A crystalline CSF-1R inhibitor acid salt, its preparation method and application

Abstract

This invention provides a crystalline CSF-1R inhibitor acid salt, its preparation method, and its applications. The CSF-1R inhibitor is a compound having the structure of formula (I), namely 3,3-dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxopyrrolidine-1-carboxamide. The crystalline acid salt compound significantly improves the physicochemical properties of the free form of formula (I), such as solubility, hygroscopicity, and chemical stability, meeting the requirements of industrial production and satisfying the needs of clinical drug formulation development. The crystalline acid salt compound can be widely used in the preparation of drugs for treating cancer, tumors, autoimmune diseases, metabolic diseases, or metastatic diseases.

Description

[0001] This application is a divisional application of the invention entitled "A crystalline CSF-1R inhibitor acid salt and its preparation method and application" filed on May 23, 2022, with application number 202280012929.9. Technical Field

[0002] This invention belongs to the field of drug development, specifically relating to a crystalline CSF-1R inhibitor acid salt, its preparation method, and its application. Background Technology

[0003] CSF-1R (cFMS) stands for Colony-Stimulating Factor-1 Receptor. CSF-1R, along with cKIT, FLT3, and PDGFR-a & b, belongs to the third family of growth hormone receptors. This receptor is a membrane protein expressed on the surface of macrophages and monocytes. Its extracellular segment binds to macrophage colony-stimulating factor, while its intracellular segment, a tyrosine kinase, activates downstream cell growth and proliferation signaling pathways in macrophages and monocytes, including MAPK and PI3K. Therefore, the CSF-1R signaling pathway has a significant impact on macrophage and monocyte development and differentiation, as well as the physiological function of tumor-associated macrophages (TAMs).

[0004] With the advancements in tumor immunotherapy in recent years, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are considered to be directly related to the formation of the immunosuppressive microenvironment within tumors and to angiogenesis that supports tumor growth. Meanwhile, clinical studies have shown a negative correlation between TAM levels and cancer patient prognosis. Furthermore, pharmacodynamic experiments in mice have demonstrated that inhibiting the CSF-1R signaling pathway can significantly reduce the number of immunosuppressive macrophages within tumors and increase the number of CD8-positive T cells. These experimental results suggest that small molecule inhibitors of CSF-1R may reverse the immunosuppressive environment within tumors, promote immune system activation, and prolong the lives of cancer patients.

[0005] Abbisko Therapeutics Co., Ltd., through long-term research, has invented a novel small molecule compound (WO2018214867A1, international publication date: November 29, 2018) with CSF-1R inhibitory effects. Representative compounds are as follows: ; The Chinese name is 3,3-dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxopyrrolidine-1-carboxamide (compound of formula (I)). This compound can significantly enhance the inhibitory effect on the CSF-1R target and the selectivity for other kinase receptors, improve the therapeutic window, reduce clinical toxicity and side effects, and meet the current domestic and international needs for targeted therapy of tumors such as lung cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, melanoma, pancreatic cancer, head and neck cancer, glioma, and tenosynovial giant cell tumor.

[0006] However, when WO2018214867A1 was filed, no further research was conducted to develop a raw material form suitable for industrial production, nor was a process method suitable for industrial application developed. Furthermore, no in-depth research was conducted on the aggregation state of the compound in formula (I) to improve its physicochemical properties and meet the needs of pharmaceutical or clinical applications. WO2018214867A1 discloses an amorphous free state or foam-like solid compound. The specific preparation method is described in Example 1: A solution of 3,3-dimethyl-2-oxopyrrolidine-1-carbonyl chloride (0.33 mmol) in dichloromethane (10 mL) was added dropwise to a solution of 6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine-2-amine (93 mg, 0.33 mmol) and pyridine (78 mg, 0.99 mmol) in dichloromethane (10 mL) under ice bath conditions. The reaction mixture was stirred at 5°C for 30 minutes, then at room temperature for 2 hours. The phases were separated by dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried with anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography [eluent: dichloromethane / methanol (15:1)] to obtain the foamy compound 3,3-dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxopyrrolidine-1-carboxamide (42 mg, yield 30.4%). The inventors identified the foamy compound as an amorphous compound, which is hygroscopic, easily softened, and cannot be stored, making it unsuitable for clinical formulation development. Therefore, to meet the needs of clinical research and marketed drug formulations, there is an urgent need to develop an aggregation form suitable for drug development to overcome the shortcomings of existing technologies. Summary of the Invention

[0007] To address the problems existing in the prior art, the inventors conducted in-depth research on the different aggregation forms of compound (I) (3,3-dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxopyrrolidine-1-carboxamide), and developed various crystalline acid salts, especially hydrochlorides. These significantly improved the physicochemical properties of compound (I), such as solubility, hygroscopicity, and chemical stability. The crystalline acid salt compounds meet the requirements of industrial production and can satisfy the needs of clinical drug formulation development. These crystalline acid salt compounds have significant clinical application value and are expected to accelerate the development into a new generation of CSF-1R small molecule inhibitors.

[0008] The first aspect of this invention provides an acid salt of a compound of crystalline form (I): .

[0009] As a preferred embodiment, the acid salt of the crystalline form (I) compound is an inorganic acid salt or an organic acid salt.

[0010] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is an inorganic acid salt, which is selected from hydrochloride, sulfate, hydrobromide, hydrofluoric acid, hydroiodide, or phosphate.

[0011] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is an organic acid salt, wherein the organic acid salt is selected from acetate, dichloroacetate, trichloroacetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, ethane-1,2-disulfonate, methanesulfonate, ethanesulfonate, benzoate, decanoate, hexanoate, octanoate, cinnamate, citrate, cyclohexanesulfonate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbate, lactate, malate, mandelate, pyroglutamate, tartrate, and dodecane. Basalts, benzoyl tartrates, formates, fumarates, galactobionates, gentianates, acetyloxyoximes, malonates, succinates, glutarates, adipates, sebates, 2-ketoglutarate, glycolates, hippurates, hydroxyethyl sulfonates, lactobionates, ascorbic acid salts, aspartate salts, laurates, maleates, nicotinates, oleates, orotates, oxalates, palmitates, dihydroxynaphthyl salts, propionates, 4-acetaminobenzoates, 4-aminobenzoates, salicylates, 4-aminosalicylic acid salts, 2,5-dihydroxybenzoates, 1-hydroxy-2-naphthyl carboxate, stearates, thiocyanates, undecenoates, or succinates.

[0012] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is an organic acid salt, which is selected from methanesulfonate, citrate, malate, fumarate or tartrate.

[0013] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a hydrochloride salt, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 9.52±0.2°, 19.72±0.2°, 10.64±0.2°, 14.32±0.2°, 16.56±0.2°, 18.52±0.2° and 27.20±0.2°.

[0014] As the most preferred embodiment, the acid salt of the crystalline form (I) compound is a hydrochloride salt, and its X-ray powder diffraction pattern is consistent with... Figure 1 The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 1: This crystalline hydrochloride is designated as hydrochloride crystal form I, with a melting point of 157.8℃.

[0015] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a hydrochloride salt, whose X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 24.32±0.2°, 17.78±0.2°, 24.58±0.2°, 19.96±0.2°, 10.18±0.2°, 21.34±0.2°, 18.06±0.2°, 28.10±0.2°, and 18.42±0.2°.

[0016] As the most preferred embodiment, the acid salt of the crystalline form (I) compound is a hydrochloride salt, and its X-ray powder diffraction pattern is consistent with... Figure 2 The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 2: This crystalline hydrochloride is designated as hydrochloride crystal form II, with a melting point of 120.6℃.

[0017] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a hydrochloride salt, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 18.74±0.2°, 22.94±0.2°, 17.64±0.2°, 9.38±0.2°, 9.10±0.2°, 9.94±0.2°, 29.70±0.2°, and 11.24±0.2°.

[0018] As the most preferred embodiment, the acid salt of the crystalline form (I) compound is a hydrochloride salt, and its X-ray powder diffraction pattern is consistent with... Figure 3 The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 3: This crystalline hydrochloride is designated as hydrochloride crystal form III, with a melting point of 110.9°C.

[0019] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a sulfate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 20.08±0.2°, 23.22±0.2°, 21.38±0.2°, 24.86±0.2°, 18.78±0.2°, 20.46±0.2° and 9.38±0.2°.

[0020] As the most preferred embodiment, the acid salt of the crystalline form (I) compound is a sulfate, and its X-ray powder diffraction pattern is consistent with... Figure 4 The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 4: This crystalline sulfate is designated as sulfate crystal form I.

[0021] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a phosphate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 8.44±0.2°, 16.82±0.2°, 10.78±0.2°, 18.10±0.2°, 24.78±0.2°, 19.62±0.2° and 23.24±0.2°. As the most preferred embodiment, the acid salt of the crystalline form (I) compound is a phosphate, and its X-ray powder diffraction pattern is consistent with... Figure 5 The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 5: This crystalline phosphate is designated as phosphate crystal form I, with a melting point of 154.2℃.

[0022] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a phosphate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 10.86±0.2°, 8.48±0.2°, 17.02±0.2°, 10.46±0.2°, 18.38±0.2°, 7.98±0.2°, 23.82±0.2°, and 16.06±0.2°.

[0023] As the most preferred embodiment, the acid salt of the crystalline form (I) compound is a phosphate, and its X-ray powder diffraction pattern is consistent with... Figure 6 The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 6: This crystalline phosphate is designated as phosphate crystal form II, with a melting point of 153.8℃.

[0024] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a phosphate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 10.84±0.2°, 8.54±0.2°, 17.14±0.2°, 16.76±0.2°, 10.36±0.2°, 18.26±0.2°, 27.88±0.2°, and 22.34±0.2°.

[0025] As the most preferred embodiment, the acid salt of the crystalline form (I) compound is a phosphate, and its X-ray powder diffraction pattern is consistent with... Figure 7 The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 7: This crystalline phosphate is designated as phosphate crystal form III, with a melting point of 147.3℃.

[0026] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a methanesulfonate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 16.28±0.2°, 20.82±0.2°, 7.78±0.2°, 26.68±0.2°, 23.36±0.2°, 26.30±0.2° and 23.62±0.2°.

[0027] As the most preferred embodiment, the acid salt of the crystalline form (I) compound is a methanesulfonate, and its X-ray powder diffraction pattern is consistent with... Figure 8The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 8: This crystalline methanesulfonate is designated as methanesulfonate crystal form I, with a melting point of 184.4℃.

[0028] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a methanesulfonate, whose X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 8.64±0.2°, 21.02±0.2°, 16.34±0.2°, 23.34±0.2°, 18.48±0.2°, 7.84±0.2°, 26.00±0.2°, and 10.82±0.2°.

[0029] As the most preferred embodiment, the acid salt of the crystalline form (I) compound is a methanesulfonate, and its X-ray powder diffraction pattern is consistent with... Figure 9 The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 9: This crystalline methanesulfonate is designated as methanesulfonate crystal form II, with a melting point of 185.5℃.

[0030] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a citrate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 16.14±0.2°, 7.12±0.2°, 14.86±0.2°, 16.64±0.2°, 21.34±0.2° and 13.70±0.2°.

[0031] As the most preferred option, the acid salt of the crystalline form (I) compound is a citrate, and its X-ray powder diffraction pattern is consistent with... Figure 10 The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 10: This crystalline citrate is designated as citrate crystal form I, with a melting point of 58.1℃.

[0032] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is an malate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 8.44±0.2°, 27.82±0.2°, 14.22±0.2°, 9.72±0.2°, 15.44±0.2°, 18.96±0.2°, and 19.28±0.2°.

[0033] As the most preferred embodiment, the acid salt of the crystalline form (I) compound is an malate, and its X-ray powder diffraction pattern is consistent with... Figure 11 The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 11: This crystalline malate is designated as malate crystal form I, with a melting point of 82.8℃.

[0034] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a tartrate salt, whose X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 9.16±0.2°, 16.64±0.2°, 19.80±0.2°, 26.84±0.2°, 18.96±0.2°, 24.06±0.2°, and 12.16±0.2°.

[0035] As the most preferred option, the acid salt of the crystalline form (I) compound is a tartrate salt, and its X-ray powder diffraction pattern is consistent with... Figure 12 The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 12: This crystalline tartrate is designated as tartrate crystal form I, with a melting point of 122.4℃.

[0036] As a further preferred embodiment, the acid salt of the crystalline form (I) compound is a fumarate, whose X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 16.82±0.2°, 18.28±0.2°, 11.62±0.2°, 15.10±0.2°, 8.44±0.2°, 21.54±0.2°, and 27.58±0.2°.

[0037] As the most preferred option, the acid salt of the crystalline form (I) compound is a fumarate, and its X-ray powder diffraction pattern is consistent with... Figure 13The peaks at the diffraction angle (2θ) shown are essentially the same (±0.2°), and their X-ray powder diffraction data are shown in Table 13: This crystalline fumarate is designated as fumarate crystal form I.

[0038] A second aspect of the present invention provides a method for preparing the acid salt of the aforementioned crystalline form (I) compound, comprising the following steps: 1) Dissolve or disperse the free form (I) compound in an aqueous solvent or a suitable organic solvent, and add a solution of an inorganic acid or an organic acid, either liquid or solid, to the above system; or add the free form (I) compound to an acid solution. 2) Collect the solid products precipitated during the above salt-forming reaction, or obtain crystalline products by creating supersaturation in the salt-forming system; The inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; the organic acid is selected from acetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-chlorobenzenesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, ethane-1,2-disulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzoic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, and tartaric acid. Dodecyl sulfuric acid, benzoyl tartaric acid, formic acid, fumaric acid, galactobionic acid, gentian acid, acetyloxyoxime acid, malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, lauric acid, maleic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthyl acid, propionic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, salicylic acid, 4-aminosalicylic acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthyl carboxylic acid, stearic acid, thiocyanate, undecenoic acid, or succinic acid.

[0039] As a preferred embodiment, the organic acid is selected from methanesulfonic acid, citric acid, malic acid, fumaric acid, or tartaric acid.

[0040] As a further preferred option, the method for creating supersaturation in the salt system in step 2) of the preparation method includes one or more of the following: adding seed crystals, evaporating solvent, adding antisolvent, or obtaining the acid salt of crystalline compound (I) by cooling.

[0041] As a further preferred embodiment, the suitable organic solvent used in step 1) of the preparation method for salt formation is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxides, or mixtures thereof, or aqueous solutions thereof.

[0042] As a further preferred embodiment, the suitable organic solvent used in step 1) of the preparation method for salt formation is selected from methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or mixtures thereof, or aqueous solutions thereof.

[0043] A third aspect of the present invention provides a method for preparing the acid salt of the aforementioned crystalline form (I) compound, comprising the following steps: converting one crystal form of the acid salt of the (I) compound into another crystal form of the salt by a crystal form conversion method, wherein the crystal form conversion method includes: heating or a suspension in a suitable solvent for crystal conversion.

[0044] As a further preferred embodiment, the suitable solvent is selected from methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or mixtures thereof, or aqueous solutions thereof.

[0045] A fourth aspect of the present invention provides a pharmaceutical composition comprising the aforementioned crystalline form (I) compound acid salt and a pharmaceutically acceptable carrier.

[0046] The fifth aspect of the present invention provides the use of the acid salt of the aforementioned crystalline form (I) compound in the preparation of a medicament for treating cancers, tumors, autoimmune diseases, metabolic diseases or metastatic diseases associated with CSF-1R.

[0047] The sixth aspect of the present invention provides an acid salt of the aforementioned crystalline form (I) compound, which is used as a medicament for treating cancers, tumors, autoimmune diseases, metabolic diseases or metastatic diseases associated with CSF-1R.

[0048] The seventh aspect of the present invention provides an acid salt of the aforementioned crystalline compound (I), which is used as a medicament for treating ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumors, solid tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, proliferative disorders, metabolic disorders, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative disorders, leukemia, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mastocytosis, or mast cell leukemia associated with CSF-1R.

[0049] As a preferred option, the aforementioned crystalline form (I) compound acid salt is used as a drug for treating CSF-1R-related ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastatic or bone metastatic cancers at primary tumor sites.

[0050] The eighth aspect of the present invention provides a treatment for cancer, tumor, autoimmune disease, metabolic disease or metastatic disease associated with CSF-1R, comprising administering the acid salt of the aforementioned crystalline formula (I) compound to a patient in need. Attached Figure Description

[0051] Figure 1 The X-ray powder diffraction pattern of the hydrochloride salt of formula (I) of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0052] Figure 2 The X-ray powder diffraction pattern of the hydrochloride crystal form II of the compound of formula (I) of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0053] Figure 3 The X-ray powder diffraction pattern of the hydrochloride crystal form III of the compound of formula (I) of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0054] Figure 4 The X-ray powder diffraction pattern of sulfate form I of the compound of formula (I) of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0055] Figure 5 The X-ray powder diffraction pattern of phosphate crystal form I of compound (I) of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0056] Figure 6 The X-ray powder diffraction pattern of phosphate crystal form II of compound (I) of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0057] Figure 7 The X-ray powder diffraction pattern of phosphate crystal form III of the compound of formula (I) of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0058] Figure 8 The X-ray powder diffraction pattern of methanesulfonate I, a compound of formula (I) of the present invention, is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0059] Figure 9 The X-ray powder diffraction pattern of methanesulfonate form II of the compound of formula (I) of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0060] Figure 10 The X-ray powder diffraction pattern of citrate crystal form I of compound (I) of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0061] Figure 11 The X-ray powder diffraction pattern of the malate salt of formula (I) of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0062] Figure 12 The X-ray powder diffraction pattern of tartrate salt I, a compound of formula (I) of the present invention, is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0063] Figure 13 The X-ray powder diffraction pattern of fumarate crystal form I of compound (I) of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0064] Figure 14 The DSC / TGA plot of crystal form I of the hydrochloride of compound (I) of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flow (w / g) / weight (%).

[0065] Figure 15 The diagram shows the DVS plot of crystal form I of the hydrochloride of compound (I) of the present invention. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%).

[0066] Figure 16The DSC / TGA plot of phosphate crystal form I of the compound of formula (I) of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flow (w / g) / weight (%).

[0067] Figure 17 The diagram shows the DVS plot of phosphate crystal form I of the compound of formula (I) of the present invention. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%).

[0068] Figure 18 The DSC / TGA plot of the methanesulfonate form II of the compound of formula (I) of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flow (w / g) / weight (%).

[0069] Figure 19 The DVS diagram of the methanesulfonate crystal form II of the compound of formula (I) of the present invention is shown. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%).

[0070] Figure 20 The DSC / TGA plot of tartrate salt I, a compound of formula (I) of the present invention, is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (w / g) / weight (%).

[0071] Figure 21 The diagram shows the DVS plot of tartrate salt I, a compound of formula (I) of the present invention. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%).

[0072] Figure 22 The diagram shows a single-crystal simulation of the hydrochloride of formula (I) of the present invention and an X-ray powder diffraction superimposed diagram of hydrochloride crystal form I, with the powder diffraction peak pattern (top) and the single-crystal simulation diagram (bottom). The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0073] Figure 23 The single-crystal unit cell structure of the hydrochloride salt of formula (I) of the present invention is shown. Detailed Implementation

[0074] The inventors of this invention studied different aggregation forms of compound (I), 3,3-dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxopyrrolidine-1-carboxamide, and provided a crystalline CSF-1R inhibitor acid salt. This significantly improves the physicochemical properties of compound (I), such as solubility, hygroscopicity, and chemical stability, enabling the crystalline acid salt to meet the needs of clinical drug formulation development. It has significant clinical application value and can be widely used in the preparation of drugs for treating cancer, tumors, autoimmune diseases, metabolic diseases, or metastatic diseases, particularly for treating ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, and metastatic or bone metastatic cancers at primary tumor sites. It is expected to accelerate the development of a new generation of CSF-1R inhibitor drugs. Based on this, this invention was completed.

[0075] Detailed explanation: Unless otherwise stated, the terms used in the specification and claims shall have the following meanings.

[0076] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0077] Compounds of formula (I) exhibit a variety of polymorphic or monocrystalline forms in their separate acid salts. For example, each of the hydrochloride, phosphate, and methanesulfonate salts is polymorphic; each of the sulfate, citrate, malate, fumarate, and tartrate salts is monomorphic. These "polymorphs" differ in terms of their X-ray powder diffraction patterns, physicochemical and pharmacokinetic properties, and thermodynamic stability.

[0078] The term "salt" as used in this article refers to compounds prepared by reacting organic acid or base drugs with pharmaceutically acceptable inorganic or organic acids or bases.

[0079] Methods and Materials Characterization of the acid salt of the compound in crystalline form (I) by X-ray powder diffraction. Thus, on a Rigaku Ultima IV powder diffractometer operating in the reflection mode using Cu Kα radiation, the X-ray powder diffraction pattern of the salt was collected. The instrument uses Cu Kα irradiation (40 kV, 40 mA) and is carried out at room temperature using a D / tex Ultra detector. The scanning range is in the 2θ interval from 3° to 45°, and the scanning speed is 20° / min. The diffraction pattern was analyzed using Jade 5 software of Materials Data, Inc. with version 5.0.37 released in 2017.

[0080] Preparation of the XRPD sample is by placing the sample on a single-crystal silicon wafer and pressing the sample powder with a glass slide or equivalent to ensure a flat surface and appropriate height of the sample. Then the sample holder is placed in the Rigaku Ultima IV XRPD instrument, and the X-ray powder diffraction pattern is collected using the instrument parameters described above. Measurement differences related to the results of such X-ray powder diffraction analysis are caused by various factors including: (a) errors in the sample preparation (such as sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including those occurring in determining the peak positions), and (e) properties of the substance (such as preferred orientation errors). Calibration errors and sample height errors often result in the displacement of all peaks in the same direction. Generally, this calibration factor will make the measured peak positions consistent with the expected peak positions and can be in the range of the expected 2θ value ±0.2 °. The angle 2θ values (°) and intensity values (as a percentage of the highest peak value) of each polymorph obtained in the embodiments of the present invention are listed in Tables 1 to 13.

[0081] The experimental method for characterizing the acid salt of the compound in crystalline form (I) by differential scanning calorimetry (DSC) is to take a small amount of the acid salt powder of the compound in crystalline form (I), place it in an aluminum pan that is compatible with the instrument and can be crimped, crimp the aluminum pan after loading the sample, and then send it into the instrument for detection. The instrument model used for all differential scanning calorimetry in this patent is TA Q2000, and the scanning parameters are set to use a nitrogen atmosphere and a heating rate of 10 °C / min.

[0082] The experimental method for characterizing the acid salt of the compound in crystalline form (I) by thermogravimetric analysis (TGA) is to take a small amount of the acid salt powder of the compound in crystalline form (I), place it in an aluminum pan compatible with the instrument, and send it into the instrument for detection after loading the sample. The instrument model used for all thermogravimetric analysis in this patent is TA Q500, and the scanning parameters are set to use a nitrogen atmosphere and a heating rate of 10 °C / min.

[0083] The experimental method for characterizing the acid salt of the compound in crystal form (I) by dynamic vapor sorption (DVS) is as follows: Take a small amount of the acid salt powder of the compound in crystal form (I) and place it in a precision sample pan compatible with the instrument. After loading the sample, send it into the instrument for detection. In this patent, the instrument model used for all dynamic vapor sorption methods is DVS Intrinsic. The experimental parameters are set as follows: nitrogen is used as the carrier gas, the constant temperature is set at 25 °C, and the mass percentage change rate per unit time (dm / dt) = 0.01% / min is used as the criterion for reaching equilibrium. The program humidity change cycle is set as follows: the initial relative humidity is 0%, the relative humidity at the end point is 90%, and the cycle is set 2 times, with a 10% R.H. change as one step.

[0084] The reagents in the embodiments of the present invention are known and commercially available, or can be synthesized by methods known in the art or according to the methods known in the art. The API raw materials are prepared according to Patent WO2018214867A1.

[0085] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the temperature unit is degrees Celsius (°C).

[0086] Unless otherwise specified, the various crystal forms referred to in the present invention can be anhydrous crystal forms or hydrated crystal forms. If it is a hydrated crystal form, it is preferred that each molecular crystal contains 1, 2, 3, 4 or 5 molecules of crystal water, and more preferably each molecular crystal contains 1 or 2 molecules of crystal water.

[0087] The present invention will be further described in detail and completely through the attached drawings and the following embodiments. These are only used to illustrate specific embodiments of the present invention and should not be construed as limiting the scope of the present invention in any way.

[0088] Preparation of Specific Embodiments Example 1 Preparation of Hydrochloride Crystal Form I Dissolve about 10 mg of the compound of formula (I) in 0.5 mL of methyl tert-butyl ether, add 0.1 mL of methyl tert-butyl ether containing 2.35 μL of concentrated hydrochloric acid, stir at room temperature for 3 days, filter, and dry the filter cake in an oven at 50 °C for XRPD analysis. Its X-ray powder diffraction pattern is as Figure 1 shown.

[0089] Example 2 Preparation of Hydrochloride Crystal Form II Dissolve about 10 mg of the compound of formula (I) in 0.5 mL of ethyl acetate, add 0.1 mL of ethyl acetate containing 2.35 μL of concentrated hydrochloric acid, stir at room temperature for 3 days, filter, and dry the filter cake in an oven at 50 °C for XRPD analysis. Its X-ray powder diffraction pattern is as Figure 2 shown.

[0090] Example 3 Preparation of hydrochloride crystal form III Approximately 10 mg of compound (I) was dissolved in 0.5 mL of acetone, and 0.1 mL of acetone containing 2.35 μL of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50°C. XRPD analysis was performed, and its X-ray powder diffraction pattern is shown below. Figure 3 As shown.

[0091] Example 4 Preparation of hydrochloride crystal form I Approximately 50 mg of compound (I) was dissolved in 1.2 mL of methyl tert-butyl ether, and then 1.2 mL of methyl tert-butyl ether containing 11.7 μL of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for 7 days, filtered, and the filter cake was dried in an oven at 50°C. XRPD, DSC, TGA, and DVS analyses were performed. Its X-ray powder diffraction pattern is consistent with... Figure 1 Consistent with the above, its DSC, TGA, and DVS analyses are as follows: Figure 14-15 As shown.

[0092] Example 5 Preparation of Sulfate Crystal Form I Approximately 10 mg of compound (I) was dissolved in 0.5 mL of methyl tert-butyl ether, and 0.1 mL of methyl tert-butyl ether containing 4.67 μL of concentrated sulfuric acid was added. The mixture was stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50°C. XRPD analysis was performed, and its X-ray powder diffraction pattern is shown below. Figure 4 As shown.

[0093] Example 6 Preparation of Phosphate Crystal Form I Approximately 10 mg of compound (I) was dissolved in 0.5 mL of methanol, and 0.1 mL of methanol containing 2.74 μL of concentrated phosphoric acid was added. The mixture was stirred and allowed to stand at -20°C for 3 days. After filtration, the filter cake was dried in an oven at 50°C and subjected to XRPD analysis. The X-ray powder diffraction pattern is shown below. Figure 5 As shown.

[0094] Example 7 Preparation of Phosphate Crystal Form II Approximately 10 mg of compound (I) was dissolved in 0.5 mL of ethyl acetate, and 0.1 mL of ethyl acetate containing 2.74 μL of concentrated phosphoric acid was added. The mixture was stirred and allowed to stand at -20°C for 3 days. After filtration, the filter cake was dried in an oven at 50°C and subjected to XRPD analysis. The X-ray powder diffraction pattern is shown below. Figure 6 As shown.

[0095] Example 8 Preparation of Phosphate Crystal Form III Approximately 10 mg of compound (I) was dissolved in 0.5 mL of 96% ethanol, and 0.1 mL of 96% ethanol containing 2.74 μL of concentrated phosphoric acid was added. The mixture was stirred and allowed to stand at -20°C for 3 days. After filtration, the filter cake was dried in an oven at 50°C and subjected to XRPD analysis. The X-ray powder diffraction pattern is shown below. Figure 7 As shown.

[0096] Example 9 Preparation of Phosphate Crystal Form I Approximately 50 mg of compound (I) was dissolved in 1.2 mL of methanol, and then 1.2 mL of methanol containing 13.7 μL of concentrated phosphoric acid was added. The mixture was stirred and allowed to stand at -20°C for 7 days. After filtration, the filter cake was dried in an oven at 50°C and analyzed by XRPD, DSC, TGA, and DVS. The X-ray powder diffraction pattern is shown below. Figure 5 As shown, its DSC, TGA, and DVS analyses are as follows: Figure 16-17 As shown.

[0097] Example 10 Preparation of Methanesulfonate Crystal Form I Approximately 10 mg of compound (I) was dissolved in 0.5 mL of tetrahydrofuran, and 0.1 mL of tetrahydrofuran containing 2.29 μL of methanesulfonic acid was added. The mixture was stirred and allowed to stand at -20°C for 3 days. After filtration, the filter cake was dried in an oven at 50°C and subjected to XRPD analysis. The X-ray powder diffraction pattern is shown below. Figure 8 As shown.

[0098] Example 11 Preparation of Methanesulfonate Crystal Form II Approximately 10 mg of compound (I) was dissolved in 0.5 mL of acetone, and 0.1 mL of acetone containing 2.29 μL of methanesulfonic acid was added. The mixture was stirred and allowed to stand at -20°C for 3 days. After filtration, the filter cake was dried in an oven at 50°C and subjected to XRPD analysis. The X-ray powder diffraction pattern is shown below. Figure 9 As shown.

[0099] Example 12 Preparation of Methanesulfonate Crystal Form II Approximately 50 mg of compound (I) was dissolved in 1.2 mL of acetone; 1.2 mL of acetone containing 11.4 μL of methanesulfonic acid was added, the mixture was stirred, and allowed to stand at -5°C for 3 days. The mixture was then filtered, and the filter cake was dried in an oven at 50°C. XRPD, DSC, TGA, and DVS analyses were performed. The X-ray powder diffraction pattern is shown below. Figure 9 As shown, its DSC, TGA, and DVS analyses are as follows: Figure 18-19 As shown.

[0100] Example 13 Preparation of citrate crystal form I Approximately 10 mg of compound (I) was dissolved in 0.5 mL of acetonitrile, and 4.57 mg of citric acid was added. The mixture was stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50°C. XRPD analysis was performed, and its X-ray powder diffraction pattern is shown below. Figure 10 As shown.

[0101] Example 14 Preparation of Malate Crystal Form I Approximately 10 mg of compound (I) was dissolved in 0.5 mL of ethyl acetate, and 2.76 mg of malic acid was added. The mixture was stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50°C. XRPD analysis was performed, and its X-ray powder diffraction pattern is shown below. Figure 11 As shown.

[0102] Example 15 Preparation of tartrate crystal form I Approximately 10 mg of compound (I) was dissolved in 0.5 mL of acetonitrile, 3.57 mg of tartaric acid was added, the mixture was stirred, the solvent was evaporated, and the solid was dried in an oven at 50 °C. XRPD analysis was performed, and its X-ray powder diffraction pattern is shown below. Figure 12 As shown.

[0103] Example 16 Preparation of tartrate crystal form I Approximately 50 mg of compound (I) was dissolved in 1.2 mL of acetonitrile. 17.87 mg of tartaric acid, 1 mL of acetonitrile, and 0.2 mL of purified water were added. The mixture was stirred until no precipitate formed. After standing at 5°C for one week, no precipitate formed. 1 mL of methyl tert-butyl ether was added, and the mixture was stirred and stood at -20°C for one week. The mixture was then filtered, and the filter cake was dried in an oven at 50°C. XRPD, DSC, TGA, and DVS analyses were performed. The X-ray powder diffraction pattern is shown below. Figure 12 As shown, its DSC, TGA, and DVS analyses are as follows: Figure 20-21 As shown.

[0104] Example 17 Preparation of fumarate crystal form I Approximately 10 mg of compound (I) was dissolved in 0.5 mL of methyl tert-butyl ether, and 2.76 mg of fumaric acid was added. The mixture was stirred and allowed to stand at -20°C for 3 days. After filtration, the filter cake was dried in an oven at 50°C, and XRPD analysis was performed to determine its X-ray powder diffraction pattern, as shown below. Figure 13 As shown.

[0105] Example 18: Structure analysis of hydrochloride crystal form I Weigh 40 mg of compound (I) into a 20 mL vial, add 3 mL of acetone to dissolve it, and then add 40 μL of concentrated hydrochloric acid (12 M) to obtain a suspension. Filter the suspension using a 0.22 μm FPTE needle filter to obtain a clear solution. Take 0.2 mL of the filtrate and place it into a 2 mL vial. Seal the vial with a sealing film, make small holes in the sealing film, and allow it to slowly evaporate at room temperature to obtain small, plate-like single crystals as seed crystals.

[0106] Weigh 40 mg of compound (I) into a 20 mL vial, add 3 mL of acetone to dissolve it, and then add 40 μL of concentrated hydrochloric acid (12 M) to obtain a suspension. Filter the suspension using a 0.22 μm FPTE needle filter to obtain a clear solution. Take 0.4 mL of the filtrate and place it into a 2 mL vial, add 0.3 mL of acetone, add a small amount of the prepared plate-like seed crystals, seal the vial with sealing film, make small holes in the sealing film, and allow it to slowly evaporate at room temperature to obtain small plate-like single crystals.

[0107] Suitable single crystals were selected and analyzed using a Bruker APEX-II CCD single crystal diffractometer. The temperature was maintained at 220 K during data collection. Using Mercury 3.10.2 (Build 189770) software, the single crystal diffraction pattern was calculated to simulate a powder crystal diffraction pattern and compared with the powder crystal diffraction pattern of compound (I) hydrochloride crystal form I. (See attached image). Figure 22 By comparison, it can be seen that hydrochloride crystal form I and single crystal simulation Figure 1 The absence of any extra peaks indicates that the hydrochloride crystal form I of compound (I) in this patent is a pure phase. It also confirms that the hydrochloride crystal form I of compound (I) is a monohydrate hydrochloride. The single-crystal unit cell structure is as follows: Figure 23 As shown. Example 19 Solubility Determination Approximately 2 mg of each crystalline acid salt and free (I) compound were accurately weighed into 2 mL glass vials. Approximately 100 μL of deionized water was added each time, followed by sonication. If the compound did not dissolve, more deionized water was added, and the mixture was sonicated until the compound was completely dissolved or its concentration was <0.2 mg / mL. The total volume of water added was recorded, and the dissolution behavior and phenomena were observed. The solubility of each compound was calculated. The solubility test results are shown in the table below: The experimental results above show that after the free (I) compound is converted into a crystalline compound, the solubility of all salt forms in water is greatly improved, which meets the needs of clinical drug formulation development. Therefore, the conversion of the free (I) compound into a crystalline compound can significantly improve both solubility and drug release behavior.

[0108] Example 20: Moisture Absorption Behavior Test The inventors of this patent used a dynamic moisture adsorption method to determine the moisture absorption weight gain (moisture absorption weight gain / weight before moisture absorption * 100%) of various crystal forms under different relative humidities, and evaluated the hygroscopicity of different crystalline compounds. The results are shown in the table below: The experimental results above show that when the relative humidity is less than 80%, the weight gain of the crystals in hydrochloride crystal form I is less than 1%. Only when the relative humidity rises to 80% does the hygroscopicity of the crystals begin to increase slowly, and only when the relative humidity rises to 90% will the hygroscopicity of the crystals increase significantly. This hygroscopic characteristic of hydrochloride crystal form I is very much in line with the storage requirements of clinical preparations, and it is also in line with the requirement that it can absorb a large amount of moisture in a high humidity environment, thereby accelerating the dissolution of the crystals, which is beneficial to the granulation process of clinical preparations.

[0109] Methionate crystal form II also exhibits similar hygroscopic properties to hydrochloride crystal form I, the only difference being that the hygroscopicity of methionate crystal form II increases significantly when the relative humidity rises to 70%. This hygroscopic property is also highly compatible with the requirements of clinical formulation granulation processes.

[0110] The hygroscopic properties of tartrate crystal form I are such that as the relative humidity increases, the weight gain of the crystal increases by approximately the same amount, showing a good linear relationship. Based on this hygroscopic property, it is beneficial for the inventors to develop special formulations in subsequent research.

[0111] Phosphate crystal form I also has a unique hygroscopic property. Regardless of the relative humidity of the environment, this crystal form always maintains a low hygroscopicity. This property can be used for storage, transportation and production in different regions, and it is also convenient to make special preparations.

[0112] As is well known, the hygroscopicity of drugs is an important physicochemical property affecting drug production, storage, and content. Different drug formulations can be developed based on different hygroscopic properties to meet diverse clinical development needs. Low hygroscopicity physical forms make drugs more stable in production, storage, and content. Therefore, the aforementioned crystalline compounds all possess good hygroscopic properties, especially hydrochloride crystal form I and phosphate crystal form I, which have greater advantages in development potential compared to other crystalline salts.

[0113] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope of this invention.

Claims

1. An acid salt of a compound of crystalline form (I): 。 2. The crystalline form (I) acid salt of the compound according to claim 1, characterized in that, The acid salts include inorganic acid salts or organic acid salts; the inorganic acid salts are selected from hydrochlorides, sulfates, hydrobroms, hydrofluorides, hydroiodates, or phosphates; the organic acid salts are selected from acetates, dichloroacetates, trichloroacetates, trifluoroacetates, benzenesulfonates, p-toluenesulfonates, 4-chlorobenzenesulfonates, 1,5-naphthalenedisulfonates, naphthalene-2-sulfonates, ethane-1,2-disulfonates, methanesulfonates, ethanesulfonates, benzoates, decanoates, hexanoates, caprylates, cinnamates, citrates, cyclohexanesulfonates, camphorsulfonates, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbate, lactate, malate, mandelate, and pyroglutamate. Tartrate, dodecyl sulfate, benzoyl tartrate, formate, fumarate, galacturonate, gentianate, acetyloxyoxime, malonate, succinate, glutarate, adipate, sebate, 2-ketoglutarate, glycolate, hippurate, hydroxyethyl sulfonate, lactobionate, ascorbate, aspartate, laurate, maleate, nicotinate, oleate, orotate, oxalate, palmitate, dihydroxynaphthyl salt, propionate, 4-acetaminobenzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthyl carboxate, stearate, thiocyanate, undecenoate, or succinate.

3. The crystalline form (I) acid salt of the compound according to claim 2, characterized in that, The acid salt of the crystalline form (I) compound is a hydrochloride salt, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 9.52±0.2°, 19.72±0.2°, 10.64±0.2°, 14.32±0.2°, 16.56±0.2°, 18.52±0.2°, and 27.20±0.2°, or includes four or more peaks located at 24.32±0.2°, 17.78±0.2°, 24.58±0.2°, 19.96±0.2°, 10.18±0.2°, and 21.34°. The peaks are at diffraction angles (2θ) of ±0.2°, 18.06±0.2°, 28.10±0.2°, and 18.42±0.2°, or include four or more peaks at diffraction angles (2θ) of 18.74±0.2°, 22.94±0.2°, 17.64±0.2°, 9.38±0.2°, 9.10±0.2°, 9.94±0.2°, 29.70±0.2°, and 11.24±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline hydrochloride is substantially the same as the peaks at diffraction angles (2θ) shown in Figures 1, 2, or 3.

4. The crystalline form (I) acid salt of the compound according to claim 2, characterized in that, The acid salt of the crystalline form (I) compound is a sulfate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 20.08±0.2°, 23.22±0.2°, 21.38±0.2°, 24.86±0.2°, 18.78±0.2°, 20.46±0.2° and 9.38±0.2°; preferably, the X-ray powder diffraction pattern of its crystalline sulfate is substantially the same as the peaks at diffraction angles (2θ) shown in Figure 4.

5. The crystalline form (I) acid salt of the compound according to claim 2, characterized in that, The acid salt of the crystalline form (I) compound is a phosphate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 8.44±0.2°, 16.82±0.2°, 10.78±0.2°, 18.10±0.2°, 24.78±0.2°, 19.62±0.2°, and 23.24±0.2°, or includes four or more peaks located at 10.86±0.2°, 8.48±0.2°, 17.02±0.2°, 10.46±0.2°, 18.38±0.2°, 7 The peaks at diffraction angles (2θ) of 0.98±0.2°, 23.82±0.2°, and 16.06±0.2°, or, including four or more peaks at diffraction angles (2θ) of 10.84±0.2°, 8.54±0.2°, 17.14±0.2°, 16.76±0.2°, 10.36±0.2°, 18.26±0.2°, 27.88±0.2°, and 22.34±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline phosphate is substantially the same as the peaks at diffraction angles (2θ) shown in Figures 5, 6, or 7.

6. The crystalline form (I) acid salt of the compound according to claim 2, characterized in that, The acid salt of the crystalline form (I) compound is a methanesulfonate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks located at diffraction angles (2θ) of 16.28±0.2°, 20.82±0.2°, 7.78±0.2°, 26.68±0.2°, 23.36±0.2°, 26.30±0.2°, and 23.62±0.2°, or includes four or more peaks. Peaks located at diffraction angles (2θ) of 8.64±0.2°, 21.02±0.2°, 16.34±0.2°, 23.34±0.2°, 18.48±0.2°, 7.84±0.2°, 26.00±0.2°, and 10.82±0.2°; preferably, the X-ray powder diffraction pattern of its crystalline methanesulfonate is substantially the same as the peaks at diffraction angles (2θ) shown in Figure 8 or Figure 9.

7. The crystalline form (I) acid salt of the compound according to claim 2, characterized in that, The acid salt of the crystalline form (I) compound is a citrate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks at diffraction angles (2θ) of 16.14±0.2°, 7.12±0.2°, 14.86±0.2°, 16.64±0.2°, 21.34±0.2°, and 13.70±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline citrate is substantially the same as the peaks at diffraction angles (2θ) shown in Figure 10.

8. The crystalline form (I) acid salt of the compound according to claim 2, characterized in that, The acid salt of the crystalline form (I) compound is a malate, and its X-ray powder diffraction (XRPD) pattern includes four or more peaks at diffraction angles (2θ) of 8.44±0.2°, 27.82±0.2°, 14.22±0.2°, 9.72±0.2°, 15.44±0.2°, 18.96±0.2°, and 19.28±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline malate is substantially the same as the peaks at diffraction angles (2θ) shown in Figure 11.

9. The crystalline form (I) acid salt of the compound according to claim 2, characterized in that, The acid salt of the crystalline form (I) compound is a tartrate salt, whose X-ray powder diffraction (XRPD) pattern includes four or more peaks at diffraction angles (2θ) of 9.16±0.2°, 16.64±0.2°, 19.80±0.2°, 26.84±0.2°, 18.96±0.2°, 24.06±0.2°, and 12.16±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline tartrate salt is substantially the same as the peaks at diffraction angles (2θ) shown in Figure 12.

10. The crystalline form (I) acid salt of the compound according to claim 2, characterized in that, The acid salt of the crystalline form (I) compound is a fumarate, whose X-ray powder diffraction (XRPD) pattern includes four or more peaks at diffraction angles (2θ) of 16.82±0.2°, 18.28±0.2°, 11.62±0.2°, 15.10±0.2°, 8.44±0.2°, 21.54±0.2°, and 27.58±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline fumarate is substantially the same as the peaks at diffraction angles (2θ) shown in Figure 13.

11. A method for preparing the acid salt of the crystalline form (I) compound according to any one of claims 1-10, characterized in that, Includes the following steps: 1) Dissolve or disperse the free form (I) compound in an aqueous solvent or a suitable organic solvent, and add a solution of an inorganic acid or an organic acid in liquid or solid form to the above system; or add the free form (I) compound to an acid solution. 2) Collect the solid products precipitated during the above salt-forming reaction, or obtain crystalline products by creating supersaturation in the salt-forming system; The inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; The organic acid is selected from acetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-chlorobenzenesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, ethane-1,2-disulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzoic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, formic acid. Fumaric acid, galactobionic acid, gentianic acid, acetyloxyoxime acid, malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethylsulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, maleic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthyl acid, propionic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, salicylic acid, 4-aminosalicylic acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthyl carboxylic acid, stearic acid, thiocyanate, undecenoic acid, or succinic acid.

12. The preparation method according to claim 11, characterized in that, The method for creating supersaturation in the salt system in step 2) includes one or more of the following: adding seed crystals, evaporating solvent, adding antisolvent, or cooling.

13. The preparation method according to claim 11, characterized in that, The suitable organic solvent is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxides, or mixtures thereof, or aqueous solutions thereof; preferably, the suitable organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or mixtures thereof, or aqueous solutions thereof.

14. A method for preparing the acid salt of the crystalline form (I) compound according to any one of claims 1-10, characterized in that, The method includes the following steps: converting one crystal form of the acid salt of compound (I) into another crystal form of the salt by a crystal form conversion method, the crystal form conversion method including: heating or suspension in a suitable solvent, the suitable solvent being selected from methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether or mixtures thereof, or aqueous solutions thereof.

15. A pharmaceutical composition comprising an acid salt of the crystalline form (I) compound according to any one of claims 1-10 and a pharmaceutically acceptable carrier.

16. Use of the acid salt of the crystalline (I) compound according to any one of claims 1-10 in the preparation of a medicament for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease associated with CSF-1R.

17. The crystalline (I) compound acid salt according to any one of claims 1-10, used as a medicament for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease associated with CSF-1R.

18. The crystalline (I) compound acid salt according to any one of claims 1-10, used as a medicament for treating ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumors, solid tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, proliferative disorders, metabolic disorders, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative disorders, leukemia, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mastocytosis, or mast cell leukemia associated with CSF-1R.

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