Crystalline CSF-and 1r inhibiting acid salt, preparation method and use thereof

Abstract

Provided are a crystalline CSF-1R inhibitor acid salt and a preparation method and use thereof.SOLUTION: The CSF-1R inhibitor has a compound represented by the structure of formula (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 the crystalline acid salt compound can greatly improve the physicochemical properties such as solubility, hygroscopicity and chemical stability of the compound represented by formula (I) in a free state, which is suitable for the requirements of industrial production and can meet the development needs of clinical drug formulations. The crystalline acid salt compound of the present invention can be widely used for preparing a medicament for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease.SELECTED DRAWING: None

Description

Detailed Description of the Invention

[0001] Technical Field The present invention belongs to the field of drug development, and specifically relates to a crystalline acid salt of a CSF-1R inhibitor and its preparation method and use.

[0002] Background technology The full name of CSF-1R (cFMS) is colony-stimulating factor-1 receptor. CSF-1R, along with cKIT, FLT3, and PDGFR-a & b, belongs to the type III growth hormone receptor family. This receptor is a membrane protein expressed on the surface of macrophages and monocytes. Its extracellular portion binds macrophage colony-stimulating factor, while its intracellular portion tyrosine kinases activate downstream proliferation signaling pathways in macrophages and monocytes, including MAPK and PI3K. Therefore, the CSF-1R signaling pathway has an important impact on the development and differentiation of macrophages and monocytes, as well as the physiological function of tumor-associated macrophages (TAMs).

[0003] With recent advances in tumor immunotherapy, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are believed to be directly related to the formation of an immunosuppressive microenvironment within tumors and the angiogenesis that supports tumor growth. Clinical studies have also shown that the content of TAMs is negatively correlated with the prognosis of tumor patients. In vivo efficacy studies in mice have demonstrated that inhibition of the CSF-1R signaling pathway significantly reduces the number of immune-suppressive macrophages within tumors and increases the content of CD8+ T cells. These experimental results suggest that CSF-1R small molecule inhibitors may reverse the immunosuppressive environment within tumors, promote immune activation, and potentially prolong the lives of tumor patients.

[0004] Through a long-term research process, Abbisko Therapeutics Co., Ltd. has invented small molecule compounds with novel structures that have CSF-1R inhibitory effects (WO2018214867A1, International Publication Date: November 29, 2018), and representative compounds are as follows:

[0005] [ka]

[0006] Its Japanese 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 (the compound represented by formula (I)), and this compound has significantly improved inhibitory activity against the CSF-1R target and selectivity over other kinase receptors, improved the therapeutic window, and reduced clinical toxic side effects, thereby meeting the current domestic and international needs for targeted treatment of tumors such as lung cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, melanoma, pancreatic cancer, head and neck cancer, glioma, and giant cell tumor of tendon sheath.

[0007] However, at the time of filing of patent WO2018214867A1, no further research had been conducted to develop a raw material form suitable for industrial production, nor had any process methods suitable for industrial use been developed. Furthermore, the aggregation state of the compound represented by formula (I) had not been extensively studied to improve the physicochemical properties of the compound and meet the needs for pharmaceutical or clinical use. WO2018214867A1 discloses an amorphous free or foamy solid compound. For a specific preparation method, see Example 1 thereof. Specifically, a solution of 3,3-dimethyl-2-oxopyrrolidine-1-carbonyl chloride (0.33 mmol) in 10 mL of dichloromethane was added dropwise to a solution of 6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (93 mg, 0.33 mmol) and pyridine (78 mg, 0.99 mmol) in 10 mL of dichloromethane under ice bath conditions. The mixture was stirred at 5°C for 30 minutes and then at room temperature for 2 hours. The mixture was partitioned between dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and separated by 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 this foamy compound as an amorphous compound, which is prone to hygroscopicity and softening, making it difficult to store and unsuitable for clinical formulation development. Therefore, to meet the needs of clinical research and commercial drug formulations, it is highly desirable to develop an aggregated form suitable for drug development and overcome the shortcomings of the prior art.

[0008] Summary of the Invention To solve the problems in the prior art, the present inventors have intensively investigated different aggregation forms of the compound represented by formula (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 several crystalline acid salts, particularly the hydrochloride salt, which significantly improved the physicochemical properties of the compound represented by formula (I), such as solubility, hygroscopicity, and chemical stability. The raw materials for these crystalline acid salt compounds meet the requirements for industrial production and the development needs of clinical drug formulations. These crystalline acid salt compounds have significant clinical value and are expected to accelerate the development of a new generation of CSF-1R small molecule inhibitors.

[0009] In a first aspect of the present invention, there is provided an acid salt of a compound represented by crystalline formula (I):

[0010] [ka]

[0011] In a preferred embodiment, the acid salt of the compound represented by the crystalline formula (I) is an inorganic acid salt or an organic acid salt. In a more preferred embodiment, the acid salt of the compound represented by the crystalline formula (I) is an inorganic acid salt, and the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide, and phosphate.

[0012] In a more preferred embodiment, the acid salt of the compound represented by the crystalline formula (I) is an organic acid salt, and the organic acid salt is acetate, dichloroacetate, trichloroacetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, ethane-1,2-disulfonate, methanesulfonate, ethanesulfonate, benzoate, caprate, caproate, caprylate, cinnamate, citrate, cyclohexanesulfamate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, erythorbate, lactate, malate, mandelate, pyroglutamate, alcohol, or the like. The salt is selected from tartrate, dodecyl sulfate, dibenzoyl tartrate, formate, fumarate, galactate, gentisate, acetohydroxamate, malonate, succinate, glutarate, adipate, sebacate, 2-ketoglutarate, glycolate, hippurate, isethionate, lactobionate, ascorbate, aspartate, laurate, maleate, nicotinate, oleate, orotate, oxalate, palmitate, pamoate, propionate, 4-acetamidobenzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, stearate, thiocyanate, undecylenate, and succinate.

[0013] In a more preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is an organic acid salt, and the organic acid salt is selected from methanesulfonate, citrate, malate, fumarate, and tartrate.

[0014] In a more preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a hydrochloride salt, and its X-ray powder diffraction pattern (XRPD) contains 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°.

[0015] In the most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a hydrochloride salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in FIG. 1, and its X-ray powder diffraction data is shown in Table 1.

[0016] [Table 1]

[0017] The crystalline hydrochloride salt is designated as hydrochloride crystalline form I and has a melting point of 157.8°C. In a more preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a hydrochloride salt, and its X-ray powder diffraction pattern (XRPD) contains 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°.

[0018] In the most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a hydrochloride salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in FIG. 2, and its X-ray powder diffraction data is shown in Table 2.

[0019] [Table 2]

[0020] The crystalline hydrochloride salt is designated as hydrochloride crystalline form II and has a melting point of 120.6°C. In a more preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a hydrochloride salt, and its X-ray powder diffraction pattern (XRPD) contains 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°.

[0021] In the most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a hydrochloride salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in FIG. 3, and its X-ray powder diffraction data is shown in Table 3.

[0022] [Table 3]

[0023] The crystalline hydrochloride salt is designated as hydrochloride crystalline form III and has a melting point of 110.9°C. In a more preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a sulfate salt, and its X-ray powder diffraction pattern (XRPD) contains 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°.

[0024] In the most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a sulfate salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in FIG. 4, and its X-ray powder diffraction data is shown in Table 4.

[0025] [Table 4]

[0026] This crystalline form of the Sulfate Salt is designated as Form I of the Sulfate Salt. In a more preferred embodiment, the acid salt of the compound represented by the crystalline formula (I) is a phosphate salt, and its X-ray powder diffraction pattern (XRPD) is 8.44±0.2°, 16.82±0.2°, 10.78±0.2°, 18.10±0.2°, 24.78±0.2°, 19. It contains four or more peaks located at diffraction angles (2θ) of 62±0.2° and 23.24±0.2°.

[0027] In the most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a phosphate salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in FIG. 5, and its X-ray powder diffraction data is shown in Table 5.

[0028] [Table 5]

[0029] The crystalline form of the phosphate is designated as phosphate form I and has a melting point of 154.2°C. In a more preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a phosphate salt, and its X-ray powder diffraction pattern (XRPD) contains 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°.

[0030] In a most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a phosphate salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in FIG. 6, and its X-ray powder diffraction data is shown in Table 6.

[0031] [Table 6]

[0032] The crystalline form of the phosphate is designated as phosphate form II and has a melting point of 153.8°C. In a more preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a phosphate salt, and its X-ray powder diffraction pattern (XRPD) contains 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°.

[0033] In a most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a phosphate salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in FIG. 7, and its X-ray powder diffraction data is shown in Table 7.

[0034] [Table 7]

[0035] The crystalline form of the phosphate is designated as phosphate form III and has a melting point of 147.3°C. In a more preferred embodiment, the acid salt of the compound represented by the crystalline formula (I) is methanesulfonate. The X-ray powder diffraction pattern (XRPD) of the compound is a benzoate salt, the X-ray powder diffraction pattern of which contains 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°.

[0036] In a most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a methanesulfonate salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in FIG. 8, and its X-ray powder diffraction data is shown in Table 8.

[0037] [Table 8]

[0038] The crystalline methanesulfonate salt is designated as methanesulfonate Form I and has a melting point of 184.4°C. In a more preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a methanesulfonate salt, and its X-ray powder diffraction pattern (XRPD) contains 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°.

[0039] In a most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a methanesulfonate salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in FIG. 9, and its X-ray powder diffraction data is shown in Table 9.

[0040] [Table 9]

[0041] The crystalline methanesulfonate salt is designated as methanesulfonate Form II and has a melting point of 185.5°C. In a more preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a citrate salt, and its X-ray powder diffraction pattern (XRPD) comprises 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°.

[0042] In the most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a citrate salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in Figure 10, and its X-ray powder diffraction data is shown in Table 10.

[0043] [Table 10]

[0044] The crystalline citrate salt is designated as Citrate Form I and has a melting point of 58.1°C. In a more preferred embodiment, the acid salt of the compound represented by the crystalline formula (I) is a malate salt, and its X-ray powder diffraction pattern (XRPD) is four or four 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°. Contains the above peaks.

[0045] In the most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a malate salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in Figure 11, and its X-ray powder diffraction data is shown in Table 11.

[0046] [Table 11]

[0047] The crystalline malate salt is designated as Malate Form I and has a melting point of 82.8°C. In a more preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a tartrate salt, and its X-ray powder diffraction pattern (XRPD) comprises 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°.

[0048] In a most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a tartrate salt, and its X-ray powder diffraction pattern is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in Figure 12, and its X-ray powder diffraction data is shown in Table 12.

[0049] [Table 12]

[0050] The crystalline tartrate salt is designated as tartrate salt form I and has a melting point of 122.4°C. In a more preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a fumarate salt, and its X-ray powder diffraction pattern (XRPD) comprises 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°.

[0051] In a most preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is a fumarate salt, and the X-ray powder diffraction pattern thereof is essentially the same (±0.2°) as the peaks located at the diffraction angles (2θ) shown in FIG. 13, and the X-ray powder diffraction data thereof is shown in Table 13.

[0052] [Table 13]

[0053] This crystalline fumarate salt is designated as Form I fumarate salt. In a second aspect of the present invention, there is provided a method for producing an acid salt of the compound represented by the crystalline formula (I), 1) dissolving or dispersing a compound of formula (I) in a free state in an aqueous solvent or a suitable organic solvent, and adding a solution of a liquid or solid inorganic or organic acid to the system, or adding the compound of formula (I) in a free state to a solution of an acid; 2) collecting the solid product precipitated during the salt-forming reaction or obtaining a crystalline product by creating supersaturation in the salt-forming system; The inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and phosphoric acid, and 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, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, methyl ... Acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, formic acid, fumaric acid, galactic acid, gentisic acid, acetohydroxamic acid, malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, lauric acid, maleic acid, nicotine acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, salicylic acid, 4-aminosalicylic acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, stearic acid, thiocyanic acid, undecylenic acid, or succinic acid.

[0054] In a preferred embodiment, the organic acid is selected from methanesulfonic acid, citric acid, malic acid, fumaric acid, or tartaric acid. In a further preferred embodiment, the method for creating supersaturation in the salt-forming system in step 2) of the production method includes one or more of adding seed crystals, volatilizing a solvent, adding an antisolvent, or cooling to obtain an acid salt of the compound represented by crystalline formula (I).

[0055] In a further preferred embodiment, the suitable organic solvent in the salt formation process in step 1) of the production method is selected from organic solvents such as alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, and sulfoxides, or mixtures thereof, or aqueous solutions thereof.

[0056] In a more preferred embodiment, the suitable organic solvent in the salt formation process in step 1) of the production method 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 a mixture thereof, or an aqueous solution thereof.

[0057] In a third aspect of the present invention, there is provided a process for preparing a crystalline form of an acid salt of a compound of formula (I), comprising converting one crystalline form of said acid salt of a compound of formula (I) into another crystalline form of said salt by a crystal form conversion process comprising heating or suspension crystal form conversion in a suitable solvent.

[0058] In 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.

[0059] In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising an acid salt of the compound represented by the crystalline form of formula (I) and a pharmaceutically acceptable carrier. In a fifth aspect, the present invention provides use of an acid salt of the compound of crystalline formula (I) in the manufacture of a medicament for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease associated with CSF1-R.

[0060] In a sixth aspect, the present invention provides an acid salt of the compound represented by the crystalline formula (I) for use as a drug for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease associated with CSF1-R.

[0061] In a seventh aspect of the present invention, the present invention relates to a method for treating CSF1-R-associated ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastasis cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumor, solid tumor, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative diseases, leukemia, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus The present invention provides an acid salt of the compound represented by the crystalline formula (I), which is used as a drug for treating Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mast cell hyperplasia, or mast cell leukemia.

[0062] In a preferred embodiment, the acid salt of the compound represented by crystalline formula (I) is used as a drug for treating CSF1-R-associated ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic disease, neurodegenerative disease, metastasis of a primary tumor site, or bone metastatic cancer.

[0063] In an eighth aspect of the present invention, there is provided a method for treating a CSF1-R-associated cancer, tumor, autoimmune disease, metabolic disease or metastatic disease, comprising administering to a patient in need thereof an acid salt of the compound represented by crystalline formula (I). [Brief explanation of the drawings]

[0064] [Figure 1] 1 shows the X-ray powder diffraction pattern of the hydrochloride crystalline form I of compound of formula (I) of the present invention, in which the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. [Figure 2]1 shows the X-ray powder diffraction pattern of the hydrochloride crystalline form II of compound of formula (I) of the present invention, where the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. [Figure 3] 1 shows the X-ray powder diffraction pattern of the hydrochloride crystalline form III of compound of formula (I) of the present invention, where the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. [Figure 4] 1 shows the X-ray powder diffraction pattern of the sulfate crystalline form I of the compound of formula (I) of the present invention, in which the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. [Figure 5] 1 shows the X-ray powder diffraction pattern of crystalline Form I of the compound of formula (I) of the present invention, in which the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. [Figure 6] 1 shows the X-ray powder diffraction pattern of crystalline Form II of the phosphate salt of compound of formula (I) of the present invention, where the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. [Figure 7] 1 shows the X-ray powder diffraction pattern of crystalline Form III of the phosphate salt of compound of formula (I) of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensity. [Figure 8] 1 shows the X-ray powder diffraction pattern of methanesulfonate crystalline form I of compound of formula (I) of the present invention, in which the abscissa represents 2θ value (degrees) and the ordinate represents peak intensity. [Figure 9] 1 shows the X-ray powder diffraction pattern of methanesulfonate crystalline form II of compound of formula (I) of the present invention, in which the abscissa represents 2θ value (degrees) and the ordinate represents peak intensity. [Figure 10] 1 shows the X-ray powder diffraction pattern of the citrate crystalline form I of the compound of formula (I) of the present invention, where the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. [Figure 11] 1 shows the X-ray powder diffraction pattern of the compound malate crystalline form I of formula (I) of the present invention, where the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. [Figure 12] 1 shows the X-ray powder diffraction pattern of the tartrate salt of compound of formula (I) of the present invention, crystalline form I. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity. [Figure 13]1 shows the X-ray powder diffraction pattern of the compound fumarate crystalline form I of formula (I) of the present invention, where the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. [Figure 14] 1 shows a DSC / TGA diagram of the hydrochloride crystalline form I of compound of formula (I) of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (w / g) / weight (%). [Figure 15] 1 shows a DVS diagram of the hydrochloride crystalline form I of compound of formula (I) of the present invention, in which the abscissa represents relative humidity (%) and the ordinate represents weight change (%). [Figure 16] 1 shows a DSC / TGA diagram of crystalline Form I of the compound of formula (I) of the present invention, in which the abscissa represents temperature (° C.) and the ordinate represents heat flow (w / g) / weight (%). [Figure 17] 1 shows a DVS diagram of crystalline Form I of the phosphate salt of compound of formula (I) of the present invention, in which the abscissa represents relative humidity (%) and the ordinate represents weight change (%). [Figure 18] 1 shows a DSC / TGA diagram of methanesulfonate crystalline form II of compound of formula (I) of the present invention, where the abscissa represents temperature (°C) and the ordinate represents heat flow (w / g) / weight (%). [Figure 19] 1 shows a DVS diagram of methanesulfonate crystalline form II of compound of formula (I) of the present invention, in which the abscissa represents relative humidity (%) and the ordinate represents weight change (%). [Figure 20] 1 shows a DSC / TGA diagram of the tartrate salt of compound of formula (I) of the present invention, Form I. The abscissa represents temperature (° C.), and the ordinate represents heat flow (w / g) / weight (%). [Figure 21] 1 shows a DVS diagram of the tartrate salt of compound of formula (I) of the present invention, Form I. The abscissa represents relative humidity (%), and the ordinate represents weight change (%). [Figure 22] The figure shows a single crystal simulation diagram of the hydrochloride salt of compound (I) of the present invention and an X-ray powder diffraction overlay diagram of the hydrochloride crystalline form I, with the powder crystal diffraction peak diagram (top) and the single crystal simulation diagram (bottom) shown. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity. [Figure 23] 1 shows the single crystal unit cell structure of crystalline Form I of the hydrochloride salt of the compound represented by formula (I) of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0065] The inventors of the present invention have investigated different aggregation forms of the compound represented by formula (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, to provide a crystalline acid salt of a CSF-1R inhibitor. The physicochemical properties of the compound represented by formula (I), such as solubility, hygroscopicity, and chemical stability, have been significantly improved. This allows the crystalline acid salt to meet the needs of clinical drug formulation development and has significant clinical value. The crystalline acid salt can be widely used in the manufacture of drugs for treating cancer, tumors, autoimmune diseases, metabolic diseases, or metastatic diseases, particularly ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, or bone metastatic cancer, and is expected to accelerate the development of a new generation of CSF-1R inhibitor drugs. The present invention was made based on this.

[0066] DETAILED DESCRIPTION: Unless stated to the contrary, terms used in the following specification and claims shall have the following meanings. A "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs with other chemical components, and other components such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism and lead to absorption of the active ingredient(s) to exert their biological activity.

[0067] The compound of formula (I) has multiple separate acid salts that exhibit the phenomenon of polycrystalline or monocrystalline forms. For example, the hydrochloride, phosphate, and methanesulfonate salts are each designated as polycrystalline forms, while the sulfate, citrate, malate, fumarate, and tartrate salts are each designated as monocrystalline forms. These "polycrystalline forms" differ in terms of their X-ray powder diffraction patterns, physicochemical and pharmacokinetic properties, and thermodynamic stability.

[0068] As used herein, "salt" refers to a compound prepared by reaction of an organic acid or base drug with a medicamentous inorganic or organic acid or base. Methods and Materials The acid salt of the compound represented by crystalline formula (I) is characterized by its X-ray powder diffraction pattern. X-ray powder diffraction patterns of the salts were collected on a IV powder diffractometer using Cu Kα radiation (40 kV, 40 mA) at room temperature using a D / tex Ultra detector. The scan range was from 3° to 45° in the 2θ interval, with a scan rate of 20° / min. Diffraction patterns were obtained using the Ma Diffraction Analyzer, version 5.0.37, released in 2017. The data was analyzed using Jade 5 software from Terials Data, Inc.

[0069] XRPD samples are prepared by placing the sample on a single-crystal silicon wafer and pressing the sample powder with a glass plate or equivalent to ensure the sample surface is flat and of appropriate height. The sample holder is then placed in a Rigaku Ultima IV XRPD instrument, and X-ray powder diffraction patterns are collected using the instrument parameters described above. Measurement discrepancies associated with the results of such X-ray powder diffraction analyses arise from multiple factors, including (a) errors in sample preparation (e.g., sample height), (b) instrument error, (c) calibration discrepancy, (d) operator error (including errors encountered when measuring peak positions), and (e) material characteristics (e.g., preferred orientation error). Calibration error and sample height error often result in all peaks shifting in the same direction. Typically, this calibration factor aligns the measured peak positions with the expected peak positions, within a range of ±0.2° of the expected 2θ value. The angle 2θ values ​​(°) and intensity values ​​(as % of the highest peak value) for each polycrystalline form obtained in the examples of this invention are shown in Tables 1 to 13.

[0070] The experimental method for characterizing the acid salt of the compound of crystalline formula (I) using differential scanning calorimetry (DSC) is to take a small amount of powder of the acid salt of the compound of crystalline formula (I), place it in an aluminum pan that can be capped and set up with an apparatus, load the sample, and then cap it with an aluminum pan, and then transfer it to the apparatus for measurement after capping. All the apparatuses used for differential scanning calorimetry in this patent are model TA Q2000, and the scanning parameters are set to use a nitrogen atmosphere and a heating rate of 10°C / min.

[0071] The experimental method for characterizing the acid salt of the compound of crystalline formula (I) using thermogravimetric analysis (TGA) is to take a small amount of powder of the acid salt of the compound of crystalline formula (I) and place it in an aluminum pan set with the instrument, and then load the sample into the instrument for measurement. All the instruments used for thermogravimetric analysis in this patent are TA Q500 models, and the scanning parameters are set to adopt a nitrogen atmosphere and a heating rate of 10°C / min.

[0072] The experimental method for characterizing the acid salt of the compound of crystalline formula (I) using dynamic vapor sorption (DVS) involves taking a small amount of powder of the acid salt of the compound of crystalline formula (I) and placing it in a precision sample pan that is set up with the instrument. After the sample is loaded, the instrument is then loaded and measured. All instruments used in this patent for dynamic vapor sorption are DVS Intrinsic models. The experimental parameters are set to use nitrogen as the carrier gas, a constant temperature of 25°C, and a mass percentage change rate per unit time (dm / dt) of 0.01% / min as the criteria for reaching equilibrium. A humidity change cycle is set with an initial relative humidity of 0% and an end-point relative humidity of 90%, with two cycles, each with a change in 10% RH.

[0073] The reagents in the embodiments of the present invention are known commercially available products or can be synthesized by methods known in the art, and the API raw materials can be prepared according to patent WO2018214867A1.

[0074] Unless otherwise stated, all reactions of this invention are carried out under continuous magnetic stirring, in an atmosphere of dry nitrogen or argon, with dry solvents, and temperatures are in degrees Celsius (°C).

[0075] Unless otherwise specified, the various crystalline forms referred to in the present invention may be anhydrous crystalline forms or hydrated crystalline forms, for example, hydrated crystalline forms, and preferably, 1 part of each crystalline form is mixed with 1, 2, 3, 4 or 5 parts of the crystalline form. It contains water of crystallization, more preferably 1 or 2 parts of water of crystallization for each part of crystal.

[0076] The present invention will be described in more detail and completely by the accompanying drawings and the following examples, which are used to illustrate only specific embodiments of the present invention and should not be construed as limiting the scope of the present invention in any way.

[0077] Preparation of specific examples Example 1 Preparation of Hydrochloride Crystalline Form I Approximately 10 mg of the compound represented by formula (I) was dissolved in 0.5 mL of methyl tert-butyl ether, and 0.1 mL of methyl tert-butyl ether containing 2.35 μL of concentrated hydrochloric acid was added thereto. The mixture was stirred at room temperature for 3 days, filtered, and the filter cake was oven-dried at 50°C. XRPD analysis was performed, and its X-ray powder diffraction pattern is shown in Figure 1.

[0078] Example 2 Preparation of Hydrochloride Crystalline Form II Approximately 10 mg of the compound represented by formula (I) was dissolved in 0.5 mL of ethyl acetate, and 0.1 mL of ethyl acetate containing 2.35 μL of concentrated hydrochloric acid was added thereto. The mixture was stirred at room temperature for 3 days, filtered, and the filter cake was oven-dried at 50°C. XRPD analysis was performed, and its X-ray powder diffraction pattern is shown in Figure 2.

[0079] Example 3 Preparation of Hydrochloride Crystalline Form III Approximately 10 mg of the compound represented by formula (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 thereto. The mixture was stirred at room temperature for 3 days, filtered, and the filter cake was oven-dried at 50°C. XRPD analysis was performed, and its X-ray powder diffraction pattern is shown in Figure 3.

[0080] Example 4 Preparation of Hydrochloride Crystalline Form I Approximately 50 mg of the compound represented by formula (I) was dissolved in 1.2 mL of methyl tert-butyl ether, and 1.2 mL of methyl tert-butyl ether containing 11.7 μL of concentrated hydrochloric acid was added thereto. The mixture was stirred at room temperature for 7 days, filtered, and the filter cake was oven-dried at 50°C. XRPD, DSC, TGA, and DVS analyses were performed. The X-ray powder diffraction pattern was consistent with that shown in FIG. 1, and the DSC, TGA, and DVS analyses are shown in FIGS. 14 and 15.

[0081] Example 5 Preparation of Sulfate Crystalline Form I Approximately 10 mg of the compound represented by formula (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 thereto. The mixture was stirred at room temperature for 3 days, filtered, and the filter cake was oven-dried at 50° C. and subjected to XRPD analysis. The X-ray powder diffraction pattern thereof is shown in FIG. 4.

[0082] Example 6 Preparation of Phosphate Crystalline Form I Approximately 10 mg of the compound represented by formula (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 thereto. The mixture was stirred and allowed to stand at −20° C. for 3 days, filtered, and the filter cake was oven-dried at 50° C. and subjected to XRPD analysis. The X-ray powder diffraction pattern thereof is shown in FIG. 5.

[0083] Example 7 Preparation of Phosphate Crystalline Form II Approximately 10 mg of the compound represented by formula (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 thereto. The mixture was stirred and allowed to stand at −20° C. for 3 days, filtered, and the filter cake was oven-dried at 50° C. and subjected to XRPD analysis. The X-ray powder diffraction pattern thereof is shown in FIG. 6.

[0084] Example 8 Preparation of Phosphate Crystalline Form III Approximately 10 mg of the compound represented by formula (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 thereto. The mixture was stirred at −20° C. for 3 days, filtered, and the filter cake was oven-dried at 50° C. and subjected to XRPD analysis. The X-ray powder diffraction pattern is shown in FIG. 7.

[0085] Example 9 Preparation of Phosphate Crystalline Form I Approximately 50 mg of the compound represented by formula (I) was dissolved in 1.2 mL of methanol, and 1.2 mL of methanol containing 13.7 μL of concentrated phosphoric acid was added thereto. The mixture was stirred and allowed to stand at −20° C. for 7 days, filtered, and the filter cake was oven-dried at 50° C. and subjected to XRPD, DSC, TGA, and DVS analyses. The X-ray powder diffraction pattern is shown in FIG. 5, and the DSC, TGA, and DVS analyses are shown in FIGS. 16 and 17.

[0086] Example 10 Preparation of Crystalline Form I of the Methanesulfonate Salt Approximately 10 mg of the compound represented by formula (I) was dissolved in 0.5 mL of tetrahydrofuran, and 0.1 mL of tetrahydrofuran containing 2.29 μL of methanesulfonic acid was added thereto. The mixture was stirred and allowed to stand at −20° C. for 3 days, filtered, and the filter cake was oven-dried at 50° C. and subjected to XRPD analysis. The X-ray powder diffraction pattern thereof is shown in FIG. 8.

[0087] Example 11 Preparation of Methanesulfonate Crystalline Form II Approximately 10 mg of the compound represented by formula (I) was dissolved in 0.5 mL of acetone, and 0.1 mL of acetone containing 2.29 μL of methanesulfonic acid was added thereto, stirred, and allowed to stand at −20° C. for 3 days. The mixture was filtered, and the filter cake was oven-dried at 50° C. and subjected to XRPD analysis. The X-ray powder diffraction pattern thereof is shown in FIG. 9.

[0088] Example 12 Preparation of Methanesulfonate Crystalline Form II Approximately 50 mg of the compound represented by formula (I) was dissolved in 1.2 mL of acetone, and 1.2 mL of acetone containing 11.4 μL of methanesulfonic acid was added thereto. The mixture was stirred and allowed to stand at −5° C. for 3 days, filtered, and the filter cake was oven-dried at 50° C. and subjected to XRPD, DSC, TGA, and DVS analyses. The X-ray powder diffraction pattern thereof is shown in FIG. 9, and the DSC, TGA, and DVS analyses thereof are shown in FIGS. 18 and 19.

[0089] Example 13 Preparation of Citrate Crystalline Form I Approximately 10 mg of the compound represented by formula (I) was dissolved in 0.5 mL of acetonitrile, 4.57 mg of citric acid was added, the mixture was stirred at room temperature for 3 days, filtered, and the filter cake was oven-dried at 50°C and subjected to XRPD analysis. The X-ray powder diffraction pattern is shown in Figure 10.

[0090] Example 14 Preparation of Malate Crystalline Form I Approximately 10 mg of the compound represented by formula (I) was dissolved in 0.5 mL of ethyl acetate, 2.76 mg of malic acid was added, the mixture was stirred at room temperature for 3 days, filtered, and the filter cake was oven-dried at 50°C and subjected to XRPD analysis. The X-ray powder diffraction pattern is shown in Figure 11.

[0091] Example 15 Preparation of Tartrate Crystalline Form I Approximately 10 mg of the compound of formula (I) was dissolved in 0.5 mL of acetonitrile, 3.57 mg of tartaric acid was added, stirred, the solvent was evaporated, and the solid was oven-dried at 50°C and subjected to XRPD analysis, the X-ray powder diffraction pattern of which is shown in Figure 12.

[0092] Example 16 Preparation of Tartrate Crystalline Form I Approximately 50 mg of the compound represented by formula (I) was dissolved in 1.2 mL of acetonitrile, and 17.87 mg of tartaric acid, 1 mL of acetonitrile, and 0.2 mL of purified water were added thereto, followed by stirring. No precipitation occurred, the mixture was allowed to stand at 5°C for 1 week, no precipitation occurred, 1 mL of methyl tert-butyl ether was added, the mixture was stirred, and the mixture was allowed to stand at -20°C for 1 week, filtered, and the filter cake was oven-dried at 50°C. XRPD, DSC, TGA, and DVS analyses were performed, and the X-ray powder diffraction pattern is shown in Figure 12, and the DSC, TGA, and DVS analyses are shown in Figures 20 and 21.

[0093] Example 17 Preparation of Fumarate Crystalline Form I Approximately 10 mg of the compound represented by formula (I) was dissolved in 0.5 mL of methyl tert-butyl ether, 2.76 mg of fumarate was added thereto, stirred, and allowed to stand at −20° C. for 3 days, filtered, and the filter cake was oven-dried at 50° C. and subjected to XRPD analysis. The X-ray powder diffraction pattern thereof is shown in FIG. 13.

[0094] Example 18 Structural analysis of hydrochloride crystalline form I 40 mg of the compound of formula (I) was weighed and placed in a 20 mL vial. 3 mL of acetone was added to dissolve the compound, and 40 μL of concentrated hydrochloric acid (12 M) was added to obtain a suspension. The solution was filtered through a 0.22 μm pore size FPTE needle filter to obtain a clear solution. 0.2 mL of the filtrate was placed in a 2 mL vial, the vial was sealed with parafilm, a small hole was made in the parafilm, and the solution was allowed to slowly evaporate at room temperature, yielding a relatively small, flake-like single crystal as a seed crystal.

[0095] 40 mg of the compound of formula (I) was weighed and placed in a 20 mL vial, and 3 mL of acetone was added to dissolve it. 40 μL of concentrated hydrochloric acid (12 M) was then added to obtain a suspension. The solution was filtered through a 0.22 μm pore size FPTE needle filter to obtain a clear solution. 0.4 mL of the filtrate was placed in a 2 mL vial, and 0.3 mL of acetone was added. A small amount of the prepared flaky seed crystals was added, and the vial was sealed with Parafilm. A small hole was made in the Parafilm, and the mixture was allowed to slowly evaporate at room temperature to obtain a relatively small volume of flaky single crystals.

[0096] A suitable single crystal was selected and detected 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 simulated into a powder crystal diffraction pattern and compared with the powder crystal diffraction pattern of the hydrochloride crystalline form I of compound represented by formula (I). As shown in Figure 22, the comparison showed that the hydrochloride crystalline form I of compound represented by formula (I) in this patent was consistent with the single crystal simulation and did not produce any extra peaks, indicating that the hydrochloride crystalline form I of compound represented by formula (I) in this patent is a pure phase. At the same time, it was also confirmed that the hydrochloride crystalline form I of compound represented by formula (I) is a monohydrochloride monohydrate. The single crystal unit cell structure is shown in Figure 23.

[0097] [Table 14]

[0098] Example 19 Solubility Measurement Approximately 2 mg of various crystalline acid salts and the compound of formula (I) in free form were weighed out and placed in a 2 mL glass vial, and each time approximately 100 μL of deionized water was added, followed by ultrasonic treatment. If the compound did not dissolve, deionized water was added until the compound was completely dissolved or the concentration was less than 0.2 mg / mL. The total volume of water added was recorded, and the dissolution behavior and phenomenon were observed, and the solubility of each compound was calculated. The results of the solubility test are shown in the table below.

[0099] [Table 15]

[0100] From the above experimental results, it can be seen that after the compound of formula (I) in free state is converted into a salt to obtain a crystalline compound, the solubility of all salts in water is greatly improved, which can meet the development needs of clinical drug formulations.Therefore, after the compound of formula (I) in free state is converted into a salt to obtain a crystalline compound, the solubility and drug release behavior can be significantly improved.

[0101] Example 20 Moisture absorption behavior test The inventors of this patent used the dynamic water vapor sorption method to measure the moisture absorption weight gain (moisture absorption weight gain / weight before moisture absorption * 100%) of various crystalline forms at each relative humidity, and evaluated the moisture absorption of different crystalline compounds. The results are shown in the table below.

[0102] [Table 16]

[0103] The above experimental results show that when the relative humidity is below 80%, the hygroscopicity of the hydrochloride crystalline form I crystals increases by less than 1%; when the relative humidity rises to 80%, the hygroscopicity of the crystals gradually increases; when the relative humidity rises to 90%, the hygroscopicity of the crystals increases significantly. This hygroscopic property of hydrochloride crystalline form I is highly suitable for the storage requirements of clinical preparations, and its ability to absorb large amounts of moisture in a high humidity environment is also suitable for accelerating the dissolution of the crystals, which is advantageous for the granulation process of clinical preparations.

[0104] The methanesulfonate salt Form II has similar hygroscopic properties to the hydrochloride salt Form I, with the only difference being that the hygroscopicity of the crystals increases significantly when the relative humidity of the methanesulfonate salt Form II is increased to 70%. This hygroscopic property is also highly suitable for the granulation process requirements of clinical formulations.

[0105] The hygroscopic properties of the tartrate salt crystalline Form I show that the increase in hygroscopic weight of the crystals increases essentially equally with increasing relative humidity, forming a good linear relationship. This hygroscopic property will be advantageous for the inventors in their subsequent research to develop specialized formulations.

[0106] The hygroscopicity of crystalline Form I of the phosphate salt is also very unique, maintaining low hygroscopicity regardless of the relative humidity of the environment. This property can be utilized for storage, transportation, and production in different regions, and is also convenient for the manufacture of special formulations.

[0107] As is well known, hygroscopicity of a drug is an important physicochemical property that affects the production, storage and content of a drug. Different drug formulations can be developed according to different hygroscopicity properties, thereby meeting different clinical development needs of drugs. A physical form with low hygroscopicity makes the production, storage and content of a drug more stable. Therefore, all of the above crystalline compounds have relatively good hygroscopicity properties, and in particular, hydrochloride crystalline form I and phosphate crystalline form I are more suitable for development than other crystalline forms of salts.

[0108] All documents related to the present invention are incorporated herein by reference as if each document were individually incorporated by reference. It is also understood that after reading the above description of the present invention, one skilled in the art may make various changes and modifications to the present invention, and that equivalents thereof are also within the scope of the present invention.

Claims

1. An acid salt of the compound represented by crystalline formula (I): 【Chemistry 1】

2. The acid salt includes an inorganic acid salt or an organic acid salt, and the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide, and phosphate, and 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, caprate, caproate, caprylate, cinnamate, citrate, cyclohexanesulfamate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, erythorbate, lactate, malate, mandelate, pyroglutamate, and tartaric acid.

2. The acid salt of the compound of crystalline formula (I) according to claim 1, wherein the acid salt is selected from the group consisting of 4-hydroxybenzoates, ...

3. The acid salt of the compound represented by crystalline formula (I) is a hydrochloride salt, and its X-ray powder diffraction pattern (XRPD) contains 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 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°.

3. The acid salt of the compound of crystalline formula (I) according to claim 2, characterized in that the X-ray powder diffraction pattern of the crystalline hydrochloride salt of the acid salt of the compound of crystalline formula (I) comprises four or more peaks located at a diffraction angle (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°, and preferably the X-ray powder diffraction pattern of the crystalline hydrochloride salt of the acid salt of the compound of crystalline formula (I) is essentially the same as the peaks located at the diffraction angles (2θ) shown in Figure 1, Figure 2 or Figure 3.

4. The acid salt of the compound represented by the crystalline formula (I) is a sulfate salt, and its X-ray powder diffraction pattern (XRPD) contains 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 acid salt of the compound represented by crystalline formula (I) according to claim 2, characterized in that the X-ray powder diffraction pattern of the crystalline sulfate salt thereof is essentially the same as the peaks located at the diffraction angles (2θ) shown in Figure 4.

5. The acid salt of the compound represented by the crystalline formula (I) is a phosphate salt, and its X-ray powder diffraction pattern (XRPD) contains 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 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°.

5. The acid salt of the compound of crystalline formula (I) according to claim 2, wherein the X-ray powder diffraction pattern of the crystalline phosphate salt comprises 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°, and preferably the X-ray powder diffraction pattern of the crystalline phosphate salt is essentially the same as the peaks located at diffraction angles (2θ) shown in FIG. 5, FIG. 6 or FIG.

7.

6. The acid salt of the compound represented by crystalline formula (I) is a methanesulfonate salt, and its X-ray powder diffraction pattern (XRPD) contains 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 four or more peaks located at diffraction angles (2θ) of 8.64±0.2°, 21.02±0.2°, 16.34±0.2°, 21.02 ...

3. The acid salt of the compound represented by crystalline formula (I) according to claim 2, characterized in that the X-ray powder diffraction pattern of the crystalline methanesulfonate salt of the acid salt of the compound comprises four or more peaks located at diffraction angles (2θ) of 10.82±0.2°, 23.34±0.2°, 18.48±0.2°, 7.84±0.2°, 26.00±0.2°, and 10.82±0.2°, and preferably the X-ray powder diffraction pattern of the crystalline methanesulfonate salt of the acid salt of the compound represented by crystalline formula (I) is essentially the same as the peaks located at diffraction angles (2θ) shown in Figure 8 or Figure 9.

7. 3. The acid salt of the compound represented by crystalline formula (I) according to claim 2, wherein the acid salt of the compound represented by crystalline formula (I) is a citrate salt, and the X-ray powder diffraction pattern (XRPD) thereof comprises 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°, and preferably the X-ray powder diffraction pattern of the crystalline citrate salt is essentially the same as the peaks located at diffraction angles (2θ) shown in FIG. 10 .

8. 11 . The acid salt of the compound represented by crystalline formula (I) according to claim 2 , wherein the acid salt of the compound represented by crystalline formula (I) is a malate salt, and the X-ray powder diffraction pattern (XRPD) thereof contains 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°, and preferably the X-ray powder diffraction pattern of the crystalline malate salt is essentially the same as the peaks located at diffraction angles (2θ) shown in FIG. 11 .

9. The acid salt of the compound represented by crystalline formula (I) is a tartrate salt, and its X-ray powder diffraction pattern (XRPD) 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°. Preferably, the X-ray powder diffraction pattern of the crystalline tartrate salt ...

3. The acid salt of the compound of crystalline formula (I) according to claim 2, wherein the peak at the position of the peak is essentially the same as that at the position of the peak ...

10. 13. The acid salt of the compound represented by crystalline formula (I) according to claim 2, wherein the acid salt of the compound represented by crystalline formula (I) is a fumarate salt, and the X-ray powder diffraction pattern (XRPD) thereof comprises 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°, and preferably the X-ray powder diffraction pattern of the crystalline fumarate salt is essentially the same as the peaks located at diffraction angles (2θ) shown in FIG.

13.

11. A method for producing an acid salt of the compound represented by crystalline formula (I) according to any one of claims 1 to 10, comprising: 1) dissolving or dispersing a compound of formula (I) in a free state in an aqueous solvent or a suitable organic solvent, and adding a solution of a liquid or solid inorganic or organic acid to the system, or adding the compound of formula (I) in a free state to a solution of an acid; 2) obtaining a crystalline product by collecting the solid product precipitated during the salt-forming reaction or 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 may be 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, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, formic acid, fluorosulfonic acid, fluoroisopropyl methyl methyl ester, fluoroisopropyl ... The method for producing the hydroxybenzoic acid is characterized in that the hydroxybenzoic acid is selected from the group consisting of malic acid, galactic acid, gentisic acid, acetohydroxamic acid, malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, maleic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, salicylic acid, 4-aminosalicylic acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, stearic acid, thiocyanic acid, undecylenic acid, and succinic acid.

12. 12. The method according to claim 11, wherein the method for creating supersaturation in the salt-forming system in step 2) includes one or more of adding seed crystals, volatilizing a solvent, adding an anti-solvent, or cooling.

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

14. A method for producing an acid salt of the compound represented by crystalline formula (I) according to any one of claims 1 to 10, comprising: A process for preparing an acid salt of the compound of formula (I), comprising the steps of: converting one crystalline form of the acid salt of the compound of formula (I) into another crystalline form of the salt by a crystalline form conversion method, including heating or a suspension crystalline form conversion method in a suitable solvent, wherein 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 a mixture thereof, or an aqueous solution thereof.

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

16. Use of an acid salt of the compound of crystalline formula (I) according to any one of claims 1 to 10 in the manufacture of a medicament for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease associated with CSF1-R.

17. 11. The acid salt of the compound represented by crystalline formula (I) according to any one of claims 1 to 10, which is used as a drug for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease associated with CSF1-R.

18. 11. The acid salt of the compound represented by crystalline formula (I) according to any one of claims 1 to 10, which is used as a drug for treating CSF1-R-associated ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastasis cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumor, solid tumor, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative diseases, leukemia, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mast cell hyperplasia, or mast cell leukemia.

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