Salt-type GLP-1 receptor agonist, crystal form and preparation method thereof, and pharmaceutical composition and application of salt-type GLP-1 receptor agonist

Abstract

The invention discloses a salt-type GLP-1 receptor agonist, a crystal form and a preparation method thereof, and a pharmaceutical composition and an application of the salt-type GLP-1 receptor agonist. In particular, the GLP-1 receptor agonist is (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl) benzyl) oxy) pyridine-2-yl) piperidine-1-yl) methyl)-1-(oxetan-2-yl methyl)-1H-benzo [d] imidazole-6-formic acid. The invention also relates to a preparation method of the GLP-1 receptor agonist.

Description

Salt-type GLP-1 receptor agonist, its crystal form and preparation method, and its pharmaceutical composition and use Technical Field

[0001] The present application relates to a salt of a GLP-1 receptor agonist, a crystal form thereof, and a preparation method thereof, as well as a pharmaceutical composition comprising the salt and the crystal form, and the use of the salt, the crystal form, and the pharmaceutical composition for treating and / or preventing GLP-1 receptor-mediated diseases or related conditions. Background Art

[0002] Diabetes mellitus is a chronic, complex disease characterized by impaired glucose metabolism, caused by absolute or relative insulin deficiency or decreased insulin sensitivity in target cells. It is categorized into type 1 and type 2 diabetes. Type 2 diabetes is an adult-onset endocrine disease characterized by chronic hyperglycemia due to insulin resistance and / or insulin secretion defects. Type 2 diabetes accounts for over 90% of all diabetic patients.

[0003] Insulin and GLP-1 receptor agonists are among the most effective treatments for type 2 diabetes. Insulin preparations remain the most commonly used diabetes medication worldwide, with approximately 30-40% of patients with type 2 diabetes ultimately requiring insulin. GLP-1 preparations primarily include exenatide, liraglutide, and semaglutide. However, current insulin and GLP-1 preparations are primarily peptide-based and injectable. Even oral semaglutide has numerous limitations. Therefore, further development of small-molecule GLP-1 receptor agonists is warranted.

[0004] Other conditions associated with type 2 diabetes include diabetic nephropathy, diabetic eye complications (diabetic retinopathy, diabetes-related uveitis, diabetic cataracts), diabetic foot, diabetic cardiovascular complications, diabetic cerebrovascular disease, diabetic neuropathy, obesity, and hypertension.

[0005] GLP-1 receptor agonists are highly promising drugs, and most are currently administered via injection. The development of oral small-molecule GLP-1 receptor agonists, which can improve patient compliance, is a key development trend for GLP-1 receptor agonists.

[0006] Summary of the Invention

[0007] (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (C 33 H 35FN4O5) is a small molecule GLP-1 receptor agonist, also referred to as Compound I in the specification and claims of this application, and has the following structure:

[0008] In one aspect, the present invention provides a pharmaceutically acceptable salt of Compound I, wherein the salt includes a methanesulfonate salt, a meglumine salt, and a tromethamine salt. The tromethamine salt is preferably (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tromethamine salt (C 33 H 35 FN4O5·C4H 11 NO3), which is also referred to as compound Z in the specification and claims of this application, has the following structure:

[0009] In another aspect, the present invention provides a pharmaceutically acceptable salt of Compound I of the present invention, which is in crystalline form. In some preferred embodiments, the salt is a crystalline form of a mesylate salt, or a crystalline form of a meglumine salt (e.g., Form A), or a crystalline form of Compound Z.

[0010] In some embodiments, the present invention provides the crystalline form of compound Z, including Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form Ix, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S, Form T, Form U, Form V and Form W, preferably Form A, Form P, Form C, Form V and Form W, more preferably Form A and Form V, as described below.

[0011] In another aspect, the present invention provides a method for preparing a pharmaceutically acceptable salt of compound I of the present invention, in particular compound Z of the present invention, wherein compound Z is preferably in a crystalline form, more preferably form A, form P, form C, form V and form W, and even more preferably form A and form V.

[0012] In another aspect, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable salt of compound I of the present invention, in particular a tromethamine salt of the present invention, preferably a crystalline form of compound Z, more preferably form A, form P, form C, form V or form W, even more preferably form A and form V.

[0013] In another aspect, the present invention provides a pharmaceutically acceptable salt of compound I of the present invention, in particular a tromethamine salt of the present invention, preferably a crystalline form of compound Z, more preferably Form A, Form P, Form C, Form V or Form W, even more preferably Form A and Form V, or a pharmaceutical composition of the present invention, for use in treating and / or preventing GLP-1 receptor-mediated diseases and related conditions.

[0014] In another aspect, the present invention provides a pharmaceutically acceptable salt of Compound I of the present invention, in particular a tromethamine salt of the present invention, preferably a crystalline form of Compound Z, more preferably Form A, Form P, Form C, Form V or Form W, even more preferably Form A and Form V, or a pharmaceutical composition of the present invention, for use in the preparation of a medicament for treating and / or preventing GLP-1 receptor-mediated diseases or related conditions.

[0015] In another aspect, the present invention provides a method for treating and / or preventing GLP-1 receptor-mediated diseases or related conditions, comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable salt of compound I of the present invention, in particular a tromethamine salt of the present invention, preferably a crystalline form of compound Z, more preferably Form A, Form P, Form C, Form V or Form W, even more preferably Form A and Form V, or a pharmaceutical composition of the present invention.

[0016] In some embodiments, the GLP-1 receptor mediated disease or related condition is selected from the group consisting of diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, non-alcoholic fatty liver disease, dyslipidemia, and hyperinsulinemia. In some embodiments, the diabetes is selected from the group consisting of type 1 diabetes (T1D) and / or type 2 diabetes (T2DM), idiopathic T1D, early-onset T2DM, latent autoimmune diabetes, atypical diabetes of the juvenile, and gestational diabetes. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is the XRPD spectrum of Compound Z Form A; Figure 2 is the DSC spectrum of the Form A; Figure 3 is the TGA spectrum of the Form A; Figure 4-1 is the 1 H NMR spectrum; Figure 4-2 is the DVS spectrum of the crystalline form A. Figure 4-3 is the DVS spectrum of the amorphous form of Compound I.

[0018] Figure 5 is an XRPD spectrum of the crystal form P of compound Z; Figure 6 is a DSC spectrum of the crystal form P; Figure 7-1 is a TGA spectrum of the crystal form P; Figure 7-2 is a 1 H NMR spectrum.

[0019] Figure 8 is an XRPD spectrum of the crystal form C of compound Z; Figure 9 is a DSC spectrum of the crystal form C; Figure 10-1 is a TGA spectrum of the crystal form C; Figure 10-2 is a 1 H NMR spectrum.

[0020] Figure 11 is an XRPD spectrum of Compound Z Form F; Figure 12 is a DSC spectrum of the Form F; Figure 13-1 is a TGA spectrum of the Form F; Figure 13-2 is a 1 H NMR spectrum.

[0021] Figure 14 is an XRPD spectrum of Compound Z Form G; Figure 15 is a DSC spectrum of the Form G; Figure 16-1 is a TGA spectrum of the Form G; Figure 16-2 is a TGA spectrum of the Form G 1 H NMR spectrum; the XRPD spectrum in Figure 16-3 shows that in the DSC experiment, the Form G is transformed into a mixture of the Form G and Compound Z Form A when heated to 110°C for 5 minutes.

[0022] Figure 17 is an XRPD spectrum of Compound Z Form H; Figure 18 is a DSC spectrum of the Form H; Figure 19-1 is a TGA spectrum of the Form H; Figure 19-2 is a TGA spectrum of the Form H 1 H NMR spectrum.

[0023] FIG20 is an XRPD spectrum of the crystalline form Ix of compound Z; FIG21 is a DSC spectrum of the crystalline form Ix; FIG22-1 is a TGA spectrum of the crystalline form Ix; FIG22-2 is a TGA spectrum of the crystalline form Ix 1 H NMR spectrum.

[0024] Figure 23 is an XRPD spectrum of the crystal form N of compound Z; Figure 24 is a DSC spectrum of the crystal form N; Figure 25-1 is a TGA spectrum of the crystal form N; Figure 25-2 is a TGA spectrum of the crystal form N 1 H NMR spectrum.

[0025] Figure 26 is an XRPD spectrum of the crystal form O of compound Z; Figure 27 is a DSC spectrum of the crystal form O; Figure 28-1 is a TGA spectrum of the crystal form O; Figure 28-2 is a TGA spectrum of the crystal form O 1 H NMR spectrum.

[0026] Figure 29 is the XRPD spectrum of Compound Z Form B.

[0027] Figure 30 is the XRPD spectrum of Compound Z Form D.

[0028] Figure 31 is the XRPD spectrum of Compound Z Form E.

[0029] Figure 32 is the XRPD spectrum of Compound Z Form J.

[0030] Figure 33 is the XRPD spectrum of Compound Z Form K.

[0031] Figure 34 is the XRPD spectrum of Compound Z Form L.

[0032] Figure 35 is the XRPD spectrum of Compound Z Form M.

[0033] Figure 36 is the XRPD spectrum of Compound Z Form Q.

[0034] Figure 37 is the XRPD spectrum of Compound Z Form R.

[0035] Figure 38-1 is the XRPD spectrum of Compound Z Form S; Figure 38-2 is the DSC spectrum of Compound Z Form S; Figure 38-3 is the TGA spectrum of Compound Z Form S.

[0036] Figure 39 is the XRPD spectrum of Compound Z Form T.

[0037] Figure 40 is the XRPD spectrum of Compound Z Form U.

[0038] FIG41 is an XRPD pattern of the amorphous form of Compound 1.

[0039] Figure 42 is the XRPD pattern of Form A of the meglumine salt of Compound 1.

[0040] Figure 43 shows the polymorphic forms of the mesylate salt of Compound 1, wherein: Curve A is the XRPD pattern of the mesylate salt Form A prepared in Example 4; Curve B is the XRPD pattern of the amorphous mesylate salt prepared in Run 1 of Example 5; Curve C is the XRPD pattern of the amorphous mesylate salt prepared in Run 2 of Example 5; Curve D is the XRPD pattern of the amorphous mesylate salt prepared in Run 3 of Example 5.

[0041] Figure 44 is the XRPD pattern of Form A of the hydrochloride salt of Compound 1.

[0042] Figure 45-1 is an XRPD spectrum of the crystal form V of compound Z; Figure 45-2 is a DSC spectrum of the crystal form V; Figure 45-3 is a TGA spectrum of the crystal form V; Figure 45-4 is a 1 H NMR spectrum.

[0043] Figure 46 is the XRPD spectrum of compound Z crystal form W; Figure 47 is the TGA spectrum of the crystal form W.

[0044] The XRPD spectrum of Figure 48 shows that the solid mixture of Form A and Form P of Compound Z in Example 8 was subjected to EtOH system (room temperature and 50°C) to obtain Form A and Form B of Compound Z.

[0045] The XRPD spectrum of Figure 49 shows that the solid mixture of Form A and Form P of Compound Z in Example 8 was prepared in an EtOAc system (room temperature and 50°C) to obtain Form A of Compound Z.

[0046] Figure 50 shows a comparison of the XRPD of the solid before and after testing of the crystalline form of Compound I (free form) in the long-term (25°C / 60% RH) and accelerated (40°C / 75% RH) solid-state stability testing of Example 12.

[0047] 51 shows a comparison of XRPDs of the solid of Compound Z Form A before and after testing in the long-term (25° C. / 60% RH) and accelerated (40° C. / 75% RH) solid-state stability testing of Example 12. DETAILED DESCRIPTION

[0048] The present invention is further explained below. It should be understood that the terms are intended to describe rather than limit the present invention.

[0049] definition

[0050] Unless otherwise stated, all technical terms and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. If there is a contradiction, the definition herein shall prevail. When a certain amount, concentration or other value or parameter is expressed in the form of a range, a preferred range or a preferred upper numerical limit and a preferred lower numerical limit, it should be understood that it is equivalent to specifically revealing any range by combining any pair of upper range limits or preferred numerical values ​​with any lower range limit or preferred numerical value. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range.

[0051] The term "about" when used in conjunction with a numerical variable generally means that the value of that variable and all values ​​of that variable are within experimental error (e.g., within a 95% confidence interval for the mean) or within a range of ±20%, ±10%, ±5%, or ±2% of the stated value.

[0052] As used herein, the term "about" when describing XRPD diffraction angles means that one of ordinary skill in the art considers to be within an acceptable standard error of the stated value, for example, ±0.05, ±0.10, ±0.20, ±0.30, ±1, ±2, or ±3, etc.

[0053] The term "comprising" or its synonyms "including," "containing," and "having" are open ended and do not exclude additional unrecited elements, steps, or ingredients. The expression "consisting of excludes any element, step, or ingredient not specified. The term "consisting essentially of" means that the scope is limited to the specified elements, steps, or ingredients, plus any optional elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the terms "comprising," "including," and similar terms encompass the terms "consisting essentially of" and "consisting of."

[0054] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring.

[0055] Unless otherwise indicated, percentages, parts, etc. herein are by weight.

[0056] As used herein, the term "crystalline form" or "crystal" refers to any solid material that exhibits a three-dimensional ordering, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.

[0057] As used herein, the term "X-ray powder diffraction pattern" or "XRPD pattern" refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. An XRPD pattern is typically characterized by peak positions (abscissa) and / or peak intensities (ordinate).

[0058] As used herein, the term "diffraction angle" or "2θ" refers to the peak position expressed in degrees (°) based on the setup in the X-ray diffraction experiment, and is usually the unit of the abscissa in the diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires that the reflected beam be recorded at an angle of 2θ. It should be understood that the specific 2θ value of a specific crystalline form mentioned herein is intended to represent the 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-Kα (Kα1 The XRPD patterns herein are preferably collected on a Bruker D8 Advance (Bruker, Germany) X-ray powder diffraction analyzer.

[0059] As used herein, the term "substantially the same" or "substantially as shown in Figure X" with respect to X-ray diffraction peaks means that variations in representative peak positions and intensities are taken into account. For example, one skilled in the art will appreciate that peak positions (2θ) will exhibit some variation, typically as much as 0.1 to 0.2 degrees, and that the instrument used to measure diffraction will also introduce some variation. In addition, one skilled in the art will appreciate that relative peak intensities will vary due to instrumental variations, as well as the degree of crystallinity, preferred orientation, the surface of the sample being prepared, and other factors known to one skilled in the art.

[0060] Similarly, as used herein, "substantially as shown in Figure X" with respect to DSC and TGA patterns is also intended to encompass variations associated with these analytical techniques known to those skilled in the art. For example, for well-defined peaks in a DSC pattern, variations of up to ±0.20°C are typical, and even greater (e.g., up to ±1°C) for broad peaks.

[0061] The NMR spectra in this application were preferably collected on a Bruker AVANCE-III or Bruker AVANCE NEO (Bruker, GER) NMR spectrometer, using MeOD-d4 as the solvent unless otherwise stated.

[0062] As used herein, the term "solvent" or "good solvent" means a solvent in which Compound 1 is soluble or has a relatively higher solubility. As used herein, the term "anti-solvent" means a solvent in which Compound 1 is insoluble or substantially insoluble or has a relatively lower solubility. Herein, the terms "solvent" or "good solvent" and "anti-solvent" may also be relative and do not indicate the absolute solubility of Compound 1 therein. The same solvent may act as a good solvent in some cases and as an anti-solvent in other cases.

[0063] As used herein, numerical ranges (e.g., "1 to 10") and subranges thereof (e.g., "2 to 10," "2 to 6," "3 to 10," etc.) encompass any number (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) in the stated numerical range.

[0064] As used herein, the term "room temperature" refers to 20°C ± 5°C.

[0065] I. Pharmaceutically Acceptable Salts of Compound 1

[0066] In one aspect, the present invention provides a pharmaceutically acceptable salt of Compound 1,

[0067] Among these salts are methanesulfonate, meglumine and tromethamine salts.

[0068] In a preferred embodiment, the pharmaceutically acceptable salt is a tromethamine salt, preferably compound Z:

[0069] In another aspect, the present invention provides a method for preparing a pharmaceutically acceptable salt of Compound 1 of the present invention, comprising reacting Compound 1 with a reagent selected from methanesulfonic acid, meglumine and tromethamine in a solvent to obtain the corresponding mesylate, meglumine or tromethamine salt of Compound 1.

[0070] In some embodiments, the present invention provides a method for preparing Compound Z of the present invention, comprising reacting Compound I with tromethamine in a solvent (preferably at room temperature).

[0071] In some embodiments, the solvent is one or a mixture of two or more selected from isopropyl alcohol, methyl isobutyl ketone, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, ethanol, methanol and water. A preferred example of the solvent is isopropyl alcohol.

[0072] In some embodiments, the molar ratio of Compound 1 to tromethamine is from about 2:1 to about 1:2.

[0073] In a salt screening experiment for Compound I, the inventors prepared four salts of Compound I: hydrochloride, methanesulfonate, meglumine, and tromethamine. The inventors found that the purity of the hydrochloride of Compound I was significantly lower than that of the free form of Compound I, while the purity of the methanesulfonate, meglumine, and tromethamine salts of Compound I did not decrease significantly. The inventors repeatedly prepared the methanesulfonate, meglumine, and tromethamine salts of Compound I at the 200 mg level and found that: for the methanesulfonate, no crystals were obtained in various solvents and the salt formation was poor (it tended to form a jelly or oil); for the meglumine, the salt formation was poor (it tended to form a jelly) and dissociated during the drying process; for the tromethamine salt, the salt formation was good and Form A of the tromethamine salt was obtained. The tromethamine salt of Compound I, preferably Compound Z, has better preparability than the methanesulfonate and meglumine salts. By providing a pharmaceutically acceptable salt of Compound I, preferably the tromethamine salt, the present invention improves the physicochemical properties of Compound I, such as providing increased water solubility, improved chemical stability and / or reduced hygroscopicity, thereby improving the bioavailability of Compound I.

[0074] II. Crystalline Forms of Pharmaceutically Acceptable Salts of Compound I

[0075] On the other hand, in order to optimize the absorption rate of the drug and the variation in absorption rate between individuals, the present invention further provides a crystalline form of a pharmaceutically acceptable salt of Compound I, so that the solubility and bioavailability of the salt and its crystalline form are improved.

[0076] Therefore, the present invention provides a pharmaceutically acceptable salt of Compound I of the present invention which is in crystalline form.

[0077] In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a crystalline mesylate salt, such as mesylate crystalline Form A. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a crystalline meglumine salt, such as meglumine crystalline Form A.

[0078] In some preferred embodiments, the pharmaceutically acceptable salt of Compound I is Compound Z in crystalline form.

[0079] At the same time, the inventors noticed that compound Z may exist in mixed crystals, indicating that polymorphism may exist. Therefore, the polymorphism of compound Z was further studied to determine a solid form suitable for drug development.

[0080] III. Crystalline Form of Compound Z

[0081] Therefore, in another aspect, the present invention provides crystalline forms of compound Z, including Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form Ix, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S, Form T, Form U, Form V, and Form W, as described below. Preferred crystalline forms are Form A, Form P, Form C, Form V, and Form W. More preferred crystalline forms are Form A and Form V.

[0082] The present invention also provides a method for preparing the crystal form, including but not limited to slow volatilization, suspension stirring at low temperature (e.g., 4-8°C), suspension stirring at room temperature, suspension stirring at high temperature (e.g., 50°C), anti-solvent addition, anti-antisolvent addition, cooling crystallization, gas-liquid diffusion, gas-solid diffusion, water vapor stress, polymer induction, grinding, rotary evaporation and cyclic heating and cooling.

[0083] i.Crystal Form A

[0084] The present invention provides a crystalline form A of compound Z, characterized in that the X-ray powder diffraction (XRPD) pattern of the crystalline form A includes diffraction peaks at the following diffraction angles (2θ): approximately 3.62±0.20°, 7.28±0.20°, 17.21±0.20° and 20.60±0.20°.

[0085] Alternatively or further, the crystalline form A has any one, two or all of the following characteristics:

[0086] (1) The differential scanning calorimetry (DSC) spectrum of the crystalline form A has an endothermic peak at approximately 159.9°C ± 3.0°C;

[0087] (2) the Form A loses approximately 0.815% weight during heating to approximately 120°C ± 3°C, as measured using thermogravimetric analysis (TGA);

[0088] (3) the crystal form A 1 The H NMR spectrum is basically as shown in Figure 4-1.

[0089] In some preferred embodiments, the XRPD pattern of the crystalline form A further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 14.66±0.20°, 15.55±0.20°, 16.66±0.20°, 21.94±0.20° and 26.04±0.20°. In some preferred embodiments, the XRPD pattern of the crystalline form A further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 7.74±0.20°, 8.54±0.20°, 10.92±0.20°, 15.28±0.20°, 17.73±0.20°, 18.05±0.20°, 18.44±0.20°, 19.47±0.20°, 19.90±0.20°, 22.38±0.20°, 23.18±0.20°, 25.04±0.20°, 27.28±0.20°, 27.82±0.20°, 28.10±0.20°, 29.52±0.20°, 31.06±0.20°, 32.97±0.20°, 33.36±0.20° and 40.57±0.20°.

[0090] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form A includes diffraction peaks at the following diffraction angles (2θ): 3.564°, 7.245°, 7.696°, 8.531°, 14.612°, 15.253°, 15.526°, 16.637°, 17.163°, 17.675°, 17.998°, 18.409°, 19.425°, 20.570°, 21.933°, 22.384°, 23.124°, 25.013°, 26.026°, 29.555° and 33.388°.

[0091] In some preferred embodiments, the DSC spectrum of the crystalline form A is substantially as shown in FIG2 .

[0092] In some preferred embodiments, the TGA spectrum of the crystalline form A is substantially as shown in FIG3 .

[0093] In some more preferred embodiments, the XRPD pattern of the crystalline form A includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG1 , and further more preferably, the XRPD pattern of the crystalline form A is as shown in FIG1 .

[0094] The TGA weight loss of the crystal form A is small, as shown in Figure 4-1. 1 The H NMR spectrum shows no obvious residual solvent. In some embodiments, the crystalline form A is not a solvate. More preferably, the crystalline form A is an anhydrate.

[0095] The crystalline form A of the tromethamine salt is a more thermodynamically stable anhydrate at room temperature and 50°C and has a water activity of w The crystalline form A is stable at a pH of ≤0.388. Furthermore, compared to the free form of Compound I, the crystalline form A has increased water solubility, improved stability (including solid-state stability, high-temperature stability, high-humidity stability, and pressure stability), and lower hygroscopicity. The crystalline form A did not undergo any changes in crystalline form during the solid-state stability, high-temperature stability, high-humidity stability, pressure stability, and hygroscopicity tests.

[0096] On the other hand, the present invention also provides a method for preparing the crystalline form A of the compound Z, which comprises stirring the compound I and tromethamine in a solvent at room temperature to obtain the crystalline form A as a solid precipitate.

[0097] In some embodiments, the solvent is selected from one or more mixtures of isopropyl alcohol, methyl isobutyl ketone, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, ethanol, methanol and water. A preferred example of a solvent is isopropyl alcohol. In some embodiments, the molar ratio of Compound 1 to tromethamine is from about 2:1 to about 1:2. In some embodiments, the stirring at room temperature can be carried out for a suitable period of time, for example, until the salt is completely formed, or for example, for about 3 days.

[0098] ii. Crystal Form P

[0099] The present invention also provides a crystalline form P of compound Z, characterized in that the XRPD spectrum of the crystalline form P includes diffraction peaks at the following diffraction angles (2θ): approximately 3.55±0.20°, 7.31±0.20°, 14.77±0.20°, 17.01±0.20° and 20.44±0.20°.

[0100] Alternatively or further, the crystalline form P has any one, two or all of the following characteristics:

[0101] (1) The DSC spectrum of the crystalline form P has two endothermic peaks at about 152.5°C ± 3.0°C and about 158.1°C ± 3.0°C, respectively;

[0102] (2) the Form P loses about 0.367% of its weight during heating to about 140°C ± 3°C, as measured using TGA;

[0103] (3) The crystal form P 1 The H NMR spectrum is essentially as shown in Figure 7-2.

[0104] In some preferred embodiments, the XRPD pattern of the crystalline form P further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 15.50±0.20°, 18.01±0.20°, 19.06±0.20°, 19.57±0.20°, 22.07±0.20° and 25.23±0.20°.

[0105] In some preferred embodiments, the XRPD of the crystalline Form P includes diffraction peaks at the following diffraction angles (2θ): 3.547°, 7.306°, 14.765°, 15.501°, 17.009°, 18.005°, 19.058°, 19.571°, 20.436°, 22.071°, 22.441° and 25.229°.

[0106] In some preferred embodiments, the DSC spectrum of the crystalline form P is substantially as shown in FIG6 .

[0107] In some preferred embodiments, the TGA spectrum of the crystalline form P is substantially as shown in Figure 7-1.

[0108] In some more preferred embodiments, the XRPD pattern of the crystalline form P includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG5 , and further more preferably, the XRPD pattern of the crystalline form P is as shown in FIG5 .

[0109] The TGA weight loss of the crystal form P is small, as shown in Figure 7-2. 1 The H NMR spectrum shows no obvious residual solvent. In some embodiments, the crystalline form P is not a solvate. More preferably, the crystalline form P is an anhydrate.

[0110] The crystalline form P of the tromethamine salt is an anhydrate that is stable at room temperature. For example, no change in crystalline form P was observed during drying at room temperature for 3 days.

[0111] In another aspect, the present invention also provides a method for preparing the crystalline form P of the compound Z, comprising suspending the compound Z in a mixture of CHCl3:EtOAc (about 1:1, v / v), and stirring the resulting suspension at a suitable temperature to obtain the crystalline form P as a solid precipitate. In some such embodiments, the compound Z is the crystalline form A of the compound Z. In some embodiments, the suitable temperature is, for example, about 1-8°C, such as about 3-8°C, about 4-8°C, or about 5-8°C, preferably about 5°C. In some embodiments, the stirring can be performed for a suitable period of time, for example, about 3 days.

[0112] iii. Form C

[0113] The present invention also provides a crystalline form C of compound Z, characterized in that the XRPD spectrum of the crystalline form C includes diffraction peaks at the following diffraction angles (2θ): approximately 3.88±0.20°, 7.81±0.20°, 15.60±0.20°, 17.49±0.20° and 19.64±0.20°.

[0114] Alternatively or further, the crystalline form C has any one, two or all of the following characteristics:

[0115] (1) The DSC spectrum of the crystalline form C has three endothermic peaks at approximately 81.8°C ± 3.0°C, approximately 93.6°C ± 3.0°C, and approximately 155.2°C ± 3.0°C, respectively;

[0116] (2) Form C loses approximately 4.560% weight during heating to approximately 100°C ± 3°C, as measured using TGA;

[0117] (3) the crystal form C 1 The H NMR spectrum is essentially as shown in Figure 10-2.

[0118] In some preferred embodiments, the XRPD pattern of the crystalline form C further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 14.86±0.20°, 19.99±0.20°, 20.24±0.20°, 22.37±0.20°, 24.21±0.20° and 24.51±0.20°.

[0119] In some preferred embodiments, the XRPD pattern of the crystalline form C further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 10.44±0.20°, 13.13±0.20°, 16.09±0.20°, 19.39±0.20°, 23.57±0.20°, 26.82±0.20°, 27.18±0.20° and 33.37±0.20°.

[0120] In some preferred embodiments, the XRPD pattern of Form C further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 6.50±0.20°, 7.42±0.20°, 9.90±0.20°, 11.74±0.20°, 13.75±0.20°, 18.15±0.20°, 18.49±0.20°, 20.65±0.20°, 21.02±0.20°, 21.25±0.20°, 21.58±0.20°, 21.82 ±0.20°, 22.86±0.20°, 23.15±0.20°, 24.97±0.20°, 25.35±0.20°, 26.05±0.20°, 26.40±0.20°, 27.41±0.20°, 28.17±0.20°, 28.79±0.20°, 30.19±0.20°, 30.63±0.20°, 31.614±0.20°, 31.87±0.20°, 35.09±0.20° and 35.30±0.20°.

[0121] In some preferred embodiments, the XRPD pattern of Form C comprises diffraction peaks at the following diffraction angles (2θ): 3.877°, 6.503°, 7.415°, 7.807°, 9.896°, 10.442°, 11.742°, 13.126°, 13.75°, 14.861°, 15.603°, 16.091°, 17.494°, 18.154°, 18.487°, 19.386°, 19.635°, 19.985°, 20.242°, 20.654°, 21.021° , 21.253°, 21.583°, 21.819°, 22.365°, 22.856°, 23.153°, 23.570°, 24.214°, 24.506°, 24.970°, 25.345°, 26.048°, 26.396°, 26.824°, 27.178°, 27.413°, 28.172°, 28.793°, 30.193°, 30.627°, 31.614°, 31.868°, 33.370°, 35.086°, and 35.303°.

[0122] In some preferred embodiments, the DSC spectrum of the Form C has an exothermic peak at about 125.0±3.0°C.

[0123] In some more preferred embodiments, the DSC spectrum of the crystalline form C is substantially as shown in FIG9 .

[0124] In some preferred embodiments, the TGA spectrum of the crystalline form C is substantially as shown in Figure 10-1.

[0125] In some more preferred embodiments, the XRPD pattern of the crystalline form C includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG8 , and further more preferably, the XRPD pattern of the crystalline form C is as shown in FIG8 .

[0126] In some embodiments, the crystalline Form C is a hydrate.

[0127] The Form C hydrate of the tromethamine salt is stable at room temperature. For example, no change in the crystalline form of the Form C was observed when the Form C was left unopened at room temperature for 3 days. In a DSC test, the Form C transformed into a mixture of the Form C and the Form A of Compound Z described above when heated to 100°C for 5 minutes; and transformed into the Form A of the tromethamine salt described above when heated to 100°C for a further 10 minutes.

[0128] In another aspect, the present invention also provides a method for preparing Form C of Compound Z, comprising suspending Compound Z in a mixed solvent of 1,4-dioxane and H2O, and stirring the resulting suspension at room temperature to obtain Form C as a solid precipitate. In some such embodiments, Compound Z is Form A of Compound Z. In some embodiments, in the mixed solvent, the volume ratio of 1,4-dioxane:H2O is about (3-10):1, for example, about (4-8):1, about (5-7):1, about (5.5-6.5):1, or about 6:1. In some embodiments, the stirring can be carried out for a suitable period of time, for example, about 3 days.

[0129] iv. Form F

[0130] The present invention also provides a crystalline form F of compound Z, characterized in that the XRPD spectrum of the crystalline form F includes diffraction peaks at the following diffraction angles (2θ): approximately 3.33±0.20°, 6.70±0.20°, 10.09±0.20° and 13.48±0.20°.

[0131] Alternatively or further, the crystalline form F has any one, two or all of the following characteristics:

[0132] (1) The DSC spectrum of Form F has four endothermic peaks at approximately 42.5°C ± 3.0°C, approximately 107.8°C ± 3.0°C, approximately 118.3°C ± 3.0°C, and approximately 154.3°C ± 3.0°C, respectively;

[0133] (2) Form F loses approximately 16.719% of its weight upon heating to approximately 180°C ± 3°C, as measured using TGA;

[0134] (3) the crystal form F 1 The H NMR spectrum is essentially as shown in Figure 13-2.

[0135] In some preferred embodiments, the XRPD pattern of the crystalline form F further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 16.89±0.20°, 19.99±0.20°, 20.32±0.20°, 23.75±0.20°, 30.71±0.20°, and 34.23±0.20°.

[0136] In some preferred embodiments, the XRPD of Form F comprises diffraction peaks at the following diffraction angles (2θ): 3.325°, 6.700°, 10.089°, 13.481°, 16.890°, 19.991°, 20.318°, 23.751°, 30.705° and 34.228°.

[0137] In some preferred embodiments, the DSC spectrum of the crystalline form F is substantially as shown in FIG12 .

[0138] In some preferred embodiments, the TGA spectrum of the crystalline form F is substantially as shown in Figure 13-1.

[0139] In some more preferred embodiments, the XRPD pattern of the crystalline form F includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG11 , and further more preferably, the XRPD pattern of the crystalline form F is as shown in FIG11 .

[0140] In some embodiments, the crystalline form F is a solvate, more specifically a solvate with N-methylpyrrolidone (NMP), wherein preferably, the stoichiometric ratio of the compound Z to the NMP is about 1:1.5.

[0141] The crystalline Form F of the tromethamine salt is stable at room temperature. For example, no change in crystalline form was observed when the crystalline Form F was left unopened at room temperature for 3 days. In a DSC test, the crystalline Form F transformed into the above-described Compound Z crystalline Form A upon heating to 120°C for 5 minutes.

[0142] In another aspect, the present invention also provides a method for preparing the crystalline form F of the compound Z, the method comprising:

[0143] (1) providing a clear solution of the compound Z in a mixture of NMP:toluene (e.g., about 1:1, v:v); and

[0144] (2) The solution was added to a container containing isopropyl acetate, and the container was sealed and allowed to stand at room temperature to obtain the crystalline form F as a solid precipitate.

[0145] In some embodiments, the sealed container can be left at room temperature for a suitable period of time, such as about 3 days.

[0146] v. Form G

[0147] The present invention also provides a crystalline form G of compound Z, characterized in that the XRPD spectrum of the crystalline form G includes diffraction peaks at the following diffraction angles (2θ): approximately 3.18±0.20°, 6.43±0.20°, 12.94±0.20°, 17.99±0.20° and 19.95±0.20°.

[0148] Alternatively or further, the crystalline form G has any one, two or all of the following characteristics:

[0149] (1) The DSC spectrum of Form G has three endothermic peaks at approximately 108.7°C ± 3.0°C, approximately 143.7°C ± 3.0°C, and approximately 156.5°C ± 3.0°C, respectively;

[0150] (2) Form G loses approximately 4.9911% weight upon heating to approximately 160°C ± 3°C, as measured using TGA;

[0151] (3) the crystal form G 1 The H NMR spectrum is essentially as shown in Figure 16-2.

[0152] In some preferred embodiments, the XRPD pattern of the crystalline form G further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 9.67±0.20°, 15.73±0.20°, 16.95±0.20°, 18.47±0.20°, 18.70±0.20°, 22.43±0.20°, 24.94±0.20° and 29.46±0.20°.

[0153] In some preferred embodiments, the XRPD pattern of the crystalline form G further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 14.05±0.20°, 14.81±0.20°, 16.69±0.20°, 19.50±0.20°, 21.79±0.20°, 22.17±0.20°, 23.06±0.20°, 23.44±0.20° and 32.794±0.20°.

[0154] In some preferred embodiments, the XRPD of Form G comprises diffraction peaks at the following diffraction angles (2θ): 3.176°, 6.427°, 9.668°, 12.936°, 14.046°, 14.807°, 15.726°, 16.692°, 16.947°, 17.982°, 18.465°, 18.701°, 19.498°, 19.953°, 21.792°, 22.170°, 22.426°, 23.062°, 23.442°, 24.937°, 29.455° and 32.794°.

[0155] In some preferred embodiments, the DSC spectrum of the crystalline form G is substantially as shown in FIG15 .

[0156] In some preferred embodiments, the TGA spectrum of the crystalline form G is substantially as shown in Figure 16-1.

[0157] In some more preferred embodiments, the XRPD pattern of the crystalline form G includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG14 , and further more preferably, the XRPD pattern of the crystalline form G is as shown in FIG14 .

[0158] In some embodiments, the crystalline form G is a solvate, more specifically a solvate with 1,4-dioxane, wherein preferably, the stoichiometric ratio of the compound Z to the 1,4-dioxane is about 1:0.4.

[0159] The Form G tromethamine salt is stable at room temperature. For example, no change in form was observed when Form G was left unattended at room temperature for three days. In a DSC test, Form G transformed into a mixture of Form G and Compound Z Form A described above upon heating to 110°C for five minutes, as shown in Figure 16-3.

[0160] In another aspect, the present invention also provides a method for preparing the crystalline form G of the compound Z, comprising suspending the compound Z in a mixture of 1,4-dioxane:EtOAc (e.g., about 1:1, v:v), and stirring the resulting suspension at a suitable temperature to obtain the crystalline form G as a solid precipitate. In some such embodiments, the compound Z is the crystalline form A of the compound Z. In some embodiments, the suitable temperature is, for example, about 1-8°C, such as about 3-8°C, about 4-8°C, or about 5-8°C, preferably about 5°C. In some embodiments, the stirring can be performed for a suitable period of time, for example, about 3 days.

[0161] vi. Crystal Form H

[0162] The present invention also provides a crystalline form H of compound Z, characterized in that the XRPD spectrum of the crystalline form H includes diffraction peaks at the following diffraction angles (2θ): approximately 3.25±0.20°, 6.56±0.20°, 15.97±0.20°, 18.19±0.20° and 19.91±0.20°.

[0163] Alternatively or further, the crystalline form H has any one, two or all of the following characteristics:

[0164] (1) The DSC spectrum of the crystalline form H has two endothermic peaks at approximately 144.47°C ± 3.0°C and approximately 160.98°C ± 3.0°C, respectively;

[0165] (2) Form H loses approximately 8.668% of its weight upon heating to approximately 170°C ± 3°C, as measured using TGA;

[0166] (3) The crystal form H 1 The H NMR spectrum is essentially as shown in Figure 19-2.

[0167] In some preferred embodiments, the XRPD pattern of the crystalline form H further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 16.93±0.20°, 17.26±0.20°, 19.42±0.20°, 19.60±0.20° and 23.20±0.20°.

[0168] In some preferred embodiments, the XRPD pattern of the crystalline form H further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 11.28±0.20°, 13.21±0.20°, 14.72±0.20°, 15.25±0.20°, 15.41±0.20°, 16.38±0.20°, 17.86±0.20°, 18.78±0.20°, 19.08±0.20°, °, 20.24±0.20°, 20.60±0.20°, 21.00±0.20°, 21.49±0.20°, 22.19±0.20°, 22.595±0.20°, 24.43±0.20°, 25.83±0.20°, 26.28±0.20°, 28.56±0.20°, 29.17±0.20°, 29.73±0.20° and 30.03±0.20°.

[0169] In some preferred embodiments, the XRPD pattern of the crystalline form H comprises diffraction peaks at the following diffraction angles (2θ): 3.253°, 6.563°, 11.275°, 13.207°, 14.715°, 15.248°, 15.407°, 15.974°, 16.384°, 16.928°, 17.261°, 17.859°, 18.194°, 18.7 76°, 19.082°, 19.422°, 19.598°, 19.911°, 20.238°, 20.601°, 21.001°, 21.491°, 22.190°, 22.595°, 23.202°, ​​24.432°, 25.826°, 26.282°, 28.559°, 29.165°, 29.727°, 30.030°.

[0170] In some preferred embodiments, the DSC spectrum of the crystalline form H is substantially as shown in FIG18 .

[0171] In some preferred embodiments, the TGA spectrum of the crystalline form H is substantially as shown in Figure 19-1.

[0172] In some preferred embodiments, the XRPD pattern of the crystalline form H includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG17 , and further more preferably, the XRPD pattern of the crystalline form H is as shown in FIG17 .

[0173] In some embodiments, the crystalline form H is a solvate, more specifically a solvate with tetrafluoroethylene (TFE), wherein preferably, the stoichiometric ratio of the compound Z to the TFE is about 1:0.65.

[0174] In the DSC test, the Form H was transformed into the above-mentioned Compound Z Form A when heated to 140°C for 5 minutes.

[0175] In another aspect, the present invention also provides a method for preparing Form H of Compound Z, the method comprising:

[0176] (1) providing a clear solution of the compound Z in TFE; and

[0177] (2) heating and evaporating the solution to obtain the crystalline form H as a solid product.

[0178] In some embodiments, the solution is heated to a temperature of about 40-70° C., such as about 45-65° C. or about 50-60° C., preferably about 50° C. In some embodiments, the solution is rotary evaporated.

[0179] vii. Crystal Form Ix

[0180] The present invention also provides a crystalline form Ix of compound Z, characterized in that the XRPD spectrum of the crystalline form Ix includes diffraction peaks at the following diffraction angles (2θ): approximately 3.25±0.20°, 6.58±0.20°, 13.21±0.20°, 17.54±0.20° and 20.63±0.20°.

[0181] Alternatively or further, the crystalline form Ix has any one, two or all of the following characteristics:

[0182] (1) The DSC spectrum of the crystalline form Ix has five endothermic peaks at approximately 44.32°C ± 3.0°C, approximately 58.81°C ± 3.0°C, approximately 77.47°C ± 3.0°C, approximately 97.14°C ± 3.0°C, and approximately 155.71°C ± 3.0°C, respectively;

[0183] (2) Form Ix loses approximately 5.416% weight upon heating to approximately 100°C ± 3°C, as measured using TGA;

[0184] (3) the crystal form Ix 1 The H NMR spectrum is essentially as shown in Figure 22-2.

[0185] In some preferred embodiments, the XRPD pattern of Form Ix further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): approximately 15.51±0.20°, 21.24±0.20°, 23.88±0.20° and 26.59±0.20°.

[0186] In some preferred embodiments, the XRPD pattern of Form Ix further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 8.21±0.20°, 9.41±0.20°, 14.63±0.20°, 16.18±0.20°, 16.99±0.20°, 18.04±0.20°, 18.39±0.20°, 18.93±0.20°, 19.36±0.20°, 22.05±0.20°, 24.97±0.20°, 25.79±0.20°, 28.58±0.20°, 29.46±0.20° and 30.08±0.20°.

[0187] In some preferred embodiments, the XRPD pattern of Form Ix comprises diffraction peaks at the following diffraction angles (2θ): 3.252°, 6.582°, 8.206°, 9.407°, 13.211°, 14.629°, 15.509°, 16.183°, 16.992°, 17.535°, 18.041°, 18.388°, 18.934°, 19.364°, 20.633°, 21.236°, 22.047°, 23.883°, 24.973°, 25.792°, 26.590°, 28.576°, 29.457°, and 30.079°.

[0188] In some preferred embodiments, the DSC spectrum of the crystalline form Ix is substantially as shown in Figure 21.

[0189] In some preferred embodiments, the TGA pattern of the crystalline form Ix is substantially as shown in Figure 22-1.

[0190] In some preferred embodiments, the XRPD pattern of the crystalline form Ix includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG. 20 , and further, the XRPD pattern of the crystalline form Ix is more preferably as shown in FIG. 20 .

[0191] In some embodiments, the crystalline form Ix is a solvate, more specifically a solvate with anisole, wherein preferably, the stoichiometric ratio of the compound Z to the anisole is about 1:0.4.

[0192] The tromethamine salt Form Ix is stable at room temperature. For example, no change in form was observed when Form Ix was left unattended at room temperature for three days. In a DSC test, Form Ix transformed into Compound Z Form A described above upon heating to 100°C for five minutes.

[0193] In another aspect, the present invention also provides a method for preparing the crystalline Form Ix of Compound Z, comprising suspending Compound Z in anisole and stirring the resulting suspension at a suitable temperature to obtain the crystalline Form Ix as a solid precipitate. In some such embodiments, Compound Z is Form A of Compound Z. In some embodiments, the suitable temperature is, for example, about 40-70°C, such as about 45-65°C or about 50-60°C, preferably about 50°C. In some embodiments, the stirring can be carried out for a suitable period of time, such as about 3 days.

[0194] viii. Form N

[0195] The present invention also provides a crystalline form N of compound Z, characterized in that the XRPD spectrum of the crystalline form N includes diffraction peaks at the following diffraction angles (2θ): approximately 3.41±0.20°, 6.93±0.20°, 17.20±0.20° and 20.51±0.20°.

[0196] Alternatively or further, the crystalline form N has any one, two or all of the following characteristics:

[0197] (1) The DSC spectrum of the crystalline form N has two endothermic peaks at approximately 120.5°C ± 3.0°C and approximately 160.1°C ± 3.0°C, respectively;

[0198] (2) Form N loses approximately 2.292% weight during heating to approximately 150°C ± 3°C, as measured using TGA;

[0199] (3) the crystal form N 1 The H NMR spectrum is essentially as shown in Figure 25-2.

[0200] In some preferred embodiments, the XRPD pattern of the crystalline form N further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 13.95±0.20°, 14.61±0.20°, 15.76±0.20°, 17.93±0.20°, 19.42±0.20°, 22.02±0.20°, 25.03±0.20° and 25.78±0.20°.

[0201] In some preferred embodiments, the XRPD pattern of the crystalline form N includes diffraction peaks at the following diffraction angles (2θ): 3.409°, 6.933°, 13.948°, 14.611°, 15.762°, 17.201°, 17.934°, 19.419°, 20.513°, 22.016°, 25.032° and 25.776°.

[0202] In some preferred embodiments, the DSC spectrum of the crystalline form N is substantially as shown in FIG24 .

[0203] In some preferred embodiments, the TGA spectrum of the crystalline form N is substantially as shown in Figure 25-1.

[0204] In some more preferred embodiments, the XRPD pattern of the crystalline form N includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 23, and further more preferably, the XRPD pattern of the crystalline form N is as shown in 23.

[0205] In some embodiments, the crystalline Form N is a solvate, more specifically a solvate with 1,4-dioxane. In some embodiments, the solvate is an incompletely solvated crystal. In some embodiments, in the crystalline Form N, the stoichiometric ratio of the compound Z to the 1,4-dioxane is about 1:0.16.

[0206] The crystalline Form N of the tromethamine salt is stable at room temperature. For example, no change in crystalline form was observed when the crystalline Form N was left unopened at room temperature for 3 days. In a DSC test, the crystalline Form N transformed into the above-described Compound Z crystalline Form A upon heating to 130°C for 5 minutes.

[0207] In another aspect, the present invention also provides a method for preparing the crystalline form N of the compound Z, comprising suspending the compound Z in a mixture of acetonitrile (ACN):1,4-dioxane (e.g., about 1:1, v:v), and stirring the resulting suspension to obtain the crystalline form N as a solid precipitate. In some such embodiments, the compound Z is the crystalline form A of the compound Z. In some embodiments, the stirring is performed under cyclic temperature increase and decrease conditions. In some embodiments, the cyclic temperature increase and decrease comprises:

[0208] (1) maintaining a temperature T1 of about 40-70° C. for a time t1 of about 90-150 minutes (min);

[0209] (2) decreasing the temperature from the temperature T1 to a temperature T2 of about 1-8°C at a rate of about 0.1°C / min;

[0210] (3) maintaining the temperature T2 for a time t2 of about 90-150 minutes;

[0211] (4) raising the temperature from the temperature T2 to the temperature T1; and

[0212] (5) Repeat the above sequence from (1) to (4) one or more times;

[0213] The condition is that in the last repetition, only the sequence from (1) to (3) is repeated.

[0214] The temperature T1 is independent in each sequence and can be the same or different. The temperature T2 is independent in each sequence and can be the same or different. In some embodiments, the temperature T1 is a temperature of about 45-65°C or about 50-60°C, preferably about 50°C. In some embodiments, the temperature T2 is such as about 3-8°C, about 4-8°C or about 5-8°C, preferably about 5°C.

[0215] The time t1 is independent in each sequence and can be the same or different. The time t2 is independent in each sequence and can be the same or different. In some embodiments, the time t1 and t2 are each about 100-140 minutes, about 110-130 minutes, or about 120 minutes.

[0216] In some embodiments, the stirring may be performed for a suitable period of time, such as about 3 days.

[0217] In some embodiments, the stirring is carried out for about 3 days under the following cyclic temperature increase and decrease conditions:

[0218] (1) maintaining the temperature at about 50° C. for about 120 minutes (min);

[0219] (2) decreasing the temperature from about 50°C to about 5°C at a rate of about 0.1°C / min;

[0220] (3) Maintain at about 5°C for about 120 minutes;

[0221] (4) increasing the temperature from about 5°C to about 50°C; and

[0222] (5) Repeat the above sequence from (1) to (3) once.

[0223] ix. Crystal Form O

[0224] The present invention also provides a crystalline form O of compound Z, characterized in that the XRPD spectrum of the crystalline form O includes diffraction peaks at the following diffraction angles (2θ): approximately 3.43±0.20°, 7.01±0.20°, 18.00±0.20° and 20.34±0.20°.

[0225] Alternatively or further, the crystalline form O has any one, two or all of the following characteristics:

[0226] (1) The DSC spectrum of the crystalline form O has two endothermic peaks at approximately 120.32°C ± 3.0°C and approximately 156.54°C ± 3.0°C, respectively;

[0227] (2) Form O loses approximately 1.601% weight during heating to approximately 140°C ± 3°C, as measured using TGA;

[0228] (3) The crystal form O 1 The H NMR spectrum is essentially as shown in Figure 28-2.

[0229] In some preferred embodiments, the XRPD pattern of the crystalline form O further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 6.54±0.20°, 13.12±0.20°, 14.12±0.20°, 17.07±0.20°, 23.05±0.20° and 25.91±0.20°.

[0230] In some preferred embodiments, the XRPD pattern of the crystalline form O includes diffraction peaks at the following diffraction angles (2θ): 3.429°, 6.544°, 7.012°, 13.115°, 14.116°, 17.074°, 18.000°, 20.339°, 23.045° and 25.905°.

[0231] In some preferred embodiments, the DSC spectrum of the crystalline form O is substantially as shown in FIG27 .

[0232] In some preferred embodiments, the TGA spectrum of the crystalline form O is substantially as shown in Figure 28-1.

[0233] In some preferred embodiments, the XRPD pattern of the crystalline form O includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 26, and more preferably, the XRPD pattern of the crystalline form O is as shown in Figure 26.

[0234] In some embodiments, the crystalline Form O is a solvate, more specifically a solvate with cyclopentyl methyl ether (CPME). In some embodiments, the solvate is an incompletely solvated crystal. In some embodiments, in the crystalline Form O, the stoichiometric ratio of the compound Z to the CPME is about 1:0.11.

[0235] The crystalline Form O of the tromethamine salt is stable at room temperature. For example, no change in crystalline form was observed when the crystalline Form O was left unopened at room temperature for 3 days. In a DSC test, the crystalline Form O transformed into the above-described Compound Z crystalline Form A upon heating to 130°C for 5 minutes.

[0236] In another aspect, the present invention also provides a method for preparing the crystalline form O of the compound Z, comprising suspending the compound Z in a mixture of acetone:CPME (e.g., about 1:1, v:v), and stirring the resulting suspension at a suitable temperature to obtain the crystalline form O as a solid precipitate. In some such embodiments, the compound Z is the crystalline form A of the compound Z. In some embodiments, the suitable temperature is, for example, a temperature of about 40-70° C., for example, a temperature of about 45-65° C. or about 50-60° C., preferably about 50° C. In some embodiments, the stirring can be carried out for a suitable period of time, for example, about 3 days.

[0237] x. Crystal Form S

[0238] The present invention also provides a crystalline form S of compound Z, whose XRPD pattern includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 38-1. More preferably, the XRPD pattern of the crystalline form S is shown in Figure 38-1.

[0239] In some embodiments, the DSC spectrum of the crystalline form S is substantially as shown in Figure 38-2.

[0240] In some embodiments, the crystalline Form S loses about 5.345% weight during heating to about 160°C ± 3°C, as measured using TGA. In some preferred embodiments, the TGA pattern of the crystalline Form S is substantially as shown in Figure 38-3.

[0241] In some embodiments, the crystalline Form S is a solvate, more specifically a solvate with TFE. In some embodiments, in the crystalline Form S, the stoichiometric ratio of the compound Z to the TFE is about 1:0.45.

[0242] The Form S of the tromethamine salt is stable at room temperature. For example, no change in form was observed when Form S was left unopened at room temperature for one day. In a DSC test, Form S transformed into Compound Z Form A described above upon heating to 140°C for 10 minutes.

[0243] In another aspect, the present invention also provides a method for preparing the crystalline form S of the compound Z, the method comprising:

[0244] (1) providing a clear solution of the compound Z in a mixture of TFE:ACN (e.g., about 1:1, v:v); and

[0245] (2) adding an antisolvent (eg, methyl tert-butyl ether) to the solution under stirring to obtain the crystalline Form S as a solid precipitate.

[0246] xi. Form V

[0247] The present invention also provides a crystalline form V of compound Z, characterized in that the XRPD spectrum of the crystalline form V includes diffraction peaks at the following diffraction angles (2θ): approximately 4.46±0.20°, 8.98±0.20°, 12.88±0.20°, 18.04±0.20° and 19.26±0.20°.

[0248] Alternatively or further, the crystalline form V has any one, two or all of the following characteristics:

[0249] (1) The DSC spectrum of the crystalline form V has two endothermic peaks at approximately 64.5°C ± 3.0°C and approximately 164.8°C ± 3.0°C, respectively;

[0250] (2) Form V loses approximately 2.987% of its weight upon heating to approximately 90°C ± 3°C, as measured using TGA;

[0251] (3) the crystal form V 1 The H NMR spectrum is essentially as shown in Figure 45-4.

[0252] In some preferred embodiments, the XRPD pattern of the Form V further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 16.68±0.20°, 18.39±0.20°, 20.75±0.20°, 23.84±0.20° and 25.42±0.20°.

[0253] In some preferred embodiments, the XRPD pattern of the crystalline Form V further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 9.16±0.20°, 9.39±0.20°, 10.31±0.20°, 12.70±0.20°, 12.99±0.20°, 14.36±0.20°, 14.70±0.20°, 19.46±0.20°, 19.62±0.20°, 21.29±0.20°, 22.03±0.20°, 22.69±0.20°, 22.93±0.20°, 24.23±0.20°, 24.66±0.20° and 27.00±0.20°.

[0254] In some preferred embodiments, the XRPD pattern of the crystalline form V further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 11.89±0.20°, 13.50±0.20°, 16.17±0.20°, 17.71±0.20°, 18.88±0.20°, 19.93±0.20°, 20.20±0.20°, 23.20±0.20°, 25.98±0.20°, 27. 23±0.20°, 28.02±0.20°, 28.40±0.20°, 28.68±0.20°, 29.01±0.20°, 29.81±0.20°, 30.25±0.20°, 31.52±0.20°, 31.87±0.20°, 32.63±0.20°, 33.74±0.20°, 36.47±0.20°, 37.48±0.20° and 7.96±0.20°.

[0255] In some preferred embodiments, the DSC spectrum of the crystalline form V is substantially as shown in Figure 45-2.

[0256] In some preferred embodiments, the TGA spectrum of the crystalline form V is substantially as shown in Figure 45-3.

[0257] In some more preferred embodiments, the XRPD pattern of the Form V includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 45-1, and further more preferably, the XRPD pattern of the Form V is as shown in Figure 45-1.

[0258] In some embodiments, the crystalline Form V is a hydrate.

[0259] The inventors found that, in a DSC test, the crystalline form V was transformed into the crystalline form W of compound Z described below when heated to 100°C for 10 minutes.

[0260] In another aspect, the present invention also provides a method for preparing Form V of Compound Z, the method comprising:

[0261] (1) providing a solution of the compound Z in acetonitrile:water (e.g., about 6:1, v:v) with an elevated temperature;

[0262] (2) transferring the solution to a lower temperature and stirring; and

[0263] (3) filtering and drying the obtained product in a hot air stream to obtain the crystalline form V.

[0264] In some embodiments, the temperature of the solution in step (1) is about 45-70° C., for example, about 50-65° C. or about 50-60° C., preferably about 55° C. In some embodiments, the lower temperature in step (2) is about 20-30° C., for example, about 25° C. In some embodiments, the stirring in step (2) is performed for a suitable period of time, for example, about 3 hours. In some embodiments, the temperature of the hot air stream in step (3) is about 40-70° C., for example, about 45-65° C. or about 50-60° C., preferably about 50° C.

[0265] In other embodiments, the present invention provides another method for preparing Form V of Compound Z, comprising:

[0266] (1) providing a clear solution of the compound Z in methanol with an elevated temperature;

[0267] (2) cooling the solution to a first lower temperature and adding seed crystals of the Form V;

[0268] (3) cooling the solution at a first rate to a second, lower temperature;

[0269] (4) further cooling the solution at a second rate to a third lower temperature; and

[0270] (5) stirring at the third lower temperature and then filtering, and vacuum drying the obtained product to obtain the crystalline form V.

[0271] In some such embodiments, the temperature of the solution described in step (1) is about 50-75°C, for example, about 55-70°C or about 55-65°C, preferably about 60°C. In some embodiments, the first lower temperature described in step (2) is about 30-55°C, for example, about 35-50°C or about 35-45°C, preferably about 40°C. In some embodiments, the second lower temperature described in step (3) is about 10-20°C, for example, about 15°C. In some embodiments, the third lower temperature described in step (4) is about -15 to -25°C, for example, about -18°C. In some embodiments, the first speed described in step (3) is different from, and preferably less than, the second speed described in step (4). Preferably, the first speed is about 5-10°C / h, for example, about 8°C / h. Preferably, the second speed is about 10-15°C / h, for example, about 12°C / h. In some embodiments, the stirring described in step (4) is carried out for a suitable period of time, for example, about 2 hours. In some embodiments, the drying in step (5) is performed at a temperature of about 40-50°C, such as about 40°C, for a suitable period of time, such as about 15-20 hours, such as about 17 hours.

[0272] In other embodiments, the present invention provides another method for preparing Form V of Compound Z, comprising:

[0273] (1) providing a saturated solution of the compound Z in a mixture of ethanol and water;

[0274] (2) suspending a solid mixture of Form V, Form A, and Form C of the compound Z in the saturated solution; and

[0275] (3) The resulting suspension was stirred at room temperature to obtain the crystalline form V as a solid precipitate.

[0276] In some such embodiments, the saturated solution described in step (1) has a water activity of not less than 0.20. In some embodiments, the saturated solution described in step (1) has a water activity of not more than 0.5. In some embodiments, the saturated solution described in step (1) has a water activity of not less than 0.20 and not more than 0.5. In some embodiments, the stirring described in step (3) is carried out for a suitable period of time, such as about 4 days.

[0277] xii. Crystal Form W

[0278] The present invention also provides a crystalline form W of compound Z, characterized in that the XRPD spectrum of the crystalline form W includes diffraction peaks at the following diffraction angles (2θ): approximately 4.62±0.20°, 12.90±0.20°, 18.06±0.20°, 19.40±0.20° and 19.60±0.20°.

[0279] In some preferred embodiments, the XRPD pattern of the crystalline form W further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 14.86±0.20°, 16.74±0.20°, 18.41±0.20°, 18.68±0.20°, 21.63±0.20°, 22.03±0.20°, 22.60±0.20°, 22.99±0.20° and 25.34±0.20°.

[0280] In some preferred embodiments, the XRPD pattern of the crystalline form W further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 9.14±0.20°, 9.37±0.20°, 10.21±0.20°, 15.35±0.20°, 20.52±0.20°, 20.77±0.20°, 23.88±0.20°, 24.27±0.20°, 24.66±0.20°, 27.04±0.20° and 28.01±0.20°.

[0281] In some preferred embodiments, the XRPD pattern of the crystalline form W further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 11.50±0.20°, 12.02±0.20°, 13.93±0.20°, 14.40±0.20°, 23.44±0.20°, 25.81±0.20°, 28.46±0.20°, 30.33±0.20°, 31.60±0.20° and 37.34±0.20°.

[0282] In some more preferred embodiments, the XRPD pattern of the crystalline form W includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 46, and further more preferably, the XRPD pattern of the crystalline form W is as shown in Figure 46.

[0283] In some embodiments, the crystalline form W is not a solvate, and more preferably is an anhydrate.

[0284] The crystalline Form W loses about 1.111% of its weight during heating to about 90°C ± 3°C, as measured using TGA. In some embodiments, the TGA pattern of the crystalline Form W is substantially as shown in FIG. 47 .

[0285] The inventors found that the crystal form W transformed into the crystal form V after being placed at room temperature for 45 minutes.

[0286] On the other hand, the present invention also provides a method for preparing the crystalline form W of compound Z, which comprises heating the crystalline form V of compound Z at about 100° C. for a suitable period of time (e.g., about 10 minutes) under the protection of an inert gas (e.g., nitrogen) to obtain the crystalline form W.

[0287] In another aspect, the present invention provides another method for preparing the crystalline form W of compound Z, the method comprising:

[0288] (1) providing a saturated solution of compound Z in a mixture of ethanol and water;

[0289] (2) suspending a solid mixture of Form V, Form A, and Form C of Compound Z in the saturated solution; and

[0290] (3) The resulting suspension was stirred at room temperature to obtain the crystalline form W as a solid precipitate.

[0291] In some such embodiments, the saturated solution in step (1) has a water activity of no more than 0.12. In some embodiments, the stirring in step (3) is performed for a suitable period of time, such as about 1 day.

[0292] xiii. Other crystal forms

[0293] The present invention also provides metastable crystalline forms of compound Z, including Form B, Form D, Form E, Form J, Form K, Form L, Form M, Form Q, Form R, Form T, and Form U. These crystalline forms transform into mixed crystals with Form A, or other single crystalline forms, such as Form A, Form F, or Form U, preferably Form A, after being left open at room temperature for, for example, 10 minutes, 20 minutes, 30 minutes, 1 hour, 5 hours, 10 hours, 15 hours, 20 hours, 1 day, 2 days, 3 days, or 4 days.

[0294] The XRPD pattern of Form B is substantially as shown in Figure 29 . Form B transforms into mixed crystals of Forms A and B after 10 minutes of airing at room temperature, and transforms into Form A after 25 minutes of airing at room temperature. The XRPD pattern of Form D is substantially as shown in Figure 30 . Form D transforms into mixed crystals of Forms A and D after 3 days of exposure at room temperature, and transforms into Form A after 4 days of exposure at room temperature. The XRPD pattern of Form E is substantially as shown in Figure 31 . Form E transforms into Form A after 3 days of exposure at room temperature. The XRPD pattern of Form J is substantially as shown in Figure 32 . Form J transforms into Form A after 3 days of exposure at room temperature. The XRPD pattern of Form K is substantially as shown in Figure 33 . Form K transforms into Form A after 3 days of exposure at room temperature. The XRPD pattern of Form L is substantially as shown in Figure 34 . Form L transforms into Form A after 3 days of exposure at room temperature. The XRPD pattern of Form M is substantially as shown in Figure 35. Form M transforms into Form E after being left unopened at room temperature for 3 days. The XRPD pattern of Form Q is substantially as shown in Figure 36. Form Q transforms into Form U after being left unopened at room temperature for 1 day. The XRPD pattern of Form R is substantially as shown in Figure 37. Form R transforms into mixed crystals of Forms A and R after being left unopened at room temperature for 1 day. The XRPD pattern of Form T is substantially as shown in Figure 39. Form T transforms into mixed crystals of Forms A and T after being left unopened at room temperature for 3 days. The XRPD pattern of Form U is substantially as shown in Figure 40. Form U transforms into mixed crystals of Forms A and U after being left unopened at room temperature for 1 day, and remains mixed crystals of Forms A and U after being left unopened at room temperature for 10 days.

[0295] IV. Pharmaceutical Compositions

[0296] In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound I of the present invention, wherein the pharmaceutically acceptable salt includes tromethamine salt, mesylate salt and meglumine salt.

[0297] In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a mesylate, preferably a crystalline mesylate, more preferably Form A of the mesylate. The XRPD pattern of Form A of the mesylate is substantially as shown in Curve A of Figure 43 .

[0298] In some embodiments, the pharmaceutically acceptable salt of Compound I is a meglumine salt, preferably a crystalline meglumine salt, more preferably Form A of the meglumine salt. The XRPD pattern of Form A of the meglumine salt is substantially as shown in Figure 42.

[0299] In some preferred embodiments, the pharmaceutically acceptable salt of Compound I is a tromethamine salt of Compound I, preferably Compound Z, more preferably a crystalline form of Compound Z. In some preferred embodiments, the crystalline form of the tromethamine salt is selected from the group consisting of Form A, Form P, Form C, Form F, Form G, Form H, Form Ix, Form N, Form O, Form B, Form D, Form E, Form J, Form K, Form L, Form M, Form Q, Form R, Form S, Form T, Form U, Form V, and Form W of Compound Z of the present invention. In some more preferred embodiments, the crystalline form of the tromethamine salt is selected from the group consisting of Form A, Form P, Form C, Form V, and Form W of Compound Z of the present invention. More preferably, the crystalline form of the tromethamine salt is Form A and Form V.

[0300] The present invention also provides a pharmaceutical composition as described above, which further comprises one, two or more other therapeutically active ingredients.

[0301] The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier.

[0302] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0303] 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, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections. 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 composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer, as needed. Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0304] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0305] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0306] The dosage forms include, but are not limited to, liquid preparations, semisolid preparations, and solid preparations. Solid or semisolid preparations include, but are not limited to, capsules, tablets, pills, lozenges, dragees, granules, powders, ointments, and creams. Liquid preparations include, but are not limited to, elixirs, syrups, emulsions, dispersions, suspensions, solutions, sprays, and drops.

[0307] As used herein, the term "therapeutically effective amount" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the disease or condition being treated.

[0308] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the 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.

[0309] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50mg per kg body weight per day, for example, about 0.01 to about 10mg / kg / day (single or divided administration). For 70kg people, this will add up to about 0.007mg / day to about 3500mg / day, for example, about 0.7mg / day to about 700mg / day. In some cases, it can be enough to be not higher than the dosage level of the lower limit of the aforementioned range, and in other cases, it is still possible to adopt a larger dose in the case of not causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0310] The compound of the present invention may be present in the pharmaceutical composition in an amount ranging from about 0.01 mg to about 1000 mg.

[0311] As used herein, the term "treating" means reversing, alleviating, inhibiting the progression of the disease or condition to which such term applies, or one or more symptoms of such a disease or condition. As used herein, the term "preventing" means preventing or arresting the development of the disease or condition to which such term applies, or the appearance of one or more symptoms of such a disease or condition.

[0312] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0313] V. Uses and treatment methods

[0314] The pharmaceutically acceptable salt of Compound I of the present invention, preferably Compound Z, more preferably the crystalline form thereof as described above, has excellent GLP-1 receptor agonist activity and can treat and / or prevent GLP-1 receptor-mediated diseases and related conditions.

[0315] Therefore, in one aspect, the present invention provides a method for treating and / or preventing GLP-1 receptor-mediated diseases or related conditions, comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable salt of Compound I of the present invention or a pharmaceutical composition of the present invention.

[0316] In another aspect, the present invention provides a pharmaceutically acceptable salt of Compound I of the present invention or a pharmaceutical composition of the present invention, which is used for treating and / or preventing GLP-1 receptor-mediated diseases and related disorders.

[0317] In another aspect, the present invention provides use of a pharmaceutically acceptable salt of Compound I of the present invention or a pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing GLP-1 receptor-mediated diseases or related conditions.

[0318] In another aspect, the present invention provides a method for treating and / or preventing metabolic-related diseases or disorders, comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable salt of Compound I of the present invention or a pharmaceutical composition of the present invention.

[0319] In another aspect, the present invention provides a pharmaceutically acceptable salt of Compound I of the present invention or a pharmaceutical composition of the present invention, which is used for treating and / or preventing metabolism-related diseases or disorders.

[0320] In another aspect, the present invention provides use of a pharmaceutically acceptable salt of Compound I of the present invention or a pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing metabolic-related diseases or disorders.

[0321] In some embodiments, the metabolic-related diseases or disorders include GLP-1 receptor-mediated diseases and related disorders.

[0322] In some embodiments, the GLP-1 receptor mediated disease or related condition is selected from the group consisting of diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, nonalcoholic fatty liver disease, dyslipidemia, and hyperinsulinemia.

[0323] In some embodiments, the diabetes is selected from the group consisting of: T1D and / or T2DM, idiopathic T1D, early-onset T2DM, latent autoimmune diabetes, atypical diabetes of the juvenile, and gestational diabetes.

[0324] In some embodiments, the GLP-1 receptor mediated disease or related condition is obesity.

[0325] In some embodiments, the GLP-1 receptor mediated disease or related condition is T2DM.

[0326] In some embodiments, the GLP-1 receptor mediated disease or related condition is non-alcoholic fatty liver disease.

[0327] In some embodiments, the pharmaceutically acceptable salt is the tromethamine salt of Compound I, preferably Compound Z of the present invention, more preferably the crystalline form of Compound Z described above, further more preferably Form A, Form P, Form C, Form V or Form W of Compound Z, more preferably Form A or Form V. Beneficial effects

[0328] Compound Z of the present invention has good salt formation and better preparability; it improves the physicochemical properties of Compound I, for example, providing increased water solubility, improved chemical stability and / or reduced hygroscopicity, thereby improving the bioavailability of Compound I. The crystalline forms of Compound Z of the present invention (preferably Form A, Form P, Form C, Form V and Form W) have improved physicochemical properties (including improved solubility, dissolution rate, light resistance; low hygroscopicity; improved solid-state stability (high temperature resistance, high humidity resistance, and high pressure resistance) and / or chemical stability), and thus may have better drugability and / or bioavailability. For example, the compound Z crystal form A is a more thermodynamically stable crystal form at room temperature and 50°C, and is stable at a water activity aw ≤ 0.388; under long-term (25°C / 60% RH) and accelerated (40°C / 75% RH) conditions, under high temperature (60°C) conditions, under high humidity (90% RH) conditions, and under high pressure (1000 MPa) conditions, there is no significant decrease in purity, and no crystal form change is observed; compared to the amorphous free form of compound I, it has reduced hygroscopicity. The crystal form V of compound Z is also a stable crystal form at room temperature, and only undergoes crystal transformation under very harsh conditions (transformation to crystal form W when heated to 100°C for 10 minutes); and it also has good stability under high temperature, high humidity, and high pressure conditions. In addition, the crystal form W of compound Z transforms into the more stable crystal form V after being placed at room temperature for 45 minutes.

[0329] Example

[0330] The present invention will be further described below by way of examples. The examples of the present invention are intended only to illustrate the technical solutions of the present invention and are not intended to limit the scope of the present invention. Those skilled in the art may make some non-essential improvements and adjustments, which still fall within the scope of protection of the present invention.

[0331] All solvents used in the examples were commercially available and used without further purification.

[0332] The abbreviations used in this application have the following meanings: rt represents room temperature; H2O represents water; CH2Cl2 represents dichloromethane; THF represents tetrahydrofuran; IPA represents isopropyl alcohol; 2-MeTHF represents 2-methyltetrahydrofuran; NMP represents N-methylpyrrolidone; DME represents ethylene glycol dimethyl ether; DCM represents dichloromethane; Xphos represents 2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl; EtOAc represents ethyl acetate; MeOH represents methanol; 2-Me-THF represents 2-methyltetrahydrofuran; DAS represents 1,2-dihydro-2,4'6'-triisopropylbiphenyl; T represents diethylaminosulfur trifluoride; TFE represents tetrafluoroethylene; ACN represents acetonitrile; CPME represents cyclopentyl methyl ether; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; TFA represents trifluoroacetic acid; TsOH represents p-toluenesulfonic acid; MIBK represents methyl isobutyl ketone; HEP represents n-heptane; IPAc represents isopropyl acetate; EtOAc represents ethyl acetate; DMF represents N,N-dimethylformamide; MTBE represents methyl tert-butyl ether; MEK represents methyl ethyl ketone; CHCl3 represents chloroform; and MCH represents methylcyclohexane.

[0333] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0334] The instruments and parameters used in this application are as follows:

[0335] 1. X-ray powder diffractometer (XRPD)

[0336] Table 1: XRPD test parameters

[0337] 2. Thermogravimetric Analysis (TGA) and Differential Scanning Calorimeter (DSC)

[0338] Table 2: TGA and DSC test parameters

[0339] 3. High Performance Liquid Chromatography (HPLC)

[0340] Table 3: HPLC test parameters

[0341] 4. Dynamic Vapor Sorption (DVS) Determination

[0342] Table 4: DVS test parameters

[0343] 5. H NMR spectroscopy (1 H NMR)

[0344] The nuclear magnetic hydrogen spectrum ( 1 H NMR spectra were acquired on a Bruker AVANCE-III or Bruker AVANCE NEO (Bruker, Germany) NMR spectra using the following parameters: full-spectrum excitation, 20-ppm spectral width single pulse, 8 scans at a 30° excitation angle, digital orthogonal detection, temperature control at 298 K, and MeOD-d4 as solvent.

[0345] Example 1: Preparation of Compound I

[0346] Synthesis route:

[0347] Preparation method:

[0348] Compound 1-2: To a solution of 1-1 (20.0 g, 98.0 mmol) in MeCN (500 mL) was added imidazole (10.0 g, 147.0 mmol), followed by TBSCl (16.3 g, 107.8 mmol). The mixture was stirred at room temperature for 5 hours. H2O (500 mL) was added, and the reaction solution was extracted with EtOAc (3×500 mL). The combined organic phases were washed with brine (500 mL), dried (Na2SO4), filtered, and concentrated. Flash chromatography (SiO2, hexane) afforded 31 g of compound 1-2. Yield: 99.6%. 1 H NMR (400MHz, DMSO-d6) δ7.35(m,3H),4.62(s,2H),0.81(s,9H),0.00(s,6H).

[0349] Compound 1-3: To a solution of 1-2 (20.0 g, 62.8 mmol) in anhydrous THF (200 mL) was added dropwise N-BuLi (2.5 M in THF, 27.6 mL, 69.1 mmol) under N2 at -78°C. The mixture was stirred at this temperature for 0.5 hours, and then oxetane-3-one (4.5 g, 62.8 mmol) was added. The mixture was then stirred at room temperature for 2.5 hours under N2 atmosphere. The reaction solution was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated. Flash chromatography (SiO2, 25% EtOAc-hexane) gave 14 g of compound 1-3. Yield: 71.0%. 1H NMR (400MHz, DMSO-d6) δ7.42–7.33(m,2H),7.26–7.18(m,1H),6.36(s,1H),4.69–4.53(m,6H),0.81(s,9H),-0.00(s,6H).

[0350] Compound 1-4: To a solution of 1-3 (14.0 g, 44.8 mmol) in anhydrous THF (200 mL) was added NaH (3.6 g, 89.7 mmol) at 0°C and the mixture was stirred at room temperature for 2 hours. CS2 (3.6 g, 44.8 mmol) and MeI (6.4 g, 44.8 mmol) were then added at 0°C under N2. The mixture was then stirred at 0°C under N2 for 0.5 hours. The reaction solution was quenched with saturated NH4Cl solution (100 mL) and extracted with EtOAc (3×200 mL). The combined organic phases were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated to give 14 g of compound 1-4. The product was used directly in the next step without further purification.

[0351] Compound 1-5: To a solution of 1-4 (14.0 g, 44.8 mmol) in toluene (200 mL) was added (n-Bu)3SnH (26.2 g, 89.7 mmol), followed by AIBN (736 mg, 4.4 mmol). Under an N2 atmosphere, the mixture was stirred at 125°C for 0.5 h. The reaction solution was concentrated and purified by flash chromatography (SiO2, 20% EtOAc-hexane) to afford 8 g of compound 1-5. Two-step yield: 60.6%. 1 H NMR(400MHz, DMSO-d6)δ7.41(t,J=8.0Hz,1H),7.23–7.16(m,2H),4.91(dd,J=8.3,5.9H z,2H),4.72(s,2H),4.59(t,J=6.3Hz,2H),4.30–4.18(m,1H),0.88(s,9H),0.07(s,6H).

[0352] Compound 1-6: To a solution of 1-5 (8.0 g, 43.0 mmol) in THF (200 mL) was added Et3N·HF3 (13.9 g, 86.0 mmol). The reaction solution was stirred at room temperature under a N2 atmosphere for 16 hours. The reaction solution was concentrated and purified by flash chromatography (SiO2, EtOAc-hexane) to afford 5 g of compound 1-6. Yield: 99.9%. 1H NMR (400MHz, DMSO-d6) δ7.44(t,J=7.8Hz,1H),7.20(t,J=9.1Hz,2H),5.22(t,J=5.7Hz,1H), 4.92(dd,J=8.0,6.1Hz,2H), 4.59(t,J=6.3Hz,2H), 4.52(d,J=5.6Hz,2H), 4.30–4.18(m,1H).

[0353] Compound 1-7: To a solution of 1-6 (4.8 g, 26.3 mmol) in DCM (100 mL) was added NBS (5.2 g, 29.0 mmol), followed by the addition of PPh (7.7 g, 29.0 mmol) at 0°C. The mixture was stirred at room temperature under an N atmosphere for 5 hours. H2O (100 mL) was added, and the reaction solution was extracted with DCM (3×100 mL). The combined organic phases were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (SiO2, EtOAc-hexane) afforded 2 g of compound 1-7. Yield: 30.7%. 1 H NMR (400MHz, DMSO-d6) δ7.53(t,J=8.0Hz,1H),7.33–7.20(m,2H),4.92(dd,J=8.3,6.0Hz,2H),4.70(s,2H),4.60(t,J=6.3Hz,2H),4.34–4.20(m,1H).

[0354] Compound 1-8: Mixture 1-7 (600 mg, 2.45 mmol) and tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (684 mg, 2.45 mmol) were added to a solvent DMF (50 mL). Cs2CO3 (2.4 g, 7.37 mmol) was then added. The reaction solution was stirred at room temperature for 16 hours. H2O (50 mL) was added and the reaction solution was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated. Flash chromatography (SiO2, EtOAc-hexane) was used to purify 500 mg of compound 1-8. Yield: 45.9%. 1H NMR(400MHz, CDCl3)δ7.60(t,J=7.7Hz,1H),7.46(t,J=7.6Hz,1H),7.17(s,1H), 7.13(d,J=11.4Hz,1H),6.75(d,J=7.3Hz,1H),6.68(d,J=8.1Hz,1H),5.43(d,J=7.5Hz,3H),5.33(s,1H),4.45(s, 2H),4.14(d,J=14.0Hz,2H),3.03(t,J=12.8Hz,1H),2.80(t,J=12.9Hz,2H),1.85(d,J=12.5Hz,2H),1.57-1.61(m 3H),1.42(s,9H). / LC-MS(ESI)m / z:443.2[M + H] + .

[0355] Compound 1-9: TFA (10 mL) was added to a DCM (10 mL) solution of 1-8 (210 mg, 0.49 mmol). The reaction solution was stirred at room temperature for 3 hours and concentrated to obtain 250 mg of compound 1-9. LC-MS: MC20-1128-086C (ESI) m / z: 343.1 [M + H] + .

[0356] Compound 1-10: Mixture 1-9 (200 mg, 0.58 mmol) and (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (172 mg, 0.58 mmol) were added to a solvent of dioxane (20 mL) and MeCN (12 mL), followed by the addition of K2CO3 (162 mg, 1.16 mmol). The reaction solution was stirred at 65°C for 3 hours. H2O (20 mL) was added, and the reaction solution was extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. Flash chromatography (SiO2, EtOAc-hexane) gave 60 mg of compound 1-10. Yield: 22.0%. 1H NMR (400MHz, DMSO-d6) δ8.30 (d, J=1.1Hz, 1H), 7.82 (dd, J=8.5, 1.6Hz, 1H), 7. 70–7.59(m,2H),7.53(t,J=7.8Hz,1H),7.27(d,J=11.3Hz,1H),7.21(d,J=9.5 Hz,1H),6.86(d,J=7.4Hz,1H),6.65(d,J=8.0Hz,1H),5.38(s,2H),5.35–5.30 (m,1H),5.12(qd,J=7.0,2.5Hz,1H),4.90(dd,J=8.3,6.0Hz,2H),4.80-4.84(m 1H),4.65-4.71(m,1H),4.58(t,J=6.4Hz,2H),4.47(dt,J=8.3,6.5Hz,1H),4.37(d t,J=9.1,5.9Hz,1H),4.21-4.28(m,1H),3.94-4.02(m,1H),3.87(s,3H),3.78(d,J= 13.6Hz,1H),3.01(d,J=9.4Hz,1H),2.85(d,J=13.5Hz,1H),2.73–2.59(m,2H),2.2 7(d,J=10.0Hz,1H),2.17(d,J=11.6Hz,1H),1.76(m,4H). / LC-MS(ESI)m / z:601.4[M + H] + .

[0357] Compound 1: To a solution of 1-10 (60 mg, 0.1 mmol) in MeOH (1 mL) and THF (5 mL) was added 1 M LiOH (2 mL). The reaction solution was stirred at room temperature for 3 hours, concentrated, and purified by preparative HPLC to give 10.95 mg of a white solid, Compound 1. Yield: 18.6%. 1H NMR (400MHz, DMSO-d6) δ8.20(s,1H),7.79(dd,J1=4.0Hz,,J2=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.54(t,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),7. 27(d,J=12.0Hz,1H),7.21(d,J=8.0Hz,1H),6.87(d,J=8.0Hz,1H),6.65( d,J=8.0Hz,1H),5.38(s,2H),5.12(m,1H),4.90(dd,J=8.0Hz,2H),4.77( dd,J1=4.0Hz,J2=16.0Hz,1H),4.64(d,J=4.0Hz,1H),4.58(m,2H),4.50– 4.44(m,1H),4.38(m,1H),4.29–4.19(m,1H),3.94(d,J=12.0Hz,1H),3.7 7(d,J=12.0Hz,1H),3.00(d,J=12.0Hz,1H),2.86(d,J=12.0Hz,1H),2.71 (m,1H),2.64–2.56(m,1H),2.47–2.42(m,1H),2.21(m,2H),1.73(m,4H).

[0358] XRPD analysis showed that Compound 1 was in an amorphous form. Its XRPD pattern is shown in FIG41 .

[0359] Example 2. GLP-1R agonist activity assay of compound I

[0360] (1) Testing instruments and reagents

[0361] Table 5: Bioactivity test instruments and reagents

[0362] (2) GLP-1R test kit

[0363] GLP-1R mediated agonist activity is determined by a cell-based functional assay using a homogeneous time-resolved fluorescence (HTRF) cAMP detection kit that measures cAMP levels in cells. This method is a competitive immunoassay. It enables direct pharmacological characterization of compounds that act on Gs-coupled receptors in adherent or suspension cells.

[0364] Native cAMP produced by cells or unlabeled cAMP standard curve competes with D2-labeled cAMP red receptor for binding to a monoclonal anti-cAMP cryptate europium donor. The specific signal is inversely proportional to the concentration of cAMP in the standard or experimental sample.

[0365] The human GLP-1R coding sequence (NCBI reference sequence NP_002053.3) was subcloned into pEGFP-N1 (tsingke), and cell lines stably expressing the receptor were isolated. The GLP-1R expression density was confirmed by observing GFP expression under a fluorescence microscope.

[0366] (3) GLP-1R-GFP-293A cell culture

[0367] 293A GFP-GLP-1R cells were cultured in DMEM growth medium, 10% heat-inactivated fetal bovine serum (GEMINI Cat#900-108), 1% Pen-3Trep (Sangom Biotech Cat#E607011-0100) and incubated at 37°C in a humidified 5% CO2 incubator.

[0368] (4) cAMP level test method

[0369] The test compound (in DMSO) at various concentrations was diluted 1:5 in distilled water in stimulation buffer, 500 μM 3-isobutyl-1-methylxanthin (IBMX; Meilunbiocat# MB5226) was added to obtain a 2X compound working solution, and then 5 μL of the compound was added to a white 384-well assay plate (Corning 3824) using a multichannel pipette. The final DMSO concentration in the assay buffer mixture was 1‰.

[0370] Cells were harvested from a T25 tissue culture flask and centrifuged at 1000 rpm for 5 minutes at room temperature. The cell pellet was then resuspended in 1 mL of stimulation buffer. A 20 μL sample of the cell suspension was counted on a STAR IC1000 counter to determine cell viability and cell count per mL. The remaining cell suspension was then adjusted with stimulation buffer to deliver 2000 viable cells per well using a multichannel pipette. 5 μL of the cell suspension was added to each well of the assay plate containing the compound. The plate was sealed and incubated at 37°C with 5% CO2 for 30 minutes.

[0371] After a 30-minute incubation, 5 μL of d2-labeled cAMP and 5 μL of anti-cAMP cryptate (both diluted 1:20 in cell lysis buffer) were added to each well of the assay plate. The plates were then incubated at room temperature, and after 60 minutes, the HTRF signal was read using a Tecan Spark plate reader, with excitation at 340 nm and emission at 615 nm and 665 nm. Raw data were converted to nM cAMP by interpolation from a cAMP standard curve, and the percent effect was determined relative to the saturating concentration of the full agonist GLP-17-37 (400 nM) included on each plate. EC 50 Assays were made from agonist dose-response curves analyzed with a curve fitting program using a 4-parameter logistic dose-response equation.

[0372] This study demonstrates that Compound I activates GLP-1R signaling through the cAMP pathway and thus acts as a GLP-1R agonist. The experimental data are presented as geometric means (EC 50 s) to present the results.

[0373] Experimental results: Compound I has a strong agonistic effect on GLP-1R.

[0374] Example 3: Preparation of Compound Z

[0375] Approximately 200 mg of Compound I sample (free form) was weighed into a 20.0 mL glass vial, 49.50 mg of tromethamine was added, and 5 mL of isopropanol was added. The sample was dissolved by vortexing and ultrasonic treatment. After suspension stirring at room temperature on a magnetic stirrer for 3 days, the resulting solid was separated by vacuum filtration and then dried in a drying oven at 50°C for 4 hours to obtain the tromethamine salt. 1 H NMR (Figure 4-1) shows that the acid-base molar ratio is 1:1, and there is no obvious solvent residue, indicating that it is anhydrous. Its structure is determined to be:

[0376] XRPD detection confirmed that it was Form A, as shown in Figure 1.

[0377] Example 4: Small-scale screening of salt forms of Compound I

[0378] Based on the structure of free compound I, 8 acidic ligands (citric acid, malic acid, succinic acid, tartaric acid, fumaric acid, hydrochloric acid, maleic acid, and methanesulfonic acid) and 7 basic ligands (sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, meglumine, choline, and tromethamine) were set up and screened in 4 solvent systems (isopropanol, methyl isobutyl ketone, water / acetonitrile, and methyl tert-butyl ether / tetrahydrofuran) by suspension stirring at room temperature.

[0379] About 20 mg of compound I (free form) was added to a 3.0 mL vial, and 1.2 times (molar) of the ligand and 0.5 mL of solvent were added. After magnetic stirring at room temperature for 3 days, the resulting solid was separated and dried in vacuo at 50°C for 2 hours, and then XRPD was measured.

[0380] Test results: The results are shown in Table E-1. Obviously, the test yielded four crystalline forms of four salts (hydrochloride crystalline form A, methanesulfonate crystalline form A, meglumine salt crystalline form A, and tromethamine salt (Compound Z) crystalline form A).

[0381] Table E-1: Salt type screening test results

[0382] As shown in Table E-1, crystalline salts of Compound 1 were successfully obtained only when the ligands were hydrochloric acid, methanesulfonic acid, meglumine, and tromethamine. In particular, in the case of tromethamine, salt formation was good, and Form A of the tromethamine salt was obtained. Compared to the methanesulfonic acid salt and meglumine salt, the tromethamine salt of Compound 1 is easier to prepare, and post-processing (e.g., separation) is also more convenient.

[0383] When other ligands are selected, either the salt of Compound I cannot be formed, or only weakly crystalline or amorphous products are obtained, or the salt formation is poor (easily forming a jelly or oil).

[0384] Since Compound I has a risk of degradation under the action of strong acid and strong base, the four salts were tested by high performance liquid chromatography (HPLC), and the results are shown in Table E-2.

[0385] Table E-2: Purity of hydrochloride, methanesulfonate, meglumine and tromethamine salts

[0386] Example 5: Preparation of Methanesulfonate and Meglumine Salts of Compound I

[0387] Experiment 1: Approximately 200 mg of Compound I (free form) was added to a 20.0 mL glass vial, 5 mL of isopropanol, and 39.34 mg of methanesulfonic acid were added. The sample was dissolved by vortexing and ultrasonic treatment. After suspension and stirring at room temperature on a magnetic stirrer for 3 days, a methanesulfonate salt was obtained, which was shown to be amorphous by XRPD detection (curve B in Figure 43).

[0388] Experiment 2: Approximately 100 mg of compound I (free form) was added to a 20.0 mL glass vial, 2.5 mL of ethyl acetate and 19.67 mg of methanesulfonic acid were added, and the sample was dissolved by vortexing and ultrasonic treatment. After suspension and stirring at room temperature on a magnetic stirrer for 2 days, the sample was centrifuged and the supernatant was removed. The residue was placed in a drying oven at 50°C and dried for 3 hours to obtain a methanesulfonate salt, which was shown to be amorphous by XRPD detection (curve C in Figure 43).

[0389] Experiment 3: The methanesulfonate salt was prepared by replacing the ethyl acetate in Experiment 2 with sec-butanol, which was shown to be amorphous by XRPD analysis (curve D in FIG43 ).

[0390] Test 4: Approximately 200 mg of compound I (free form) was added to a 20.0 mL glass vial, 79.91 mg of meglumine was added, and 5 mL of isopropanol was added. The sample was dissolved by vortexing and ultrasonic treatment. After suspension stirring at room temperature on a magnetic stirrer for 3 days, the sample was dried in a drying oven at 50°C for 4 hours to obtain the meglumine salt, which was shown to be Form A by XRPD detection.

[0391] Example 6: Preparation of Compound Z Crystalline Form

[0392] 1. Crystalline Form A

[0393] Approximately 4.6 g of Compound I and 867.75 mg of tromethamine were placed in a 250 mL eggplant-shaped flask, 120 mL of IPA was added, and the mixture was stirred at room temperature for 3 days to obtain a crystalline solid, Compound Z Form A. Its XRPD pattern was substantially identical to that of Form A obtained in Example 3.

[0394] 2. Crystal form P

[0395] Approximately 20 mg of Form A of Compound Z was suspended in 0.5 mL of CHCl3 / EtOAc (1:1 v:v). The resulting suspension was magnetically stirred at 5°C for approximately 3 days, and then the solid was separated to obtain a crystalline solid, Form P of Compound Z. Its XRPD pattern is shown in Figure 5.

[0396] 3. Crystalline Form C

[0397] Approximately 20 mg of Form A of Compound Z was suspended in 0.5 mL of 1,4-dioxane / H2O (6:1 v:v). The resulting suspension was magnetically stirred at room temperature for approximately 3 days, and then the solid was separated to obtain a crystalline solid, Form C of Compound Z. Its XRPD pattern is shown in Figure 8.

[0398] 4. Crystal Form F

[0399] Approximately 20 mg of Compound Z was dissolved in 0.2 mL of NMP / toluene (1:1 v:v) and filtered to obtain a clear solution. This solution was placed in a 20 mL vial containing 3 mL of IPAc. The vial was sealed and maintained at room temperature to allow sufficient time for the organic vapor to interact with the solution. After 3 days of gas-liquid diffusion, the solid was isolated to obtain a crystalline solid, Form F of Compound Z, whose XRPD pattern is shown in Figure 11.

[0400] 5. Crystal Form G

[0401] Approximately 20 mg of Form A of Compound Z was suspended in 0.5 mL of 1,4-dioxane / EtOAc (1:1 v:v). The resulting suspension was magnetically stirred at 50° C. for approximately 3 days, and then the solid was separated to obtain a crystalline solid, Form G of Compound Z. Its XRPD pattern is shown in FIG14 .

[0402] 6. Crystal Form H

[0403] About 50 mg of compound Z was dissolved in 3.0 mL of TFE and filtered. The filtrate was rotary evaporated at 50° C. to collect the solid to obtain a crystalline solid, which is the H form of compound Z. Its XRPD pattern is shown in FIG17 .

[0404] 7. Crystal Form Ix

[0405] About 20 mg of Form A of Compound Z was suspended in 0.5 mL of anisole. The resulting suspension was magnetically stirred at 50° C. for about 3 days, and then the solid was separated to obtain a crystalline solid, Form Ix of Compound Z. Its XRPD pattern is shown in FIG20 .

[0406] 8. Crystal Form N

[0407] Approximately 20 mg of Form A of Compound Z was suspended in 0.5 mL of ACN / 1,4-dioxane (1:1 v:v). The resulting suspension was magnetically stirred under temperature cycling conditions for 2 days. The solid was then separated to obtain a crystalline solid, Form N of Compound Z, whose XRPD pattern is shown in Figure 23. The temperature cycling procedure was as follows, with a total of 2 cycles:

[0408] 9. Crystal form O

[0409] Approximately 20 mg of Form A of Compound Z was suspended in 0.5 mL of acetone / CPME (1:1 v:v). The resulting suspension was magnetically stirred at 50°C for approximately 3 days, and then the solid was separated to obtain a crystalline solid, Form O of Compound Z, whose XRPD pattern is shown in Figure 26.

[0410] 10. Crystal Form S

[0411] Approximately 20 mg of Compound Z was dissolved in 0.6 mL of TFE / ACN (1:1 v:v) and filtered to obtain a clear solution. 1.5 mL of MTBE was added to the solution under magnetic stirring until precipitation occurred. The solid was isolated to obtain a crystalline solid, Form S of Compound Z. Its XRPD pattern is shown in Figure 38-1.

[0412] 11. Crystalline Form V

[0413] Method 1: Add 5.0 g of compound Z to a 250 ml three-necked flask, followed by 60 ml of acetonitrile and 10 ml of water. Heat at 55°C to dissolve, then transfer to 25°C and stir for 3 h before filtering. The filter cake is air-dried at 50°C for 18 h to yield 4.52 g of a solid (90.4% yield). The XRPD pattern is shown in Figure 45-1.

[0414] Method 2:

[0415] 8.0 g of compound Z was placed in a 100 ml three-necked flask, followed by 48 ml of methanol. The solution was heated at 60°C to dissolve, then cooled to 40°C and seeded with 8 mg of Form V. The solution was cooled to 15°C at a rate of 8°C / h, then further cooled to -18°C at a rate of 12°C / h. The mixture was stirred at this temperature for 2 h before filtration. The filter cake was vacuum dried at 40°C for 17 h to yield 6.67 g of a solid (83.3% yield), whose XRPD pattern was essentially the same as that in Figure 45-1.

[0416] Method 3:

[0417] A solid mixture of Form V, Form A, and Form C of Compound Z was suspended in a saturated solution of Compound Z in a mixture of ethanol and water (0.205 ≤ water activity ≤ 0.49), slurried at room temperature for 4 days, and then the resulting solid was isolated, and its XRPD pattern was essentially the same as that in Figure 45-1.

[0418] 12. Crystal form W

[0419] Method 1: The crystalline form V of the compound Z was heated at 100° C. for 10 minutes under nitrogen protection to obtain the crystalline form W, whose XRPD pattern is shown in FIG46 .

[0420] Method 2:

[0421] A solid mixture of Form V, Form A and Form C of Compound Z was suspended in a saturated solution of Compound Z in a mixture of ethanol and water (water activity ≤ 0.12), slurried at room temperature for 1 day, and then the resulting solid was separated, and its XRPD pattern was essentially the same as that in Figure 46.

[0422] Example 7: Preparation of a metastable crystalline form of compound Z

[0423] 1. Crystal Form B

[0424] A suspension of Compound Z in ethanol:water (93:7 v:v) equilibrated at room temperature for 2 hours was filtered to obtain a saturated solution of Compound Z at room temperature, and then a solid mixture of Form A and Form C of Compound Z was added. After stirring for 3 days, Form B was obtained, whose XRPD pattern is shown in Figure 29.

[0425] 2. Crystal Form D

[0426] About 20 mg of Form A of Compound Z was suspended in 0.5 mL of DMSO / EtOAc (1:9 v:v). The resulting suspension was magnetically stirred at 50°C for about 3 days, and then the solid was separated to obtain Form D, whose XRPD pattern is shown in Figure 30.

[0427] 3. Crystal Form E

[0428] Approximately 20 mg of Form A of Compound Z was suspended in 0.5 mL of DMF / 2-MeTHF (1:9 v:v). The resulting suspension was magnetically stirred for 2 days under the temperature cycling conditions described for Form N in Example 6. The solid was then isolated to provide Form E, whose XRPD pattern is shown in Figure 31.

[0429] 4. Crystal Form J

[0430] About 20 mg of Form A of Compound Z was suspended in 0.5 mL of 2-MeTHF. The resulting suspension was magnetically stirred at room temperature for about 3 days, and then the solid was separated to obtain Form J, whose XRPD pattern is shown in Figure 32.

[0431] 5. Crystal Form K

[0432] Approximately 20 mg of Form A of Compound Z was suspended in 0.5 mL of CHCl3 / MEK (1:1 v:v). The resulting suspension was magnetically stirred at 50°C for approximately 3 days, and then the solid was isolated to obtain Form K, whose XRPD pattern is shown in Figure 33.

[0433] 6. Crystal Form L

[0434] Approximately 20 mg of Form A of Compound Z was suspended in 1.0 mL of EtOH / HEP (3:1 v:v). The resulting suspension was then heated to 50°C, equilibrated for approximately two hours, and filtered. The filtrate was slowly cooled to room temperature in a water bath, and the resulting solid was isolated to obtain Form L, whose XRPD pattern is shown in Figure 34.

[0435] 7. Crystal Form M

[0436] Approximately 20 mg of Compound Z was dissolved in 0.2 mL of NMP and filtered to obtain a clear solution. 2.0 mL of MTBE was added to the solution under magnetic stirring until precipitation occurred. The solid was isolated to obtain Form M, whose XRPD pattern is shown in Figure 35.

[0437] 8. Crystal Form Q

[0438] Approximately 20 mg of compound Z was dissolved in 2.0 mL of TFE / MEK (v:v 1:1) and filtered to obtain a clear solution. The vial containing the filtrate was sealed with parafilm, which was then punctured and allowed to slowly evaporate at room temperature for 7 days. A small amount of solid precipitated, which was then oven-dried at 50°C for 6 hours. The resulting solid was collected to obtain Form Q, whose XRPD pattern is shown in Figure 36.

[0439] 9. Crystal form R

[0440] Approximately 20 mg of compound Z was dissolved in 1.0 mL of TFE / MEK (v:v 1:1) and filtered to obtain a clear solution. This solution was then placed in a 20 mL vial containing 3 mL of CHCl₃. The vial was sealed and maintained at room temperature to allow sufficient time for the organic vapor to interact with the solution. After 7 days of vapor-liquid diffusion, the clear solution was maintained and then oven-dried at 50°C for 6 hours. The solid was collected to obtain Form R, whose XRPD pattern is shown in Figure 37.

[0441] 10. Crystal Form T

[0442] Approximately 20 mg of Form A of Compound Z was suspended in 0.5 mL of toluene / IPA (1:1 v:v). The resulting suspension was magnetically stirred for 2 days under the temperature cycling conditions described for Form N in Example 6. The solid was then isolated to provide Form T, whose XRPD pattern is shown in Figure 39.

[0443] 11. Crystal Form U

[0444] Form U was obtained by leaving Form Q of Compound Z exposed at room temperature for one day, and its XRPD pattern is shown in FIG40 .

[0445] Example 8: Conversion test between crystal form A and crystal form P of compound Z

[0446] To confirm the interconversion relationship between Form A and Form P of Compound Z, suspension competition experiments in different solvents were set up at room temperature and 50°C.

[0447] The suspension of compound Z equilibrated at the corresponding temperature and solvent for 2 hours was filtered to obtain saturated solutions of compound Z at different temperatures and solvents, and then a solid mixture of Form A and Form P of compound Z was added. After the suspension competition was carried out for 1 day, the solid was isolated and characterized by XRPD.

[0448] The experimental results are shown in Figures 48 and 49 and Table E-3. Form A and Form B of Compound Z were obtained in an EtOH system (room temperature and 50°C). (Water activity tests showed that Form B is a metastable form, which transforms to Form A during drying at room temperature.) Form A of Compound Z was obtained in an EtOAc system (room temperature and 50°C). The results indicate that Form A of Compound Z is thermodynamically more stable at room temperature and 50°C.

[0449] Table E-3: Suspension competition test

[0450] Example 9: Equilibrium Solubility Determination of Compound Z

[0451] The equilibrium solubility of amorphous form of Compound I (free form, Figure 41) and Compound Z Form A was determined at 37°C for 24 hours in four media, namely H2O (purified water), SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid) and FeSSIF (fed state simulated intestinal fluid).

[0452] 10 mg of amorphous Compound I and Form A of Compound Z were added to 1 mL of the corresponding medium to prepare a suspension, and the suspension was magnetically stirred at 37 ± 2°C. After 24 hours, a sample was collected and centrifuged, and the supernatant was filtered for solubility determination.

[0453] The results shown in Table E-4 indicate that compared with the amorphous form of Compound I, the solubility of Form A of Compound Z in water and simulated gastrointestinal fluid is improved.

[0454] Table E-4: Equilibrium Solubility of Form A of Compound Z and Amorphous Form of Compound I

[0455] Example 10: Hygroscopicity determination of Form A of Compound Z

[0456] To assess the stability risk of samples at 25°C due to humidity fluctuations, DVS testing was performed on the amorphous form of Compound I (free form, Figure 41) and Compound Z Form A. Hygroscopicity is based on the weight gain of the sample when the humidity is increased to 80% RH at 25°C, with a weight gain of 0.2%-2% being considered slightly hygroscopic, and a weight gain of 2%-15% being considered hygroscopic.

[0457] The DVS spectrum of Compound Z Form A is shown in Figure 4-2, and the DVS spectrum of the free compound is shown in Figure 4-3. The results show that at 80% RH, the amorphous form of Compound I absorbed water and gained 4.029% weight, indicating hygroscopicity; while the Form A of Compound Z absorbed water and gained 1.696% weight, indicating slight hygroscopicity.

[0458] Through the same test method, it was found that compound Z crystalline form P, crystalline form C, crystalline form V and crystalline form W also have good low hygroscopicity.

[0459] Example 11: Solid-state stability determination of Form A of Compound Z

[0460] The crystalline forms of Compound I (free form) and Compound Z Form A were placed under long-term (25°C / 60% RH) and accelerated (40°C / 75% RH) conditions for 10 days, and then their HPLC purity and crystalline form were determined. The free form of Compound I is a crystalline form, and has the XRPD pattern indicated by the arrow in Figure 50.

[0461] The test results are summarized in Figures 50 and 51 and Table E-5. The results show that Form A of Compound Z showed no significant decrease in purity after 10 days under both long-term and accelerated conditions, demonstrating excellent chemical stability. The purity of the crystalline form of Compound I did not decrease significantly after 10 days under long-term conditions, but decreased by approximately 2.4% after 10 days under accelerated conditions. These results demonstrate that Form A of Compound Z exhibits superior solid-state chemical stability compared to the crystalline form of Compound I. No changes in crystalline form were observed for any of the samples.

[0462] Table E-5: Solid-state stability test results

[0463] Using the same experimental method, it was found that Compound Z Form V also has good solid-state stability.

[0464] Example 12: High Temperature Stability Test of Form A of Compound Z

[0465] The crystalline form of Compound I (free form, Figure 50) and Compound Z Form A were placed at 60°C and then tested for HPLC purity (area %) and crystal form changes. The results showed that the purity of Compound Z Form A did not decrease significantly after 1 day (initial purity 97.41% vs. 97.34% after 1 day); the purity of the crystalline form of Compound I decreased by approximately 0.8% after 1 day (initial purity 97.31% vs. 96.56% after 1 day). Both showed a similar decrease in purity after 10 days. No crystal form change was observed for any of the samples.

[0466] Through the same experimental method, it was found that compound Z crystal form P, crystal form C, crystal form V and crystal form W also have good high temperature stability.

[0467] Example 13: Determination of high humidity stability of Form A of Compound Z

[0468] The crystalline form of Compound I (free form, Figure 50) and Compound Z Form A were placed under high humidity (90% RH) conditions for 10 days and then tested for HPLC purity (area %) and crystal form change. The initial purities of Compound Z Form A and Compound I were 97.41% and 97.31%, respectively. The results showed that the purity of Compound Z Form A did not decrease significantly; the purity of Compound I decreased by approximately 0.3% (97.06% after 10 days). No crystal form change was observed for any of the samples.

[0469] Through the same experimental method, it was found that compound Z crystal form P, crystal form C, crystal form V and crystal form W also have good stability under high humidity conditions.

[0470] Example 14: Pressure Stability Determination of Form A of Compound Z

[0471] The crystalline form of Compound I (free form, Figure 50) and Compound Z Form A were subjected to a pressure of 1000 MPa for 5 minutes and then tested for HPLC purity (area %) and crystal form change. The initial purities of Compound Z Form A and Compound I were 97.31% and 97.13%, respectively. The results showed that the purity of Compound Z Form A did not decrease significantly; the purity of Compound I decreased by approximately 0.5% (96.60% at the end of the experiment). No crystal form change was observed for any of the samples.

[0472] Through the same experimental method, it was found that compound Z crystalline form P, crystalline form C, crystalline form V and crystalline form W also have good pressure stability.

[0473] Example 15: Dynamic Solubility Determination of Form A of Compound Z

[0474] The dynamic solubility of free-state Compound I and Compound Z Form A in water / simulated gastrointestinal fluid was tested. In these tests, the solid dosage of free-state Compound I or Compound Z Form A in each solvent system was approximately 10 mg / mL and mixed at 37°C ± 2°C. The suspension was sampled at 1, 2, 4, and 24 hours. The supernatant was filtered and the concentration was determined. The solid was then analyzed by XRPD. The results are shown in Table E-6.

[0475] Table E-6: Dynamic solubility test data Note: “N / A” indicates insufficient residual solids for detection.

[0476] The results showed that within 24 hours, the solubility of Compound Z Form A in water was significantly higher than that of free Compound I. In FaSSGF (simulated fasting gastric fluid), the solubility of Compound Z Form A was significantly higher than that of free Compound I at 1 and 2 hours (gastric emptying time). In FaSSIF (simulated fasting intestinal fluid), the solubility of Compound Z Form A was also significantly higher than that of free Compound I at 1 and 2 hours, indicating that Compound Z Form A may have a faster onset of action than free Compound I.

[0477] The principles and embodiments of the present invention are described herein using examples. The above examples are intended to facilitate understanding of the present invention and are not intended to limit the present invention. It should be noted that those skilled in the art may make various improvements and modifications to the present invention without departing from the principles of the present invention, and such improvements and modifications also fall within the scope of the claims of the present invention.

Claims

1. A pharmaceutically acceptable salt of compound I ((S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid), wherein the salt includes a methanesulfonate salt, a meglumine salt, and a tromethamine salt, preferably a compound Z ((S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tromethamine salt).

2. The pharmaceutically acceptable salt of Compound 1 according to claim 1, which is in crystalline form, Preferably, the salt is the mesylate salt in crystalline form, or the meglumine salt in crystalline form, or Compound Z in crystalline form.

3. The pharmaceutically acceptable salt of Compound 1 according to claim 2, wherein the salt is a crystalline form of Compound Z, and wherein the crystalline form is Form A, and The X-ray powder diffraction (XRPD) pattern of the crystalline form A includes diffraction peaks at the following diffraction angles (2θ): about 3.62±0.20°, 7.28±0.20°, 17.21±0.20° and 20.60±0.20°; preferably also includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 14.66±0.20°, 15.55±0.20°, 16.66±0.20°, 21.94±0.20° and 26.04±0.20°; and / or The differential scanning calorimetry (DSC) spectrum of the crystalline form A has an endothermic peak at a peak value of about 159.9°C±3.0°C; and / or The Form A loses about 0.815% weight during heating to about 120°C ± 3°C, as measured using thermogravimetric analysis (TGA); and / or The crystal form A 1 H NMR spectrum substantially as shown in Figure 4; and / or More preferably, the XRPD pattern of the crystalline form A further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 7.74±0.20°, 8.54±0.20°, 10.92±0.20°, 15.28±0.20°, 17.73±0.20°, 18.05±0.20°, 18.44±0.20°, 19.47±0.20°, 19. 90±0.20°, 22.38±0.20°, 23.18±0.20°, 25.04±0.20°, 27.28±0.20°, 27.82±0.20°, 28.10±0.20°, 29.52±0.20°, 31.06±0.20°, 32.97±0.20°, 33.36±0.20°, and 40.57±0.20°; or The X-ray powder diffraction pattern of the crystalline form A includes diffraction peaks at the following diffraction angles (2θ): 3.623°, 7.281°, 7.742°, 8.537°, 10.916°, 14.655°, 15.279°, 15.553°, 16.660°, 17.207°, 17.732°, 18.047°, 18.444° , 19.472°, 19.896°, 20.604°, 21.935°, 22.382°, 23.183°, 25.043°, 26.041°, 27.280°, 27.820°, 28.097°, 29.520°, 31.063°, 32.971°, 33.357°, 40.566°; and / or The DSC spectrum of the crystalline form A is substantially as shown in FIG2 ; and / or The TGA spectrum of the crystalline form A is substantially as shown in FIG3 ; More preferably, the XRPD pattern of the crystalline form A includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG1 , and further preferably, the XRPD pattern of the crystalline form A is shown in FIG1 ; Even more preferably, the crystalline form A is not a solvate, and more preferably is an anhydrate.

4. The pharmaceutically acceptable salt of Compound 1 according to claim 2, wherein the salt is a crystalline form of Compound Z, and wherein the crystalline form is Form P, and The XRPD pattern of the crystalline form P includes diffraction peaks at the following diffraction angles (2θ): about 3.55±0.20°, 7.31±0.20°, 14.77±0.20°, 17.01±0.20° and 20.44±0.20°; and / or The DSC spectrum of the crystalline form P has two endothermic peaks at about 152.5°C±3.0°C and about 158.1°C±3.0°C, respectively; and / or The Form P loses about 0.367% weight during heating to about 140°C ± 3°C, as measured using TGA; and / or The crystal form P 1 H NMR spectrum substantially as shown in Figure 7-2; and / or Preferably, the XRPD pattern of the crystalline form P further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 15.50±0.20°, 18.01±0.20°, 19.06±0.20°, 19.57±0.20°, 22.07±0.20° and 25.23±0.20°; or The XRPD of the crystalline Form P comprises diffraction peaks at the following diffraction angles (2θ): 3.547°, 7.306°, 14.765°, 15.501°, 17.009°, 18.005°, 19.058°, 19.571°, 20.436°, 22.071°, 22.441° and 25.229°; and / or The DSC spectrum of the crystalline form P is substantially as shown in FIG6 ; and / or The TGA spectrum of the crystal form P is substantially as shown in Figure 7-1; and / or More preferably, the XRPD pattern of the crystalline form P includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG5 , and even more preferably, the XRPD pattern of the crystalline form P is shown in FIG5 ; Even more preferably, the crystalline form P is not a solvate, and more preferably is an anhydrate.

5. The pharmaceutically acceptable salt of Compound 1 according to claim 2, wherein the salt is a crystalline form of Compound Z, and wherein the crystalline form is Form C, and The XRPD pattern of Form C includes diffraction peaks at the following diffraction angles (2θ): about 3.88±0.20°, 7.81±0.20°, 15.60±0.20°, 17.49±0.20° and 19.64±0.20°; and / or The DSC spectrum of the crystalline form C has three endothermic peaks at about 81.8°C±3.0°C, about 93.6°C±3.0°C, and about 155.2°C±3.0°C, respectively; and / or The Form C loses about 4.560% weight during heating to about 100°C ± 3°C, as measured using TGA; and / or The crystal form C 1 H NMR spectrum substantially as shown in Figure 10-2; and / or Preferably, the XRPD pattern of the crystalline form C further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 14.86±0.20°, 19.99±0.20°, 20.24±0.20°, 22.37±0.20°, 24.21±0.20° and 24.51±0.20°; More preferably, the XRPD pattern of the crystalline form C further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 10.44±0.20°, 13.13±0.20°, 16.09±0.20°, 19.39±0.20°, 23.57±0.20°, 26.82±0.20°, 27.18±0.20° and 33.37±0.20°; Still more preferably, the XRPD pattern of the crystalline form C further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 6.50±0.20°, 7.42±0.20°, 9.90±0.20°, 11.74±0.20°, 13.75±0.20°, 18.15±0.20°, 18.49±0.20°, 20.65±0.20°, 21.02±0.20°, 21.25±0.20°, 21.58±0.20°, 21.82±0.20°. or 20°, 22.86±0.20°, 23.15±0.20°, 24.97±0.20°, 25.35±0.20°, 26.05±0.20°, 26.40±0.20°, 27.41±0.20°, 28.17±0.20°, 28.79±0.20°, 30.19±0.20°, 30.63±0.20°, 31.614±0.20°, 31.87±0.20°, 35.09±0.20°, and 35.30±0.20°; Preferably, the XRPD pattern of the crystalline form C includes diffraction peaks at the following diffraction angles (2θ): 3.877°, 6.503°, 7.415°, 7.807°, 9.896°, 10.442°, 11.742°, 13.126°, 13.75°, 14.861°, 15.603°, 16.091°, 17.494°, 18.154°, 18.487°, 19.386°, 19.635°, 19.985°, 20.242°, 20.654°, 21.021°, 21. and / or The DSC spectrum of the crystalline form C has an exothermic peak at about 125.0±3.0°C; Preferably, the DSC spectrum of the crystalline form C is substantially as shown in Figure 9; and / or Preferably, the TGA spectrum of the crystalline form C is substantially as shown in Figure 10-1; and / or More preferably, the XRPD pattern of the crystalline form C includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG8 , and even more preferably, the XRPD pattern of the crystalline form C is shown in FIG8 ; Even more preferably, the crystalline form C is a hydrate.

6. The pharmaceutically acceptable salt of Compound 1 according to claim 2, wherein the salt is a crystalline form of Compound Z, and wherein the crystalline form is Form V, and The XRPD pattern of Form V comprises diffraction peaks at the following diffraction angles (2θ): about 4.46±0.20°, 8.98±0.20°, 12.88±0.20°, 18.04±0.20°, and 19.26±0.20°; and / or The DSC spectrum of the crystalline form V has two endothermic peaks at about 64.5°C±3.0°C and about 164.8°C±3.0°C, respectively; and / or The Form V loses about 2.987% weight during heating to about 90°C ± 3°C, as measured using TGA; and / or The crystal form V 1 H NMR spectrum substantially as shown in Figure 45-4; and / or Preferably, the XRPD pattern of the crystalline form V further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 16.68±0.20°, 18.39±0.20°, 20.75±0.20°, 23.84±0.20° and 25.42±0.20°; More preferably, the XRPD pattern of Form V further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 9.16±0.20°, 9.39±0.20°, 10.31±0.20°, 12.70±0.20°, 12.99±0.20°, 14.36±0.20°, 14.70±0.20°, 19.46±0.20°, 19.62±0.20°, 21.29±0.20°, 22.03±0.20°, 22.69±0.20°, 22.93±0.20°, 24.23±0.20°, 24.66±0.20° and 27.00±0.20°; More preferably, the XRPD pattern of the crystalline form V further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 11.89±0.20°, 13.50±0.20°, 16.17±0.20°, 17.71±0.20°, 18.88±0.20°, 19.93±0.20°, 20.20±0.20°, 23.20±0.20°, 25.98±0.20°, 27.23 ±0.20°, 28.02±0.20°, 28.40±0.20°, 28.68±0.20°, 29.01±0.20°, 29.81±0.20°, 30.25±0.20°, 31.52±0.20°, 31.87±0.20°, 32.63±0.20°, 33.74±0.20°, 36.47±0.20°, 37.48±0.20°, and 7.96±0.20°; and / or Preferably, the DSC spectrum of the crystalline form V is substantially as shown in Figure 45-2; and / or Preferably, the TGA spectrum of the crystalline form V is substantially as shown in Figure 45-3; and / or More preferably, the XRPD pattern of the crystalline Form V includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 45-1, and even more preferably, the XRPD pattern of the crystalline Form V is shown in Figure 45-1; Even more preferably, the crystalline form V is a hydrate.

7. The pharmaceutically acceptable salt of Compound 1 according to claim 2, wherein the salt is a crystalline form of Compound Z, and wherein the crystalline form is Form W, and The XRPD pattern of the crystalline form W includes diffraction peaks at the following diffraction angles (2θ): about 4.62±0.20°, 12.90±0.20°, 18.06±0.20°, 19.40±0.20° and 19.60±0.20°; and / or The Form W loses about 1.111% weight during heating to about 90°C ± 3°C, as measured using TGA; and / or Preferably, the XRPD pattern of the crystalline form W further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 14.86±0.20°, 16.74±0.20°, 18.41±0.20°, 18.68±0.20°, 21.63±0.20°, 22.03±0.20°, 22.60±0.20°, 22.99±0.20° and 25.34±0.20°; More preferably, the XRPD pattern of the crystalline form W further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 9.14±0.20°, 9.37±0.20°, 10.21±0.20°, 15.35±0.20°, 20.52±0.20°, 20.77±0.20°, 23.88±0.20°, 24.27±0.20°, 24.66±0.20°, 27.04±0.20° and 28.01±0.20°; Even more preferably, the XRPD pattern of the crystalline form W further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 11.50±0.20°, 12.02±0.20°, 13.93±0.20°, 14.40±0.20°, 23.44±0.20°, 25.81±0.20°, 28.46±0.20°, 30.33±0.20°, 31.60±0.20° and 37.34±0.20°; Preferably, the TGA spectrum of the crystalline form W is substantially as shown in Figure 47; and / or More preferably, the XRPD pattern of the crystalline form W includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG46 , and even more preferably, the XRPD pattern of the crystalline form W is shown in FIG46 ; It is further more preferred that the crystalline form W is not a solvate, and more preferably an anhydrate.

8. A method for preparing a pharmaceutically acceptable salt of Compound 1 according to claim 1, wherein: The method comprises reacting the compound I with a reagent selected from methanesulfonic acid, meglumine and tromethamine in a solvent to obtain a methanesulfonic acid salt, meglumine salt or tromethamine salt of the corresponding compound I; or The method comprises reacting the compound I with tromethamine in a solvent (preferably at room temperature) to obtain a pharmaceutically acceptable salt of the compound I, wherein the salt is the compound Z according to claim 1; or The method comprises stirring the compound I and tromethamine in a solvent at room temperature to obtain a solid precipitate, wherein the precipitated solid is the compound Z, preferably the crystalline form A according to claim 3; in; The solvent is selected from one or a mixture of two or more selected from isopropyl alcohol, methyl isobutyl ketone, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, ethanol, methanol and water, and Preferably, the molar ratio of the compound I to the tromethamine is about 2:1 to about 1:2; Preferably, the stirring at room temperature is carried out for a suitable period of time, for example until the salt formation is complete, or for example for about 3 days; or The method comprises suspending the compound Z according to claim 1, in particular the crystalline form A according to claim 3, in a mixture of CHCl3:EtOAc (e.g., about 1:1, v:v), and stirring the resulting suspension at a suitable temperature to obtain a solid precipitate, wherein the precipitated solid is the crystalline form P according to claim 4, wherein: preferably, the suitable temperature is about 1-8°C, about 3-8°C, about 4-8°C or about 5-8°C, preferably about 5°C; and / or preferably, the stirring is carried out for a suitable period of time, for example, about 3 days; or The method comprises suspending the compound Z according to claim 1, in particular the crystalline form A according to claim 3, in a mixed solvent of 1,4-dioxane and H2O, and stirring the resulting suspension at room temperature to obtain a solid precipitate, wherein the precipitated solid is the crystalline form C according to claim 5, wherein: preferably, in the mixed solvent, the volume ratio of 1,4-dioxane:H2O is about (3-10):1, about (4-8):1, about (5-7):1, about (5.5-6.5):1, or about 6:1; and / or preferably, the stirring can be carried out for a suitable period of time, for example, about 3 days; or The method comprises: (1) providing a solution of the compound Z as claimed in claim 1 in acetonitrile: water (e.g., about 6:1, v:v) with an elevated temperature; (2) transferring the solution to a lower temperature and stirring; and (3) filtering and drying the obtained product in a hot air stream to obtain the crystalline form V as claimed in claim 6; Wherein: preferably, the temperature of the solution in step (1) is about 45-70°C, for example, about 50-65°C or about 50-60°C, preferably about 55°C; and / or preferably, the lower temperature in step (2) is about 20-30°C, for example, about 25°C; and / or preferably, the stirring in step (2) is carried out for a suitable period of time, for example, about 3 hours; and / or preferably, the temperature of the hot air flow in step (3) is about 40-70°C, for example, about 45-65°C or about 50-60°C, preferably about 50°C; or The method comprises heating the crystalline form V according to claim 6 at about 100° C. for a suitable period of time (eg, about 10 minutes) under the protection of an inert gas (eg, nitrogen) to obtain the crystalline form W according to claim 7.

9. A pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1 according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier. in: Preferably, the pharmaceutically acceptable salt is compound Z according to claim 1, more preferably compound Z in crystalline form according to claim 2, further more preferably form A according to claim 3, form P according to claim 4, form C according to claim 5, form V according to claim 6, or form W according to claim 7.

10. A pharmaceutically acceptable salt of Compound 1 according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 9, for treating and / or preventing GLP-1 receptor-mediated diseases and related conditions. in: Preferably, the pharmaceutically acceptable salt is compound Z according to claim 1, more preferably compound Z in crystalline form according to claim 2, further more preferably form A according to claim 3, form P according to claim 4, form C according to claim 5, form V according to claim 6, or form W according to claim 7.

11. Use of a pharmaceutically acceptable salt of Compound 1 according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 9, in the preparation of a medicament for treating and / or preventing GLP-1 receptor-mediated diseases or related conditions, in: Preferably, the pharmaceutically acceptable salt is compound Z according to claim 1, more preferably compound Z in crystalline form according to claim 2, further more preferably form A according to claim 3, form P according to claim 4, form C according to claim 5, form V according to claim 6, or form W according to claim 7.

12. A method for treating and / or preventing a GLP-1 receptor-mediated disease or related condition, comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable salt of Compound 1 according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 9, in: Preferably, the pharmaceutically acceptable salt is compound Z according to claim 1, more preferably compound Z in crystalline form according to claim 2, further more preferably form A according to claim 3, form P according to claim 4, form C according to claim 5, form V according to claim 6, or form W according to claim 7.

13. The pharmaceutically acceptable salt or pharmaceutical composition of Compound 1 according to claim 10, the use according to claim 11, or the method according to claim 12, wherein the GLP-1 receptor-mediated disease or related condition is selected from the group consisting of diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, non-alcoholic fatty liver disease, dyslipidemia, and hyperinsulinemia; Preferably, the diabetes is selected from: T1D and / or T2DM, idiopathic T1D, early-onset T2D, latent autoimmune diabetes, juvenile atypical diabetes and gestational diabetes.

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