salt of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetonitrile, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is tartaric acid crystal form A.

[0201] Example 22: Preparation of fumarate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of solvent (ethanol / n-heptane = 1:1), stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is fumarate crystal form A.

[0202] Example 23: Preparation of fumarate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetone, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is fumaric acid crystal form A.

[0203] Example 24: Preparation of fumarate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of tetrahydrofuran, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is fumarate crystal form A.

[0204] Example 25: Preparation of fumarate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetonitrile, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is fumarate crystal form A.

[0205] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 10.9°, 11.7°, 14.1°, 16.7°, 18.7°, 20.7°, and 22.5° (see...). Figure 37 (Table 23); TGA results show that the weight loss before 150℃ is approximately 1.43%, and DSC results show an endothermic peak at 225.3℃ (see Table 23). Figures 38-39 ). 1 ¹H NMR results showed that the acid-base molar ratio of the sample was 1:1. The solid obtained by the above preparation method was compound A, ethanol fumarate of formula 1.

[0206] Example 26: Preparation of citrate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of solvent (ethanol / n-heptane = 1:1), stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is citrate crystal form A.

[0207] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 5.4°, 6.0°, 11.1°, 14.8°, 15.4°, 16.5°, and 20.3° (see...). Figure 40 (Table 24); TGA results show that the weight loss before 150℃ is approximately 7.71%, and DSC results show endothermic peaks at 94.1℃ and 149.3℃ (see Table 24). Figures 41-42 ). 1 ¹H NMR results showed that the acid-base molar ratio of the sample was 1:1. The solid obtained by the above preparation method was citrate A, a compound of formula 1.

[0208] Example 27: Preparation of citrate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetone, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is citric acid crystal form B.

[0209] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 4.7°, 7.9°, 11.2°, 12.9°, 14.1°, 15.4°, 19.9°, and 26.6° (see...). Figure 43 (Table 25); TGA results show that the weight loss before 150℃ is approximately 4.85%, and DSC results show endothermic peaks at 68.2℃, 162.0℃, and 175.2℃ (see Table 25). Figures 44-45 ). 1 ¹H NMR results showed that the acid-base molar ratio of the sample was 1:1. The solid obtained by the above preparation method was citrate of Formula 1, crystal form B.

[0210] Example 28: Preparation of citrate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of tetrahydrofuran, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is citrate crystal form C.

[0211] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 9.9°, 10.4°, 12.5°, 14.5°, 15.7°, 16.1°, 16.9°, 19.2°, and 22.0° (see...). Figure 46 (Table 26); TGA results show that the weight loss before 150℃ is approximately 3.52%, and DSC results show endothermic peaks at 68.2℃, 162.0℃, and 175.2℃ (see Table 26). Figures 47-48 ). 1 ¹H NMR results showed that the acid-base molar ratio of the sample was 1:1. The solid obtained by the above preparation method was citrate of Formula 1, crystal form C.

[0212] Example 29: Preparation of citrate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetonitrile, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is citric acid crystal form D.

[0213] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 8.3°, 11.1°, 12.0°, 13.2°, 14.5°, 15.4°, 16.6°, 17.2°, and 20.0° (see...). Figure 49 (Table 27); TGA results show that the weight loss before 150℃ is approximately 2.31%, and DSC results show endothermic peaks at 49.7℃, 174.1℃, and 179.3℃ (see Table 27). Figures 50-51 The solid obtained by the above preparation method is citrate crystal form D of compound of formula 1.

[0214] Example 30: Preparation of p-toluenesulfonate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetonitrile, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is p-toluenesulfonic acid crystal form A.

[0215] Example 31: Preparation of p-toluenesulfonate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of solvent (ethanol / n-heptane = 1:1), stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is p-toluenesulfonate crystal form A.

[0216] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 11.1°, 12.0°, 12.9°, 15.4°, 16.6°, 17.0°, 18.1°, 18.7°, and 20.3° (see...). Figure 52 (Table 28); TGA results show that the weight loss before 150℃ is approximately 2.17%, and DSC results show endothermic peaks at 63.7℃ and 228.7℃ (see Table 28). Figures 53-54 The solid obtained by the above preparation method is p-toluenesulfonate of Formula 1, crystal form A.

[0217] Example 32: Preparation of p-toluenesulfonate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetone, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is p-toluenesulfonic acid crystal form A.

[0218] Example 33: Preparation of p-toluenesulfonate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of tetrahydrofuran, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is p-toluenesulfonate crystal form A.

[0219] Example 34: Preparation of p-toluenesulfonate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetonitrile, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is p-toluenesulfonic acid crystal form A.

[0220] Example 35: Preparation of methanesulfonate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of solvent (ethanol / n-heptane = 1:1), stir at room temperature for about 3 days, centrifuge to separate the solid and test XRPD. The obtained solid is methanesulfonic acid crystal form A.

[0221] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 11.3°, 12.8°, 15.7°, 19.1°, and 20.2° (see...). Figure 55 (Table 29); TGA results show that the weight loss before 150℃ is approximately 1.64%, and DSC results show endothermic peaks at 54.8℃ and 234.4℃ (see Table 29). Figures 56-57 The solid obtained by the above preparation method is the methanesulfonate crystal form A of compound of formula 1.

[0222] Example 36: Preparation of methanesulfonate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetone, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is methanesulfonic acid crystal form B.

[0223] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 6.7°, 10.1°, 11.0°, 12.5°, 13.3°, 17.1°, and 21.0° (see...). Figure 58 (Table 30); TGA results show that the weight loss before 150℃ is approximately 0.88%, and DSC results show endothermic peaks at 42.9℃ and 226.9℃ (see Table 30). Figures 59-60 ). 1 ¹H NMR results showed that the acid-base molar ratio of the sample was 1:1. The solid obtained by the above preparation method was the methanesulfonate crystal form B of compound 1.

[0224] Example 37: Preparation of methanesulfonate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of tetrahydrofuran, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is methanesulfonate crystal form B.

[0225] Example 38: Preparation of methanesulfonate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetonitrile, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is methanesulfonate crystal form B.

[0226] Example 39: Preparation of Succinate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of solvent (ethanol / n-heptane = 1:1), stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is succinate crystal form A.

[0227] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 12.0°, 12.9°, 13.4°, 16.3°, 17.3°, 18.8°, and 21.6° (see...). Figure 61 (Table 31); TGA results show that the weight loss before 150℃ is approximately 4.28%, and DSC results show endothermic peaks at 94.3℃, 163.9℃, and 191.4℃ (see Table 31). Figures 62-63 ). 1 ¹H NMR results showed that the acid-base molar ratio of the sample was 0.5:1. The solid obtained by the above preparation method was succinate A, a compound of formula 1.

[0228] Example 40: Preparation of Succinate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of acetone, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is succinic acid crystal form B.

[0229] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at angles of 2θ at 10.9°, 11.7°, 13.8°, 16.9°, 18.5°, 20.3°, and 22.3° (see...). Figure 64 (Table 32); TGA results show that the weight loss before 150℃ is approximately 0.79%, and DSC results show an endothermic peak at 192.0℃ (see Table 32). Figures 65-66 ). 1 ¹H NMR results showed that the acid-base molar ratio of the sample was 1:1. The solid obtained by the above preparation method was succinate B, a compound of formula 1.

[0230] Example 41: Preparation of Succinate of Formula 1 Weigh approximately 20 mg of compound 1 and an equimolar ratio of ligand acid, add them to 0.5 ml of tetrahydrofuran, stir at room temperature for about 3 days, centrifuge to separate the solid and test for XRPD. The obtained solid is succinate crystal form A.

[0231] Example 42: Preparation of crystal form A of the hydrochloride salt of compound 1 Weigh 299.9 mg of free base sample at room temperature into a 20 ml vial, add 4 ml of ethanol / n-heptane solvent, and dissolve until basically clear; Hydrochloric acid solution was slowly added to the sample to obtain a suspension; the suspension was stirred for 3 days; after centrifugation, a solid was obtained and vacuum dried at room temperature for 22 hours. XRPD was detected, and the obtained solid was hydrochloride crystal form A.

[0232] Example 43: Preparation of fumarate crystal form A of compound of formula 1 Weigh 300.5 mg of free base sample and 83.1 mg of fumaric acid into a 20 ml vial at room temperature, add 5 ml of acetonitrile to obtain a suspension; Stir for 3 days; after centrifugation, a solid was obtained and vacuum dried at room temperature for 22 hours. XRPD was detected, and the obtained solid was fumaric acid crystal form A.

[0233] Example 44: Preparation of Succinate Crystal Form B of Compound Formula 1 Weigh 200.9 mg of free alkali sample into a 20 ml vial at room temperature, add 4 ml of acetonitrile solvent, and obtain a suspension; 56.9 mg of succinic acid was slowly added to the sample to obtain a suspension; the suspension was stirred for 1 day; after centrifugation, a solid was obtained and vacuum dried at room temperature for 22 hours. XRPD was detected, and the obtained solid was succinate crystal form B.

[0234] Example 45: Preparation of Succinate Crystal Form C of Compound Formula 1 Weigh 499.9 mg of free base sample into a 20 mL vial at room temperature, add 8.0 mL of ACN solvent to obtain a suspension. Weigh 140.3 mg of succinic acid into the API suspension and stir at 50ºC. After stirring for 1 day, centrifuge the sample under vacuum (10000 rpm, 2 min). Dry the solid after centrifugation at 50ºC for 4 hours, and then vacuum dry overnight at room temperature. Collect the solid and test XRPD; the obtained solid is succinic acid crystal form C.

[0235] The obtained solid-state X-ray diffraction pattern shows characteristic diffraction peaks at 2θ angles of 7.9°, 11.9°, 14.1°, 17.3°, and 19.6° (see...). Figure 67 (Table 33); TGA results show that the weight loss before 150℃ is approximately 1.51%, and DSC results show endothermic peaks at 168.1℃ and 195.1℃ (see Table 33). Figures 68-69 ).1 1H NMR results showed that the acid-base molar ratio of the sample was 1:1.

[0236] Comparative Example 1 Weigh approximately 20 mg of compound 1 and 0.5 molar ratio of succinic acid, add them to 0.5 ml of ethanol, stir at room temperature for about 2 days, centrifuge to separate the solid and test for XRPD. The resulting wet product is succinate crystal form D.

[0237] The X-ray diffraction pattern of the obtained wet sample shows characteristic diffraction peaks at angles of 2θ at 3.4°, 10.0°, 11.1°, 12.0°, 12.9°, 13.2°, and 13.9° (see...). Figure 70 (Table 34); TGA results show that the weight loss before 130℃ is approximately 6.40%, and DSC results show endothermic peaks at 115.4℃ and 136.5℃ (see Table 34). Figure 71 , Figure 72 ). 1 ¹H NMR results showed that the acid-base molar ratio of the sample was 0.5:1. After being dried in the open at room temperature, the wet sample transformed into succinate crystal form A, which is presumably an unstable crystal form.

[0238] Comparative Example 2 Weigh approximately 20 mg of compound 1 and succinic acid in an equimolar ratio, add them to 0.5 ml of ethanol, stir at room temperature for about 2 days, centrifuge to separate the solid and test for XRPD. The resulting wet product is succinate crystal form E.

[0239] The X-ray diffraction pattern of the obtained wet sample shows characteristic diffraction peaks at 2θ angles of 7.9°, 9.6°, 9.9°, 13.4°, and 15.8° (see...). Figure 73 (Table 35). After being dried in the open at room temperature, the wet sample transformed into succinate crystal form C, which is presumably an unstable crystal form.

[0240] Example 46 The free base of the compound of formula I obtained in Example 1 has a good therapeutic effect on cisplatin-induced acute kidney injury, ischemia-reperfusion-induced kidney injury, and gentamicin-induced acute kidney injury.

[0241] Examples 2-45 of this invention are different crystal forms of the compound in Example 1. They have the same effect as in Example 1 in cisplatin-induced acute kidney injury, ischemia-reperfusion-induced kidney injury, and gentamicin-induced acute kidney injury.

[0242] 1. Cisplatin-induced kidney injury test Experimental animals: Male C57BL / 6J mice, aged 6-8 weeks and weighing 20-23 g, were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. After purchase, the animals underwent veterinary quarantine (quarantine period of 3 days).

[0243] Animal grouping: Quarantined mice were randomly divided into control group, model group and drug administration group, with 5 mice in each group.

[0244] Modeling method: Cisplatin injection was administered intraperitoneally to the model group and the drug administration group at a dose of 15 mg / kg (0.1 mL / 10 g), and an equal volume of physiological saline was injected into the control group.

[0245] Preparation of drug formulations: Weigh the drug powder separately, grind it in a mortar until there are no obvious large particles, add 0.5% CMC-Na solution, and sonicate it to disperse it evenly. Prepare solutions of 10 mg / kg respectively, and use them immediately.

[0246] The administration method, frequency, time, and volume for the treatment group were as follows: oral administration, 48 h, 24 h, and 2 h before modeling, and 24 h and 48 h after modeling, for a total of 5 times, once daily. The administration volume was 0.1 mL / 10 g.

[0247] The control group and the model group were given the same amount of solvent.

[0248] Biochemical index detection: 72 h after cisplatin-induced modeling, blood was collected from the eyes of mice and placed in anticoagulant-free EP tubes. The tubes were incubated at room temperature for 30 min, then centrifuged at 3000 rpm for 10 min to obtain serum. Serum urea nitrogen (Bun) and creatinine (SCr) were measured using a serum biochemistry analyzer. The inhibition rate of biochemical indexes was calculated using the formula: Inhibition rate (%) = (Model group - Drug treatment group) / (Model group - Control group) * 100%.

[0249] Kidney appearance: After the mice were euthanized by cervical dislocation, the kidneys were dissected and separated, the capsule was removed, and the kidneys were rinsed with physiological saline. After removing the residual water on the surface of the kidneys with absorbent paper, they were placed in a photography box for photography.

[0250] Pathology: After photographing the kidneys, they were fixed by immersing them in 4% paraformaldehyde fixative. Two days later, they were dehydrated, embedded in paraffin, sectioned, stained, photographed, and finally interpreted.

[0251] Statistical Analysis: GraphPad Prism v9.0.0 software was used for statistical analysis. Experimental data are expressed as mean ± standard error (Mean ± SEM). For biochemical test data, one-way ANOVA (Dunnett's multiple comparison test) was used to assess differences between the model group and the control group, and between the drug-treated group and the model group. All statistical analyses were performed using GraphPad Prism software. P < 0.05 was considered statistically significant, and P > 0.05 was considered not statistically significant. Serum urea nitrogen (Bun) and creatinine (SCr) showed significant differences between the model group and the control group, and between the drug-treated group and the model group.

[0252] The test results are shown in Table 5.

[0253] Table 5 shows the inhibitory activity of the free base of compound I on biochemical indicators of cisplatin-induced kidney injury.

[0254] 2. Ischemia-reperfusion induced kidney injury test Experimental animals: Male C57BL / 6J mice, aged 6-8 weeks and weighing 20-23 g, were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. After purchase, the animals underwent veterinary quarantine (quarantine period of 3 days).

[0255] Animal grouping: Quarantined mice were randomly divided into control group, model group and drug administration group, with 5 mice in each group.

[0256] Modeling was performed in both the model group and the drug-treated group. The modeling method was as follows: Ischemia: Incise the peritoneum to expose the abdominal organs, gently push the intestines to one side to locate the kidneys and expose their pedicles. Use miniature arterial clamps to clamp both renal pedicles, ensuring complete occlusion of renal blood flow.

[0257] Reperfusion: Carefully remove the microarterial clamp after 40 minutes to restore blood flow to the renal pedicle.

[0258] The control group underwent sham surgery.

[0259] Preparation of drug formulations: Weigh the drug powder separately, grind it in a mortar until there are no obvious large particles, add 2% DMSO, 5% Cremophor® EL and 93% sterile water for injection in sequence, and sonicate to disperse it evenly. Prepare and use immediately.

[0260] The administration method, frequency, timing, and volume for the treatment group were as follows: intravenous injection, twice a day for the two days prior to modeling, with an interval of 6 hours; on the day of modeling, administration was given 1 hour before and 1 hour after modeling, with an interval of 6 hours. A total of 6 administrations were administered.

[0261] The model group and the control group were given the same amount of solvent.

[0262] Biochemical index detection: 24 h after ischemia-reperfusion modeling, blood was collected from the eyes of mice and placed in anticoagulant-free EP tubes. The tubes were incubated at room temperature for 30 min, then centrifuged at 3000 rpm for 10 min to obtain serum. Serum urea nitrogen (Bun) and creatinine (SCr) were measured using a serum biochemistry analyzer. The inhibition rate of biochemical indexes was calculated using the formula: Inhibition rate (%) = (Model group - Drug treatment group) / (Model group - Control group) * 100%.

[0263] Pathology: The kidneys were fixed by immersion in 4% paraformaldehyde fixative. Two days later, they were dehydrated, embedded in paraffin, sectioned, stained, photographed, and finally interpreted.

[0264] Statistical analysis: GraphPad Prism v9.0.0 software was used for statistical analysis. Experimental data are expressed as mean ± standard error (Mean ± SEM). For biochemical test data, one-way ANOVA (Dunnett's multiple comparison test) was used to assess the differences between each treatment group and the model group. All statistical analyses were performed using GraphPad Prism software. P < 0.05 was considered statistically significant, and P > 0.05 was considered not statistically significant.

[0265] Serum urea nitrogen (Bun) and creatinine (SCr) showed significant differences between the model group and the control group, and significant differences between the drug-treated group and the model group.

[0266] The test results are shown in Table 6.

[0267] Table 6. Inhibitory activity of free base of Formula I compound on biochemical indicators of ischemia-reperfusion-induced renal injury.

[0268] 3. Gentamicin-induced acute kidney injury experiment Experimental animals: Male Wistar rats, aged 6-8 weeks and weighing 220-250 g, were purchased from Spiford (Beijing) Biotechnology Co., Ltd. After purchase, the animals underwent veterinary quarantine (3-day quarantine period) and were acclimatized for one week.

[0269] Animal grouping: Quarantined rats were randomly grouped into control group, model group and drug administration group.

[0270] Modeling was performed in the model group and the drug treatment group. The modeling method was as follows: Gentamicin was weighed and added to physiological saline to prepare a solution with a concentration of 10 mg / mL, which was prepared and used immediately. Except for the normal control group, rats in the other groups were given gentamicin intraperitoneally 2 hours after administration to induce the model, and the injection was continued for 7 days. The control group was given the corresponding volume of physiological saline.

[0271] Preparation of oral administration formulations: Weigh the drug powder separately, grind it in a mortar until there are no obvious large particles, add 0.5% CMC-Na solution, and sonicate it to disperse it evenly. Prepare solutions of 10 mg / kg respectively, and use them immediately.

[0272] Frequency, timing and volume of administration in the treatment groups: rats in each test group and positive drug group were given the corresponding drug 2 hours before modeling with gentamicin every day, while the control group and model control group were given the corresponding solvent by gavage. The administration was carried out for 7 consecutive days.

[0273] Biochemical index detection: Blood samples were collected from the jugular vein of rats in each group 24 h after the last administration of gentamicin. The samples were placed in anticoagulant-free EP tubes, incubated at room temperature for 30 min, and centrifuged at 3000 rpm for 10 min to obtain serum. Serum urea nitrogen (Bun) and creatinine (SCr) were measured using a serum biochemistry analyzer. The inhibition rate of biochemical indexes was calculated using the formula: Inhibition rate (%) = (Model group - Drug-treated group) / (Model group - Control group) * 100%.

[0274] Pathology: The kidneys were fixed by immersion in 4% paraformaldehyde fixative. Two days later, they were dehydrated, embedded in paraffin, sectioned, stained, photographed, and finally interpreted.

[0275] Statistical analysis: Data statistical analysis was performed using GraphPad Prism v9.0.0 software. Experimental data are expressed as mean ± standard error (Mean ± SEM). For biochemical test data, one-way ANOVA (Dunnett's multiple comparison test) was used to assess the differences between the drug-treated groups and the model group. All statistical analyses were performed using GraphPad Prism software. P < 0.05 was considered statistically significant, and P > 0.05 was considered not statistically significant. Serum urea nitrogen (Bun) and creatinine (SCr) showed significant differences between the model group and the control group, and significant differences between the drug-treated groups and the model group.

[0276] The test results are shown in Table 7.

[0277] Table 7. Inhibitory activity of the free base of Formula I compound against biochemical indicators of gentamicin-induced kidney injury.

[0278] In summary, the compound of formula I has good therapeutic effects on acute kidney injury caused by various inducing factors such as cisplatin, ischemia-reperfusion, and gentamicin, and has broad application value in the prevention and treatment of acute kidney injury.

[0279] Example 47 Comparison of dynamic solubility of salt-type compounds and free bases The dynamic solubility of the free alkali crystal form A in Example 1, the hydrochloride crystal form A prepared in Example 2, the fumarate crystal form A prepared in Example 25, and the succinate crystal form B prepared in Example 40 in pure water was evaluated. The results are shown in Table 8, and the dynamic solubility curves are shown in the figure. Figure 83 .

[0280] The dynamic solubility of each sample in pure water was determined at 37 °C (25 rpm) using a rotary mixer at a feed concentration of 5 mg / mL (calculated as free alkali) for 1, 2, 4, and 24 hours. Samples at each time point were centrifuged and filtered (using a 0.45 μm PTFE filter), and the HPLC concentration and pH of the filtrate were determined. The solid samples after centrifugation were tested for XRPD. Dynamic solubility results showed that all salt forms in water exhibited significantly increased solubility relative to the free alkali. Simultaneously, the free alkali crystal form A showed a decrease in solubility and precipitated solid upon standing in pure water. After solid separation, XPRD analysis revealed it to be a new crystal form. Details of the new crystal form detection results and a comparison with the XPRD results of the 0-hour free alkali crystal form A solid are available in [link to relevant documentation]. Figure 82 In summary, free alkali crystal form A will transform into a new crystal form in pure water, and the solubility of the new crystal form in water will be greatly reduced, leading to the precipitation of solids.

[0281] Table 8 Results of dynamic solubility test

[0282] Example 48 Solution Stability At a concentration of 0.2 mg / mL (based on free base), the free base crystal form A from Example 1, the hydrochloride crystal form A prepared in Example 2, the fumarate crystal form A prepared in Example 25, and the succinate crystal form B prepared in Example 40 were dissolved in physiological saline (0.9% NaCl) and allowed to stand for 24 hours and 48 hours under light irradiation (25℃ / 4500 lux), respectively. Their chemical stability was tested by HPLC. The results showed that the free base degraded significantly under light irradiation, while the degradation rate of the other salt forms was significantly slowed. Fumarate crystal form A and succinate crystal form B showed high stability and are more suitable for development into solution formulations. The amino groups of compounds of Formula I are easily oxidized via a free radical mechanism under trace oxygen and light conditions. The protective effect of the salt forms against photodegradation of compounds of Formula I may be due to the acid radical reducing the electrophilicity of the amino groups, thus blocking / delaying the oxidation reaction, resulting in an unexpected technical effect.

[0283] The experimental results are shown in Table 9.

[0284] Table 9. Evaluation of solution photostability

[0285] Example 49 Solid stability The solid stability of the free alkali crystal form A from Example 1, the hydrochloride crystal form A prepared in Example 2, the fumarate crystal form A prepared in Example 25, and the succinate crystal form B prepared in Example 40 was evaluated by placing them at 40ºC / 75%RH (accelerated test conditions) for one week. Their physical and chemical stability was tested by XRPD and HPLC (dissolved in physiological saline), respectively. The results showed that the purity of the free alkali crystal form A decreased significantly after stabilization. No significant changes in purity or crystal form transformation were observed in the succinate crystal form B, hydrochloride crystal form A, and fumarate crystal form A after stabilization. Therefore, the succinate crystal form B, hydrochloride crystal form A, and fumarate crystal form A have a significant stability advantage compared to the free alkali crystal form A. The experimental results are shown in Table 10.

[0286] Table 10 Solid stability assessment

[0287]

[0288] Example 50 The following crystal forms were prepared: free alkali crystal form A from Example 1, hydrochloride crystal form A from Example 2, hydrochloride crystal form B from Example 3, sulfate crystal form A from Example 6, sulfate crystal form B from Example 7, maleate crystal form A from Example 13, phosphate crystal form A from Example 14, phosphate crystal form B from Example 15, phosphate crystal form C from Example 16, phosphate crystal form D from Example 17, tartrate crystal form A from Example 18, tartrate crystal form B from Example 19, and the rich alkali crystal form A from Example 25. The following crystal forms were subjected to XRPD diffraction, TGA detection, and DSC detection: malate crystal form A, citrate crystal form A prepared in Example 26, citrate crystal form B prepared in Example 27, citrate crystal form C prepared in Example 28, citrate crystal form D prepared in Example 29, p-toluenesulfonate crystal form A prepared in Example 31, methanesulfonate crystal form A prepared in Example 35, methanesulfonate crystal form B prepared in Example 36, succinate crystal form A prepared in Example 39, succinate crystal form B prepared in Example 40, and succinate crystal form C prepared in Example 45.

[0289] The experimental results are shown in Figure 1 -Figure 69 and Tables 11-33.

[0290] Table 11 List of XRPD diffraction peaks in Example 1

[0291] Table 12 List of XRPD diffraction peaks for hydrochloride crystal form A in Example 2

[0292] Table 13 List of XRPD diffraction peaks for hydrochloride crystal form B in Example 3

[0293] Table 14 List of XRPD diffraction peaks for sulfate crystal form A in Example 6

[0294] Table 15 List of XRPD diffraction peaks for sulfate crystal form B in Example 7

[0295] Table 16 List of XRPD diffraction peaks for maleate crystal form A in Example 13

[0296] Table 17 List of XRPD diffraction peaks for phosphate crystal form A in Example 14

[0297] Table 18 List of XRPD diffraction peaks for phosphate crystal form B in Example 15

[0298] Table 19 List of XRPD diffraction peaks for phosphate crystal form C in Example 16

[0299] Table 20 List of XRPD diffraction peaks for phosphate crystal form D in Example 17

[0300] Table 21 List of XRPD diffraction peaks for tartrate crystal form A in Example 18

[0301] Table 22 List of XRPD diffraction peaks for tartrate crystal form B in Example 19

[0302] Table 23 List of XRPD diffraction peaks for fumarate crystal form A in Example 25

[0303] Table 24 List of XRPD diffraction peaks for citrate crystal form A in Example 26

[0304] Table 25 List of XRPD diffraction peaks for citrate crystal form B in Example 27

[0305] Table 26 List of XRPD diffraction peaks for citrate crystal form C in Example 28

[0306] Table 27 List of XRPD diffraction peaks for citrate crystal form D in Example 29

[0307] Table 28 List of XRPD diffraction peaks for p-toluenesulfonate crystal form A in Example 31

[0308] Table 29 List of XRPD diffraction peaks for methanesulfonate crystal form A in Example 35

[0309] Table 30 List of XRPD diffraction peaks for methanesulfonate crystal form B in Example 36

[0310] Table 31 List of XRPD diffraction peaks for succinate crystal form A in Example 39

[0311] Table 32 List of XRPD diffraction peaks for succinate crystal form B (829140-17-D4) in Example 40

[0312] Table 33 List of XRPD diffraction peaks for succinate crystal form C in Example 45

[0313] Table 34 List of XRPD diffraction peaks for succinate crystal form D in Comparison Column 1

[0314] Table 35 List of XRPD diffraction peaks for succinate crystal form E in Comparison Column 2

[0315] The free alkali crystal form A from Example 1, the hydrochloride crystal form A prepared in Example 2, the fumarate crystal form A prepared in Example 25, and the succinate crystal form B prepared in Example 40 were subjected to DVS detection.

[0316] The experimental results are shown in Figure 74-81 .

[0317] in, Figure 74 , Figure 76 and Figure 78 The horizontal axis represents humidity, and the vertical axis represents moisture adsorption; the numbers in the graph represent... The corresponding color line graph shows the percentage of water adsorption at 80% humidity. Cycle 1 Sorp is the dynamic adsorption line during the first increase in humidity, Cycle 1 Desorp (blue line) is the adsorption line during the decrease in humidity, and Cycle 2 Sorp is the adsorption line during the second increase in humidity.

[0318] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A hydrochloride crystal form of a benzofuranone compound of formula I, characterized in that, The hydrochloride crystal form is one of hydrochloride crystal form A and hydrochloride crystal form B; The X-ray powder diffraction pattern of the hydrochloride crystal form A shows characteristic peaks at 2θ angles of 4.3±0.2°, 11.7±0.2°, 14.4±0.2°, 17.4±0.2°, 19.9±0.2°, 20.8±0.2°, 23.4±0.2°, 24.6±0.2°, 26.1±0.2°, and 30.6±0.2°. The X-ray powder diffraction pattern of the hydrochloride crystal form B has characteristic peaks at 2θ angles of 6.1±0.2°, 13.8±0.2°, 15.5±0.2°, 18.3±0.2°, 21.7±0.2°, and 22.9±0.2°. 。 2. A sulfate crystal form of a benzofuranone compound of formula I, characterized in that, The sulfate crystal form is one of sulfate crystal form A and sulfate crystal form B; The X-ray powder diffraction pattern of the sulfate crystal form A has characteristic peaks at 2θ angles of 8.5±0.2°, 11.7±0.2°, 11.9±0.2°, 12.7±0.2°, 15.3±0.2°, 16.1±0.2°, 19.2±0.2°, and 21.1±0.2°. The X-ray powder diffraction pattern of the sulfate crystal form B has characteristic peaks at 2θ angles of 10.7±0.2°, 14.7±0.2°, 11.9±0.2°, 17.8±0.2°, 18.5±0.2°, and 19.2±0.2°. 。 3. A maleate crystal form of a benzofuranone compound of formula I, characterized in that, The maleate crystal form is maleate crystal form A, and its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 12.0±0.2°, 12.6±0.2°, 13.3±0.2°, 16.3±0.2°, 17.2±0.2°, 20.5±0.2°, and 21.1±0.2°. 。 4. A phosphate crystal form of a benzofuranone compound represented by Formula I, characterized in that, The phosphate crystal form is one of phosphate crystal form A, phosphate crystal form B, phosphate crystal form C, or phosphate crystal form D; The X-ray powder diffraction pattern of the phosphate crystal form A has characteristic peaks at 2θ angles of 8.1±0.2°, 9.4±0.2°, 10.8±0.2°, 12.1±0.2°, and 16.7±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form B has characteristic peaks at 2θ angles of 12.3±0.2°, 16.1±0.2°, 22.5±0.2°, 22.8±0.2°, and 24.8±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form C has characteristic peaks at 2θ angles of 8.2±0.2°, 12.3±0.2°, 15.2±0.2°, 16.3±0.2°, and 19.0±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form D has characteristic peaks at 2θ angles of 9.6±0.2°, 11.0±0.2°, 12.3±0.2°, 14.3±0.2°, 16.5±0.2°, and 19.2±0.2°. 。 5. A tartrate crystal form of a benzofuranone compound represented by Formula I, characterized in that, The tartrate crystal form is either tartrate crystal form A or tartrate crystal form B. The X-ray powder diffraction pattern of tartrate crystal form A has characteristic peaks at 2θ angles of 5.8±0.2°, 11.6±0.2°, 13.2±0.2°, 13.9±0.2°, 16.3±0.2°, 17.4±0.2°, and 20.6±0.2°. The X-ray powder diffraction pattern of the tartrate crystal form B has characteristic peaks at 2θ angles of 6.1±0.2°, 7.1±0.2°, 14.7±0.2°, 17.0±0.2°, 19.8±0.2°, and 21.6±0.2°. 。 6. A fumarate crystal form of a benzofuranone compound represented by Formula I, characterized in that, The fumarate crystal form is fumarate crystal form A, and its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 10.9±0.2°, 11.7±0.2°, 14.1±0.2°, 16.7±0.2°, 18.7±0.2°, 20.7±0.2°, 21.5±0.2°, 22.5±0.2°, 24.6±0.2°, and 25.2±0.2°. 。 7. A citrate crystal form of a benzofuranone compound of formula I, characterized in that, The citrate crystal form is one of citrate crystal form A, citrate crystal form B, citrate crystal form C, or citrate crystal form D; The X-ray powder diffraction pattern of the citrate crystal form A has characteristic peaks at 2θ angles of 5.4±0.2°, 6.0±0.2°, 11.1±0.2°, 14.8±0.2°, 15.4±0.2°, 16.5±0.2°, and 20.3±0.2°. The X-ray powder diffraction pattern of the citrate crystal form B shows characteristic peaks at 2θ angles of 4.7±0.2°, 7.9±0.2°, 11.2±0.2°, 12.9±0.2°, 14.1±0.2°, 15.4±0.2°, 19.9±0.2°, and 26.6±0.2°. The X-ray powder diffraction pattern of the citrate crystal form C shows characteristic peaks at 2θ angles of 9.9±0.2°, 10.4±0.2°, 12.5±0.2°, 14.5±0.2°, 15.7±0.2°, 16.1±0.2°, 16.9±0.2°, 19.2±0.2°, and 22.0±0.2°. The X-ray powder diffraction pattern of the citrate crystal form D shows characteristic peaks at 2θ angles of 8.3±0.2°, 11.1±0.2°, 12.0±0.2°, 13.2±0.2°, 14.5±0.2°, 16.6±0.2°, 17.2±0.2°, and 20.0±0.2°. 。 8. A p-toluenesulfonate crystal form of a benzofuranone compound represented by Formula I, characterized in that, The p-toluenesulfonate crystal form is p-toluenesulfonate crystal form A, and its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 11.1±0.2°, 12.0±0.2°, 12.9±0.2°, 15.4±0.2°, 16.6±0.2°, 17.0±0.2°, 18.1±0.2°, 18.7±0.2°, and 20.3±0.2°. 。 9. A methanesulfonate crystal form of a benzofuranone compound of formula I, characterized in that, The methanesulfonate crystal form is either methanesulfonate crystal form A or methanesulfonate crystal form B; The X-ray powder diffraction pattern of the methanesulfonate crystal form A has characteristic peaks at 2θ angles of 11.3±0.2°, 12.8±0.2°, 15.7±0.2°, 19.1±0.2°, and 20.2±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form B has characteristic peaks at 2θ angles of 6.7±0.2°, 10.1±0.2°, 11.0±0.2°, 12.5±0.2°, 13.3±0.2°, 17.1±0.2°, and 21.0±0.2°. 。 10. A succinate crystal form of a benzofuranone compound represented by Formula I, characterized in that, The succinate crystal form is one of succinate crystal form A, succinate crystal form B, and succinate crystal form C; The X-ray powder diffraction pattern of the succinate crystal form A has characteristic peaks at 2θ angles of 12.0±0.2°, 12.9±0.2°, 13.4±0.2°, 16.3±0.2°, 17.3±0.2°, 18.8±0.2°, and 21.6±0.2°. The X-ray powder diffraction pattern of the succinate crystal form B shows characteristic peaks at 2θ angles of 8.5±0.2°, 10.9±0.2°, 11.7±0.2°, 13.8±0.2°, 16.9±0.2°, 18.5±0.2°, 20.3±0.2°, 21.5±0.2°, 21.8±0.2°, 22.3±0.2°, 24.1±0.2°, and 24.8±0.2°. The X-ray powder diffraction pattern of the succinate crystal form C shows characteristic peaks at 2θ angles of 7.9±0.2°, 11.9±0.2°, 13.4±0.2°, 14.1±0.2°, 14.7±0.2°, 17.3±0.2°, 19.6±0.2°, 20.4±0.2°, 22.9±0.2°, and 24.3±0.2°. 。 11. The method for preparing the crystal form according to any one of claims 1-10, characterized in that, Includes the following steps: The compound of formula I, the ligand acid, and the solvent are mixed, stirred, and then separated into solid and liquid components to obtain the product. The ligand acid is one of hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, tartaric acid, fumaric acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, and succinic acid. When the ligand acid is maleic acid, the solvent is acetonitrile; when the ligand acid is hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, fumaric acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, or succinic acid, the solvent is at least one of ethanol / n-heptane mixture, acetonitrile, acetone, and tetrahydrofuran.

12. The preparation method according to claim 11, characterized in that, The molar ratio of the compound to the ligand acid is 0.8-2.4:

1.

13. The preparation method according to claim 11, characterized in that, The stirring time is 60-80 hours, and the temperature is 20-30℃.

14. A pharmaceutical composition, characterized in that, It includes at least one of the crystal forms described in any one of claims 1-10.

15. A drug, characterized in that, It comprises the pharmaceutical composition of claim 14 and pharmaceutically acceptable excipients.

16. The use of the crystal form according to any one of claims 1-10 in the preparation of a medicament for the prevention or treatment of acute kidney injury.

17. The application according to claim 16, characterized in that, The acute kidney injury is at least one of the following: ischemic acute kidney injury, acute kidney injury caused by systemic infection, drug-induced acute kidney injury, surgery-related acute kidney injury, acute kidney injury caused by crush syndrome, acute kidney injury caused by cardiorenal syndrome, and acute kidney injury caused by hepatorenal syndrome.

18. The application according to claim 17, wherein the drug-induced acute kidney injury is cisplatin- or gentamicin-induced acute kidney injury.

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