Solid forms of diaminopyrimidine compounds or hydrates thereof, their preparation method and applications

Abstract

The present invention relates to a solid form of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine or a hydrate thereof, a process for preparing the solid form, a pharmaceutical composition comprising the solid form, and the use of the solid form for the prevention or treatment of diseases modulated by P2X3 and / or P2X2 / 3 receptor antagonists.

Description

[Technical field]

[0001] The present invention relates to a solid form of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine (hereinafter referred to as "Compound A") or a hydrate thereof, a process for preparing the solid form, a pharmaceutical composition comprising the solid form, and the use of the solid form for the prevention or treatment of diseases mediated by P2X3 and / or P2X2 / 3 receptor antagonists. [Background technology]

[0002] Purine compounds act via cell surface purinergic receptors and are believed to have a variety of physiological and pathological roles. ATP, and to a lesser extent adenosine, can stimulate sensory nerve endings, resulting in intense pain and a marked increase in sensory nerve discharge. ATP receptors have been classified into two main families, P2Y- and P2X-purinergic receptors, based on molecular structure, transduction mechanism, and pharmacological characteristics. P2Y-purinergic receptors are G protein-coupled receptors, while P2X-purinergic receptors are a family of ATP-gated cation channels. Purinergic receptors, especially P2X receptors, can form homo- or heteromultimers. To date, cDNAs for several P2X receptor subtypes have been cloned (six homologous receptors: P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7; and three heterologous receptors: P2X2 / 3, P2X4 / 6, and P2X1 / 5). The structure and chromosomal mapping of the mouse genomic P2X3 receptor subunit has also been reported.

[0003] Studies have shown that P2X3 and / or P2X2 / 3 receptor antagonists can be used to treat diseases, such as pain, etc. Applicant has identified diaminopyrimidine compounds, specifically 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine, that can be used as effective P2X3 and / or P2X2 / 3 receptor antagonists (see International Application PCT / CN2018 / 112829, the entirety of which is incorporated herein by reference). Summary of the Invention [Means for solving the problem]

[0004] In one aspect, the present invention provides a crystalline form of Compound A 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine as shown below, or a hydrate thereof.

[0005] [ka]

[0006] The preferred crystalline forms of the present invention not only have excellent effects in preventing or treating diseases mediated by P2X3 and / or P2X2 / 3 receptor antagonists, but also have other advantages.For example, the preferred crystalline forms of the present invention have excellent physical properties (including solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, high humidity resistance, flowability, etc.), and the preferred crystalline forms of the present invention can have better properties in terms of bioavailability, physical and / or chemical stability and ease of preparation.The preferred crystalline forms of the present invention have good powder properties, are more suitable and convenient for mass production and formulation, can reduce irritation and enhance absorption, solve the problems in metabolic rate, significantly reduce the toxicity caused by drug accumulation, improve safety, and effectively guarantee the quality and efficacy of pharmaceutical products.

[0007] In another aspect, the present invention provides a method for preparing the crystalline forms of the present invention.

[0008] In another aspect, the present invention provides pharmaceutical compositions comprising any one or more of the crystalline forms of the present invention and one or more pharma- ceutically acceptable carriers.

[0009] In another aspect, the present invention provides the use of a crystalline form of the present invention in the manufacture of a medicament for the treatment of a disease mediated by a P2X3 and / or P2X2 / 3 receptor antagonist. [Brief description of the drawings]

[0010] [Figure 1] 1 is a powder X-ray diffraction pattern of crystalline Form I of Compound A anhydrate. [Diagram 2] 1 is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of crystalline Form I of Compound A anhydrous. [Diagram 3] 1 is a scanning electron microscope image of crystalline Form I of Compound A anhydrate. [Figure 4] 1 is a powder X-ray diffraction pattern of crystalline form II of Compound A monohydrate. [Diagram 5] 1 is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of crystalline Form II of Compound A monohydrate. [Figure 6] 1 is a powder X-ray diffraction pattern of crystalline Form III of Compound A hemihydrate. [Figure 7] 1 is a differential scanning calorimetry (DSC) graph of Compound A hemihydrate crystalline Form III. [Figure 8] 1 is a powder X-ray diffraction pattern of crystalline Form IV of Compound A sesquihydrate. [Figure 9] 1 is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of crystalline Form IV of Compound A sesquihydrate. [Figure 10] 1 is a powder X-ray diffraction pattern of crystalline form V of Compound A monohydrate. [Figure 11] 1 is a differential scanning calorimetry (DSC) graph of crystalline Form V of Compound A monohydrate. [Figure 12]1 is a powder X-ray diffraction pattern of crystalline Form VI of Compound A monohydrate. [Figure 13] 1 is a differential scanning calorimetry (DSC) graph of crystalline Form VI of Compound A monohydrate. [Figure 14] 1 is a powder X-ray diffraction pattern of crystalline Form VII of Compound A sesquihydrate. [Figure 15] 1 is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of crystalline Form VII of Compound A sesquihydrate. [Figure 16] 1 is a powder X-ray diffraction pattern of crystalline Form VIII of Compound A hemihydrate. [Figure 17] 1 is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of crystalline Form VIII of Compound A hemihydrate. [Figure 18] FIG. 1 is a comparison of XRPD patterns of crystalline Form I of Compound A anhydrate before and after room temperature stability testing. [Figure 19] FIG. 1 is a comparison of XRPD patterns of crystalline Form I of Compound A anhydrate before and after high temperature stability testing. [Figure 20] FIG. 1 is a comparison of XRPD patterns of crystalline Form I of Compound A anhydrate before and after high humidity stability testing. [Figure 21] FIG. 1 is a comparison of XRPD patterns of crystalline Form I of Compound A anhydrate before and after a physical grinding stability test. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] definition Unless otherwise defined by the context, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. References to techniques used herein are intended to refer to techniques as commonly understood in the art, including modifications to these techniques or equivalent technical alternatives that would be obvious to those skilled in the art. It is believed that most of the following terms will be easily understood by those skilled in the art, but the following definitions are nevertheless set forth to better explain the present invention.

[0012] As used herein, the terms "containing," "including," "including," "having," or "related to," as well as other variations, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0013] The term "about" as used herein refers to a range within an acceptable standard error of a value, such as ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2 or ±3, as would be appreciated by one of ordinary skill in the art.

[0014] The term "solid form", as used herein, includes all solid forms of Compound A or any hydrates thereof, such as crystalline or amorphous forms.

[0015] The term "amorphous" as used herein refers to any solid material that has lost three-dimensional order. In some cases, amorphous solids can be characterized by known techniques, including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As described below, amorphous solids typically exhibit a diffuse XRPD pattern composed of one or two broad peaks (i.e., a base width of about 5° 2θ or greater).

[0016] The term "crystalline form" or "crystal", as used herein, refers to any solid material that exhibits three-dimensional order and exhibits a distinctive XRPD pattern with clearly defined peaks, in contrast to amorphous solid materials.

[0017] The term "X-ray powder diffraction pattern (XRPD pattern)" as used herein refers to experimentally observed diffractograms or parameters derived therefrom. XRPD patterns are typically characterized by peak positions (abscissa) and peak intensities (ordinate).

[0018] The term "2θ" as used herein refers to the peak position in degrees based on the experimental setup of an X-ray diffraction experiment, which is the common abscissa unit in a diffraction pattern. The experimental setup requires that the reflected light is recorded in 2 theta (2θ) degrees, where the reflected light diffracts when the incident light forms a theta (θ) degree in a certain lattice plane. It should be understood that references herein to specific 2θ values ​​for a particular solid form are intended to mean the 2θ values ​​(in degrees) as measured using the X-ray diffraction experimental conditions as described herein. For example, as described herein, Cu-Kα (Kα1(Å): 1.540598 and Kα2(Å): 1.544426 Å) was used as the radiation source.

[0019] As used herein, "I%" refers to the percentage of peak intensity.

[0020] The term "differential scanning calorimetry (DSC) graph" as used herein refers to a curve recorded on a differential scanning calorimeter. Unless otherwise specified, temperatures mentioned when describing characteristic peaks in a DSC graph refer to the onset temperature of the peak.

[0021] The term "thermogravimetric analysis (TGA) graph" as used herein refers to a curve recorded on a thermogravimetric analyzer.

[0022] As used herein, the term "essentially the same" with respect to X-ray diffraction peak positions means that typical peak position and intensity variability is taken into account. For example, one skilled in the art will appreciate that peak positions (2θ) will show some variability, typically on the order of 0.1-0.2 degrees, as will the instrument used to measure the diffraction. Furthermore, one skilled in the art will appreciate that relative peak intensities will show intra-instrument variability as well as variability due to degree of crystallinity, preferred orientation, sample surface prepared, and other factors known to those skilled in the art. Similarly, as used herein, "essentially the same" with respect to DSC graphs is also intended to encompass the variability associated with these analytical techniques known to those skilled in the art. For example, differential scanning calorimetry graphs will typically have a variability of up to ±0.2°C for well-defined peaks and a greater variability (e.g., up to ±1°C) for broad lines.

[0023] Liquid crystal nuclear magnetic resonance spectra in this application are preferably collected on a Bruker 400M nuclear magnetic resonance spectrometer using DMSO-d6 as the solvent unless otherwise indicated.

[0024] Polarized light microscopy data in this application is preferably collected on a polarized light microscope ECLIPSE LV100POL (Nikon, JPN).

[0025] Numerical ranges (e.g., "1 to 10," "1 to 6," "2 to 10," "2 to 6," "3 to 10," "5 to 10," "3 to 6"), etc., when used herein include any point within the numerical range (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0026] The prepared salt or its crystalline form can be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for recovery of solids under pressure or reduced pressure. The recovered solids can be optionally dried. "Drying" in the present invention is performed under reduced pressure (preferably vacuum) until the amount of remaining solvent falls within the limits set forth in the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use ("ICH") guidelines. The amount of remaining solvent depends on the type of solvent, but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm. Drying can be performed in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, etc. Drying can be carried out at less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C or any other suitable temperature, at atmospheric or reduced pressure (preferably in vacuum), for any desired period of time (e.g., about 1, 2, 3, 5, 10, 15, 20, 24 hours or overnight) until the desired result is achieved, provided that the quality of the salt is not degraded. Drying can be carried out for any desired time until the desired product quality is achieved. The dried product can optionally be subjected to a size reduction procedure to produce the desired particle size. Milling or micronization can be carried out before drying or after the product has been dried. Techniques that can be used for particle size reduction include, but are not limited to, ball, roller and hammer milling, and jet milling.

[0027] The term "anhydrous" as used herein preferably means a crystalline form that does not include water molecules as a structural element.

[0028] [Crystal form and its preparation method] In one embodiment, the present invention provides Compound A anhydride. [ka] Crystalline form I of: Crystalline Form I of Compound A anhydrate is provided, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of about 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 19.8±0.2°, and 20.3±0.2°.

[0029] In a preferred embodiment, crystalline Form I has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2°, and 20.3±0.2°.

[0030] In a more preferred embodiment, crystalline Form I has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 6.2±0.2°, 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 16.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.3±0.2°, 21.8±0.2°, 23.0±0.2°, 23.6±0.2°, 24.1±0.2°, 26.2±0.2°, 26.5±0.2°, 27.8±0.2°, 28.5±0.2°, 29.3±0.2°, and 30.6±0.2°.

[0031] In a more preferred embodiment, crystalline Form I has an XRPD pattern comprising peaks at the following diffraction angles (2θ):

[0032] [Table 1]

[0033] In a more preferred embodiment, crystalline Form I has an XRPD pattern comprising peaks at diffraction angles (2θ) essentially the same as those shown in Figure 1. In a most preferred embodiment, the XRPD peak positions for crystalline Form I are essentially the same as those shown in Figure 1.

[0034] In a more preferred embodiment, crystalline Form I has a DSC graph that includes an endothermic / exothermic peak at about 245 / 255°C.

[0035] In a more preferred embodiment, crystalline Form I has a weight loss of about 0.1% when heated to about 100-150° C. by thermogravimetric analysis.

[0036] In a more preferred embodiment, crystalline Form I has a DSC-TGA graph containing characteristic peaks essentially the same as that shown in Figure 2. In a most preferred embodiment, crystalline Form I has a DSC-TGA graph essentially the same as that shown in Figure 2.

[0037] In a more preferred embodiment, crystalline Form I has a scanning electron microscope image essentially similar to that shown in FIG.

[0038] In some preferred embodiments, the present invention provides a method for preparing crystalline Form I, comprising the steps of: 1) adding compound A to water, followed by adding an acid (e.g., an organic acid (e.g., acetic acid or trifluoroacetic acid) or an inorganic acid (e.g., hydrochloric acid or sulfuric acid, preferably hydrochloric acid), stirring to dissolve compound A to obtain a solution, and optionally filtering to obtain a filtrate; 2) adding a base (e.g., sodium hydroxide, potassium hydroxide, or ammonia) to the solution or filtrate obtained in step 1) and collecting the precipitated solid by filtration; and 3) adding the resulting solid to water, stirring (e.g., for 0.5-5 hours, preferably 1-3 hours), filtering to collect the solid, and optionally drying to obtain crystalline Form I.

[0039] In some preferred embodiments, the present invention provides a method for preparing crystalline form I, comprising dissolving compound A in a good solvent (at room temperature or under heating (e.g., heating to 30-60° C., preferably 50° C.)) to form a solution (the mixture can be filtered if necessary to provide a solution), and then adding an anti-solvent thereto and stirring (the addition of anti-solvent and stirring can be performed at room temperature or under cooling (e.g., cooling to 0-10° C., preferably 5° C.)), precipitating a solid, which is filtered to obtain the crystalline form.

[0040] In some preferred embodiments, the good solvent is an ether having 3 to 10 carbon atoms, preferably a cyclic ether, such as furan (including tetrahydrofuran) and dioxane, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane; the anti-solvent is a hydrocarbon having 5 to 10 carbon atoms (alkanes, halogenated alkanes, alkenes, alkynes and aromatic hydrocarbons including but not limited to dichloromethane, trichloromethane (chloroform), n-hexane, n-heptane and toluene), or an ether having 2 to 6 carbon atoms (preferably a straight chain ether, such as diethyl ether, diisopropyl ether or methyl tert-butyl ether).

[0041] In some preferred embodiments, the weight / volume ratio (g / mL) of compound A to the good solvent is about 1:(30-120), preferably about 1:40 or 1:100.

[0042] In some preferred embodiments, the volume ratio of the good solvent to the anti-solvent is about 1:1 to 1:5.

[0043] In another embodiment, the present invention provides Compound A monohydrate. [ka] %. The compound according to claim 1, wherein: Crystalline Form II of Compound A monohydrate is provided, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of about 13.0±0.2°, 19.5±0.2°, and 19.9±0.2°.

[0044] In one preferred embodiment, crystalline Form II has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 9.6±0.2°, 13.0±0.2°, 19.5±0.2°, 19.9±0.2°, and 22.7±0.2°.

[0045] In a more preferred embodiment, crystalline Form II has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 9.6±0.2°, 10.9±0.2°, 13.0±0.2°, 14.9±0.2°, 15.8±0.2°, 16.8±0.2°, 19.5±0.2°, 19.9±0.2°, 22.7±0.2°, 23.7±0.2°, 25.2±0.2°, 26.0±0.2°, 28.5±0.2°, 29.0±0.2°, 30.0±0.2°, and 32.5±0.2°.

[0046] In a more preferred embodiment, crystalline Form II has an XRPD pattern comprising peaks at the following diffraction angles (2θ):

[0047] [Table 2]

[0048] In a more preferred embodiment, crystalline Form II has an XRPD pattern comprising peaks at diffraction angles (2θ) essentially the same as those shown in Figure 4. In a most preferred embodiment, the XRPD peak positions for crystalline Form II are essentially the same as those shown in Figure 4.

[0049] In a more preferred embodiment, crystalline Form II has a DSC graph comprising an endothermic peak at about 73.9°C and an endothermic / exothermic peak at about 245 / 255°C.

[0050] In a more preferred embodiment, crystalline Form II has a weight loss of about 6.2% when heated to about 100° C. by thermogravimetric analysis.

[0051] In a more preferred embodiment, crystalline Form II has a DSC-TGA graph containing characteristic peaks essentially similar to those shown in Figure 5. In a most preferred embodiment, crystalline Form II has a DSC-TGA graph essentially similar to those shown in Figure 5.

[0052] In some preferred embodiments, the present invention provides a method for preparing crystalline Form II, comprising suspending Compound A in an aqueous alcoholic solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol) and stirring (e.g., at room temperature) (e.g., for 1-5 days, e.g., 3 days) and filtering to obtain the crystalline form.

[0053] In some preferred embodiments, the weight / volume ratio (g / mL) of Compound A to the hydroalcoholic solvent is about 1:(30-100), preferably about 1:50.

[0054] In another embodiment, the present invention provides Compound A hemihydrate. [ka] %. The compound according to claim 1, wherein: Crystalline Form III of Compound A hemihydrate is provided, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of about 10.8±0.2° and 20.5±0.2°.

[0055] In one preferred embodiment, crystalline Form III has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 10.8±0.2°, 19.3±0.2°, 20.5±0.2°, 21.7±0.2°, and 26.9±0.2°.

[0056] In a more preferred embodiment, crystalline Form III has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 10.8±0.2°, 13.0±0.2°, 15.0±0.2°, 15.4±0.2°, 16.5±0.2°, 17.3±0.2°, 19.3±0.2°, 19.9±0.2°, 20.5±0.2°, 21.7±0.2°, 23.3±0.2°, 25.1±0.2°, 26.5±0.2°, 26.9±0.2°, 28.7±0.2°, and 32.2±0.2°.

[0057] In a more preferred embodiment, crystalline Form III has an XRPD pattern comprising peaks at the following diffraction angles (2θ):

[0058] [Table 3]

[0059] In a more preferred embodiment, crystalline Form III has an XRPD pattern comprising peaks at diffraction angles (2θ) essentially the same as those shown in Figure 6. In a most preferred embodiment, the XRPD peak positions for crystalline Form III are essentially the same as those shown in Figure 6.

[0060] In a more preferred embodiment, crystalline Form III has a DSC graph comprising an endothermic peak at about 62.2°C and an endothermic / exothermic peak at about 245 / 255°C.

[0061] In a more preferred embodiment, crystalline Form III has a weight loss of about 3.6% when heated to about 80° C. by thermogravimetric analysis.

[0062] In a more preferred embodiment, crystalline Form III has a DSC graph containing characteristic peaks essentially similar to that shown in Figure 7. In a most preferred embodiment, crystalline Form III has a DSC graph essentially similar to that shown in Figure 7.

[0063] In some preferred embodiments, the present invention provides a method for preparing crystalline Form III, comprising dissolving Compound A in a good solvent (e.g., at room temperature) to form a solution (the mixture can be filtered if necessary to provide a solution), then adding an anti-solvent thereto and stirring (the addition of the anti-solvent and stirring is carried out, for example, at room temperature), precipitating a solid, which is filtered to obtain the crystalline form.

[0064] In some preferred embodiments, the good solvent is a sulfone or sulfoxide having 2 to 10 carbon atoms, including but not limited to dimethylsulfoxide; the anti-solvent is preferably water.

[0065] In some preferred embodiments, the weight / volume ratio (g / mL) of compound A to the good solvent is about 1:(1-20), preferably about 1:12.5.

[0066] In some preferred embodiments, the volume ratio of the good solvent to the anti-solvent is about 1:1 to 1:3.

[0067] In another embodiment, the present invention provides Compound A sesquihydrate. [ka] 4. Crystalline Form IV of the compound of the formula: Crystalline Form IV of Compound A sesquihydrate is provided, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of about 12.3±0.2°, 21.3±0.2°, and 24.1±0.2°.

[0068] In a preferred embodiment, crystalline Form IV has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 12.3±0.2°, 12.6±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.3±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2°, and 27.9±0.2°.

[0069] In a more preferred embodiment, crystalline Form IV has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 12.3±0.2°, 12.6±0.2°, 14.3±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.3±0.2°, 23.2±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2°, 25.7±0.2°, 27.9±0.2°, 31.2±0.2°, and 31.7±0.2°.

[0070] In a more preferred embodiment, crystalline Form IV has an XRPD pattern comprising peaks at the following diffraction angles (2θ):

[0071] [Table 4]

[0072] In a more preferred embodiment, crystalline Form IV has an XRPD pattern comprising peaks at diffraction angles (2θ) essentially the same as those shown in Figure 8. In a most preferred embodiment, the XRPD peak positions for crystalline Form IV are essentially the same as those shown in Figure 8.

[0073] In a more preferred embodiment, crystalline Form IV has a DSC graph comprising an endothermic peak at about 42.6°C, an endothermic peak at about 66.9°C, and an endothermic / exothermic peak at about 245 / 255°C.

[0074] In a more preferred embodiment, crystalline Form IV has a weight loss of about 9.4% when heated to about 100° C. by thermogravimetric analysis.

[0075] In a more preferred embodiment, crystalline Form IV has a DSC-TGA graph containing characteristic peaks essentially the same as that shown in Figure 9. In a most preferred embodiment, crystalline Form IV has a DSC-TGA graph essentially the same as that shown in Figure 9.

[0076] In some preferred embodiments, the present invention provides a method for preparing crystalline form IV, comprising stirring compound A in water (e.g., at room temperature, for example, for 1-5 days, preferably 2-4 days) and filtering to obtain the crystalline form.

[0077] In some preferred embodiments, the weight / volume ratio (g / mL) of compound A to water is about 1:(30-100), preferably about 1:50.

[0078] In some preferred embodiments, the present invention provides a method for preparing crystalline form IV, comprising dissolving compound A in a good solvent (e.g., at room temperature) to form a solution (the mixture can be filtered if necessary to provide a solution), then adding an anti-solvent thereto and stirring (the addition of the anti-solvent and stirring is performed, for example, at room temperature), precipitating a solid, which is filtered to obtain the crystalline form.

[0079] In some preferred embodiments, the good solvent is an ether having 3 to 10 carbon atoms, preferably a cyclic ether, such as furan (including tetrahydrofuran) and dioxane, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane; the antisolvent is preferably water.

[0080] In some preferred embodiments, the weight / volume ratio (g / mL) of compound A to the good solvent is about 1:(50-120), preferably about 1:100.

[0081] In some preferred embodiments, the volume ratio of the good solvent to the anti-solvent is about 1:1 to 1:5.

[0082] In another embodiment, the present invention provides Compound A monohydrate. [ka] Crystal form V of: Crystalline Form V of Compound A monohydrate is provided, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of about 14.1±0.2°, 21.0±0.2°, and 29.6±0.2°.

[0083] In a preferred embodiment, crystalline form V has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 8.7±0.2°, 9.4±0.2°, 11.9±0.2°, 14.1±0.2°, 15.8±0.2°, 16.8±0.2°, 18.9±0.2°, 19.9±0.2°, 20.6±0.2°, 21.0±0.2°, 22.5±0.2° and 29.6±0.2°.

[0084] In a more preferred embodiment, crystalline form V has a molecular weight of about 8.7±0.2°, 9.4±0.2°, 11.6±0.2°, 11.9±0.2°, 12.4±0.2°, 14.1±0.2°, 14.5±0.2°, 15.8±0.2°, 16.2±0.2°, 16.8±0.2°, 17.6±0.2°, 18.2±0.2°, 18.7±0.2°, 19.7±0.2°, 20.7±0.2°, 21.7±0.2°, 22.7±0.2°, 23.7±0.2°, 24.7±0.2°, 25.7±0.2°, 26.7±0.2°, 27.7±0.2°, 28.7±0.2°, 29.7±0.2°, 30.7±0.2°, 31.7±0.2°, 32.7±0.2°, 33.7±0.2°, 34.7±0.2°, 35.7±0.2°, 36.7±0.2°, 37.7±0.2°, 38.7±0.2°, 39.7±0.2°, 40.7±0.2°, 41.7±0.2°, 42.7±0.2°, 43.7±0.2°, 44.7±0.2°, 45.7±0.2°, 46.7±0.2°, 47.7±0.2°, 48.7±0.2°, 49.7±0.2°, 50.7±0.2°, 5 The XRPD pattern includes characteristic peaks at diffraction angles (2θ) of 0.9±0.2°, 19.9±0.2°, 20.6±0.2°, 21.0±0.2°, 22.5±0.2°, 23.0±0.2°, 23.6±0.2°, 24.4±0.2°, 25.2±0.2°, 27.0±0.2° and 29.6±0.2°.

[0085] In a more preferred embodiment, crystalline form V has an XRPD pattern comprising peaks at the following diffraction angles (2θ):

[0086] [Table 5]

[0087] In a more preferred embodiment, crystalline form V has an XRPD pattern comprising peaks at diffraction angles (2θ) essentially the same as those shown in Figure 10. In a most preferred embodiment, the XRPD peak positions of crystalline form V are essentially the same as those shown in Figure 10.

[0088] In a more preferred embodiment, crystalline form V has a DSC graph comprising an endothermic peak at about 52.6°C and an endothermic / exothermic peak at about 245 / 255°C.

[0089] In a more preferred embodiment, crystalline form V has a weight loss of about 6.8% when heated to about 80° C. by thermogravimetric analysis.

[0090] In a more preferred embodiment, crystalline form V has a DSC graph containing characteristic peaks essentially the same as that shown in Figure 11. In a most preferred embodiment, crystalline form V has a DSC graph essentially the same as that shown in Figure 11.

[0091] In some preferred embodiments, the present invention provides a method for preparing crystalline form V, comprising dissolving compound A in a good solvent (e.g., at room temperature) to form a solution (the mixture can be filtered if necessary to provide a solution), then adding an anti-solvent thereto and stirring (the addition of the anti-solvent and stirring is carried out, for example, at room temperature), precipitating a solid, which is filtered to obtain the crystalline form.

[0092] In some preferred embodiments, the good solvent is a sulfone or sulfoxide having 2 to 10 carbon atoms, including but not limited to dimethyl sulfoxide; the anti-solvent is preferably an aqueous alcoholic solvent (preferably an alcohol having 1 to 6 carbon atoms, including but not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol, and tert-butanol).

[0093] In some preferred embodiments, the weight / volume ratio (g / mL) of compound A to the good solvent is about 1:(1-20), preferably about 1:12.5.

[0094] In some preferred embodiments, the volume ratio of the good solvent to the anti-solvent is about 1:1 to 1:3.

[0095] In another embodiment, the present invention provides Compound A monohydrate. [ka] %. The compound according to claim 1, wherein: Crystalline Form VI of Compound A monohydrate is provided, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of about 10.4±0.2°, 12.1±0.2°, 16.6±0.2°, 20.7±0.2°, 22.8±0.2°, and 27.3±0.2°.

[0096] In a preferred embodiment, crystalline Form VI has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 8.7±0.2°, 10.4±0.2°, 12.1±0.2°, 15.4±0.2°, 16.6±0.2°, 19.5±0.2°, 20.7±0.2°, 21.2±0.2°, 22.8±0.2°, and 27.3±0.2°.

[0097] In a more preferred embodiment, crystalline Form VI has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 8.7±0.2°, 10.4±0.2°, 12.1±0.2°, 13.4±0.2°, 14.7±0.2°, 15.4±0.2°, 16.6±0.2°, 17.4±0.2°, 19.5±0.2°, 20.7±0.2°, 21.2±0.2°, 22.1±0.2°, 22.8±0.2°, 23.6±0.2°, 26.0±0.2°, 27.3±0.2°, 28.0±0.2°, and 30.4±0.2°.

[0098] In a more preferred embodiment, crystalline Form VI has an XRPD pattern comprising peaks at the following diffraction angles (2θ):

[0099] [Table 6]

[0100] In a more preferred embodiment, crystalline Form VI has an XRPD pattern comprising peaks at diffraction angles (2θ) essentially the same as those shown in Figure 12. In a most preferred embodiment, the XRPD peak positions for crystalline Form VI are essentially the same as those shown in Figure 12.

[0101] In a more preferred embodiment, crystalline Form VI has a DSC graph that includes an endothermic peak at about 51.6° C., an endothermic peak at about 77.5° C. and an endothermic / exothermic peak at about 245 / 255° C.

[0102] In a more preferred embodiment, crystalline Form VI has a DSC graph containing characteristic peaks essentially the same as that shown in Figure 13. In a most preferred embodiment, crystalline Form VI has a DSC graph essentially the same as that shown in Figure 13.

[0103] In some preferred embodiments, the present invention provides a method for preparing crystalline Form VI, comprising stirring Compound A in a mixture of a ketone solvent (e.g., a ketone having 3-6 carbon atoms, including but not limited to, acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone) and water (e.g., at room temperature) (e.g., for 1-5 days) and filtering to obtain the crystalline form.

[0104] In some preferred embodiments, the volume ratio of ketone solvent to water is about 10:1 to 1:1, preferably about 5:1 to 2:1.

[0105] In some preferred embodiments, the weight / volume ratio (g / mL) of compound A to the mixed solvent is about 1:(1-30), preferably about 1:20.

[0106] In another embodiment, the present invention provides Compound A sesquihydrate. [ka] 4. Crystalline Form VII of the compound of the present invention, Crystalline Form VII of Compound A sesquihydrate is provided, having an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of about 13.1±0.2°, 19.9±0.2°, and 20.2±0.2°.

[0107] In one preferred embodiment, crystalline Form VII has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 13.1±0.2°, 16.9±0.2°, 19.9±0.2°, 20.2±0.2°, 24.9±0.2° and 28.8±0.2°.

[0108] In a more preferred embodiment, crystalline Form VII has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 9.4±0.2°, 10.8±0.2°, 13.1±0.2°, 15.4±0.2°, 16.9±0.2°, 18.8±0.2°, 19.9±0.2°, 20.2±0.2°, 22.2±0.2°, 23.2±0.2°, 24.9±0.2°, 26.4±0.2°, and 28.8±0.2°.

[0109] In a more preferred embodiment, crystalline Form VII has an XRPD pattern comprising peaks at the following diffraction angles (2θ):

[0110] [Table 7]

[0111] In a more preferred embodiment, crystalline Form VII has an XRPD pattern comprising peaks at diffraction angles (2θ) essentially the same as those shown in Figure 14. In a most preferred embodiment, the XRPD peak positions for crystalline Form VII are essentially the same as those shown in Figure 14.

[0112] In a more preferred embodiment, crystalline Form VII has a DSC graph comprising an endothermic peak at about 54.8°C and an endothermic / exothermic peak at about 245 / 255°C.

[0113] In a more preferred embodiment, crystalline Form VII has a weight loss of about 9.5% when heated to about 75° C. by thermogravimetric analysis.

[0114] In a more preferred embodiment, crystalline Form VII has a DSC-TGA graph containing characteristic peaks essentially the same as that shown in Figure 15. In a most preferred embodiment, crystalline Form VII has a DSC-TGA graph essentially the same as that shown in Figure 15.

[0115] In some preferred embodiments, the present invention provides a method for preparing crystalline Form VII, comprising stirring Compound A in a mixture of an alcohol solvent (e.g., an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 1-butanol, 2-butanol, and tert-butanol) and water under heating (e.g., heating to 30-60° C., preferably 50° C.) to obtain a solution (the mixture can be filtered if necessary to provide a solution), cooling the solution (e.g., cooling to 0-10° C., preferably 5° C.), precipitating a solid, and filtering it to obtain the crystalline form.

[0116] In some preferred embodiments, the volume ratio of the alcohol solvent to water is about 5:1 to 0.5:1, preferably about 3:1 to 1:1.

[0117] In some preferred embodiments, the weight / volume ratio (g / mL) of compound A to the mixed solvent is about 1:(20-80), preferably about 1:50.

[0118] In another embodiment, the present invention provides Compound A hemihydrate. [ka] 4. Crystalline Form VIII of the formula: Crystalline Form VIII of Compound A hemihydrate is provided, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of about 13.0±0.2°, 16.8±0.2°, 19.4±0.2°, 21.7±0.2°, 22.9±0.2°, and 27.4±0.2°.

[0119] In a preferred embodiment, crystalline Form VIII has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 10.3±0.2°, 13.0±0.2°, 16.8±0.2°, 19.1±0.2°, 19.4±0.2°, 21.1±0.2°, 21.7±0.2°, 22.9±0.2°, 25.8±0.2°, and 27.4±0.2°.

[0120] In a more preferred embodiment, crystalline Form VIII has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 8.7±0.2°, 10.3±0.2°, 10.8±0.2°, 13.0±0.2°, 14.1±0.2°, 14.8±0.2°, 16.8±0.2°, 17.5±0.2°, 19.1±0.2°, 19.4±0.2°, 21.1±0.2°, 21.7±0.2°, 22.3±0.2°, 22.9±0.2°, 25.8±0.2°, 27.4±0.2°, 27.8±0.2°, 30.4±0.2°, and 31.6±0.2°.

[0121] In a more preferred embodiment, crystalline Form VIII has an XRPD pattern comprising peaks at the following diffraction angles (2θ):

[0122] [Table 8]

[0123] In a more preferred embodiment, crystalline Form VIII has an XRPD pattern comprising peaks at diffraction angles (2θ) essentially the same as those shown in Figure 16. In a most preferred embodiment, the XRPD peak positions for crystalline Form VIII are essentially the same as those shown in Figure 16.

[0124] In a more preferred embodiment, crystalline Form VIII has a DSC graph comprising an endothermic peak at about 50.9°C, an endothermic peak at about 79.1°C, an endothermic peak at about 124.9°C, and an endothermic / exothermic peak at about 245 / 255°C.

[0125] In a more preferred embodiment, crystalline Form VIII has a weight loss of about 3.6% when heated to about 105° C. by thermogravimetric analysis.

[0126] In a more preferred embodiment, crystalline Form VIII has a DSC-TGA graph containing characteristic peaks essentially similar to that shown in Figure 17. In a most preferred embodiment, crystalline Form VIII has a DSC-TGA graph essentially similar to that shown in Figure 17.

[0127] In some preferred embodiments, the present invention provides a method for preparing crystalline Form VIII, comprising stirring Compound A in a mixture of a ketone solvent (e.g., a ketone having 3-6 carbon atoms, including but not limited to acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone) and water under heating (e.g., heating to 30-60° C., preferably 50° C.) to obtain a solution (the mixture can be filtered if necessary to provide a solution), cooling the solution (e.g., cooling to 0-10° C., preferably 5° C.), precipitating a solid, and filtering it to obtain the crystalline form.

[0128] In some preferred embodiments, the volume ratio of the alcohol solvent to water is about 5:1 to 0.5:1, preferably about 3:1 to 1:1.

[0129] In some preferred embodiments, the weight / volume ratio (g / mL) of compound A to the mixed solvent is about 1:(20-80), preferably about 1:50.

[0130] Pharmaceutical compositions, methods of treatment and uses thereof In another embodiment, the present invention provides a pharmaceutical composition comprising any one or more of crystalline Forms I, II, III, IV, V, VI, VII or VIII of the present invention and one or more pharma- ceutically acceptable carriers.

[0131] In another embodiment, the present invention provides the use of crystalline Forms I, II, III, IV, V, VI, VII or VIII of the present invention in the manufacture of a medicament for the prevention or treatment of a disease mediated by P2X3 and / or P2X2 / 3 receptor antagonists.

[0132] In another embodiment, the present invention provides crystalline Forms I, II, III, IV, V, VI, VII or VIII of the present invention for use in the prevention or treatment of a disease mediated by P2X3 and / or P2X2 / 3 receptor antagonists.

[0133] In another embodiment, the present invention provides a method for the prevention or treatment of a disease mediated by P2X3 and / or P2X2 / 3 receptor antagonists, comprising the step of administering to a subject, preferably a mammal, in need thereof a prophylactically or therapeutically effective amount of any one or more of crystalline Forms I, II, III, IV, V, VI, VII or VIII of the present invention.

[0134] In a preferred embodiment, the disease mediated by P2X3 and / or P2X2 / 3 receptor antagonists is a disease of the urinary tract selected from reduced bladder capacity, urinary frequency, urge incontinence, stress incontinence, overactive bladder, prostatic hyperplasia, prostatitis, detrusor hyperreflexia, nocturia, urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis and idiopathic bladder hypersensitivity; inflammatory pain, post-operative pain, visceral pain, toothache, menstrual pain, central pain, burn pain, migraine and cluster headache, nerve injury, neuritis, neuralgia, poisoning, ischemic disorders, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic disorders. pain disorders selected from pain disorders associated with irritable bowel syndrome (IRS), chronic obstructive pulmonary disease (COPD), asthma, and bronchospasm; cardiovascular disorders, preferably hypertension; respiratory disorders selected from chronic obstructive pulmonary disease, asthma, and bronchospasm; gastrointestinal disorders selected from pain disorders associated with irritable bowel syndrome (preferably diarrhea-predominant irritable bowel syndrome), inflammatory bowel disease, biliary colic, renal colic, and gastrointestinal distension.

[0135] As used herein, the term "pharmaceutically acceptable carrier" in the present invention refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered, which is, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0136] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is a typical carrier when the pharmaceutical composition is administered intravenously. Saline and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Oral formulations can include standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutical carriers are described, for example, in Remington's Pharmaceutical Sciences (1990).

[0137] The compositions of the invention can act systemically and / or locally. To achieve this goal, the compositions of the invention can be administered via a suitable route, such as injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or transdermal administration, or topically as oral, buccal, intranasal, transmucosal, ophthalmic formulations, or by inhalation.

[0138] For these administration routes, the compositions of the present invention can be administered in suitable dosage forms.

[0139] Dosage forms can be solid, semi-solid, liquid or gaseous formulations, including, but not limited to, tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, salves, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs and syrups, among others.

[0140] The pharmaceutical compositions of the present invention can be manufactured by any method well known in the art, for example, by means of mixing, dissolving, granulating, dragee-making, wet-milling, emulsifying, lyophilizing processes, and the like.

[0141] As used herein, the term "therapeutically effective amount" refers to that amount of the compound being administered that will relieve to some extent one or more of the symptoms of the disorder being treated.

[0142] Dosage regimen can be adjusted to provide optimal desired response. For example, a single bolus can be administered, or several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the needs of the therapeutic situation. It should be noted that dosage can vary according to the type and severity of the condition to be alleviated, and can include single or multiple administrations. It should be further understood that for any particular individual, specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0143] The amount of the compound of the present invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the judgment of the prescribing physician. In general, an effective dosage is in the range of about 0.0001 to about 50 mg per kg of body weight per day, e.g., about 0.01 to about 10 mg / kg / day, in single or divided doses. For a 70 kg human, an effective dosage would be about 0.007 mg to about 3500 mg / day, e.g., about 0.7 mg to about 700 mg / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases, even higher doses may be utilized without causing any adverse side effects, provided that such higher doses are first divided into several smaller doses for administration throughout the day.

[0144] The content or dosage of the compound of the present invention in the pharmaceutical composition is about 0.01 mg to about 1000 mg, suitably 0.1 to 500 mg, preferably 0.5 to 300 mg, more preferably 1 to 150 mg, particularly preferably 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, and 25 mg.

[0145] Unless otherwise specified, the terms "treat" or "treatment" as used herein means to ameliorate, alleviate, prevent the progression of, or prevent the disorder, condition, or disease to which such term applies, or one or more symptoms of such disorder, condition, or disease.

[0146] As used herein, the term "subject" includes humans or non-human animals. Representative human subjects include human subjects (referred to as patients) with diseases (such as those described herein) or healthy subjects. The term "non-human animals" as used herein includes all vertebrates, such as non-mammals (e.g., birds, amphibians and reptiles), as well as mammals, such as non-human primates, domestic and / or farm animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0147] [Advantageous Effects of the Crystalline Form of the Invention] 1) The preferred crystalline forms of the present invention have good stability, and the color and properties of the crystalline form remain unchanged after long-term storage at ambient temperature (e.g., 180 days of storage). In addition, the preferred crystalline forms of the present invention also have good stability under high temperature or high humidity conditions. For example, after crystalline form I was stored under high temperature conditions (e.g., 60°C) for 30 days, its crystalline form did not change.

[0148] 2) The preferred crystalline form of the present invention has good flowability, is easy to grind, and is suitable for the preparation of pharmaceutical compositions.

[0149] 3) The preparation method of the preferred crystalline form of the present invention is simple and easy to carry out, and the reaction conditions are mild. In addition, multiple purification steps are not required, and the procedure is safe and environmentally friendly, which will facilitate the industrial production of the crystalline form. EXAMPLES

[0150] The present invention will be described in more detail below with reference to examples, which are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope thereof. Those skilled in the art may make some non-essential improvements and adjustments that still fall within the scope of the present invention.

[0151] Unless otherwise specified, all starting materials and reagents utilized in the following examples are commercially available products or can be prepared through known methods.

[0152] The detection instruments and conditions used in the following examples are as follows: (1) X-ray powder diffraction (XRPD) Instrument model: Bruker D8 advance with LynxEye detector Test conditions: the target material of the anode was copper, the light pipe was set at (40 KV 40 mA), the 2θ scanning angle to the sample was 3°-40°, and the scanning step was 0.02°. (2) Differential scanning calorimetry (DSC) Instrument model: TA Discovery DSC 250 (TA Instruments, US) Test conditions: heating rate was 10° C. / min and dry nitrogen was used as the purge gas. (3) Thermogravimetric analysis (TGA) Instrument model: Discovery TGA 55 (TA Instruments, US) Test conditions: automatic weighing in furnace, heating rate of 10° C. / min, dry nitrogen was used as purge gas. (4) Polarized Light Microscopy (PLM) Equipment model: Polarizing microscope ECLIPSE LV100POL (Nikon, JPN)

[0153] Example 1: Preparation of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine (Compound A) (See International Application PCT / CN2018 / 112829, which is incorporated by reference in its entirety)

[0154] [ka]

[0155] Step 1: Compound A-1 (100 g, 0.54 mol) was dissolved in 1,4-dioxane (700 mL), and the starting materials SM1 (136 g, 0.81 mol), K2CO3 (149 g, 1.08 mol), and Pd(PPh3)4 (6.2 g, 5.4 mmol) were added in sequence, followed by purified water (35 mL), and purging with nitrogen three times. Under the protection of nitrogen, the reaction was carried out at 100° C. for 18 hours. LC-MS showed that the reaction of the starting materials was essentially complete. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 1,4-dioxane (200 mL). The filtrate was concentrated under reduced pressure to remove 1,4-dioxane, followed by the addition of purified water (200 mL), and extracted with ethyl acetate (400 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate (100 g) for 30 min, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=20:1 to 10:1) to obtain compound A-2 (79 g, yellow oil, yield: 99.75%).

[0156] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 5.6 Hz, 1H), 8.22 (s, 1H), 7.04 (d, J = 5.6 Hz, 1H), 5.18 (s, 1H), 5.09 (s, 1H), 3.85 (s, 3H), 2.05 (s, 3H); MS m / z (ESI): 150.0 [M+H] + .

[0157] Step 2: Compound A-2 (79 g, 0.53 mol) was dissolved in anhydrous methanol (700 mL), 10% palladium / carbon (16 g) was added, and the reaction was carried out at room temperature under hydrogen (0.4 MPa) for 18 hours. LC-MS showed that a small amount of starting material remained. Palladium / carbon (4 g) was supplemented, and the reaction was continued at room temperature under hydrogen (0.4 MPa) for 18 hours. LC-MS showed that the reaction of starting material was complete. The reaction solution was filtered, the filter cake was washed with methanol (100 mL), and the filtrate was concentrated under reduced pressure to give the crude product compound A-3 (80 g, orange oily liquid, yield: 99.96%).

[0158] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 5.6 Hz, 1H), 8.28 (s, 1H), 6.98 (d, J = 5.6 Hz, 1H), 3.86 (s, 3H), 3.21 - 3.09 (m, 1H), 1.21 (d, J = 7.2 Hz, 6H); MS m / z (ESI): 152.1 [M+H] + .

[0159] Step 3: Compound N,N-dimethylethanolamine (46.3 g, 0.52 mol) was dissolved in n-hexane (400 mL). Under the protection of nitrogen, the reaction was cooled to -15°C to -20°C, and 2.4 M / L n-butyllithium (434 mL, 1.04 mol) was slowly added dropwise. After completion of the dropwise addition, the reaction was held at this temperature for 30 minutes, and then a solution of compound A-3 (40 g, 0.26 mol) in toluene (200 mL) was slowly added dropwise at -15°C to -20°C. After completion of the dropwise addition, the reaction was held at this temperature for 30 minutes. The reaction solution was cooled to -70°C, and a solution of carbon tetrabromide (172.4 g, 0.52 mol) in toluene (500 mL) was slowly added dropwise, and the temperature was adjusted at -70°C to -75°C. After completion of the dropwise addition, the reaction was held at this temperature for 1 hour. LC-MS showed the reaction of starting material was complete. The reaction was quenched by adding water (500 mL) and extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate (400 g) for half an hour, filtered and concentrated. The crude product was isolated by column chromatography on silica gel (petroleum ether:ethyl acetate = 200:1 to 50:1) to give compound A-4 (25 g, pale yellow oily liquid, yield: 41.81%).

[0160] 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.20 (s, 1H), 3.89 (s, 3H), 3.13-3.05 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H); MS m / z (ESI): 229.9 [M+H] + .

[0161] Step 4: Compound A-4 (25 g, 0.11 mol) was dissolved in dichloromethane (300 mL). Under the protection of nitrogen, the reaction was cooled to 0°C-5°C and a solution of boron tribromide (140.3 g, 0.55 mol) was added slowly. After the addition was complete, the reaction solution was warmed to reflux and the reaction was run for 18 h. LC-MS showed that the reaction of the starting material was complete. The reaction solution was cooled to room temperature and slowly added dropwise to 500 g of ice. After the dropwise addition was complete, a saturated solution of sodium bicarbonate was added dropwise to adjust the pH to 7-8. The reaction was filtered, the filter cake was washed three times with ethyl acetate (400 mL), the filtrate was separated and the aqueous phase was extracted again with ethyl acetate (400 mL x 3). All the organic phases were combined, dried over anhydrous sodium sulfate (500 g) for half an hour, filtered, and the filtrate was concentrated under reduced pressure to give compound A-5 (20 g, pale yellow solid, yield: 84.17%).

[0162] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.99 (s, 1H), 6.90 (s, 1H), 3.10 - 3.02 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H); MS m / z (ESI): 215.9 [M+H] + .

[0163] Step 5: Compound A-5 (10 g, 0.047 mol) was dissolved in DMF (50 mL). Under the protection of nitrogen, potassium carbonate (12.8 g, 0.093 mol) and bromoacetonitrile (8.4 g, 0.07 mol) were added successively, and the reaction was stirred at room temperature for 2 h. LC-MS showed the reaction of starting material was complete. The reaction was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL x 4). The combined organic phase was washed with saturated brine (50 mL x 3), added with anhydrous sodium sulfate, dried for half an hour, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was isolated on silica gel by column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give compound A-6 (4 g, pale yellow solid, yield: 33.38%).

[0164] 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.40 (s, 1H), 5.37 (s, 2H), 3.14 - 3.06 (m, 1H), 1.21 (d, J = 6.8 Hz, 6H); MS m / z (ESI): 254.8 [M+H] + .

[0165] Step 6: Compound A-6 (4 g, 0.016 mol) was dissolved in DMF (50 mL). Under the protection of nitrogen, tert-butoxybis(dimethylamino)methane (8.2 g, 0.048 mol) was added and the reaction was heated to 100 °C and stirred for 2 h. LC-MS showed the reaction of starting material was complete. The reaction solution was cooled to room temperature and quenched by adding water (50 mL), then extracted with ethyl acetate (50 mL x 3). The organic phase was then washed with saturated brine (50 mL x 3), anhydrous sodium sulfate was added, dried for half an hour, and filtered. The filtrate was concentrated under reduced pressure and the crude product was isolated on silica gel by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to give compound A-7 (3.8 g, pale yellow solid, yield: 66.90%). MS m / z (ESI): 309.7 [M-45+H] + .

[0166] Step 7: Compound A-7 (3.54 g, 0.01 mol) was dissolved in DMF (25 mL). Under the protection of nitrogen, aniline hydrobromide (2.08 g, 0.012 mol) was added and the reaction was heated to 100 °C and stirred for 2 h. LC-MS showed the reaction of starting material was complete. The reaction solution was cooled to room temperature, quenched by adding water (25 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was then washed with saturated brine (20 mL x 3), added with anhydrous sodium sulfate, dried for half an hour and filtered. The filtrate was concentrated under reduced pressure and the crude product was isolated on silica gel by column chromatography (petroleum ether: ethyl acetate = 20: 1 to 5: 1) to give compound A-8 (3.1 g, pale yellow solid, yield: 86.59%).

[0167] 1 H NMR (400 MHz, DMSO-d6) δ 9.36 (d, J = 12.8 Hz, 1H), 8.28 (s, 1H), 7.95 (d, J = 12.8 Hz, 1H), 7.32 - 7.24 (m, 4H), 7.20 (s, 1H), 6.99 (t, J = 7.2 Hz, 1H), 3.31 - 3.26 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H); MS m / z (ESI): 357.7 [M+H] + .

[0168] Step 8: Guanidine hydrochloride (2.4 g, 25.2 mmol) was added to absolute ethanol (50 mL). Under the protection of nitrogen, sodium methoxide (2.4 g, 25.2 mmol) was added and the reaction was stirred at room temperature for half an hour, followed by the addition of compound A-8 (3 g, 8.4 mmol). After the addition was complete, the reaction solution was heated to reflux and the reaction was carried out for 18 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the crude product was isolated on silica gel by column chromatography (DCM:MeOH=50:1 to 20:1) to obtain compound A-9 (900 mg, pale yellow solid, yield: 33.17%, compound 2).

[0169] 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.62 (s, 1H), 6.56 (s, 1H), 6.47 (s, 2H), 6.06 (s, 2H), 3.32 - 3.27 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H); MS m / z (ESI): 323.7 [M+H] + .

[0170] Step 9: Compound A-9 (3 g, 9.29 mmol) was dissolved in 1,4-dioxane (40 mL), trimethylsilylacetylene (9 g, 92.9 mmol), DIEA (12 g, 92.9 mmol), CuI (0.6 g) and Pd(PPh3)2Cl2 (0.6 g) were added in sequence, and the mixture was purged with nitrogen three times. Under the protection of nitrogen, the reaction was carried out at 50° C. for 2 hours. LC-MS showed that the reaction of the starting material was substantially complete. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with 1,4-dioxane (10 mL), and the filtrate was concentrated under reduced pressure to remove dioxane, followed by the addition of purified water (100 mL) and extraction with ethyl acetate (100 mL×3). The organic phases were combined, anhydrous sodium sulfate (20 g) was added, dried for 30 min, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=20:1 to 5:1) to obtain compound A-10 (2 g, 63.1% yield). MS m / z (ESI): 341.9 [M+H] + .

[0171] Step 10: Compound A-10 (2 g, 5.87 mmol) was dissolved in THF (20 mL) and TBAF (1.53 g, 5.87 mmol) was added. The reaction was carried out at room temperature for 10 min. LC-MS showed that the reaction of the starting material was complete. The reaction solution was rotary evaporated to dryness to give an oily residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=1:3) to give compound A (0.7 g, yellow solid, 44.6% yield).

[0172] 1 H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.56 (s, 1H), 6.50 (s, 1H), 6.41 (s, 2H), 6.01 (s, 2H), 4.20 (s, 1H), 3.37 - 3.31 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H). MS m / z (ESI): 269.8 [M+H] + .

[0173] Example 2: Preparation of Crystalline Form I of Compound A Anhydrate (Method 1) 10.0 g of compound A was added to 100 mL of water, and 6 M hydrochloric acid was added dropwise at 0 °C until the solid was completely dissolved, and the mixture was stirred at room temperature for 1 hour. After the solution was filtered, the filtrate was collected, and 1 M NaOH aqueous solution was added dropwise at 0 °C until the pH was 12, causing a white solid to precipitate. The solid was collected after filtration. The obtained solid was stirred in 100 mL of water for 2 hours, and the solid was filtered. The solid was dried in vacuum at 50 °C for 6 hours, and the obtained solid was the target crystalline form. The XRPD pattern obtained by powder X-ray diffraction detection is shown in Figure 1; the DSC and TGA graphs obtained by DSC and TGA analysis are shown in Figure 2; the sample was observed under a scanning electron microscope, and the crystalline morphology is shown in Figure 3.

[0174] Thermogravimetric analysis (TGA) showed that the crystalline form sample had a weight loss of 0.1% between 25 and 150 °C and that crystalline form I does not contain water of crystallization.

[0175] Example 3: Preparation of Crystalline Form I of Compound A Anhydrate (Method 2) 1.3 g of compound A was added to 100 mL of tetrahydrofuran and stirred at room temperature until dissolution was complete, the resulting solution was filtered, and the filtrate was collected. 300 ml of n-heptane was slowly added dropwise to the filtrate, the mixture was stirred at room temperature overnight to precipitate the solid, and the suspension was filtered to obtain the crystalline form. The XRPD pattern obtained by powder X-ray diffraction detection is the same as that in Figure 1.

[0176] Example 4: Preparation of Crystalline Form I of Compound A Anhydrate (Method 3) 2.0 g of compound A was added to 80 mL of tetrahydrofuran, stirred at 50° C. until dissolution was complete, and filtered while hot. The filtrate was cooled to 5° C., 100 ml of methyl tert-butyl ether was slowly added dropwise to the filtrate, and the mixture was stirred at 5° C. for 30 minutes. The solid was allowed to precipitate, and the suspension was filtered to obtain the crystalline form. The XRPD pattern obtained by powder X-ray diffraction detection is the same as that in FIG. 1.

[0177] Example 5: Preparation of Crystalline Form II of Compound A Monohydrate 2.0 g of compound A was suspended in 100 mL of methanol (containing 1 wt% water) and stirred at room temperature for 3 days, and the solid was collected by filtration. The XRPD pattern obtained by powder X-ray diffraction detection is shown in Figure 4; the DSC and TGA graphs obtained by DSC and TGA analysis are shown in Figure 5. Thermogravimetric analysis (TGA) showed that the crystalline form II contains one molecule of crystal water, since the crystalline form sample had a weight loss of 6.2% between 25 and 100 °C, and the theoretical water content of a sample containing one molecule of crystal water is 6.27%.

[0178] Example 6: Preparation of Crystalline Form III of Compound A Hemihydrate 4.0 g of compound A was added to 50 mL of dimethyl sulfoxide and stirred at room temperature until dissolution was complete. The resulting solution was filtered and the filtrate was collected. 100 ml of water was slowly added dropwise to the filtrate and the resulting mixture was stirred at room temperature overnight to precipitate the solid. The suspension was filtered to obtain the crystalline form. The XRPD pattern obtained by powder X-ray diffraction detection is shown in Figure 6; the DSC and TGA graphs obtained by DSC and TGA analysis are shown in Figure 7. Thermogravimetric analysis (TGA) showed that the crystalline form sample had a weight loss of 3.6% between 25 and 80 °C and the theoretical water content of the sample containing 0.5 molecules of crystal water is 3.24%, so the crystalline form III contains 0.5 molecules of crystal water.

[0179] Example 7: Preparation of Crystalline Form IV of Compound A Sesquihydrate (Method 1) 2.0 g of compound A was suspended in 100 mL water and stirred at room temperature for 3 days, and the solid was collected by filtration. The XRPD pattern obtained by powder X-ray diffraction detection is shown in Figure 8; the DSC and TGA graphs obtained by DSC and TGA analysis are shown in Figure 9. Thermogravimetric analysis (TGA) showed that the crystalline form sample had a weight loss of 9.4% between 25 and 100 °C, and the theoretical water content of the sample containing 1.5 molecules of crystal water is 9.12%, so the crystalline form IV contains 1.5 molecules of crystal water.

[0180] Example 8: Preparation of Crystalline Form IV of Compound A Sesquihydrate (Method 2) 1.3g of compound A was added to 100mL of tetrahydrofuran and stirred at room temperature until dissolution was complete. The resulting solution was filtered and the filtrate was collected. 300ml of water was slowly added dropwise to the filtrate and the mixture was stirred at room temperature overnight to precipitate the solid. The suspension was filtered to obtain the crystalline form. The XRPD pattern obtained by powder X-ray diffraction detection is the same as that in Figure 8.

[0181] Example 9: Preparation of Crystalline Form V of Compound A Monohydrate 4.0 g of compound A was added to 50 mL of dimethyl sulfoxide and stirred at room temperature until dissolution was complete, and the filtrate was collected after filtration. 100 ml of methanol (containing 1 wt% water) was slowly added dropwise to the filtrate and stirred at room temperature overnight to precipitate the solid. The suspension was filtered to obtain the crystalline form. The XRPD pattern obtained by powder X-ray diffraction detection is shown in Figure 10; the DSC and TGA graphs obtained by DSC and TGA analysis are shown in Figure 11. Thermogravimetric analysis (TGA) showed that the crystalline form sample had a weight loss of 6.8% between 25 and 80 °C, and the theoretical water content of a sample containing one molecule of crystal water is 6.27% so that the crystalline form V contains one molecule of crystal water.

[0182] Example 10: Preparation of Crystalline Form VI of Compound A Monohydrate 5.0g of compound A was added to 100mL of a mixed solvent of acetone and water (4 / 1) to form a suspension, which was stirred at room temperature for 3 days, and the solid was filtered out. The XRPD pattern obtained by powder X-ray diffraction detection is shown in Figure 12; the DSC and TGA graphs obtained by DSC and TGA analysis are shown in Figure 13.

[0183] The water content determined by utilizing a V20 Karl Fischer moisture meter was 6.3%, indicating that crystalline form VI contains one molecule of water of crystallization since the theoretical water content of a sample containing one molecule of water of crystallization is 6.27%.

[0184] Example 11: Preparation of Crystalline Form VII of Compound A Sesquihydrate 2.0 g of compound A was added to 100 mL of a mixed solvent of ethanol and water (1 / 1), stirred at 50°C until dissolution was complete, and filtered while hot. The filtrate was slowly cooled to 5°C, and the solid was collected by filtration. The XRPD pattern obtained by powder X-ray diffraction detection is shown in Figure 14; the DSC and TGA graphs obtained by DSC and TGA analysis are shown in Figure 15. Thermogravimetric analysis (TGA) showed that the crystalline form VII contains 1.5 molecules of crystal water, since the theoretical water content of the sample containing 1.5 molecules of crystal water is 9.12%, while the crystalline form sample has a weight loss of 9.5% between 25 and 75°C.

[0185] Example 12: Preparation of Crystalline Form VIII of Compound A Hemihydrate 2.0 g of compound A was added to 100 mL of a mixed solvent of acetone and water (1 / 1), stirred at 50°C until dissolution was complete, and filtered while hot. The filtrate was slowly cooled to 5°C, and the solid was filtered off. The XRPD pattern obtained by powder X-ray diffraction detection is shown in Figure 16; the DSC and TGA graphs obtained by DSC and TGA analysis are shown in Figure 17. Thermogravimetric analysis (TGA) showed that the crystalline form sample had a weight loss of 3.6% between 25 and 105°C, and the theoretical water content of the sample containing 0.5 molecules of crystal water is 3.24%, so the crystalline form VIII contains 0.5 molecules of crystal water.

[0186] Experimental Example Experimental Example 1: Room temperature stability test Crystalline form I prepared in Example 2, crystalline form II prepared in Example 5, crystalline form III prepared in Example 6, crystalline form IV prepared in Example 7, crystalline form V prepared in Example 9, crystalline form VI prepared in Example 10, crystalline form VII prepared in Example 11, and crystalline form VIII prepared in Example 12 were respectively placed in pharmaceutical low density polyethylene bags, sealed, and stored at room temperature for 180 days. XRPD was measured with a Bruker D8 advance powder X-ray diffractometer. The results showed that the samples of crystalline forms I, II, III, IV, V, VI, VII, and VIII had no change in crystal form after 180 days, and had good stability. Figure 18 shows a comparison of the XRPD patterns of crystalline form I before and after storing at room temperature for 180 days.

[0187] Experimental example 2: High temperature stability test The stability of crystalline form I prepared in Example 2 was investigated at 60°C, and the XRPD pattern was measured by a Bruker D8 advance X-ray powder diffractometer (see Figure 19). The results showed that the sample of crystalline form I had no change in crystalline form after 5, 10 and 30 days, and the stability of crystalline form I was excellent.

[0188] Experimental Example 3: High humidity stability test The stability of the crystalline form I prepared in Example 2 was investigated under the condition of 92.5% RH / 25°C, and the XRPD pattern was measured by a Bruker D8 advance powder X-ray diffractometer (see Figure 20). The results showed that the sample of crystalline form I had no change in crystalline form after 5, 10 and 30 days, and the stability of crystalline form I was excellent.

[0189] Experimental Example 4: Physical abrasion stability test The crystalline form I prepared in Example 2 was physically polished for 2 minutes, and then the XRPD pattern was measured by a Bruker D8 advance powder X-ray diffractometer (see FIG. 21). The results showed that the sample of crystalline form I had no change in crystal morphology, and the stability of crystalline form I was excellent.

[0190] In addition to those described herein, various modifications to the present invention will become apparent to those skilled in the art from the preceding description. Such modifications are intended to fall within the scope of the appended claims. Each reference, including all patents, applications, journal articles, books, and any other disclosures referred to in this specification, is incorporated herein by reference in its entirety. Further embodiments are as follows. [Embodiment 1] Compound A anhydride [ka] Crystalline form I of: The characteristic peaks are at diffraction angles (2θ) of about 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 19.8±0.2° and 20.3±0.2°, preferably at diffraction angles (2θ) of about 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2° and 20.3±0.2°, most preferably at diffraction angles (2θ) of about 6.2±0.2°, 10.1±0.2°, 11.9±0.2°, Crystalline Form I of Compound A Anhydrous having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of 12.3±0.2°, 13.9±0.2°, 16.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.3±0.2°, 21.8±0.2°, 23.0±0.2°, 23.6±0.2°, 24.1±0.2°, 26.2±0.2°, 26.5±0.2°, 27.8±0.2°, 28.5±0.2°, 29.3±0.2° and 30.6±0.2°. [Embodiment 2] A method for preparing crystalline Form I of Compound A anhydrate according to embodiment 1, comprising the steps of: 1) adding compound A to water, followed by adding acid, stirring to dissolve compound A to obtain a solution, and optionally filtering to obtain a filtrate; 2) adding a base to the solution or filtrate obtained in step 1) and collecting the precipitated solid by filtration; and 3) adding the resulting solid to water, stirring, filtering to collect the solid, and optionally drying to obtain crystalline Form I; Alternatively, a method comprising dissolving compound A in a good solvent to form a solution, then adding an anti-solvent to the solution, stirring, precipitating the solid, and filtering to obtain the crystalline form. [Embodiment 3] Compound A monohydrate [ka] %. The compound according to claim 1, wherein: The characteristic peaks are at diffraction angles (2θ) of about 13.0±0.2°, 19.5±0.2° and 19.9±0.2°, preferably at diffraction angles (2θ) of about 9.6±0.2°, 13.0±0.2°, 19.5±0.2°, 19.9±0.2° and 22.7±0.2°, most preferably at diffraction angles (2θ) of about 9.6±0.2°, 10.9±0.2°, 13.0±0.2°, 14.9±0.2°, 15.0±0.2°, 16.0±0.2°, 17.0±0.2°, 18 ... Crystalline Form II of Compound A monohydrate having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of 15.2±0.2°, 15.8±0.2°, 16.8±0.2°, 19.5±0.2°, 19.9±0.2°, 22.7±0.2°, 23.7±0.2°, 25.2±0.2°, 26.0±0.2°, 28.5±0.2°, 29.0±0.2°, 30.0±0.2° and 32.5±0.2°. [Embodiment 4] Compound A hemihydrate [ka] %. The compound according to claim 1, wherein: The characteristic peaks are at diffraction angles (2θ) of about 10.8±0.2° and 20.5±0.2°, preferably at diffraction angles (2θ) of about 10.8±0.2°, 19.3±0.2°, 20.5±0.2°, 21.7±0.2° and 26.9±0.2°, most preferably at diffraction angles (2θ) of about 10.8±0.2°, 13.0±0.2°, 15.0±0.2°, 15.4±0.2°, 16.0±0.2°, 17.0±0.2°, 18.0±0.2°, 19.3±0.2°, 20.5±0.2°, 21.7±0.2° and 26.9±0.2°, Crystalline Form III of Compound A hemihydrate having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of 6.5±0.2°, 17.3±0.2°, 19.3±0.2°, 19.9±0.2°, 20.5±0.2°, 21.7±0.2°, 23.3±0.2°, 25.1±0.2°, 26.5±0.2°, 26.9±0.2°, 28.7±0.2°, and 32.2±0.2°. [Embodiment 5] Compound A sesquihydrate [ka] 4. Crystalline Form IV of the compound of the formula: The characteristic peaks are at diffraction angles (2θ) of about 12.3±0.2°, 21.3±0.2° and 24.1±0.2°, preferably at diffraction angles (2θ) of about 12.3±0.2°, 12.6±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.3±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2° and 27.9±0.2°, most .... Crystalline Form IV of Compound A sesquihydrate having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of 0.2°, 12.6±0.2°, 14.3±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.3±0.2°, 23.2±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2°, 25.7±0.2°, 27.9±0.2°, 31.2±0.2° and 31.7±0.2°. [Embodiment 6] Compound A monohydrate

change

change

change

change

Claims

1. Compound A anhydride 【Chemistry 1】 The crystalline form I of Crystalline Form I of Compound A Anhydrate, having an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 19.8±0.2°, and 20.3±0.2°.

2. 2. The crystalline form I of Compound A anhydrate of claim 1, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2° and 20.3±0.2°.

3. 3. The crystalline Form I of Compound A Anhydrous of claim 1 or 2, having an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 6.2±0.2°, 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 16.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.3±0.2°, 21.8±0.2°, 23.0±0.2°, 23.6±0.2°, 24.1±0.2°, 26.2±0.2°, 26.5±0.2°, 27.8±0.2°, 28.5±0.2°, 29.3±0.2° and 30.6±0.2°.

4. The crystalline form I of compound A anhydrate according to any one of claims 1 to 3, having a DSC graph containing endothermic / exothermic peaks at 245 / 255°C.

5. The crystalline form I of Compound A anhydrate according to any one of claims 1 to 4, having a weight loss of 0.1% when heated to 100-150°C in thermogravimetric analysis.

6. A process for preparing crystalline form I of compound A anhydrate according to any one of claims 1 to 5, comprising the following steps: 1) adding compound A to water, followed by adding acid, stirring to dissolve compound A to obtain a solution, and optionally filtering to obtain a filtrate; 2) adding a base to the solution or filtrate obtained in step 1) and collecting the precipitated solid by filtration; and 3) adding the resulting solid to water, stirring, filtering to collect the solid, and optionally drying to obtain crystalline Form I; Alternatively, a method comprising dissolving compound A in a good solvent to form a solution, then adding an anti-solvent to the solution, stirring, precipitating the solid, and filtering to obtain the crystalline form.

7. 7. The method of claim 6, wherein the acid is acetic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid.

8. 7. The method of claim 6, wherein the base is sodium hydroxide, potassium hydroxide or ammonia.

9. the good solvent is a cyclic ether having 3 to 10 carbon atoms, and / or The method of claim 6, wherein the anti-solvent is a carbohydrate having 5 to 10 carbon atoms or a straight chain ether having 2 to 6 carbon atoms.

10. the good solvent is tetrahydrofuran, 2-methyltetrahydrofuran or dioxane; and / or The method of claim 6, wherein the anti-solvent is dichloromethane, trichloromethane, n-hexane, n-heptane, toluene, diethyl ether, diisopropyl ether or methyl tert-butyl ether.

11. The good solvent is tetrahydrofuran, The method of claim 10, wherein the anti-solvent is n-heptane or methyl tert-butyl ether.

12. The method according to claim 6, wherein the weight / volume ratio (g / mL) of compound A to the good solvent is 1:(30 to 120).

13. The method according to claim 6, wherein the weight / volume ratio (g / mL) of compound A to the good solvent is 1:40 or 1:

100.

14. The method according to claim 6, wherein the volume ratio of the good solvent to the anti-solvent is from 1:1 to 1:

5.

15. Compound A monohydrate 【Chemistry 2】 The crystalline form II of Crystalline Form II of Compound A monohydrate having an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 13.0±0.2°, 19.5±0.2°, and 19.9±0.2°.

16. 16. Crystalline Form II of Compound A monohydrate according to claim 15, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of 9.6±0.2°, 13.0±0.2°, 19.5±0.2°, 19.9±0.2° and 22.7±0.2°.

17. 17. Crystalline Form II of Compound A monohydrate according to claim 15 or 16, having an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 9.6±0.2°, 10.9±0.2°, 13.0±0.2°, 14.9±0.2°, 15.8±0.2°, 16.8±0.2°, 19.5±0.2°, 19.9±0.2°, 22.7±0.2°, 23.7±0.2°, 25.2±0.2°, 26.0±0.2°, 28.5±0.2°, 29.0±0.2°, 30.0±0.2° and 32.5±0.2°.

18. Compound A hemihydrate 【Chemistry 3】 The crystalline form III of Crystalline Form III of Compound A hemihydrate having an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 10.8±0.2° and 20.5±0.2°.

19. 20. The crystalline form III of compound A hemihydrate of claim 18, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of 10.8±0.2°, 19.3±0.2°, 20.5±0.2°, 21.7±0.2°, and 26.9±0.2°.

20. 20. The crystalline Form III of Compound A hemihydrate of claim 18 or 19, having an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 10.8±0.2°, 13.0±0.2°, 15.0±0.2°, 15.4±0.2°, 16.5±0.2°, 17.3±0.2°, 19.3±0.2°, 19.9±0.2°, 20.5±0.2°, 21.7±0.2°, 23.3±0.2°, 25.1±0.2°, 26.5±0.2°, 26.9±0.2°, 28.7±0.2° and 32.2±0.2°.

21. Compound A sesquihydrate 【Chemistry 4】 The crystalline form IV of Crystalline Form IV of Compound A sesquihydrate having an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 12.3±0.2°, 21.3±0.2°, and 24.1±0.2°.

22. 22. The crystalline form IV of Compound A sesquihydrate of claim 21, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of 12.3±0.2°, 12.6±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.3±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2° and 27.9±0.2°.

23. 23. The crystalline Form IV of Compound A sesquihydrate of claim 21 or 22, having an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 12.3±0.2°, 12.6±0.2°, 14.3±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.3±0.2°, 23.2±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2°, 25.7±0.2°, 27.9±0.2°, 31.2±0.2° and 31.7±0.2°.

24. Compound A monohydrate 【Chemistry 5】 The crystalline form V of Crystalline Form V of Compound A monohydrate, having an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 14.1±0.2°, 21.0±0.2°, and 29.6±0.2°.

25. 25. Crystalline Form V of Compound A monohydrate according to claim 24, having an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 8.7±0.2°, 9.4±0.2°, 11.9±0.2°, 14.1±0.2°, 15.8±0.2°, 16.8±0.2°, 18.9±0.2°, 19.9±0.2°, 20.6±0.2°, 21.0±0.2°, 22.5±0.2° and 29.6±0.2°.

26. 8.7±0.2°, 9.4±0.2°, 11.6±0.2°, 11.9±0.2°, 12.4±0.2°, 14.1±0.2°, 14.5±0.2°, 15.8±0.2°, 16.2±0.2°, 16.8±0.2°, 17.6±0.2°, 18.2±0.2°, 18.9±0.2°, 19.9±0.2°, 20.6±0.

26. Crystalline Form V of Compound A monohydrate according to claim 24 or 25, having an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 2°, 21.0±0.2°, 22.5±0.2°, 23.0±0.2°, 23.6±0.2°, 24.4±0.2°, 25.2±0.2°, 27.0±0.2° and 29.6±0.2°.

27. Compound A monohydrate 【Chemistry 6】 The crystalline form VI of Crystalline Form VI of Compound A monohydrate, having an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 10.4±0.2°, 12.1±0.2°, 16.6±0.2°, 20.7±0.2°, 22.8±0.2°, and 27.3±0.2°.

28. 28. Crystalline Form VI of Compound A monohydrate according to claim 27, having an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 8.7±0.2°, 10.4±0.2°, 12.1±0.2°, 15.4±0.2°, 16.6±0.2°, 19.5±0.2°, 20.7±0.2°, 21.2±0.2°, 22.8±0.2° and 27.3±0.2°.

29. 29. Crystalline Form VI of Compound A monohydrate according to claim 27 or 28, having an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 8.7±0.2°, 10.4±0.2°, 12.1±0.2°, 13.4±0.2°, 14.7±0.2°, 15.4±0.2°, 16.6±0.2°, 17.4±0.2°, 19.5±0.2°, 20.7±0.2°, 21.2±0.2°, 22.1±0.2°, 22.8±0.2°, 23.6±0.2°, 26.0±0.2°, 27.3±0.2°, 28.0±0.2° and 30.4±0.2°.

30. Compound A sesquihydrate 【Chemistry 7】 The crystalline form VII of Crystalline Form VII of Compound A sesquihydrate having an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 13.1±0.2°, 19.9±0.2°, and 20.2±0.2°.

31. 31. Crystalline Form VII of Compound A sesquihydrate according to claim 30, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of 13.1±0.2°, 16.9±0.2°, 19.9±0.2°, 20.2±0.2°, 24.9±0.2° and 28.8±0.2°.

32. 32. The crystalline form VII of Compound A sesquihydrate of claim 30 or 31, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of 9.4±0.2°, 10.8±0.2°, 13.1±0.2°, 15.4±0.2°, 16.9±0.2°, 18.8±0.2°, 19.9±0.2°, 20.2±0.2°, 22.2±0.2°, 23.2±0.2°, 24.9±0.2°, 26.4±0.2° and 28.8±0.2°.

33. Compound A hemihydrate 【Chemistry 8】 The crystalline form VIII of Crystalline Form VIII of Compound A hemihydrate having an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 13.0±0.2°, 16.8±0.2°, 19.4±0.2°, 21.7±0.2°, 22.9±0.2°, and 27.4±0.2°.

34. 34. Crystalline Form VIII of Compound A hemihydrate according to claim 33, having an XRPD pattern including characteristic peaks at diffraction angles (2θ) of 10.3±0.2°, 13.0±0.2°, 16.8±0.2°, 19.1±0.2°, 19.4±0.2°, 21.1±0.2°, 21.7±0.2°, 22.9±0.2°, 25.8±0.2° and 27.4±0.2°.

35. 35. The crystalline Form VIII of Compound A hemihydrate of claim 33 or 34, having an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 8.7±0.2°, 10.3±0.2°, 10.8±0.2°, 13.0±0.2°, 14.1±0.2°, 14.8±0.2°, 16.8±0.2°, 17.5±0.2°, 19.1±0.2°, 19.4±0.2°, 21.1±0.2°, 21.7±0.2°, 22.3±0.2°, 22.9±0.2°, 25.8±0.2°, 27.4±0.2°, 27.8±0.2°, 30.4±0.2° and 31.6±0.2°.

36. 32. A pharmaceutical composition comprising crystalline form I according to any one of claims 1 to 5, crystalline form II according to any one of claims 15 to 17, crystalline form III according to any one of claims 18 to 20, crystalline form IV according to any one of claims 21 to 23, crystalline form V according to any one of claims 24 to 26, crystalline form VI according to any one of claims 27 to 29, crystalline form VII according to any one of claims 30 to 32 or crystalline form VIII according to any one of claims 33 to 35, and one or more pharma- ceutically acceptable carriers.

37. Use of crystalline form I according to any one of claims 1 to 5, crystalline form II according to any one of claims 15 to 17, crystalline form III according to any one of claims 18 to 20, crystalline form IV according to any one of claims 21 to 23, crystalline form V according to any one of claims 24 to 26, crystalline form VI according to any one of claims 27 to 29, crystalline form VII according to any one of claims 30 to 32 or crystalline form VIII according to any one of claims 33 to 35 in the manufacture of a medicament for the prevention or treatment of a disease mediated by P2X3 and / or P2X2 / 3 receptor antagonists.

38. The disease is a urinary tract disease selected from bladder capacity reduction, frequent urination, urge incontinence, stress incontinence, overactive bladder, prostatic hyperplasia, prostatitis, detrusor hyperreflexia, nocturia, urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, and idiopathic bladder hypersensitivity; inflammatory pain, postoperative pain, visceral pain, toothache, menstrual pain, central pain, pain due to burns, migraine and cluster headache, nerve injury, neuritis, neuralgia, central pain, pain due to burns ...

38. The use according to claim 37, wherein the pain disorder is selected from the group consisting of pain disorders selected from pain associated with toxins, ischemic disorders, interstitial cystitis, cancer pain, viral, parasitic or bacterial infections, post-traumatic disorders and irritable bowel syndrome; cardiovascular disorders; respiratory disorders selected from chronic obstructive pulmonary disease, asthma and bronchospasm; gastrointestinal disorders selected from pain associated with irritable bowel syndrome, inflammatory bowel disease, biliary colic, renal colic and gastrointestinal distension.

39. 39. The use of claim 38, wherein the cardiovascular disease is hypertension and the irritable bowel syndrome is diarrhea-predominant irritable bowel syndrome.

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