Acid addition salts, crystal forms, composition and drug use for rock inhibitor

Abstract

This invention discloses an acid addition salt of a ROCK inhibitor, its crystal form, composition, and pharmaceutical uses. The acid addition salt is an acid addition salt of compound A with any of the following acids: hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, maleic acid, tartaric acid, oxalic acid, fumaric acid, sulfuric acid, methanesulfonic acid, phosphoric acid, succinic acid, or citric acid. The acid addition salt of compound A and its crystal form exhibit high solubility, good stability, high purity, few impurities, and high bioequivalence, which is beneficial for drug storage, quality control, and pharmaceutical properties.

Description

[Technical Field]

[0001] This application claims priority to the following prior applications: Patent Application No. 202110533087.9, filed with the China National Intellectual Property Administration on May 14, 2021, entitled "An Acid Addition Salt of a ROCK Inhibitor and its Crystal Form, Composition, and Pharmaceutical Use"; and Patent Application No. 202210500178.7, filed with the China National Intellectual Property Administration on May 7, 2022, also entitled "An Acid Addition Salt of a ROCK Inhibitor and its Crystal Form, Composition, and Pharmaceutical Use". The entire contents of the earlier applications are incorporated herein by reference.

[0002] This invention belongs to the field of medicinal chemistry, specifically relating to an acid addition salt of a ROCK inhibitor, the crystal form of the salt, the composition, and the pharmaceutical use. [Previous Technology]

[0003] Idiopathic interstitial pulmonary fibrosis (IPF) is a chronic, diffuse interstitial lung disease of unknown cause, characterized by changes similar to common interstitial pneumonia. Its histopathology and imaging findings often resemble those of common interstitial pneumonia. Due to its complex pathogenesis, irreversible disease progression, and difficulty in early diagnosis, the survival rate of patients after diagnosis declines significantly over time. The 3-year survival rate is 50%, and the 5-year survival rate is only 20%, lower than the survival rates of most cancers (e.g., leukemia, breast cancer, colon cancer, uterine fibroids, kidney cancer, etc.), earning it the nickname "the cancer that is not cancer." Currently, there are no definitively effective treatments for IPF. Based on the results of recent randomized controlled clinical trials and considering the actual clinical situation in China, drugs such as pirfenidone and nintedanib can be used as appropriate. However, nintedanib is only recommended for IPF patients with mild to moderate pulmonary dysfunction. Whether nintedanib can benefit IPF patients with severe pulmonary dysfunction, and the duration of treatment, requires further investigation.

[0004] Rho GTPase was discovered in 1985 and belongs to the Ras superfamily, sharing 25% homology with Ras. Currently, the main Rho GTPase members distributed in mammalian tissue cells are Rho (A, B, C), Rac (1, 2, 3), Cdc42 (Cdc42Hs / G25K, TC10, Tcl), Rho D, Rho G, Chp (1, 2), Rnd (Rho E / Rnd3, Rnd1 / Rho6, Rnd2 / Rho7), Rho H / TTF, Rif, Wrch1, and Rho BTB (1, 2), among which Rho (A, B, C) is one of the most important members of the Rho GTPase family. ROCK (Rho-associated protein kinase), also known as Rho kinase, is a serine / threonine protein kinase with a molecular weight of approximately 160 kDa. It is currently the most functionally studied downstream target molecule of Rho. ROCK includes two isoforms: ROCK1 (ROKβ, p160-ROCK) and ROCK2 (ROKα). The two isoforms share 65% amino acid sequence identity and high similarity (92% identity) in their kinase domains. ROCK is distributed throughout the body; comparatively, ROCK1 is more highly expressed in non-nervous tissues (blood, small intestine, thymus, etc.), while ROCK2 is more highly expressed in the brain, heart, and colon.

[0005] ROCK is involved in the development of various cardiovascular and cerebrovascular diseases, including hypertension, atherosclerosis, ischemic stroke, heart disease, diabetic nephropathy, eye diseases, tumors, neurological injuries, radiation damage, and autoimmune diseases. For example, the Rho / ROCK signaling pathway is involved in the initiation of NAD(P)H oxidase, inducing oxidative stress, and triggering microvascular damage in the heart and C-reactive protein-induced atherosclerotic thrombosis; high glucose can activate the Rho / ROCK pathway, inducing the expression of visceral adipokines and type I procollagen in cardiomyocytes, leading to cardiomyocyte overproliferation and inducing diabetic cardiomyopathy; the activation of the Rho / ROCK signaling pathway can regulate the NF-κB signaling pathway, upregulate inflammatory genes, and induce diabetic nephropathy; the Rho / ROCK signaling pathway alters biomembrane permeability, affecting cancer cell metastasis; during spinal cord injury, Rho is activated, thereby inducing atrophy of the growth cone leading to impaired axonal regeneration, and simultaneously inducing the inhibitory effect of chondroitin sulfate proteoglycan on neuronal growth.

[0006] In addition, the Rho / ROCK signaling pathway is also involved in the occurrence and development of fibrotic diseases. Activation of the Rho / ROCK signaling pathway can increase the level of fibrosis in ischemic myocardium, and the expression of Rho and ROCK in the heart tissue of rats with acute myocardial fibrosis is significantly increased. Activation of the Rho / ROCK signaling pathway can induce actin phosphorylation, triggering cellular fibrosis. In vivo and in vitro experimental results have demonstrated that the cardiopulmonary physiological and pathological damage caused by radiation exposure over a period of time is related to fibrosis induced by the Rho / ROCK pathway. Ionizing radiation-induced endothelial adhesion fibronectin and focal adhesion formation, reduced endothelial cell migration, and endothelial dysfunction are related to actin cytoskeleton remodeling and stress fiber formation induced by the activation of the Rho / ROCK signaling pathway.

[0007] Lung injury in IPF primarily targets alveolar epithelial cells (ACEs). ACE death triggers the wound healing response, including innate immune activation, vascular leakage and extravascular coagulation, fibroblast recruitment, proliferation and activation, extracellular matrix synthesis and cross-linking, alveolar collapse, and epithelial cell regeneration. ROCK signaling can fundamentally regulate the activity of these cells involved in the healing response, especially epithelial cells, endothelial cells, and fibroblasts. The crucial role of ROCK in these responses further suggests the potential of ROCK inhibitors for treating pulmonary fibrosis.

[0008] Currently, there are no marketed drugs that inhibit the ROCK pathway to treat numerous diseases, including fibrosis. The development of new drugs requires careful optimization of the chemical and biological properties of lead compounds. Furthermore, the compound must possess the desired pharmacokinetic and pharmacodynamic characteristics. This arduous development process typically requires extensive testing. In many cases, determining the optimal compound often necessitates the preparation of thousands of structurally similar compounds. Therefore, improving ROCK kinase inhibitors and developing new skeletal compounds with ROCK1 and / or ROCK2 kinase inhibitory activity is of positive significance for the treatment of these diseases. Simultaneously, developing drug solid forms suitable for these compounds, such as solid forms that improve stability, hygroscopicity, and / or efficacy, to achieve good results in the pharmaceutical and drug administration stages, has become an urgent technical problem to be solved. [Summary of the Invention]

[0009] This invention provides a salt of compound A, wherein compound A has the following structure: The salt is an acid addition salt, for example, an acid addition salt of compound A with any of the following acids: hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, maleic acid, tartaric acid (including L-tartaric acid or R-tartaric acid), oxalic acid, fumaric acid, sulfuric acid, methanesulfonic acid, phosphoric acid, succinic acid, or citric acid, preferably hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, maleic acid, tartaric acid, oxalic acid, or fumaric acid. Preferably, the acid addition salt is the hydrochloride salt of compound A, the p-toluenesulfonate salt of compound A, the benzenesulfonate salt of compound A, the maleate salt of compound A, the tartrate salt of compound A, the oxalate salt of compound A, or the fumarate salt of compound A. According to the technical solution of the present invention, in the salt of compound A, the molar ratio of compound A to acid is 5:1 to 1:5, for example, 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5, or 1:3. According to the technical solution of the present invention, the salt of compound A can be amorphous or crystalline. For example, the hydrochloride salt of compound A can be an amorphous or crystalline form of the hydrochloride salt of compound A; the p-toluenesulfonate salt of compound A can be an amorphous or crystalline form of the p-toluenesulfonate salt of compound A; the benzenesulfonate salt of compound A can be an amorphous or crystalline form of the benzenesulfonate salt of compound A; the maleate salt of compound A can be an amorphous or crystalline form of the maleate salt of compound A; the tartrate salt of compound A can be an amorphous or crystalline form of the tartrate salt of compound A; the oxalate salt of compound A can be an amorphous or crystalline form of the oxalate salt of compound A; and the fumarate salt of compound A can be an amorphous or crystalline form of the fumarate salt of compound A. Preferably, the acid addition salt of compound A is selected from the hydrochloride crystal form of compound A, the p-toluenesulfonate crystal form of compound A, the benzenesulfonate crystal form of compound A, the maleate crystal form of compound A, the tartrate crystal form of compound A, the oxalate crystal form of compound A, or the fumarate crystal form of compound A. According to the technical solution of the present invention, the hydrochloride salt of compound A is a crystal form, named hydrochloride crystal form I. The hydrochloride crystal form I exhibits characteristic peaks at 5.93±0.20°, 14.92±0.20°, and 24.07±0.20° using Cu-Kα radiation and X-ray powder diffraction expressed in 2θ angles. Preferably, the hydrochloride crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.93±0.20°, 11.96±0.20°, 14.92±0.20°, 17.98±0.20°, 24.07±0.20°, 26.61±0.20°, and 27.18±0.20° in 2θ angles.Preferably, the hydrochloride crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.93±0.20°, 11.96±0.20°, 12.56±0.20°, 14.92±0.20°, 17.98±0.20°, 18.96±0.20°, 21.02±0.20°, 24.07±0.20°, 25.53±0.20°, 26.61±0.20°, 27.18±0.20°, and 31.66±0.20° in 2θ angles. Preferably, the hydrochloride crystal form I has the characteristic X-ray powder diffraction peaks in 2θ angles as shown in Table 5', with an error range of ±0.2°. Preferably, the hydrochloride crystal form I is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, is shown in Figure 1(b), with an error range of ±0.20°. According to the technical solution of the present invention, the hydrochloride crystal form I has an XRPD spectrum substantially as shown in Figure 1(a). According to the technical solution of the present invention, the molar ratio of compound A to hydrochloric acid in the hydrochloride crystal form I is 1:1. According to the technical solution of the present invention, the hydrochloride crystal form I is a hydrate, preferably a monohydrate. According to the technical solution of the present invention, the hydrochloride crystal form I has a weight loss of approximately 5.4% at room temperature to approximately 110°C. In some embodiments, the hydrochloride crystal form I has a weight loss of 5.4±2% at room temperature to 110±3°C. According to the technical solution of the present invention, the hydrochloride crystal form I has a broad endothermic peak at a peak temperature of approximately 97°C, preferably a peak temperature of 97±5°C, for example, 97±2°C. According to the technical solution of the present invention, the hydrochloride crystal form I has DSC and TGA spectra substantially as shown in Figure 2. According to the technical solution of the present invention, the hydrochloride crystal form I contains no organic solvent. According to the technical solution of the present invention, the p-toluenesulfonate of compound A is a crystal form, named p-toluenesulfonate crystal form I. The p-toluenesulfonate crystal form I exhibits characteristic peaks at 7.55±0.20°, 8.61±0.20°, 14.75±0.20°, 15.99±0.20°, and 23.38±0.20° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angles. Preferably, the p-toluenesulfonate crystal form I is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, exhibits characteristic peaks at 7.55±0.20°, 8.61±0.20°, 14.75±0.20°, 15.99±0.20°, 19.64±0.20°, 19.91±0.20°, 23.38±0.20°, 24.02±0.20°, and 24.60±0.20°.Preferably, the p-toluenesulfonate crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.49±0.20°, 7.55±0.20°, 8.61±0.20°, 9.14±0.20°, 10.05±0.20°, 14.39±0.20°, 14.75±0.20°, 15.99±0.20°, 19.64±0.20°, 19.91±0.20°, 20.67±0.20°, 23.38±0.20°, 24.02±0.20°, and 24.60±0.20° in 2θ angles. Preferably, the p-toluenesulfonate crystal form I has the characteristic X-ray powder diffraction peaks in 2θ angles as shown in Table 8', with an error range of ±0.2°. Preferably, the p-toluenesulfonate crystal form I is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, is shown in Figure 4(b), with an error range of ±0.20°. According to the technical solution of the present invention, the p-toluenesulfonate crystal form I has an XRPD spectrum essentially as shown in Figure 4(a). According to the technical solution of the present invention, the molar ratio of compound A to p-toluenesulfonic acid in the p-toluenesulfonate crystal form I is 1:1. According to the technical solution of the present invention, the p-toluenesulfonate crystal form I is a hydrate, preferably a monohydrate. According to the technical solution of the present invention, the p-toluenesulfonate crystal form I experiences a weight loss of approximately 2.5% from room temperature to approximately 105°C. In some embodiments, the p-toluenesulfonate crystal form I experiences a weight loss of 2.5±2% from room temperature to 105±3°C. According to the technical solution of the present invention, the p-toluenesulfonate crystal form I has two absorption peaks, the first absorption peak having a peak temperature of approximately 89°C (the peak shape exhibits a broad endothermic peak), and the second absorption peak having a peak temperature of approximately 127°C. In some embodiments, the p-toluenesulfonate crystal form I has two absorption peaks: the peak temperature of the first absorption peak is 89℃±5℃, for example, 89±2℃; and the peak temperature of the second absorption peak is 127±5℃, for example, 127±2℃. According to the technical solution of the present invention, the p-toluenesulfonate crystal form I has the DSC and TGA spectra shown in Figure 5. According to the technical solution of the present invention, the p-toluenesulfonate crystal form I contains an organic solvent, preferably with a content of less than 1%, and more preferably less than 0.6%. The organic solvent is selected from one, two, or more of the following organic solvents: ethanol (EtOH), methyl tert-butyl ether (MTBE), ethyl acetate (EA), acetonitrile (ACN), dichloromethane (DCM), etc. For example, the p-toluenesulfonate crystal form I contains 0.5% ethanol (EtOH) and 0.1% methyl tert-butyl ether (MTBE).According to the technical solution of the present invention, the benzenesulfonate of compound A is a crystalline form, named benzenesulfonate crystalline form I. The benzenesulfonate crystalline form I exhibits characteristic peaks at 7.96±0.20°, 9.00±0.20°, 15.80±0.20°, 20.49±0.20°, and 24.61±0.20° when X-ray powder diffraction is performed at 7.96±0.20°, 9.00±0.20°, 15.28±0.20°, 15.80±0.20°, 19.97±0.20°, 20.49±0.20°, and 24.61±0.20° when X-ray powder diffraction is performed at 7.96±0.20°, 9.00±0.20°, 15.28±0.20°, 15.80±0.20°, 19.97±0.20°, 20.49±0.20°, and 24.61±0.20° when X-ray powder diffraction is performed at 2θ angles. Preferably, the benzenesulfonate crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 7.96±0.20°, 9.00±0.20°, 9.79±0.20°, 10.30±0.20°, 14.48±0.20°, 15.28±0.20°, 15.80±0.20°, 17.09±0.20°, 17.29±0.20°, 19.24±0.20°, 19.97±0.20°, 20.49±0.20°, 23.29±0.20°, 24.61±0.20°, and 25.24±0.20°. Preferably, the benzenesulfonate crystal form I has X-ray powder diffraction characteristic peaks expressed in 2θ angles as shown in Table 10', with an error range of ±0.2°. Preferably, the benzenesulfonate crystal form I is subjected to Cu-Kα radiation, and the X-ray powder diffraction of the benzenesulfonate crystal form I expressed in 2θ angles is shown in Figure 7(b), with an error range of ±0.20°. According to the technical solution of the present invention, the benzenesulfonate crystal form I has an XRPD spectrum basically as shown in Figure 7(a). According to the technical solution of the present invention, the molar ratio of compound A to benzenesulfonic acid in the benzenesulfonate crystal form I is 1:1. According to the technical solution of the present invention, the benzenesulfonate crystal form I is a hydrate, preferably a monohydrate. According to the technical solution of the present invention, the benzenesulfonate crystal form I has a weight loss of about 3.0% at room temperature to about 117°C. In some embodiments, the benzenesulfonate crystal form I has a weight loss of 3.0±2% at room temperature to 117±3°C. According to the technical solution of the present invention, the benzenesulfonate crystal form I has a broad, overlapping endothermic peak with a peak temperature of approximately 114°C. In some embodiments, the benzenesulfonate crystal form I has a broad, overlapping endothermic peak with a peak temperature of 114±5°C, for example, 114±2°C. According to the technical solution of the present invention, the benzenesulfonate crystal form I has DSC and TGA spectra as shown in Figure 8. According to the technical solution of the present invention, the benzenesulfonate crystal form I contains an organic solvent, preferably less than 1%, and more preferably less than 0.6%.The organic solvent is selected from one, two, or more of the following organic solvents: ethanol (EtOH), methyl tert-butyl ether (MTBE), ethyl acetate (EA), acetonitrile (ACN), dichloromethane (DCM), etc. For example, the benzenesulfonate crystal form I contains 0.4% ethanol (EtOH) and 0.2% methyl tert-butyl ether (MTBE). According to the technical solution of the present invention, the maleate of compound A is a crystal form, named maleate crystal form I. The maleate crystal form I exhibits characteristic peaks at 4.22±0.20°, 7.29±0.20°, 16.13±0.20°, 17.19±0.20°, and 26.07±0.20° when X-ray powder diffracted using Cu-Kα radiation and expressed in 2θ angles. Preferably, the maleate crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 4.22±0.20°, 7.29±0.20°, 12.25±0.20°, 14.68±0.20°, 15.34±0.20°, 16.13±0.20°, 17.19±0.20°, 19.21±0.20°, 22.59±0.20°, and 26.07±0.20° in 2θ angles. Preferably, the maleate crystal form I has the characteristic peaks in X-ray powder diffraction at 2θ angles as shown in Table 12', with an error range of ±0.2°. Preferably, the maleate crystal form I, when subjected to Cu-Kα radiation, exhibits X-ray powder diffraction at 2θ angles as shown in Figure 10(b), with an error range of ±0.20°. According to the technical solution of the present invention, the maleate crystal form I has an XRPD spectrum substantially as shown in Figure 10(a). According to the technical solution of the present invention, the molar ratio of compound A to maleic acid in the maleate crystal form I is 1:1. According to the technical solution of the present invention, the maleate crystal form I has a weight loss of approximately 8.4% at room temperature to approximately 100°C. In some embodiments, the maleate crystal form I has a weight loss of 8.4±2% at room temperature to 100±3°C. According to the technical solution of the present invention, the maleate crystal form I has a broad, overlapping endothermic peak with a peak temperature of approximately 83°C. In some embodiments, the maleate crystal form I has a broad, overlapping endothermic peak with a peak temperature of 83±5°C, for example, 83±2°C. According to the technical solution of the present invention, the maleate crystal form I has DSC and TGA spectra substantially as shown in Figure 12. According to the technical solution of the present invention, the maleate crystal form I contains an organic solvent, preferably less than 20%, more preferably less than 15%, and exemplary values ​​are 14%, 13%, 12%, and 10%.The organic solvent is selected from one, two, or more of the following organic solvents: ethanol (EtOH), methyl tert-butyl ether (MTBE), ethyl acetate (EA), acetonitrile (ACN), dichloromethane (DCM), etc., preferably ethyl acetate (EA). Exemplarily, maleate crystal form I contains 13% ethyl acetate (EA). In some embodiments, maleate crystal form I is a solvate, wherein the content of the solvent is less than 20%, more preferably less than 15%, exemplarily 14%, 13%, 12%, and 10%. Preferably, maleate crystal form I is an ethyl acetate solvate. According to the technical solution of the present invention, the maleate of compound A is a crystal form, named maleate crystal form II, which exhibits characteristic peaks at 7.99±0.20° and 20.17±0.20° using Cu-Kα radiation and X-ray powder diffraction in 2θ angles. Preferably, the maleate crystal form II, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 3.96±0.20°, 7.99±0.20°, 20.17±0.20°, 24.23±0.20°, and 28.31±0.20° in 2θ angles. More preferably, the maleate crystal form II, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 3.96±0.20°, 7.99±0.20°, 9.25±0.20°, 11.19±0.20°, 13.25±0.20°, 20.17±0.20°, 23.85±0.20°, 24.23±0.20°, 27.47±0.20°, and 28.31±0.20° in 2θ angles. Preferably, the maleate crystal form II has X-ray powder diffraction characteristic peaks expressed in 2θ angles as shown in Table 12'', with an error range of ±0.2°. Preferably, the maleate crystal form II uses Cu-Kα radiation, and the X-ray powder diffraction of the maleate crystal form II expressed in 2θ angles is shown in Figure 11(b), with an error range of ±0.20°. According to the technical solution of the present invention, the maleate crystal form II has an XRPD spectrum basically as shown in Figure 11(a). According to the technical solution of the present invention, the molar ratio of compound A to maleic acid in the maleate crystal form II is 1:1. According to the technical solution of the present invention, the maleate crystal form II has a weight loss of about 3.0% from room temperature to about 104°C. In some embodiments, the maleate crystal form II has a weight loss of 3.0±2% from room temperature to 104±3°C. According to the technical solution of the present invention, the maleate crystal form II has a broad overlapping endothermic peak with a peak temperature of about 108°C. In some embodiments, the maleate crystal form II has a broad, overlapping endothermic peak with a peak temperature of 108±5°C, for example, 108±2°C.According to the technical solution of the present invention, the maleate crystal form II has a DSC and TGA spectrum as shown in FIG13. According to the technical solution of the present invention, the maleate crystal form II contains an organic solvent, preferably less than 20%, more preferably less than 15%, exemplarily 14%, 13%, 12%, and 10%. The organic solvent is selected from one, two, or more organic solvents listed below: ethanol (EtOH), methyl tert-butyl ether (MTBE), ethyl acetate (EA), acetonitrile (ACN), dichloromethane (DCM), methanol (MeOH), etc., for example, methyl tert-butyl ether (MTBE). Exemplarily, the maleate crystal form II contains 2% MTBE. In some embodiments, the maleate crystal form II is a solvate and / or hydrate, wherein the solvent content is less than 20%, more preferably less than 15%, exemplarily 14%, 13%, 12%, and 10%. Preferably, the maleate crystal form II is a methyl tert-butyl ether (MTBE) solvate and / or hydrate. According to the technical solution of the present invention, the oxalate of compound A is a crystalline form, named oxalate crystalline form I. Oxalate crystalline form I exhibits characteristic peaks in X-ray powder diffraction (expressed as 2θ angle) using Cu-Kα radiation at 5.26±0.20°, 12.24±0.20°, and 25.75±0.20°. Preferably, oxalate crystalline form I exhibits characteristic peaks in X-ray powder diffraction (expressed as 2θ angle) using Cu-Kα radiation at 4.94±0.20°, 5.26±0.20°, 7.25±0.20°, 12.24±0.20°, 14.77±0.20°, 16.55±0.20°, 20.95±0.20°, and 25.75±0.20°. Preferably, the oxalate crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 4.94±0.20°, 5.26±0.20°, 7.25±0.20°, 12.24±0.20°, 14.17±0.20°, 14.77±0.20°, 16.03±0.20°, 16.55±0.20°, 20.21±0.20°, 20.95±0.20°, 25.75±0.20°, and 30.87±0.20° in 2θ angles. Preferably, the oxalate crystal form I has the characteristic X-ray powder diffraction peaks in 2θ angles as shown in Table 14', with an error range of ±0.2°. Preferably, the oxalate crystal form I is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed at a 2θ angle, is shown in Figure 15(b), with an error range of ±0.20°. According to the technical solution of the present invention, the oxalate crystal form I has an XRPD spectrum essentially as shown in Figure 15(a). According to the technical solution of the present invention, the molar ratio of compound A to maleic acid in the oxalate crystal form I is 1:1.According to the technical solution of the present invention, the oxalate crystal form I is an anhydrous hydrate. According to the technical solution of the present invention, the oxalate crystal form I experiences a weight loss of approximately 0.5% at room temperature to approximately 150°C. In some embodiments, the oxalate crystal form I experiences a weight loss of 0.5±0.4% at room temperature to 150±3°C. According to the technical solution of the present invention, the oxalate crystal form I has a sharp endothermic peak with a peak temperature of approximately 206°C. In some embodiments, the oxalate crystal form I has a sharp endothermic peak with a peak temperature of 206±5°C, for example, 206±2°C. According to the technical solution of the present invention, the oxalate crystal form I has DSC and TGA spectra essentially as shown in Figure 16. According to the technical solution of the present invention, the oxalate crystal form I does not contain organic solvents. According to the technical solution of the present invention, the fumarate of compound A comprises a salt formed by compound A and fumaric acid in a molar ratio of 1:1 or 2:1 (i.e., a monofumarate or a hemifumarate of compound A). According to the technical solution of the present invention, the crystal form of the fumarate can be selected from fumarate crystal form I and fumarate crystal form II. According to the technical solution of the present invention, the fumarate crystal form I has characteristic peaks at 3.90±0.20°, 13.93±0.20°, 16.86±0.20°, and 26.37±0.20° when X-ray powder diffraction is expressed in 2θ angle using Cu-Kα radiation. Preferably, the fumarate crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 3.90±0.20°, 10.45±0.20°, 13.93±0.20°, 16.86±0.20°, 17.73±0.20°, 21.39±0.20°, 23.68±0.20°, 26.37±0.20°, 27.40±0.20°, and 27.87±0.20° in 2θ angles. Preferably, the fumarate crystal form I has the characteristic peaks in X-ray powder diffraction at 2θ angles as shown in Table 19', with an error range of ±0.2°. Preferably, the fumarate crystal form I, when subjected to Cu-Kα radiation, exhibits X-ray powder diffraction at 2θ angles as shown in Figure 21(b), with an error range of ±0.20°. According to the technical solution of the present invention, the fumarate crystal form I has an XRPD spectrum basically as shown in Figure 21(a). According to the technical solution of the present invention, the molar ratio of compound A to fumaric acid in the fumarate crystal form I is 2:1. According to the technical solution of the present invention, the fumarate crystal form I is anhydrous. According to the technical solution of the present invention, the fumarate crystal form I has almost no weight loss from room temperature to approximately 150°C. In some embodiments, the fumarate crystal form I has no weight loss from room temperature to 150 ± 3°C. According to the technical solution of the present invention, the fumarate crystal form I has a sharp endothermic peak with a peak temperature of approximately 157°C.In some embodiments, the fumarate crystal form I has a sharp endothermic peak with a peak temperature of 157±5°C, for example, 157±2°C. According to the technical solution of the present invention, the fumarate crystal form I has the DSC and TGA spectra shown in Figure 22. According to the technical solution of the present invention, the fumarate crystal form I does not contain organic solvents. According to the technical solution of the present invention, the fumarate crystal form of compound A is named fumarate crystal form II, and the fumarate crystal form II exhibits characteristic peaks at 22.06±0.20° and 25.20±0.20° in X-ray powder diffraction using Cu-Kα radiation, expressed in 2θ angles. Preferably, the fumarate crystal form II exhibits characteristic peaks at 22.06±0.20°, 22.50±0.20°, 25.20±0.20°, and 27.54±0.20° in X-ray powder diffraction using Cu-Kα radiation, expressed in 2θ angles. Preferably, the fumarate crystal form II, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 11.44±0.20°, 13.74±0.20°, 22.06±0.20°, 22.50±0.20°, 24.60±0.20°, 25.20±0.20°, 27.54±0.20°, and 28.78±0.20° in 2θ angles. Preferably, the fumarate crystal form II has characteristic X-ray powder diffraction peaks in 2θ angles as shown in Table 20', with an error range of ±0.2°. Preferably, the fumarate crystal form II, when subjected to Cu-Kα radiation, exhibits X-ray powder diffraction in 2θ angles as shown in Figure 24(b), with an error range of ±0.20°. According to the technical solution of the present invention, the fumarate crystal form II has an XRPD spectrum essentially as shown in Figure 24(a). According to the technical solution of the present invention, the molar ratio of compound A to fumaric acid in fumarate crystal form II is 2:1. According to the technical solution of the present invention, fumarate crystal form II is anhydrous. According to the technical solution of the present invention, fumarate crystal form II has almost no weight loss from room temperature to approximately 100°C. In some embodiments, the weight loss of fumarate crystal form II from room temperature to 100±3°C is less than 0.1%. According to the technical solution of the present invention, fumarate crystal form II has a sharp endothermic peak with a peak temperature of approximately 181°C. In some embodiments, fumarate crystal form II has a sharp endothermic peak with a peak temperature of 181±5°C, for example, 181±2°C. According to the technical solution of the present invention, fumarate crystal form II has a TGA spectrum as shown in Figure 25 and a DSC spectrum as shown in Figure 26. According to the technical solution of the present invention, fumarate crystal form II contains an organic solvent, the content of which is less than 0.5%, for example less than 0.2%, exemplarily 0.1%.The organic solvent is selected from one, two, or more of the following organic solvents: ethanol (EtOH), methyl tert-butyl ether (MTBE), ethyl acetate (EA), acetonitrile (ACN), dichloromethane (DCM), acetone, etc., with acetone being an example. According to the technical solution of the present invention, the tartrate salt of compound A is a crystalline form, named tartrate crystal form I. The tartrate crystal form I exhibits characteristic peaks at 16.98±0.20°, 17.85±0.20°, 19.66±0.20°, and 25.58±0.20° using Cu-Kα radiation and X-ray powder diffraction in 2θ angles. Preferably, the tartrate crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 13.38±0.20°, 16.98±0.20°, 17.85±0.20°, 18.53±0.20°, 19.66±0.20°, 25.58±0.20°, and 26.72±0.20° in 2θ angles. Preferably, the tartrate crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 13.38±0.20°, 16.98±0.20°, 17.27±0.20°, 17.85±0.20°, 18.53±0.20°, 19.66±0.20°, 20.46±0.20°, 22.86±0.20°, 25.58±0.20°, 26.08±0.20°, and 26.72±0.20° in 2θ angles. Preferably, the tartrate crystal form I has the characteristic peaks in X-ray powder diffraction at 2θ angles as shown in Table 22', with an error range of ±0.2°. Preferably, the tartrate crystal form I is X-ray powder diffraction using Cu-Kα radiation, expressed in 2θ angles as shown in Figure 33(b), with an error range of ±0.20°. According to the technical solution of the present invention, the tartrate crystal form I has an XRPD spectrum essentially as shown in Figure 33(a). According to the technical solution of the present invention, the molar ratio of compound A to tartaric acid in the tartrate crystal form I is 1:1. According to the technical solution of the present invention, the tartrate crystal form I is anhydrous. According to the technical solution of the present invention, the tartrate crystal form I loses approximately 0.8% weight at room temperature to approximately 150°C. In some embodiments, the tartrate crystal form I has a weight loss of 0.8% to 150±3°C. According to the technical solution of the present invention, the tartrate crystal form I has a sharp endothermic peak with a peak temperature of approximately 135°C. In some embodiments, the tartrate crystal form I has a sharp endothermic peak with a peak temperature of 135±5°C, for example, 135±2°C. According to the technical solution of the present invention, the tartrate crystal form I has the DSC and TGA spectra shown in Figure 34. According to the technical solution of the present invention, the tartrate crystal form I contains an organic solvent.The organic solvent is selected from one, two, or more of the following organic solvents: ethanol (EtOH), methyl tert-butyl ether (MTBE), ethyl acetate (EA), acetonitrile (ACN), dichloromethane (DCM), etc., for example, MTBE. Exemplarily, the tartrate crystal form I contains 0.8% MTBE. This invention also provides a method for preparing the salt of the above-mentioned ROCK inhibitor compound A, comprising reacting compound A with an acid to form a salt, wherein the acid is selected from hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, maleic acid, tartaric acid, oxalic acid, fumaric acid, sulfuric acid, methanesulfonic acid, phosphoric acid, succinic acid, or citric acid, preferably hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, maleic acid, tartaric acid, oxalic acid, or fumaric acid. According to the technical solution of this invention, the method for preparing the salt comprises the following steps: reacting compound A with an acid in a solvent to form a salt, stirring until a precipitate forms, drying, and obtaining the salt; if no precipitate forms during stirring, adding an antisolvent to the system, and after the precipitate forms, drying, and obtaining the salt. According to the technical solution of the present invention, the solvent may be selected from one, two or more of EA (ethyl acetate), 2-Me-THF (2-methyl-tetrahydrofuran), ACN (acetonitrile), DCM (dichloromethane), EtOH (ethanol), MeOH (methanol), IPA (isopropanol), THF (tetrahydrofuran), IPAc (isopropyl acetate), and MTBE, or a mixture of any one, two or more of the above solvents with MTBE (methyl tert-butyl ether); for example, a mixture of EA, 2-Me-THF, ACN, DCM, MeOH, MTBE, IPA, EtOH, EA and MeOH, or a mixture of MeOH, THF and ACN. According to the technical solution of the present invention, the antisolvent may be selected from MTBE (methyl tert-butyl ether) and / or ACN (acetonitrile). According to the technical solution of the present invention, the mass ratio of compound A to the volume of solvent is 1g:(5-50)mL, for example 1g:(6-40)mL, and exemplary ratios are 1g:4.5mL, 1g:6.7mL, 1g:7mL, 1g:10mL, 1g:12.5mL, 1g:15mL, 1g:17mL, 1g:20mL, 1g:24mL, 1g:30mL, and 1g:36mL. According to the technical solution of the present invention, the molar ratio of compound A to the acid is 5:1 to 1:5, for example 1:(0.55-2.5), and exemplary ratios are 1:0.55, 1:0.7, 1:0.75, 1:0.9, 1:1, 1:1.1, 1:1.2, and 1:2.2. According to the technical solution of the present invention, the volume ratio of the antisolvent to the solvent is (1-5):1, for example, 2:1, 3:1, or 4:1. According to the technical solution of the present invention, the stirring temperature is 15-35°C, preferably 20-25°C.According to the technical solution of the present invention, the stirring time is 1-100 hours, for example 3-80 hours, exemplarily 3 hours, 5 hours, 10 hours, 15 hours, 20 hours, 30 hours, 50 hours, and 72 hours. According to some embodiments of the present invention, high-temperature stirring can be performed before stirring at 15-35°C; for example, the high temperature is 60-70°C; for example, the high-temperature stirring time is 0.5-2 hours. According to the technical solution of the present invention, the drying is vacuum drying. The drying time can be adjusted as needed by those skilled in the art; preferably, the drying time is 3-15 hours, more preferably, the drying time is 3-10 hours, for example 5-8 hours. Preferably, the drying temperature is 40-60°C, for example 50°C. According to a preferred embodiment of the present invention, the preparation method includes the following steps: dissolving or suspending compound A in the solvent, adding acid to the system to react and form a salt, stirring until a precipitate forms, and drying to obtain the salt; if no precipitate forms during stirring, adding an antisolvent to the system, and drying after the precipitate forms to obtain the salt; the acid is selected from hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, maleic acid, tartaric acid, oxalic acid, or fumaric acid; the mass ratio of compound A to the volume of the solvent is 1 g:(5-50) mL; the molar ratio of compound A to the acid is 1:(0.5-2.5). The present invention also provides a pharmaceutical composition containing the above-mentioned salt. According to the present invention, the pharmaceutical composition may further contain a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be selected from carriers known in the art, such as, but not limited to, one, two, or more of excipients, lubricants, binders, disintegrants, inorganic salts, solvents, solubilizers, suspending agents, isotonic agents, buffers, preservatives, antioxidants, colorants, foaming agents, and flavoring agents. According to the technical solution of the present invention, the pharmaceutical composition may further contain a second active ingredient, for example, the second active ingredient being one, two, or more of other ROCK inhibitors, tyrosine kinase inhibitors, tyrosinase inhibitors, fibrotic cytokine inhibitors, serum amyloid P inhibitors, autolysin-lecithin pathway inhibitors, GPR40 agonists, GPR84 antagonists, antacids, and antibiotics. The present invention also provides the use of the above-mentioned salt or pharmaceutical composition in formulation preparation. The present invention also provides a formulation containing the salt; preferably, the formulation further contains a pharmaceutically acceptable carrier; preferably, the formulation contains the pharmaceutical composition. According to the technical solution of the present invention, the preparation can be a powder, tablet (e.g., coated tablet, sustained-release or controlled-release tablet), lozenge, capsule (e.g., soft capsule or hard capsule), granule, pill, dispersible powder, suspension, solution, emulsion, elixir, syrup, aerosol, cream, ointment, gel, injection, lyophilized powder for injection or suppository, etc.According to the technical solution of the present invention, the formulation can be administered in any of the following ways: oral, oral, sublingual, inhalation, topical application, intravenous, subcutaneous, acupoint or intramuscular injection after parenteral administration, or rectal administration. According to the technical solution of the present invention, the formulation is a ROCK antagonist. Preferably, the ROCK antagonist is used to prevent and / or treat diseases caused by overexpression of one or more ROCKs or overactivation of ROCK. For example, the diseases are selected from cardiovascular and cerebrovascular diseases, nervous system diseases, fibrotic diseases, eye diseases, tumors, arterial thrombosis, radiation damage, respiratory diseases, metabolic diseases, and autoimmune diseases, such as atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, ischemic stroke, restenosis, heart disease, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes, diabetic nephropathy, cancer, neuronal degeneration, neurological injury, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte aggregation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis (such as idiopathic pulmonary fibrosis), liver fibrosis, kidney fibrosis, COPD, kidney dialysis, glomerulosclerosis, fatty liver disease, steatohepatitis, or neuronal degenerative inflammation. The present invention also provides a method for preventing and / or treating diseases caused by high expression of ROCK or overactivation of ROCK, comprising administering a therapeutically effective amount of a salt, crystal form of the salt, pharmaceutical composition, or formulation of said compound A to a subject.

[0010] [Terminology Explanation] The term "crystal form" refers to a crystal form having the same chemical composition but with different spatial arrangements of molecules and / or ions that form crystals. The term "amorphous" refers to a solid form of molecules and / or ions that are not crystalline. Amorphous solids do not display a definite X-ray powder diffraction pattern with clear maximum values. Compound A is "free base," and "free base crystal form" is "compound A crystal form." The term "X-ray powder diffraction pattern as shown in the figure" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the major peaks shown in the X-ray powder diffraction pattern appear in the X-ray powder diffraction pattern; its major peaks refer to peaks with a relative intensity greater than 10%, preferably greater than 20%, and more preferably greater than 30%, with the highest peak as a reference (the relative intensity of the highest peak is specified as 100%). Those skilled in the art will understand that compounds can have multiple salt-forming sites. Therefore, the salt of the compounds of the present invention includes not only the salt formed at one salt-forming site of the compound, but also the salt formed at two, three, or all of the salt-forming sites. For this purpose, the molar ratio of the compound to the anion of the acid required for salt formation can vary over a wide range, for example, from 5:1 to 1:5, such as 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, etc. In this invention, "object," "patient," and "subject" have the same meaning, referring to humans or other warm-blooded mammals. Humans as "objects" of this invention include adults and infants / children. Other warm-blooded mammals include, but are not limited to, non-human primates such as chimpanzees, other apes or monkeys, as well as other zoo animals, domesticated mammals, or laboratory animals such as cats, pigs, dogs, cattle, sheep, mice, rats, and guinea pigs. Preferably, the "object" of this invention is a human. The term "effective amount" or "therapeutic effective amount" refers to the amount of any mixture, pharmaceutical composition, or formulation of any proportion of any two of the crystal forms I and II described in this invention, sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined above), determined by methods mastered by a physician with clinical qualifications in the art. Determining the therapeutically effective dose is within the capabilities of a clinician or researcher in the art and can vary depending on factors such as the intended application (in vitro or in vivo), the subject being treated, and the condition of the disease, including the subject's weight and age, general health status, severity of the disease, route of administration, and other factors affecting efficacy, such as a history of drug allergies. The specific dosage will vary depending on factors such as the specific compound or crystal form selected, the administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system used. The term "room temperature" refers to a temperature of 15-30°C, preferably 20-25°C.The term "hydrate" can include hemihydrate, monohydrate, dihydrate, trihydrate, and tetrahydrate. The crystal forms of compound A of the present invention include both the non-solvent (anhydrous) and solvate (solvent-containing) crystal forms of compound A. The term "about" is used herein to mean substantially, roughly, approximately, or in the range of… When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the indicated value. Generally, the term "about" is used herein to modify the value as varying within a reasonable range of fluctuation as understood by those skilled in the art. Specifically, when "about" is used in conjunction with a temperature range, it refers to a temperature fluctuating within, for example, ±5°C, ±4°C, ±3°C, ±2°C, ±1°C. When "about" is used in conjunction with a range indicating weight loss, it refers, as appropriate, to a weight loss fluctuating within, for example, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.4%. "Almost no weight loss" herein means a weight loss percentage of less than 0.2%, preferably less than 0.1%. In this article, the "%" content of organic solvents refers to the percentage content of organic solvents by quality.

Implementation Method

[0012] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are only illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0013] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0014] Characteristics and tests involved in the following embodiments:

[0015] X-ray powder diffractometer (XRPD)

[0016] Solid morphology analysis of the solid products obtained in the experiment was performed using a PANalytical Empyrean X-ray powder diffractometer equipped with a PIXcel1D detector. The X-ray tube target material was a copper target (K-Alpha (λ=1.5418μ)). The tube voltage and current were 45 kV and 40 mA, respectively. The sample scanning range was from 3° 2θ to 40° 2θ, with a step size of 0.013° 2θ. The sample disk rotation speed and the test speed were 60 rpm and 0.164° 2θ / s, respectively.

[0017] Differential Scanning Calorimetry (DSC)

[0018] Thermal analysis of the sample was performed using a Discovery DSC 250 (TA Instruments, US). An appropriate amount of sample was weighed and placed in the DSC sample tray, and a hole was punched in it. After equilibration at 25 °C, the sample was heated to the final temperature at a rate of 10 °C / min.

[0019] Thermogravimetric analysis (TGA)

[0020] Thermogravimetric analysis of the sample was performed using a TGA 55 (TA Instruments, US). The sample was placed in a peeled, closed aluminum sample pan. After the sample mass was automatically weighed in the TGA furnace, the sample was heated from room temperature to the final temperature at a rate of 10 °C / min.

[0021] H1NMR analysis

[0022] The 1H NMR spectrum of the sample was confirmed by 1H-NMR. The instrument used for 1H-NMR analysis was a Bruker AVANCE III HD 300 / 400 equipped with a Sample Xpress 60 autosampler.

[0023] Dynamic moisture adsorption-desorption analysis (DVS)

[0024] The moisture adsorption / desorption of the samples was tested using a Vsorp (ProUmid GmbH & Co. KG, Germany) moisture adsorption analyzer. The samples were placed in a peeled sample tray, and the changes in sample quality with humidity (0-90%RH) at 25 °C were recorded. The specific DVS test parameters are shown in Table 1 below.

[0025] Table 1. DVS test method for hygroscopicity Equilibrium conditions 0.01% / 45min Circular weighing time 10 min Minimum time interval 50 min Maximum time interval 2.0 h Equilibrium conditions 40 ℃@0 %RH (relative humidity) for 6 h Sample temperature 25℃ Humidity adsorption 0, 10, 20, 30, 40, 50, 60, 70, 80, 90 %RH Desorption humidity 80, 70, 60, 50, 40, 30, 20, 10, 0%RH

[0026] High Performance Liquid Chromatography (HPLC) Analysis

[0027] The instrument used for HPLC analysis was an Agilent HPLC 1260 series. The HPLC methods used for solubility are shown in Table 1-1. The HPLC methods used for stability tests are shown in Tables 2 and 3.

[0028] Table 1-1. HPLC method for solubility test instrument Aglient NB-MS-HPLC-3 chromatographic column YMC-pack Pro C18 150 mm*4.6 mm S-3μm, 8 nm mobile phase A: Water; B: ACN (acetonitrile) Gradient (T / B%) Time [min] B [%] 0.00 10.0 9.00 90.0 10.00 90.0 10.10 10.0 Column temperature 30℃ detector DAD, 265 nm Flow rate 1.0 mL / min Injection volume 5 μL Washout time 10.10 min diluent ACN / Water(1 / 1, v / v)

[0029] Table 2. HPLC method for 7-day stability test instrument Aglient NB-MS-HPLC-2 chromatographic column YMC-pack Pro C18 150 mm*4.6 mm S-5μm, 12 nm mobile phase A: 0.05% TFA (trifluoroacetic acid) aqueous solution; B: ACN solution of 0.05% TFA Gradient (T / B%) Time [min] B [%] 0.00 10.0 2.00 30.0 11.00 45.0 13.00 90.0 Column temperature 35 ℃ detector DAD, 265 nm Flow rate 1.0 mL / min Injection volume 2 μL Washout time 13 min diluent ACN / Water(1 / 1, v / v)

[0030] Table 3. HPLC method for 14-day stability test instrument Aglient NB-MS-HPLC-2 chromatographic column YMC-pack Pro C18 150 mm*4.6 mm S-5μm, 12 nm mobile phase A: 0.05% TFA aqueous solution; B: ACN solution of 0.05% TFA Gradient (T / B%) Time [min] B [%] 0.00 10.0 2.00 30.0 11.00 45.0 13.00 90.0 23.00 90.0 Column temperature 35 ℃ detector DAD, 265 nm Flow rate 1.0 mL / min Injection volume 2 μL Washout time 23 min diluent ACN / Water(1 / 1, v / v)

[0031] Ion chromatography (IC)

[0032] The instrument used for IC analysis was a Thermo ICS-6000. The methods used for ion chromatography are shown in Table 4.

[0033] Table 4. Parameters for Ion Chromatography Tests (Cl- and C2O42-) instrument Thermo ICS-6000 workstation Chomeleon Workstation Rinse solution generator EGC 500 KOH Suppressor Dionx ASRS 300 4 mm Protective pillar Dionex IonPacTMAG11-HC (4*50 mm) chromatographic column Dionex IonPacTMAG11-HC (4*250 mm) Conductivity cell temperature 35.0 ℃ Rinse solution concentration 30 mm Suppressor operating mode External Mode Suppressor current 75 mA Column temperature 30.0 ℃ Flow rate 1.0 mL / min elution gradient Isocratic elution Execution time 10 min Injection volume 25 μL External water circulation velocity 1.5 mL / min

[0034] Polarization Microscopy Analysis (PLM)

[0035] The instrument used in PLM is a Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN).

[0036] Laser Fineness Analyzer (PSD)

[0037] The instrument used for PSD analysis was a Mastersizer 3000. The testing methods are shown in Table 4'.

[0038] Table 4'. Parameters of Laser Fineness Test Method instrument Mastersizer3000 Test range 0.01-3500μm Sample Information Particle Type Non-spherical Material Name organic compounds Refractive Index 1.59 Absorption Index 0.1 Duration Red background time 10s Red measurement time 10s Test program Number of measurements 3 times Delay between measurements: 0s Light blocking Particles < 10 μm 5% -10% Particles ≥ 10 μm 5% -20% Sample dispersion method External sonication 30s Internal sonication N / A Dispersant water Dispersant Refractive Index 1.33 Pre-dispersant 0.1% Tween 80 aqueous solution Stirring speed 2000 rpm Tank fill Manual Degas after filling. yes Cleaning type none Analysis Pattern General purpose Result type Volume distribution

[0039] Preparation Example: Preparation of Compound A

[0040] Preparation of compound 5-(3-amino-1H-pyrazol-4-yl)-6-fluoro-N-(3-methoxybenzyl)dihydroindole-1-methamide (compound A).

[0041] (1) Preparation of compound 4-nitrophenyl-5-bromo-6-fluorodihydroindole-1-carboxylic acid ester (M001)

[0042] Phenyl 4-nitrochloroformate (CAS No.: 7693-46-1, 6.21 g) was dissolved in dichloromethane (40 mL). The resulting solution was cooled to 0 °C, and a dichloromethane (50 mL) solution of 5-bromo-6-fluorodihydroindole (6.00 g) and pyridine (8.86 g) was added dropwise. The mixture was heated to room temperature and stirred overnight (15 h). The reaction solution was diluted with dichloromethane (100 mL), washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography (petroleum ether (PE): dichloromethane = 3:1, volume ratio) to give 7.20 g of gray solid, designated as compound M001, with a yield of 68%. LC-MS [M+H]+ = 380.9.

[0043] (2) Preparation of compound 5-bromo-6-fluoro-N-(3-methoxybenzyl)dihydroindole-1-methamide (M009-1)

[0044] Compound M001 (1600 mg) and 3-methoxybenzamine (1150 mg) were added to THF (tetrahydrofuran, 20 mL). Then, N,N-diisopropylethylamine (2714 mg) was added to the resulting solution under stirring at room temperature. The reaction mixture was stirred in an oil bath at 75°C for 15 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1, v / v) to give 1500 mg of a yellow solid, designated as compound M009-1, with a yield of 94.2%. LC-MS [M+H]+ = 381.1.

[0045] (3) Preparation of compound 6-fluoro-N-(3-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)dihydroindole-1-methamide (M009)

[0046] Under nitrogen protection, compound M009-1 (1500 mg), pinacol diborate (CAS: 73183-34-3, 2010 mg), potassium acetate (AcOK, 1940 mg), and (1,1'-bis(diphenylphosphine)ferrocene)palladium dichloride (Pd(dppf)Cl2, 579 mg) were added to 1,4-dioxane (1,4-dioxane, 20 mL). The resulting reaction solution was stirred in an oil bath at 90°C for 5 hours. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1, v / v) to give 800 mg of a yellow oil, designated as compound M009, with a yield of 47.4% and LC-MS [M+H]+ = 427.1.

[0047] (4)Synthesis of 4-bromo-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (M002)

[0048] Weigh 4-bromo-3-nitro-1H-pyrazole (CAS No.: 89717-64-6, 40 g) and dissolve it in THF (400 mL); cool the resulting solution and maintain the temperature at 0-5℃, then add NaH (12.5 g) in 2-4 batches; keep the mixture at 0-5℃ for 0.5 h, and add 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (41.6 g) dropwise. Then raise the reaction solution to room temperature and keep it at room temperature for 2 h. Add water (600 mL) to the reaction solution, extract once with EA (500 mL), extract twice with EA (300 mL), take the organic phase, wash once with ammonium chloride solution (300 mL) and once with saturated brine (300 mL), dry with anhydrous sodium sulfate, and concentrate to dryness to obtain 70.2 g of crude product. Add n-heptane (50 mL) to the crude product and beat at room temperature for 3 h. Wash with PE (50 mL) to obtain 51.2 g of white solid, which is denoted as compound M002. The yield is 76%, the HPLC purity is 96.8%, and the LC-MS [M+H]+=322.0.

[0049] (5)Preparation of compound 6-fluoro-N-(3-methoxybenzyl)-5-(3-nitro-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)dihydroindole-1-carbamate (A-1)

[0050] Under nitrogen protection, compound M009 (800 mg), 4-bromo-3-nitro-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (544 mg), anhydrous potassium carbonate (1040 mg), and (1,1'-bis(diphenylphosphine)ferrocene)palladium dichloride (137 mg) were added to 1,4-dioxane:water (20:1, 10 mL). The resulting reaction solution was stirred in an oil bath at 80°C for 2 hours. After the reaction was complete, water (50 mL) was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined. The obtained organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the residue after concentration of the filtrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1, v / v) to give 650 mg of yellow oil. mg, denoted as compound A-1, yield 63.9%, LC-MS [M+H]+=542.1.

[0051] (6)Preparation of compound 6-fluoro-N-(3-methoxybenzyl)-5-(3-nitro-1H-pyrazol-4-yl)dihydroindole-1-methamide (A-2)

[0052] Compound A-1 (650 mg) was dissolved in ethanol (10 mL), and concentrated hydrochloric acid (1 mL, 38%) was added to the resulting solution. The resulting reaction solution was refluxed in an oil bath at 80 °C and stirred for 5 h. After the reaction was complete, compound A-2 was obtained, which was directly proceeded to the next step without further treatment. LC-MS [M+H]+=412.1.

[0053] (7)Preparation of compound 5-(3-amino-1H-pyrazol-4-yl)-6-fluoro-N-(3-methoxybenzyl)dihydroindole-1-methamide (compound A)

[0054] Activated zinc powder (Zn, 798 mg) was added to the reaction solution obtained in step (6) under an ice-water bath, followed by the addition of acetic acid (AcOH, 3 mL). The reaction solution was brought back to room temperature and stirred for 2 hours before being concentrated under reduced pressure. Then, saturated sodium bicarbonate (10 mL) was added. The resulting mixture was extracted with ethyl acetate (5 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol 20:1). 98 mg of compound A was obtained as a white solid, with a two-step yield of 21.4% and LC-MS [M + H]+ = 382.2.

[0055] 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 7.61 (d, J = 12.9 Hz, 1H), 7.46 (s, 1H), 7.31 (dd, J = 11.5, 6.1 Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 6.93 – 6.87 (m, 2H), 6.80 (dd, J = 7.3, 1.9 Hz, 1H), 4.59 (s, 2H), 4.31 (d, J = 5.8 Hz, 2H), 3.99 (t, J = 8.7 Hz, 2H), 3.74 (s, 3H), 3.12 (t, J = 8.5 Hz, 2H).

[0056] Example

[0057] Example 1: Preparation of Hydrochloride Salts Appropriate amounts (20-30 mg) of compound A were weighed and placed in sample vials at room temperature. Then, 0.2 mL of each of the different solvents shown in Table 5 was added, followed by 1 M hydrochloric acid to form a salt. The mixture was stirred at room temperature for 3-6 hours. If no precipitate formed, an antisolvent (MTBE) was added to induce precipitation. If a solid was formed, the sample was filtered, collected, and vacuum dried at 50°C for approximately 3 hours. XRPD, TGA, DSC, and 1H-NMR characterization were then performed. Specific information on the raw materials and results are listed in Table 5. The XRPD spectrum and analysis of the hydrochloride salt of crystal form I prepared in Group 1 are shown in Figure 1 and Table 5'. Table 5. Preparation of Hydrochloride Salts Group solvent Solvent volume / quality of compound A (ml / g) Acid (μL) antisolvent (v / v) anti ) result 1 EA 6.7 86 N / A Hydrochloride crystal form I 2 2-Me-THF 6.7 86 Hydrochloride crystal form I 3 ACN 10 52 Hydrochloride crystal form I 4 DCM 10 52 Hydrochloride crystal form I 5 EA 6.7 172 Hydrochloride crystal form I Table 5' XRPD analysis of hydrochloride crystal form I 2θ / ° Relative strength I / % 2θ / ° Relative strength I / % 5.927 100.0 21.021 5.2 11.957 22.7 24.074 84.9 12.556 8.3 25.533 7.4 14.922 49.3 26.610 23.1 17.981 26.7 27.186 21.5 18.964 8.0 31.662 8.7 In this embodiment, a hydrochloride crystal form was obtained, named hydrochloride crystal form I. The TGA, DSC, 1H-NMR, and IC characterization results are summarized in Table 6 and Figures 2-3. Hydrochloride crystal form I exhibits approximately 5.4% weight loss before 110℃. 1H-NMR analysis showed no organic solvent residue in the sample; therefore, the TGA weight loss is attributed to dehydration (approximately 1 equivalent of H₂O). Multiple thermodynamic events were observed in the DSC spectrum, with a broad endothermic peak at approximately 97℃, also attributed to dehydration. IC analysis indicated that the sample contained approximately 1 equivalent of chloride ions, resulting in a salt formation ratio of 1 / 1. Hydrochloride crystal form I is determined to be a hydrate. Table 6. Solid-state characterization results of hydrochloride crystal form I. Crystal form Solvation DSC, Endothermic Onset / Peak (Endothermic Peak Onset Temperature / Peak Temperature) (°C) ΔH (J / g) TGA Wt. loss (weight loss)% / @T (℃) 1 H-NMR IC acid-base ratio Hydrochloride crystal form I hydrates 83 / 97, 144 5.4 RT (room temperature) - 110 No organic solvent residue 1:1 Table 7. IC data for hydrochloride crystal form I sample Quality (mg) Theoretical concentration (μg / mL) IC peak area (μS*min) Remark Hydrochloride crystal form I 2.84 9.6 2.2061 Approximately 1 equivalent of Cl -

[0058] Example 2: Preparation of p-toluenesulfonate Appropriate amounts (20-30 mg) of compound A were weighed and placed in sample vials at room temperature. The vials were then dissolved or suspended in 0.2 mL of the solvent selected in Table 8. Solid p-toluenesulfonic acid or 1M p-toluenesulfonic acid methanol solution was added to react and form salts. The solution or suspension was stirred at room temperature for 5-15 hours. If no precipitate formed, an antisolvent was added to induce precipitation. If a solid was formed, the sample was filtered, washed, collected, and vacuum dried at 50°C for approximately 3 hours. XRPD, TGA, DSC, and 1H-NMR characterization were then performed. Specific information and results are listed in Table 8. The XRPD spectrum and analysis of p-toluenesulfonate crystal form I prepared in Group 1 are shown in Figure 4 and Table 8'. Table 8. Preparation of p-toluenesulfonate Group solvent Solvent volume / quality of compound A (ml / g) acid result 1 EtOH 6.7 15 mg p-Toluenesulfonate crystal form I 2 EA 6.7 p-Toluenesulfonate crystal form I 3 2-Me-THF 6.7 Oil 4 ACN 10 p-Toluenesulfonate crystal form I 5 DCM 10 52 μL p-Toluenesulfonate crystal form I Table 8' XRPD analysis of p-toluenesulfonate crystal form I 2θ / ° Relative strength I / % 2θ / ° Relative strength I / % 5.495 33.0 19.912 50.5 7.555 93.7 20.675 30.3 8.608 100.0 22.344 13.6 9.145 31.9 22.709 7.3 10.052 35.9 23.380 60.6 11.193 12.6 24.022 49.0 12.035 25.8 24.600 40.6 12.363 10.9 25.205 21.9 12.706 10.2 25.743 6.4 13.755 23.5 25.989 8.9 14.397 32.5 26.269 7.9 14.752 64.7 26.594 12.4 15.999 65.3 26.938 7.5 16.734 28.2 28.013 13.2 17.167 20.2 28.251 19.9 17.431 15.0 29.696 4.5 17.876 17.2 30.301 4.3 18.101 12.4 31.056 5.2 18.638 28.8 32.002 4.8 19.191 13.9 32.702 3.6 19.637 46.0 34.279 7.7 This embodiment yielded a p-toluenesulfonate crystal form, p-toluenesulfonate crystal form I. The TGA, DSC, and 1H-NMR characterization results are summarized in Table 9 and Figures 5-6. p-Toluenesulfonate crystal form I exhibited approximately 2.5% weight loss before 105 °C. 1H-NMR analysis showed the sample contained 0.5% EtOH and 0.1% MTBE organic solvents; therefore, the TGA weight loss was attributed to the removal of water and organic solvents. Two thermodynamic events appeared on the DSC spectrum. The broad endothermic peak at approximately 89 °C was attributed to dehydration, while the second endothermic peak at approximately 127 °C was determined to be due to melting. Therefore, p-toluenesulfonate crystal form I was identified as a hydrate. Table 9. Solid-state characterization results of p-toluenesulfonate crystal form I. Crystal form Solvation DSC, endo Onset / Peak (°C) ΔH (J / g) TGA Wt. loss% / @T (℃) 1 H-NMR p-Toluenesulfonate crystal form I hydrates 40 / 89, 42 122 / 127, 31 2.5 / RT – 105 0.5% EtOH and 0.1% MTBE; 1 equivalent acid

[0059] Example 3: Preparation of benzenesulfonates. Appropriate amounts (20-30 mg) of compound A base were weighed and placed in sample vials at room temperature. The samples were then dissolved or suspended in 0.2 mL of the solvent selected in Table 10. Solid benzenesulfonic acid or 1M benzenesulfonic acid methanol solution was added to react and form salts. The solutions or suspensions were stirred at room temperature for 5-15 hours. If no precipitate formed, an antisolvent was added to induce precipitation. If a solid was formed, the sample was filtered, collected, and vacuum-dried at 50 °C for approximately 3 hours. XRPD, TGA, DSC, and 1H-NMR characterization were then performed. Specific information and results are listed in Table 10. The XRPD spectrum and analysis of benzenesulfonate crystal form I prepared in Group 1 are shown in Figure 7 and Table 10'. Table 10. Preparation of benzenesulfonates. Group solvent Solvent volume / quality of compound A (ml / g) acid antisolvent (v / v)anti ) result 1 EtOH 6.7 14mg MTBE (1 / 3) Benzenesulfonate crystal form I 2 EA 6.7 NA Low crystallinity 3 2-Me-THF 6.7 Oil 4 ACN 10 52 μL Benzenesulfonate crystal form I 5 DCM 10 Benzenesulfonate crystal form I Table 10' XRPD analysis of benzenesulfonate crystal form I 2θ / ° Relative strength I / % 2θ / ° Relative strength I / % 5.464 23.0 19.438 18.3 5.720 14.5 19.768 32.1 7.962 66.2 19.978 55.6 9.001 100.0 20.489 63.6 9.790 40.8 21.854 8.6 10.299 44.2 22.432 22.9 11.980 28.0 23.299 48.7 12.614 31.7 23.756 20.8 13.689 22.1 24.207 12.3 14.071 10.7 24.613 96.9 14.488 44.0 25.243 46.5 15.276 58.6 25.952 13.2 15.802 63.3 27.014 7.3 16.841 18.1 27.764 14.4 17.090 41.1 28.222 21.1 17.298 45.7 28.656 9.2 17.772 12.5 30.153 8.1 18.020 16.3 33.489 7.5 18.204 19.0 33.684 7.2 18.792 10.4 34.589 5.5 19.242 42.1 In this embodiment, a benzenesulfonate crystal form was obtained, named benzenesulfonate crystal form I. Benzenesulfonate crystal form I was characterized by 1H-NMR, TGA, and DSC. The relevant characterization results are summarized in Table 11 and Figures 8-9. Benzenesulfonate crystal form I exhibited approximately 3.0% weight loss before 117 °C. 1H-NMR analysis showed that the sample contained 0.4% EtOH and 0.2% MTBE organic solvents; therefore, the TGA weight loss was attributed to the removal of water and organic solvent residues. The broad, overlapping endothermic peak with a peak temperature of approximately 114 °C on the DSC spectrum was attributed to dehydration (approximately 1 equivalent of H₂O). Benzenesulfonate crystal form I was determined to be a hydrate. Table 11. Solid-state characterization results of benzenesulfonate crystal form I. Crystal form Solvation DSC, endo Onset / Peak (°C) ΔH (J / g) TGA Wt. loss% / @T (℃) 1 H-NMR Benzenesulfonate crystal form I hydrates 71 / 114, 68 3 / RT – 117 0.4% EtOH and 0.2% MTBE; 1 equivalent acid

[0060] Example 4: Preparation of maleate salts. 30 mg of compound A was weighed and placed in a sample vial at room temperature. The vials were then dissolved or suspended in 0.2 mL of the solvent selected in Table 12. Solid maleic acid or 1M maleic acid methanol solution was added to react and form salts. The solution or suspension was stirred at room temperature for 15 hours. If no precipitate formed, an antisolvent was added to induce precipitation. If a solid was formed, the sample was filtered and collected, then vacuum dried at 50 °C for approximately 3 hours to obtain the product. The product was characterized by XRPD, TGA, DSC, and 1H-NMR. Specific information and results are summarized in Table 12. The XRPD spectra and analyses of maleate crystal forms I and II prepared in Groups 2 and 1 are shown in Figures 10 and Table 12', and Figures 11 and Table 12'', respectively. Table 12. Preparation of maleate salts. Group solvent Solvent volume / quality of compound A (ml / g) Acid (mg) antisolvent (v / v) anti ) result 1 MeOH 6.7 10 MTBE (1 / 3) Maleate crystal form II 2 EA 6.7 NA Maleate crystal form I 3 2-Me-THF 6.7 Oil Table 12' XRPD analysis of maleate crystal form I 2θ / ° Relative strength I / % 2θ / ° Relative strength I / % 4.221 71.4 19.216 22.3 7.294 81.7 20.163 12.8 10.589 5.6 21.068 16.5 11.193 12.6 22.223 10.4 12.255 24.0 22.591 23.7 12.915 7.9 23.551 6.0 14.687 21.1 25.083 12.4 15.343 20.9 26.071 100.0 16.129 61.3 27.122 17.8 17.194 71.0 28.171 18.5 18.258 7.3 30.088 9.7 18.568 10.2 Table 12'' XRPD analysis of maleate crystal form II 2θ / ° Relative strength I / % 2θ / ° Relative strength I / % 3.959 14.1 23.851 10.9 7.989 100.0 24.232 15.7 9.250 13.1 25.768 7.5 11.194 10.2 26.766 3.7 13.254 11.1 27.040 9.4 16.106 3.7 27.475 11.4 16.643 3.3 28.315 23.4 18.665 5.5 29.102 3.2 20.174 30.7 30.430 4.6 21.487 5.0 36.377 2.5 22.658 8.1 In this embodiment, two maleate crystal forms were obtained, which were identified and named maleate crystal forms I and II, respectively. The maleate samples were characterized by 1H-NMR, TGA, and DSC. The relevant characterization results are summarized in Table 13 and Figures 12, 13, 14-1, and 14-2. Maleate crystal form I showed approximately 8.4% weight loss before 100 °C. 1H-NMR analysis showed the sample contained approximately 13% EA, therefore the TGA weight loss was attributed to EA removal. The broad, overlapping endothermic peak with a peak temperature of approximately 83 °C on the DSC spectrum was attributed to the removal of organic solvent. Maleate crystal form I was determined to be an EA solvate. Maleate crystal form II showed approximately 3.0% weight loss before 104 °C. 1H-NMR analysis showed the sample contained approximately 2.0% MTBE, therefore the TGA weight loss was attributed to the removal of MTBE and water. The presence of a broad, overlapping endothermic peak with a peak temperature of approximately 108 °C in the DSC spectrum is attributed to the removal of organic solvent and water. Table 13. Solid-state characterization results of maleate crystal forms. Crystal form Solvation DSC, endo Onset / Peak (°C) ΔH (J / g) TGA Wt. loss% / @T (℃) 1 H-NMR Maleate crystal form I EA solvates 73 / 83, 57 8.4 / RT – 100 13% EA; 1 equivalent acid Maleate crystal form II hydrates / solvates 94 / 108, 45 3 / RT – 104 2% MTBE; 1 equivalent acid

[0061] Example 5: Preparation of Oxalate 30 mg of compound A was weighed and placed in a sample vial at room temperature. The vial was then dissolved or suspended in 0.2 mL of the solvent selected in Table 14. 1 M oxalic acid methanol solution was added to react and form a salt. The solution or suspension was stirred at room temperature for approximately 15 hours. If no precipitate formed, an antisolvent was added to induce precipitation. If a solid was formed, the sample was filtered, collected, and vacuum dried at 50 °C for approximately 5 hours. XRPD, TGA, DSC, and 1H-NMR characterization were then performed. Specific information and results are listed in Table 14. The XRPD spectrum and analysis of oxalate crystal form I prepared in Group 3 are shown in Figure 15 and Table 14'. Table 14. Preparation of Oxalate Group solvent Solvent volume / quality of compound A (ml / g) Acid (μL) antisolvent (v / v) anti ) result 1 MeOH 6.7 87 MTBE (1 / 3) amorphous 2 EA 6.7 NA Oxalate crystal form I 3 2-Me-THF 6.7 Oxalate crystal form I Table 14' XRPD analysis of oxalate crystal form I 2θ / ° Relative strength I / % 2θ / ° Relative strength I / % 4.944 19.8 16.550 35.2 5.261 48.2 18.638 7.5 7.255 19.4 19.139 7.7 10.620 8.5 20.212 13.0 12.244 58.7 20.949 19.6 12.961 6.1 24.352 7.7 13.492 6.9 25.755 100.0 14.172 14.0 26.503 9.7 14.776 15.9 27.199 6.5 16.034 11.5 30.876 14.0 In this embodiment, an oxalate crystal form was obtained, named oxalate crystal form I. The oxalate samples from group 3 were characterized by 1H-NMR, TGA, DSC, and IC. The relevant characterization results are summarized in Tables 15-16 and Figures 16-17. Oxalate crystal form I exhibited approximately 0.5% weight loss before 150 °C. 1H-NMR analysis showed no residual organic solvent in the sample; therefore, the TGA weight loss was attributed to the removal of adsorbed water. The sharp endothermic peak at approximately 206 °C on the DSC spectrum was attributed to sample melting accompanied by decomposition. IC results showed that the acid-base ratio of the sample was approximately 1 / 1. Oxalate crystal form I was determined to be anhydrous. Table 15. Solid-state characterization results of oxalate crystal form I. Crystal form Solvation DSC, endo Onset / Peak (°C) ΔH (J / g) TGA Wt. loss% / @T (℃) 1 H-NMR IC Oxalate crystal form I Anhydrous 202 / 206, 168 0.5 / RT – 150 No organic solvent residue 1 equivalent acid Table 16. IC data for oxalate crystal form I sample Quality (mg) Theoretical concentration (μg / mL) IC peak area (μS*min) Actual measurement of C2O4 2- equivalent C2O4 2- Standard solution (C2O4) 2- -STD) NA 10 0.8253 NA Oxalate crystal form I 1.30 9.7 0.8197 1

[0062] Example 6: Magnification of Oxalate Crystal Form I Approximately 300 mg of compound A was weighed and dissolved in 100 μL MeOH, followed by the addition of 78 mg of oxalic acid. Then, 2 mL of 2-Me-THF was added, and the suspension was stirred for 3 days. The sample was collected by filtration and dried under vacuum at 50 °C for approximately 15 hours, followed by characterization by XRPD, IC, TGA, DSC, and 1H-NMR. Approximately 200 mg of oxalate crystal form I was prepared, with a yield of approximately 53%. The sample was analyzed by XRPD, DSC, TGA, DVS, and 1H-NMR. IC results showed an acid-base ratio of 1:1 for the oxalate. TGA data showed approximately 1.9% weight loss before 150 °C. NMR analysis showed that the sample contained 2.1% 2-Me-THF. An endothermic peak with a peak temperature of 203 °C was observed on the DSC spectrum, attributed to sample melting and decomposition. Detailed characterization results are shown in Table 17 and Figures 18-20. Table 17. Characterization results of oxalate crystal form I. DSC, endo Onset / Peak (°C) ΔH (J / g) TGA Wt. loss% / @T (℃) DVS (Wt. gain%, 80 / 90%R) 1 H-NMR 196 / 203, 153 1.9 / RT-150 2.3 / 3.1 2.1% 2-Me-THF

[0063] Example 7: Preparation of Fumarate and its Crystal Form I Appropriate amounts of compound A were weighed and placed in sample vials at room temperature. The vials were then dissolved or suspended in 0.2 mL of the solvent selected in Table 18. Solid fumaric acid was added to react and form a salt. The solution or suspension was stirred at room temperature for a certain period (approximately 3-15 hours). If no precipitate formed, an antisolvent was added to induce precipitation. If a solid was formed, the sample was filtered, collected, and vacuum-dried at 50 °C for approximately 5 hours. XRPD, TGA, DSC, and 1H-NMR characterization were then performed. Specific information and results are listed in Table 18. Table 18. Preparation of Fumarate Group solvent Solvent volume / quality of compound A (ml / g) Mohr ratio of acid to compound A result 1 MeOH 6.7 1.1 Fumarate crystal form I 2 EA 6.7 Fumarate crystal form I+ fumaric acid 3 2-Me-THF 6.7 Oil 4 EA / MeOH (v / v, 60:1) 4.5 0.55 Fumarate crystal form I 5 EA 10 Fumarate crystal form I The XRPD and analytical spectra of the fumarate crystal products prepared according to Group 4 are shown in Figure 21 and Table 19'. They were characterized by 1H-NMR, TGA, and DSC, and the relevant characterization results are summarized in Table 19 and Figures 22-23. The fumarate crystal form I showed almost no weight loss before 150 °C. 1H-NMR analysis indicated that the sample contained 0.5 equivalents of fumaric acid (i.e., the fumarate is a salt formed by compound A and fumaric acid in a molar ratio of 1:0.5). The sharp endothermic peak at approximately 157 °C on the DSC spectrum was attributed to sample melting accompanied by decomposition. Fumarate crystal form I was determined to be anhydrous. Table 19' XRPD analysis of fumarate crystal form I. 2θ / ° Relative strength I / % 2θ / ° Relative strength I / % 3.907 43.3 21.396 21.4 10.456 21.5 22.579 3.1 11.690 14.9 23.680 38.8 12.217 6.7 25.168 6.6 13.938 84.0 25.645 2.9 15.776 8.8 26.372 100.0 16.866 40.0 27.409 32.4 17.732 20.1 27.870 24.5 18.612 7.9 29.707 6.9 19.015 5.6 31.243 9.5 19.673 2.0 32.308 4.2 20.202 3.6 34.593 7.7 20.686 3.0 36.139 5.1 Table 19. Solid-state characterization results of fumarate crystal form I Crystal form Solvation DSC, endo Onset / Peak (°C) ΔH (J / g) TGA Wt. loss% / @T (℃) 1 H-NMR Fumarate crystal form I Anhydrous 155 / 157, 127 0 / RT – 150 0.5 equivalent acid

[0064] Example 8: Preparation of Fumarate Crystal Form II 6.56 g of crude compound A was added to 46 mL of a mixed solvent with a volume ratio of ACN:THF = 2:1. After reflux at 60-70℃, the solid showed no signs of dissolution. 1.10 g (0.55 eq) of fumaric acid was added, but the solid still did not dissolve. The mixture was stirred at 60-70℃ for 1 h, then naturally cooled to 10-20℃ and stirred for 16 h. After filtration, the filter cake was evaporated to dryness, yielding 7.32 g of a yellow solid, i.e., fumarate. The fumarate was characterized by XRPD, TGA, DSC, and 1H-NMR. The relevant characterization results are summarized in Table 20 and Figures 24-27. The molar ratio of fumaric acid to compound A was 0.5:1, indicating an amorphous form with a chemical purity of 99.3%, exhibiting high crystallinity. This was designated as fumarate crystal form II. PLM results show that the fumarate crystal form II obtained in this embodiment consists of irregularly shaped particles with a diameter of 10-80 µm. PSD results show that its Dv(10) is 8.52 µm and Dv(90) is 43.2 µm. Table 20. Solid-state characterization results of fumarate crystal form II. Crystal form Solvation DSC, endo Onset / Peak (°C) ΔH (J / g) TGA Wt. loss% / @T (℃) 1 H-NMR Fumarate crystal form II Anhydrous 180 / 181, 143 0.1 / RT – 150 0.5 equivalent acid Table 20' XRPD analysis of fumarate crystal form II 2θ / ° Relative strength I / % 2θ / ° Relative strength I / % 8.603 2.8 23.157 3.5 10.039 4.7 23.859 3.8 11.441 28.9 24.601 30.5 11.841 8.1 25.199 92.5 12.241 16.4 25.923 4.4 12.639 14.3 26.279 4.3 13.741 25.3 27.539 45.2 14.698 3.2 28.779 22.6 15.842 9.7 29.720 3.6 16.099 15.3 30.560 8.0 17.119 10.0 31.221 5.4 17.540 3.8 33.139 5.5 18.440 4.9 33.921 7.6 19.060 12.6 34.684 2.9 19.681 4.7 35.362 2.2 20.059 4.7 36.481 2.2 20.803 6.1 37.260 4.3 21.202 11.9 38.380 3.3 22.059 100.0 39.122 3.2 22.499 45.1 Other examples of preparing fumarate crystal form II are shown in Table 20-1. Table 20-1 Group Salt formation system (v represents the ratio of the volume of the solvent in the salt-forming system (mL) to the mass (g) of compound A.) operate yield result Purity (HPLC test) 1 MeOH:THF:ACN (v=24, volume ratio 4:10:10) Take 5.0 g of compound A and add 70 mL of a mixed solvent with a volume ratio of MeOH:THF = 4:10. After reflux at 60-70°C, the solid showed no signs of dissolution. After adding 1.14 g of fumaric acid, the system dissolved completely. Stir at 60-70°C for 1 h, then allow to cool naturally to 20-30°C. Add 50 mL of ACN and continue stirring. The solid slowly precipitated. After stirring for another 12 h, a large amount of solid precipitated. Filter the mixture, and dry the filter cake using a rotary evaporator. 55% XRPD: Fumarate crystal form II 99.76% (Figure 28) 2 MeOH:THF:ACN (v = 24, volume ratio 10:4:10) Take 3.0 g of compound A and add 52 mL of a mixed solvent with a volume ratio of MeOH:THF = 10:4. After heating to 60-70℃, the solid showed no signs of dissolution. After adding 685 mg of fumaric acid, the solid gradually dissolved until the system was completely clear. After naturally cooling to 10-20℃, no solid precipitated. Add 30 mL of ACN (10 v) and continue stirring for 1 h. The solid slowly precipitated. Continue stirring at 10-20℃ for 12 h. 45% XRPD: Fumarate crystal form II 99.83% 3 MeOH:THF:ACN (v=17, volume ratio 3:5:9) Take 5.0 g of compound A, add 40 mL of a mixed solvent with a volume ratio of MeOH:THF = 3:5, heat to 60-70 °C and reflux, then add 1.14 g of fumaric acid. The solid gradually dissolves completely until the system is clear. Stir at 60-70 °C for 1 h, then allow to cool naturally to 40-50 °C, add 45 mL of ACN, and continue cooling to 10-20 °C. After stirring for 30 min, a large amount of solid precipitates. Continue stirring at 10-20 °C for 12 h. 65% XRPD: Fumarate crystal form II 99.72% 4 EA:MeOH (v = 36, volume ratio 35:1) Take 2.0 g of compound A, add 72 mL of a mixed solvent with a volume ratio of EA:MeOH = 35:1, heat to 20-30℃, add 457 mg of fumaric acid, stir at 20-30℃ for 12 h, filter, and dry the filter cake using a rotary evaporator. (The salt was never completely dissolved during the salt formation process) 87% XRPD: Fumarate crystal form II 99.62% (Figure 29) 5 MeOH:THF:ACN (v = 17, volume ratio 3:6:15) Take 10 g of compound A and add 170 mL of a mixed solvent with a volume ratio of MeOH:THF:ACN = 3:6:8. Heat the mixture to 60-70 °C and then add 3.00 g of fumaric acid. The solid gradually dissolves completely until the system is clear. Add 70 mL of ACN and stir at 60-70 °C for 1 h. After naturally cooling to 53 °C, add fumarate crystal type II seed crystals. [1] Continue cooling to 10-20℃. During the cooling process, a large amount of solid precipitates out. Continue stirring at 10-20℃ for 12 hours, then filter and evaporate the filter cake. 80% XRPD: Fumarate crystal form II N / A Note: [1] Those skilled in the art will understand that the added fumarate crystal type II seed crystal is a fumarate crystal type II that has been prepared, such as the fumarate crystal type II obtained by referring to groups 1 to 4 in Table 20.

[0065] Example 9: Scale-up Preparation of Fumarate Crystal Form I Approximately 300 mg of compound A and 50.21 mg of fumaric acid were dispersed in 4.5 mL of mixed solvent (EA / MeOH, volume ratio 35 / 1). The mixture was then placed at room temperature and stirred overnight (approximately 15 h). The sample was collected by filtration and dried under vacuum at 50 °C for approximately 3 h, yielding approximately 315 mg of fumarate crystal form I, with a yield of approximately 90%. The sample was analyzed by XRPD, DSC, TGA, DVS, and 1H-NMR. TGA data showed almost no weight loss before 100 °C. NMR analysis showed no organic solvent residue. An endothermic peak with a peak temperature of 159 °C was observed on the DSC spectrum, attributed to sample melting accompanied by decomposition. Detailed characterization results are shown in Table 21 and Figures 30-32. Table 21. Characterization Results of Fumarate Crystal Form I sample batch number# DSC, endo Onset / Peak (°C) ΔH (J / g) TGA Wt. loss% / @T (℃) DVS (Wt. gain%, 80 / 90%R) 1 H-NMR Fumarate crystal form I 157 / 159, 115 0 / RT – 100 <0.2 No organic solvent residue; 0.5 equivalent acid

[0066] Example 10: Preparation of Tartrate Salts 30 mg of compound A was weighed and placed in a sample vial at room temperature. The vials were then dissolved or suspended in 0.2 mL of the solvent selected in Table 22. L-tartaric acid solid was added to react and form salts. The solution or suspension was stirred overnight (approximately 15 hours) at room temperature. If no precipitate formed, an antisolvent was added to induce precipitation. If a solid was formed, the sample was collected by filtration and dried under vacuum at 50 °C for approximately 3 hours. XRPD, TGA, DSC, and 1H-NMR characterization were performed. Specific information and results are listed in Table 22. The XRPD spectra and analysis of the tartrate salts prepared in Group 1 are shown in Figure 33 and Table 22'. Table 22. Preparation of Tartrate Salts Group solvent Solvent volume / quality of compound A (ml / g) Acid (mg) antisolvent (v / v) anti ) result 1 MeOH 6.7 13 MTBE (1 / 3) Tartrate crystal form I 2 EA 6.7 NA Tartrate crystal form I Table 22' XRPD analysis of tartrate crystal form I 2θ / ° Relative strength I / % 2θ / ° Relative strength I / % 8.909 11.5 23.969 11.4 11.403 15.0 24.915 24.6 13.386 69.7 25.584 100.0 15.251 10.1 26.084 43.3 16.983 80.8 26.727 57.9 17.274 39.9 27.565 18.4 17.850 71.6 28.343 8.6 18.297 24.5 29.276 6.0 18.534 63.8 31.571 11.8 19.095 8.5 33.639 4.5 19.662 89.7 34.290 13.3 20.462 40.4 35.696 10.8 22.277 10.1 37.178 9.6 22.866 46.8 In this embodiment, a tartrate crystal form was obtained, named tartrate crystal form I. The tartrate sample was characterized by 1H-NMR, TGA, and DSC. The relevant characterization results are summarized in Table 23 and Figures 34-35. Tartrate crystal form I showed only a 0.8% weight loss before 150 °C. 1H-NMR analysis showed the sample contained 0.8% MTBE and 1 equivalent of acid. A sharp endothermic peak with a peak temperature of approximately 135 °C on the DSC spectrum was attributed to sample melting. Tartrate crystal form I was determined to be anhydrous. Table 23. Solid-state characterization results of tartrate crystal form I. Crystal form Solvation DSC, endo Onset / Peak (°C) ΔH (J / g) TGA Wt. loss% / @T (℃) 1 H-NMR Tartrate crystal form I Anhydrous 127 / 135, 54 0.8 / RT – 150 0.8% MTBE; 1 equivalent acid

[0067] Example 11 Preparation of Free Base Crystal Form I 30 mg of compound A was added to 0.2 ml of ethyl acetate to obtain a suspension. The suspension was stirred at room temperature for 15 hours, filtered, and the collected sample was vacuum dried at 50 °C for 3 hours to obtain free base crystal form I. The XRPD detection spectrum and analysis are shown in Figure 36, and the DSC-TGA detection results are shown in Figure 37; DSC: 157 °C. The 1H-NMR spectrum is shown in Figure 37-2. Table 24. Solid-state characterization results of free base crystal form I. Crystal form Solvation DSC, endo Onset / Peak (°C) ΔH (J / g) TGA Wt. loss% / @T (℃) Remark Free alkali crystal type I Anhydrous 157 / 168, 57 2.4 / RT – 150 1.9% EA

[0068] Example 12 Preparation of Free Base Crystal Form II 300 mg of compound A was dispersed in 2 mL of a mixed solvent (EtOH / Water, v / v = 1 / 10), stirred at room temperature for 3 days, and filtered. The filtered sample was vacuum dried at 50 °C for about 15 hours to obtain free base crystal form II. The XRPD detection spectrum and analysis of the obtained crystal form II are shown in Figure 38, the DSC-TGA detection results are shown in Figure 39, and the 1H-NMR spectrum is shown in Figure 39-1. Table 25. Solid-state characterization results of free base crystal form II Crystal form Solvation DSC, endo Onset / Peak (°C) ΔH (J / g) TGA Wt. loss% / @T (℃) Remark Free alkali crystal type II Anhydrous 172 / 179, 59 0 / RT – 150 No EtOH residue High melting point

[0069] Example 13: Hygroscopicity Test of Free Base Crystal Form II, Oxalate Crystal Form I, Fumarate Crystal Form I, and Fumarate Crystal Form II Approximately 40 mg of each of the following crystal forms were weighed into a peeled DVS dish and their hygroscopicity was evaluated using the aforementioned Dynamic Moisture Adsorption-Desorption Analysis (DVS) method. DVS data showed that the weight of free base crystal form II increased by 1.3% and 1.5% respectively within the range of 0.0%RH to 80 / 90%RH, indicating slight hygroscopicity. Detailed characterization results are shown in Figure 40. The XRPD spectrum of free base crystal form II remained unchanged before and after the DVS test, indicating that the crystal form remained unchanged. DVS data showed that the weight of oxalate crystal form I increased by 2.3% and 3.1% respectively within the range of 0.0%RH to 80 / 90%RH, indicating slight hygroscopicity. Detailed characterization results are shown in Figure 41. The XRPD spectrum of oxalate crystal form I remained consistent before and after the DVS test, indicating that the crystal form remained unchanged. DVS data show that fumarate crystal form I exhibits a weight increase of less than 0.2% within the RH range from 0.0% to 80 / 90% and is non-hygroscopic. Detailed characterization results are shown in Figure 42. The XRPD spectra of fumarate crystal form I remain consistent before and after DVS testing, indicating no change in crystal form. DVS data shows that fumarate crystal form II absorbs approximately 0.2% moisture from 0.0% to 95% RH and is non-hygroscopic. The XRPD spectra of fumarate crystal form II remain consistent before and after DVS testing, indicating no change in crystal form. Detailed characterization results are shown in Figures 43 and 44.

[0070] Example 14: Solubility Test of Free Base Crystal Form II, Oxalate Crystal Form I, Fumarate Crystal Form I, and Fumarate Crystal Form II The solubilities of free base crystal form II, oxalate crystal form I, fumarate crystal form I, and fumarate crystal form II were measured in a bio-related medium at 37 °C. 15 mg of each of the three crystal forms were weighed and dispersed in 5.0 mL of a bio-related medium. The medium was shaken on a shaker at 100 rpm at 37 °C. 1 mL of the dispersion was collected at 0.5, 2, and 24 hours and filtered. The filtrate was analyzed for solubility by HPLC and pH by pH meter. The filter cake was characterized by XRPD. The relevant characterization results are summarized in Table 26. Table 26. Results in Bio-Related Medium sample medium Solubility (μg / mL) XRPD pH 0.5h 2h 24h 0h 24h Free alkali crystal type II FaSSIF 8.24 5.14 6.44 remain unchanged 6.50 6.49 FeSSIF 33.38 42.87 48.68 remain unchanged 5.00 4.99 SGF 1010 1027 1167 remain unchanged 1.20 1.29 Oxalate crystal form I FaSSIF 19.34 12.35 13.41 Oxalate crystal form I + free base crystal form II (trace) 6.50 5.94 FeSSIF 96.23 194.1 255.4 remain unchanged 5.00 4.94 SGF 73.75 123.4 139.9 remain unchanged 1.20 1.24 Fumarate crystal form I FaSSIF 12.19 3.57 4.25 Free alkali crystal type II 6.50 5.96 FeSSIF 109.2 75.30 61.39 Free alkali crystal type II 5.00 4.90 SGF 1899 2135 2146 Trace solids 1.20 1.29 Fumarate crystal form II FaSSIF — — 0.28 Mixed crystals of free alkali crystal type I and free alkali crystal type II 6.50 6.2 FeSSIF — — 132.92 Crystal form II, free alkali crystal form I Mixed crystals with free alkali crystal type II 5.00 4.9 SGF — — 1425.24 remain unchanged 1.20 1.2 In the three biorelevant media, fumarate form I exhibited higher solubility than free base form II (0.5 hours). The highest solubility of both solid forms was observed in SGF medium at 0.5 hours (1.0 mg / mL vs. 1.9 mg / mL), almost 10 times that of oxalate form I (0.07 mg / mL). Both salt forms dissociated into free base during the solubility tests. In the solubility tests, free base form II remained unchanged in the biorelevant media for 24 hours. Oxalate form I remained unchanged in FeSSIF and SGF for 24 hours, but partially dissociated into free base form II in FaSSIF for 24 hours. Fumarate form I dissociated into free base form II in FaSSIF and FeSSIF media after 0.5 hours. The solubility test results show that the solubility of fumarate form I in all three biorelevant media at 0.5 hours is approximately twice that of free base form II.

[0071] Example 15: Solid-state stability test of free alkali crystal form II, oxalate crystal form I, fumarate crystal form I, and fumarate crystal form II. Appropriate amounts of free alkali crystal form II, oxalate crystal form I, fumarate crystal form I, and fumarate crystal form II were placed under two conditions: 60 ℃ / closed and 40 ℃ / 75% RH open, for 1 week and 2 weeks respectively. Samples from 0 days, 1 week, and 2 weeks were dissolved in diluent to prepare solutions of approximately 1.0 mg / mL. Chemical stability was analyzed by HPLC. Solid samples after 1 or 2 weeks were analyzed by XRPD. The relevant characterization results are summarized in Tables 27-28. Table 27 Stability assessment results (7 days) sample Purity -0 and 1 week (Area%) 265 nm XRPD – 1 week initial purity 40℃ / 75%RH 60℃ / Closed mouth 40℃ / 75%RH 60℃ / Closed mouth Free alkali crystal type II 98.62 98.62 98.64 remain unchanged remain unchanged Oxalate crystal form I 96.97 96.97 96.13 remain unchanged remain unchanged Fumarate crystal form I 99.85 99.85 99.86 remain unchanged remain unchanged Fumarate crystal form II 99.30 99.20 99.20 remain unchanged remain unchanged Table 28. Stability assessment results (14 days) sample Purity -0 and 2 weeks (Area%) 265 nm XRPD – 2 weeks initial purity 40℃ / 75%RH 60℃ / Closed mouth 40℃ / 75%RH 60℃ / Closed mouth Free alkali crystal type II 99.83 99.83 99.83 remain unchanged remain unchanged Fumarate crystal form I 99.73 99.74 99.75 remain unchanged remain unchanged Stability results showed that both free alkali crystalline form II and fumarate crystalline form I were physically and chemically stable for one week under both 60 °C / closed-cell and 40 °C / 75%RH open-cell conditions, but oxalate degradation occurred. 14-day stability tests showed that both free alkali crystalline form II and fumarate crystalline form I were physically and chemically stable for two weeks under both 60 °C / closed-cell and 40 °C / 75%RH open-cell conditions.

[0072] Example 16: Pharmacokinetic Study of Free Base Crystal Form II and Fumarate Crystal Form I In the comparative experiment, 12 SD rats (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.), weighing 180-280g, were used, with half being male and half female. They were randomly divided into four groups of 3 rats each. Groups 1 and 3 were female, and groups 2 and 4 were male. Free base crystal form II and fumarate crystal form I of compound A were dissolved in 5% TPGS at a drug concentration of 20mg / ml (calculated as compound A). The drug was administered by gavage at a volume of 10ml / kg and a dose of 20mg / kg, with a frequency of QD (once a day). Blood samples were collected from the orbital venous plexus of rats at different time points after administration (0.167, 0.5, 1, 2, 3, 4, 6, 9, 12 and 24h). The concentration of compound A in plasma was measured. Data will be analyzed using WinNonlin (version 5.2.1, Pharsight, Mountain View, CA) via a non-compartmental model to obtain pharmacokinetic parameters (C0, Cmax, Tmax, AUC0-last, AUCinf, T1 / 2, CL, Vz, etc., selected according to different routes of administration). See Table 29 for all pharmacokinetic parameters. Table 29 Compounds / Groups C max (ng / mL) T max (h) T 1 / 2 (h) AUC last(ng / mL*h) AUC inf (ng / mL*h) Group 1 - Free Alkali Crystal Type II 3617±321 0.67±0.17 2.88 ±0.46 14778±3318 18164±150 Group II - Free Alkali Crystal Type II 3297±676 1.00±0.00 3.33±0.40 19604±2132 19790±2233 Group 3 - Fumarate Crystal Form I 6357±342 0.83±0.17 3.01±0.22 32884±1318 33018±1303 Group 4 - Fumarate Crystal Form I 3053±198 0.67±0.17 3.44±0.29 23896±2934 24142±2905 Comparison of pharmacokinetic parameters between female and male rats administered the same dose of free base and compound A fumarate by gavage revealed that the exposure of compound A in rats after gavage administration of compound A fumarate was 2.23 times and 1.22 times that after gavage administration of free base to female and male rats, respectively.

[0073] The acid addition salt of compound A and the crystal form of the salt provided by the present invention have the characteristics of high solubility, good stability, high purity, few impurities and high bioequivalence, which are beneficial to drug storage, quality control and drug-likeness.

[0074] This invention provides an acid addition salt of compound A, the crystal form of the salt, and a method for its preparation. The preparation method is simple, easy to implement, and operates under mild reaction conditions, resulting in high product yield. Furthermore, it eliminates the need for multiple purification processes, is safe and environmentally friendly, and is beneficial for the industrial production of polymorphs.

[0075] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention. [Simplified Explanation of the Diagram]

[0011] [Figure 1] shows the XRPD spectrum (a) and spectrum analysis (b) of crystal form I of hydrochloride. [Figure 2] shows the DSC and TGA spectra of crystal form I of hydrochloride. [Figure 3] shows the 1H-NMR spectrum of crystal form I of hydrochloride. [Figure 4] shows the XRPD spectrum (a) and spectrum analysis (b) of crystal form I of p-toluenesulfonate. [Figure 5] shows the DSC and TGA spectra of crystal form I of p-toluenesulfonate. [Figure 6] shows the 1H-NMR spectrum of crystal form I of p-toluenesulfonate. [Figure 7] shows the XRPD spectrum (a) and spectrum analysis (b) of crystal form I of benzenesulfonate. [Figure 8] shows the DSC and TGA spectra of crystal form I of benzenesulfonate. [Figure 9] shows the 1H-NMR spectrum of crystal form I of benzenesulfonate. [Figure 10] shows the XRPD spectrum (a) and spectrum analysis (b) of crystal form I of maleate. [Figure 11] XRPD spectrum (a) and spectrum analysis (b) of maleate crystal form II. [Figure 12] DSC and TGA spectra of maleate crystal form I. [Figure 13] DSC and TGA spectra of maleate crystal form II. [Figure 14-1] 1H-NMR spectrum of maleate crystal form I. [Figure 14-2] 1H-NMR spectrum of maleate crystal form II. [Figure 15] XRPD spectrum (a) and spectrum analysis (b) of oxalate crystal form I. [Figure 16] DSC and TGA spectra of oxalate crystal form I. [Figure 17] 1H-NMR spectrum of oxalate crystal form I. [Figure 18] XRPD spectrum of oxalate crystal form I obtained by magnification. [Figure 19] DSC and TGA superimposed image of oxalate crystal form I obtained by magnification. [Figure 20] 1H-NMR spectrum of oxalate crystal form I obtained by magnification. [Figure 21] XRPD spectrum (a) and spectrum analysis (b) of fumarate crystal form I. [Figure 22] DSC and TGA spectra of fumarate crystal form I. [Figure 23] 1H-NMR spectrum of fumarate crystal form I. [Figure 24] XRPD spectrum (a) and spectrum analysis (b) of fumarate crystal form II. [Figure 25] TGA spectrum of fumarate crystal form II. [Figure 26] DSC spectrum of fumarate crystal form II. [Figure 27] 1H-NMR spectrum of fumarate crystal form II. [Figure 28] HPLC purity test of fumarate crystal form II obtained in group 1 of Example 8. [Figure 29] HPLC purity test of fumarate crystal form II obtained in group 4 of Example 8. [Figure 30] XRPD spectrum of fumarate crystal form I obtained by scale-up preparation in Example 9. [Figure 31] is a superimposed DSC and TGA image of the fumarate crystal form I prepared at magnification. [Figure 32] is a magnified 1H-NMR image of the fumarate crystal form I prepared at magnification. [Figure 33] is the XRPD spectrum (a) and spectrum analysis (b) of the tartrate. [Figure 34] is the DSC and TGA spectrum of the tartrate crystal form I.[Figure 35] shows the 1H-NMR spectrum of tartrate crystal form I. [Figure 36] shows the XRPD spectrum (a) and spectrum analysis (b) of free alkali crystal form I. [Figure 37] shows the DSC and TGA spectra of free alkali crystal form I. [Figure 37-2] shows the 1H-NMR spectrum of free alkali crystal form I. [Figure 38] shows the XRPD spectrum (a) and spectrum analysis (b) of free alkali crystal form II. [Figure 39] shows the DSC and TGA spectra of free alkali crystal form II. [Figure 39-1] shows the 1H-NMR spectrum of free alkali crystal form II. [Figure 40] shows the DVS spectrum of free alkali crystal form II. [Figure 41] shows the DVS spectrum of oxalate crystal form I. [Figure 42] shows the DVS spectrum of fumarate crystal form I. [Figure 43] shows the DVS spectrum of fumarate crystal form II. [Figure 44] shows the XRPD spectra of fumarate crystal form II before and after DVS testing.

Claims

1. A salt of compound A, wherein compound A has the following structure: The salt is an acid addition salt of compound A with any of the following acids: hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, maleic acid, tartaric acid, oxalic acid, fumaric acid, sulfuric acid, methanesulfonic acid, phosphoric acid, succinic acid, or citric acid.

2. A salt of compound A as claimed in claim 1, wherein, The salt is a hydrochloride salt of compound A, a p-toluenesulfonate salt of compound A, a benzenesulfonate salt of compound A, a maleate salt of compound A, a tartrate salt of compound A, an oxalate salt of compound A, or a fumarate salt of compound A; and / or, in the salt of compound A, the molar ratio of compound A to acid is 5:1 to 1:

5.

3. A crystal form of a salt of compound A as described in claim 2, wherein, The crystal form is hydrochloride crystal form I; the hydrochloride crystal form I exhibits characteristic peaks in X-ray powder diffraction at 5.93±0.20°, 11.96±0.20°, 14.92±0.20°, 17.98±0.20°, 24.07±0.20°, 26.61±0.20°, and 27.18±0.20° when irradiated with Cu-Kα radiation and expressed in 2θ angles. Alternatively, the crystal form is p-toluenesulfonate crystal form I; p-toluenesulfonate crystal form I exhibits characteristic peaks in X-ray powder diffraction at 7.55±0.20°, 8.61±0.20°, 14.75±0.20°, 15.99±0.20°, 19.64±0.20°, 19.91±0.20°, 23.38±0.20°, 24.02±0.20°, and 24.60±0.20° when irradiated with Cu-Kα radiation and expressed in 2θ angles. Alternatively, the crystal form is benzenesulfonate crystal form I, and the benzenesulfonate crystal form I exhibits characteristic peaks at 7.96±0.20°, 9.00±0.20°, 15.28±0.20°, 15.80±0.20°, 19.97±0.20°, 20.49±0.20°, and 24.61±0.20° when X-ray powder diffracted using Cu-Kα radiation and expressed in 2θ angles. Alternatively, the crystal form is maleate crystal form I, and the maleate crystal form I exhibits characteristic peaks in X-ray powder diffraction at 4.22±0.20°, 7.29±0.20°, 12.25±0.20°, 14.68±0.20°, 15.34±0.20°, 16.13±0.20°, 17.19±0.20°, 19.21±0.20°, 22.59±0.20°, and 26.07±0.20° when irradiated with Cu-Kα radiation and expressed in 2θ angles. Alternatively, the crystal form is maleate crystal form II, and the maleate crystal form II exhibits characteristic peaks in X-ray powder diffraction at 3.96±0.20°, 7.99±0.20°, 9.25±0.20°, 11.19±0.20°, 13.25±0.20°, 20.17±0.20°, 23.85±0.20°, 24.23±0.20°, 27.47±0.20°, and 28.31±0.20° when irradiated with Cu-Kα radiation and expressed in 2θ angles. Alternatively, the crystal form is oxalate crystal form I, and the oxalate crystal form I exhibits characteristic peaks in X-ray powder diffraction at 4.94±0.20°, 5.26±0.20°, 7.25±0.20°, 12.24±0.20°, 14.77±0.20°, 16.55±0.20°, 20.95±0.20°, and 25.75±0.20° when irradiated with Cu-Kα.Characteristic peaks are present at 90±0.20°, 10.45±0.20°, 13.93±0.20°, 16.86±0.20°, 17.73±0.20°, 21.39±0.20°, 23.68±0.20°, 26.37±0.20°, 27.40±0.20°, and 27.87±0.20°. Alternatively, the crystal form is fumarate crystal form II, and the fumarate crystal form II exhibits characteristic peaks in X-ray powder diffraction at 11.44±0.20°, 13.74±0.20°, 22.06±0.20°, 22.50±0.20°, 24.60±0.20°, 25.20±0.20°, 27.54±0.20°, and 28.78±0.20° when irradiated with Cu-Kα radiation and expressed in 2θ angles. Alternatively, the crystal form is tartrate crystal form I, and the tartrate crystal form I exhibits characteristic peaks in X-ray powder diffraction (expressed as 2θ angles) using Cu-Kα radiation at 13.38±0.20°, 16.98±0.20°, 17.85±0.20°, 18.53±0.20°, 19.66±0.20°, 25.58±0.20°, and 26.72±0.20°.

4. The crystal form as described in claim 3, wherein, The hydrochloride crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.93±0.20°, 11.96±0.20°, 12.56±0.20°, 14.92±0.20°, 17.98±0.20°, 18.96±0.20°, 21.02±0.20°, 24.07±0.20°, 25.53±0.20°, 26.61±0.20°, 27.18±0.20°, and 31.66±0.20° in 2θ angles. The p-toluenesulfonate crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.49±0.20°, 7.55±0.20°, 8.61±0.20°, 9.14±0.20°, 10.05±0.20°, 14.39±0.20°, 14.75±0.20°, 15.99±0.20°, 19.64±0.20°, 19.91±0.20°, 20.67±0.20°, 23.38±0.20°, 24.02±0.20°, and 24.60±0.20° in terms of 2θ angles. The benzenesulfonate crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 7.96±0.20°, 9.00±0.20°, 9.79±0.20°, 10.30±0.20°, 14.48±0.20°, 15.28±0.20°, 15.80±0.20°, 17.09±0.20°, 17.29±0.20°, 19.24±0.20°, 19.97±0.20°, 20.49±0.20°, 23.29±0.20°, 24.61±0.20°, and 25.24±0.20° in 2θ angles. The maleate crystal form I exhibits characteristic peaks in X-ray powder diffraction at 2θ angles as shown in Table 12', with an error range of ±0.2°. The maleate crystal form II has X-ray powder diffraction characteristic peaks in 2θ angles as shown in Table 12'', with an error range of ±0.2°; the oxalate crystal form I, using Cu-Kα radiation, exhibits characteristic peaks in 2θ angles at 4.94±0.20°, 5.26±0.20°, 7.25±0.20°, 12.24±0.20°, 14.17±0.20°, 14.77±0.20°, 16.03±0.20°, 16.55±0.20°, 20.21±0.20°, 20.95±0.20°, 25.75±0.20°, and 30.87±0.20°; the fumarate crystal form I has X-ray powder diffraction characteristic peaks in 2θ angles as shown in Table 19', with an error range of ±0.2°; The fumarate crystal form II has X-ray powder diffraction characteristic peaks represented by the 2θ angle as shown in Table 20', with an error range of ±0.2°; The tartrate crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction (expressed as 2θ angles) at 13.38±0.20°, 16.98±0.20°, 17.27±0.20°, 17.85±0.20°, 18.53±0.20°, 19.66±0.20°, 20.46±0.20°, 22.86±0.20°, 25.58±0.20°, 26.08±0.20°, and 26.72±0.20°.

5. The crystal form as described in claim 3, wherein, The hydrochloride crystal form I has X-ray powder diffraction characteristic peaks represented by 2θ angles as shown in Table 5', with an error range of ±0.2°; the p-toluenesulfonate crystal form I has X-ray powder diffraction characteristic peaks represented by 2θ angles as shown in Table 8', with an error range of ±0.2°; the benzenesulfonate crystal form I has X-ray powder diffraction characteristic peaks represented by 2θ angles as shown in Table 10', with an error range of ±0.2°; the maleate crystal form I has an XRPD spectrum basically as shown in Figure 10(a); the maleate crystal form II has an XRPD spectrum basically as shown in Figure 11(a); the oxalate crystal form I has X-ray powder diffraction characteristic peaks represented by 2θ angles as shown in Table 14', with an error range of ±0.2°; the tartrate crystal form I has X-ray powder diffraction characteristic peaks represented by 2θ angles as shown in Table 22', with an error range of ±0.2°.

6. The crystal form as described in claim 3, wherein, The hydrochloride crystal form I has an XRPD spectrum that is basically as shown in Figure 1(a); the p-toluenesulfonate crystal form I has an XRPD spectrum that is basically as shown in Figure 4(a); the benzenesulfonate crystal form I has an XRPD spectrum that is basically as shown in Figure 7(a); the oxalate crystal form I has an XRPD spectrum that is basically as shown in Figure 15(a); the fumarate crystal form I has an XRPD spectrum that is basically as shown in Figure 21(a); the fumarate crystal form II has an XRPD spectrum that is basically as shown in Figure 24(a); and the tartrate crystal form I has an XRPD spectrum that is basically as shown in Figure 33(a).

7. The crystal form as described in claim 3, wherein, The molar ratio of compound A to hydrochloric acid in crystal form I of the hydrochloride salt is 1:1; the molar ratio of compound A to p-toluenesulfonic acid in crystal form I of the p-toluenesulfonate salt is 1:1; the molar ratio of compound A to benzenesulfonic acid in crystal form I of the benzenesulfonate salt is 1:1; the molar ratio of compound A to maleic acid in crystal form I of the maleate salt is 1:1; the molar ratio of compound A to maleic acid in crystal form II of the maleate salt is 1:1; the molar ratio of compound A to fumaric acid in crystal form I of the fumarate salt is 2:1; the molar ratio of compound A to fumaric acid in crystal form II of the fumarate salt is 2:1; the molar ratio of compound A to fumaric acid in crystal form I of the tartrate salt is 1:1; and the molar ratio of compound A to oxalic acid in crystal form I of the oxalate salt is 1:

1.

8. A method for preparing a salt of compound A as described in claim 1 or 2, characterized in that the compound A is reacted with an acid in a solvent to form a salt, stirred until a precipitate is formed, dried, and the salt is obtained; if no precipitate is formed by stirring, an antisolvent is added to the system, and after the precipitate is formed, it is dried to obtain the salt; the acid is as defined in claim 1.

9. The preparation method as described in claim 8, wherein, The solvent is selected from one, two or more of EA (ethyl acetate), 2-Me-THF (2-methyl-tetrahydrofuran), ACN (acetonitrile), DCM (dichloromethane), EtOH (ethanol), MeOH (methanol), IPA (isopropanol), THF (tetrahydrofuran), IPAc (isopropyl acetate), or a mixture of any one, two or more of the above solvents with MTBE (methyl tert-butyl ether); the antisolvent is selected from MTBE (methyl tert-butyl ether) and / or ACN (acetonitrile).

10. A pharmaceutical composition, characterized in that the pharmaceutical composition contains a crystal form of the salt as described in claim 1 or 2 or the salt as described in any one of claims 3 to 7; and / or a pharmaceutically acceptable carrier.

11. A formulation comprising a crystalline form of the salt as described in claim 1 or 2, or the salt as described in any one of claims 3 to 7, or a pharmaceutical composition as described in claim 10, wherein, The preparations are powders, tablets, capsules, granules, pills, suspensions, solutions, emulsions, elixirs, syrups, aerosols, creams, ointments, gels, injections, or suppositories.

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