Novel crystalline forms of GLP-1 receptor agonists, methods for preparing the same, pharmaceutical compositions thereof and uses thereof

Abstract

A novel crystalline form of a GLP-1 receptor agonist, its preparation method, its pharmaceutical composition, and its use are provided. The GLP-1 receptor agonist is designated Compound I, i.e., (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.

Description

[Technical Field]

[0001] This application relates to novel crystalline forms of GLP-1 receptor agonists, methods for their preparation, pharmaceutical compositions containing the crystalline forms, and uses of the crystalline forms and pharmaceutical compositions for treating and / or preventing GLP-1 receptor-mediated diseases or related disorders.

[0002] Diabetes mellitus (DDM) is a chronic, comprehensive disease caused by absolute or relative insulin deficiency or reduced sensitivity of target cells to insulin, and is primarily characterized by impaired glucose metabolism. It is divided into type I and type II diabetes. Type II diabetes is adult-onset diabetes, an endocrine disorder caused by insulin resistance and / or defective insulin secretion, and is primarily characterized by chronic hyperglycemia. Type II diabetes patients account for more than 90% of diabetes patients.

[0003] Insulin and GLP-1 receptor agonists are among the most effective drugs for the treatment of type 2 diabetes. Insulin remains the most widely used diabetes medication worldwide, with approximately 30–40% of type 2 diabetes patients eventually requiring insulin therapy. GLP-1 agents include exenatide, liraglutide, and semaglutide, but insulin and GLP-1 agents are currently primarily polypeptide drugs and injectable formulations. Even oral semaglutide has many dosing limitations. Therefore, further development of small molecule GLP-1 receptor agonists is needed.

[0004] Other disorders 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] As promising drugs, most GLP-1 receptor agonists currently on the market are administered in the form of injections. The development of oral small molecule GLP-1 receptor agonists could improve patient compliance, which is a development trend for GLP-1 receptor agonists. Summary of the Invention

[0006] (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 35 FN4O5), also referred to herein and in the claims as Compound I, is a small molecule GLP-1 receptor agonist having the following structure: [ka]

[0007] The present inventors have prepared Compound I and through studies have shown that: (1) It is an amorphous form having an X-ray powder diffraction (XRPD) pattern shown in Figure 1-1; (2) In the differential scanning calorimetry (DSC) test, no melting point was detected until the temperature rose to 300°C, and the DSC pattern was as shown in Figure 1-2; (3) In the thermogravimetric analysis (TGA) test, a weight loss of 4.66% was observed when the temperature was increased by 160°C, and the TGA pattern was as shown in Figure 1-3.

[0008] It is an object of the present invention to further provide novel crystalline forms of Compound I.

[0009] Accordingly, in one aspect, the present invention provides a crystalline form of Compound I (including crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form Ix, crystalline form J, crystalline form K, crystalline form L, crystalline form M, crystalline form N, crystalline form O and crystalline form P as described below, preferably crystalline form A and crystalline form G, more preferably crystalline form G).

[0010] The crystalline form of Compound I of the present invention has good physical and chemical properties such as low hygroscopicity, good physicochemical stability (thermodynamic stability, solid-state stability, high temperature resistance, high humidity resistance, and / or high pressure resistance), and potentially good druggability and / or bioavailability.

[0011] In another aspect, the present invention provides a method for preparing a crystalline form of Compound I of the present invention.

[0012] In another aspect, the present invention provides a pharmaceutical composition comprising a crystalline form of Compound I of the present invention (preferably, crystalline form A or crystalline form G, more preferably, crystalline form G).

[0013] In another aspect, the present invention provides a crystalline form of compound I of the present invention, preferably crystalline form A or crystalline form G, more preferably crystalline form G, for use in the treatment and / or prevention of GLP-1 receptor-mediated diseases and related disorders.

[0014] In another aspect, the present invention provides the use of a crystalline form of compound I of the present invention, preferably crystalline form A or crystalline form G, more preferably crystalline form G, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for treating and / or preventing a GLP-1 receptor-mediated disease or related disorder.

[0015] In another aspect, the present invention provides a method for treating and / or preventing a GLP-1 receptor-mediated disease or related disorder, comprising administering to a subject in need thereof an effective amount of a crystalline form of compound I of the present invention, preferably crystalline form A or crystalline form G, more preferably crystalline form G, or a pharmaceutical composition of the present invention.

[0016] In some embodiments, the GLP-1 receptor mediated disease or related disorder is selected from 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, diabetes is selected from type I diabetes (T1D) and / or type II diabetes mellitus (T2DM), idiopathic T1D, early-onset T2DM, latent autoimmune diabetes, atypical diabetes of juveniles and gestational diabetes. [Brief explanation of the drawings]

[0017] [Figure 1-1] FIG. 1-1 shows the XRPD pattern of the amorphous form of Compound I. [Figure 1-2] Figure 1-2 shows the DSC pattern of the amorphous form. [Figure 1-3] Figures 1-3 show the TGA patterns of the amorphous form. [Figure 2-1] FIG. 2-1 shows the XRPD pattern of crystalline form A of Compound I. [Figure 2-2] FIG. 2-2 shows the DSC pattern of crystalline form A. [Figure 2-3] Figure 2-3 shows the TGA pattern of crystalline form A. [Figure 2-4] Figure 2-4 shows the 1H NMR spectrum of crystalline form A. [Figure 2-5] Figure 2-5 shows the DVS pattern of crystalline form A. [Figure 3-1] FIG. 3-1 is an XRPD pattern of crystalline form G of Compound I. [Figure 3-2] Figure 3-2 shows the DSC pattern of crystalline form G. [Figure 3-3] Figure 3-3 is the TGA pattern of crystalline form G. [Figure 3-4] Figure 3-4 is the 1H NMR spectrum of crystalline form G. [Figure 3-5] Figure 3-5 shows the DVS pattern of crystalline form G. [Figure 4-1] FIG. 4-1 is an XRPD pattern of crystalline form C of Compound I. [Figure 4-2] Figure 4-2 is the DSC pattern of crystalline form C. [Figure 4-3] Figure 4-3 is the TGA pattern of crystalline form C. [Figure 4-4] Figure 4-4 is the 1H NMR spectrum of crystalline form C. [Figure 5-1] FIG. 5-1 is an XRPD pattern of crystalline form D of Compound I. [Figure 5-2] Figure 5-2 is the DSC pattern of crystalline form D. [Figure 5-3] Figure 5-3 is the TGA pattern of crystalline form D. [Figure 5-4] Figure 5-4 is the 1H NMR spectrum of crystalline form D. [Figure 6-1] FIG. 6-1 is an XRPD pattern of crystalline form E of Compound I. [Figure 6-2] Figure 6-2 shows the DSC pattern of crystalline form E. [Figure 6-3] Figure 6-3 is the TGA pattern of crystalline form E. [Figure 6-4] Figure 6-4 is the 1H NMR spectrum of crystalline form E. [Figure 7-1] FIG. 7-1 is an XRPD pattern of crystalline form Ix of compound I. [Figure 7-2] Figure 7-2 is the DSC pattern of crystalline form Ix. [Figure 7-3] Figure 7-3 is the TGA pattern of crystalline form Ix. [Figure 7-4] Figure 7-4 is the 1H NMR spectrum of crystalline form Ix. [Figure 8-1] FIG. 8-1 is an XRPD pattern of crystalline form J of compound I. [Figure 8-2] Figure 8-2 is the DSC pattern of crystalline form J. [Figure 8-3] Figure 8-3 is the TGA pattern of crystalline form J. [Figure 8-4] Figure 8-4 is the 1H NMR spectrum of crystalline form J. [Figure 9-1] FIG. 9-1 is an XRPD pattern of crystalline form K of Compound I. [Figure 9-2] Figure 9-2 shows the DSC pattern of crystalline form K. [Figure 9-3] Figure 9-3 is the TGA pattern of crystalline form K. [Figure 9-4] Figure 9-4 is the 1H NMR spectrum of crystalline form K. [Figure 10-1] FIG. 10-1 is an XRPD pattern of crystalline form L of compound I. [Figure 10-2] FIG. 10-2 is the DSC pattern of crystalline form L. [Figure 10-3] FIG. 10-3 is a TGA pattern of crystalline form L. [Figure 10-4] Figure 10-4 is the 1H NMR spectrum of crystalline form L. [Figure 11-1] FIG. 11-1 is an XRPD pattern of crystalline form M of compound I. [Figure 11-2] Figure 11-2 is the DSC pattern of crystalline form M. [Figure 11-3] FIG. 11-3 is a TGA pattern of crystalline form M. [Figure 11-4] Figure 11-4 is the 1H NMR spectrum of crystalline form M. [Figure 12-1] FIG. 12-1 is an XRPD pattern of crystalline form N of Compound I. [Figure 12-2] Figure 12-2 is the DSC pattern of crystalline form N. [Figure 12-3] Figure 12-3 is the TGA pattern of crystalline form N. [Figure 12-4] Figure 12-4 is the 1H NMR spectrum of crystalline form N. [Figure 13-1] FIG. 13-1 is an XRPD pattern of crystalline form O of Compound I. [Figure 13-2] Figure 13-2 is the DSC pattern of crystalline form O. [Figure 13-3] Figure 13-3 is the TGA pattern of crystalline form O. [Figure 13-4]Figure 13-4 is the 1H NMR spectrum of crystalline form O. [Figure 14] FIG. 14 is an XRPD pattern of crystalline form B of Compound I. [Figure 15] FIG. 15 is an XRPD pattern of crystalline form H of Compound I. [Figure 16] FIG. 16 is an XRPD pattern of crystalline form F of Compound I. [Figure 17] FIG. 17 is an XRPD pattern of crystalline form P of Compound I.

[0018] Detailed Description of the Invention The present invention will be further described and illustrated below, and it should be understood that these terms are for illustrative purposes only and do not impose any limitations on the present invention.

[0019] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. In the event of a conflict, the definitions herein shall prevail. When amounts, concentrations, other values, or parameters are expressed in the form of a range, a preferred range, or an upper and lower preferred numerical limit, it should be understood that this is equivalent to specifically disclosing the range obtained by combining any pair of the upper or preferred numerical limit of the range with the lower or preferred numerical limit of the range. Unless otherwise specified, the numerical ranges recited herein are intended to include the endpoints of the range, and all integers and fractions (decimals) within the range.

[0020] The term "about," when used in connection with a numerical variable, generally means that the numerical value of the variable and all numerical values ​​of the variable are within experimental error (e.g., within a 95% confidence interval of the mean), or within ±20%, ±10%, ±5%, or ±2% of the particular numerical value.

[0021] As used herein, the term "about," when describing diffraction angles in XRPD, means within an acceptable standard error of the value as would be considered by one of ordinary skill in the art, e.g., ±0.05, ±0.10, ±0.20, ±0.30, ±1, ±2, or ±3.

[0022] The terms "comprise" or similar equivalent expressions such as "include," "containing," and "having" are open and do not exclude additional, unrecited elements, steps, or components. The term "consisting of" does not include unspecified elements, steps, or ingredients. The term "consisting essentially of" means that the scope is limited to the specified elements, steps, or components and may include additional elements, steps, or components, optionally present to the extent that they do not materially affect the basic and novel characteristics. The terms "comprise," "include," and similar terms should be understood to encompass the terms "consisting essentially of" and "consisting of."

[0023] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur.

[0024] Unless otherwise specified, all percentages, parts, etc. herein are by weight.

[0025] As used herein, the term "crystal form" or "crystal" refers to a solid substance that has a three-dimensional ordered structure and, unlike amorphous solid substances, exhibits a characteristic XRPD pattern with distinct peaks.

[0026] As used herein, the term "X-ray powder diffraction pattern" or "XRPD pattern" means an experimentally observed diffraction pattern or parameters, data, or values ​​derived therefrom. XRPD patterns are typically characterized by peak positions (abscissa) and / or peak intensities (ordinate).

[0027] As used herein, the term "diffraction angle" or "2θ" refers to the peak position expressed in degrees (°) based on the X-ray diffraction experimental setup, and is usually the unit of the horizontal axis of the diffraction pattern. If a reflection is diffracted when the incident beam makes an angle θ with respect to a particular lattice plane, the experimental setup requires that the reflected beam be recorded at angle 2θ. It should be understood that the specific 2θ values ​​for the specific crystalline forms described herein refer to the 2θ values ​​(in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, monochromatic radiation of Cu-Kα (Kα1(Å): 1.5406) ​​is used. The XRPD patterns described herein are preferably obtained using a Bruker D8 Advance (Bruker, Germany) X-ray powder diffractometer.

[0028] As used herein, the terms "substantially the same" or "substantially as shown in Figure 1" in reference to X-ray diffraction peaks means that variations in representative peak positions and intensities are taken into account. For example, those skilled in the art will understand that peak positions (2θ) typically exhibit some variation of 0.1 to 0.2 degrees, and that the instrument used to measure diffraction also causes some variation. In addition, those skilled in the art will understand that relative peak intensities will vary depending on differences between instruments, as well as the degree of crystallinity, preferred orientation, surface of the prepared sample, and other factors known to those skilled in the art.

[0029] Similarly, as used herein, the phrase "substantially as shown in Figure x" with respect to DSC and TGA patterns is intended to encompass variations associated with these analytical techniques known to those skilled in the art. For example, there is typically a variation of up to ±0.20°C for well-defined peaks in a DSC pattern, and even greater (e.g., up to ±1°C) for broad peaks.

[0030] Nuclear magnetic resonance spectra in this application are preferably collected on a Bruker AVANCE-III or Bruker AVANCE NEO (Bruker, Germany) nuclear magnetic resonance spectrometer. MeOD-d4 is used as the solvent unless otherwise specified.

[0031] As used herein, the term "solvent" or "good solvent" refers to a solvent in which Compound I can be dissolved or has relatively high solubility. As used herein, the term "anti-solvent" refers to a solvent in which Compound I is insoluble or substantially insoluble or has relatively low solubility. In this application, the terms "solvent" or "good solvent" and "anti-solvent" may also be relative and do not represent the absolute solubility of Compound I therein. The same solvent can act as a good solvent in some cases and as an anti-solvent in other cases.

[0032] 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.) contemplate any number within the numerical range (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0033] As used herein, the term "room temperature" means 20°C ± 5°C.

[0034] I. Crystalline Form of Compound I The present invention provides crystalline forms of Compound I (including crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form Ix, crystalline form J, crystalline form K, crystalline form L, crystalline form M, crystalline form N, crystalline form O, and crystalline form P, as described below). Preferred crystalline forms are crystalline form A and crystalline form G, with crystalline form G being more preferred.

[0035] The present invention also provides methods for preparing crystalline forms, including, but not limited to, slow evaporation, suspension with stirring at low temperature (e.g., 4-8°C), suspension with stirring at room temperature, suspension with stirring at high temperature (e.g., 50°C), addition of anti-solvent, addition of anti-anti-solvent, cooling crystallization, gas-liquid diffusion, gas-solid diffusion, water vapor stress, polymer induction, grinding, rotary evaporation, and cyclic temperature increase and decrease.

[0036] i. Crystalline form A The present invention provides crystalline form A of compound I, characterized in that the X-ray powder diffraction (XRPD) pattern of crystalline form A contains diffraction peaks at diffraction angles (2θ) of about 4.97±0.2°, 11.74±0.2°, 13.27±0.2°, 21.04±0.2°, and 24.06±0.2°.

[0037] Alternatively or additionally, crystalline form A has any one, two or all of the following properties: (1) The differential scanning calorimetry (DSC) pattern of crystalline form A has one endothermic peak at about 177.8°C ± 3.0°C; (2) Form A has a weight loss of about 0.037% upon heating to about 150°C ± 3°C as measured by thermogravimetric analysis (TGA); and (3) Crystalline form A 1 1 H NMR spectrum substantially as shown in Figures 2-4.

[0038] In some preferred embodiments, the XRPD pattern of crystalline form A further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 15.88±0.2°, 16.26±0.2°, 16.44±0.2°, 18.43±0.2°, 19.17±0.2°, 19.48±0.2°, 19.65±0.2°, 19.89±0.2°, 20.11±0.2°, 20.67±0.2°, 21.27±0.2°, 22.81±0.2°, and 23.4±0.2°.

[0039] In some preferred embodiments, the XRPD pattern of crystalline form A further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 9.99±0.2°, 17.65±0.2°, 20.32±0.2°, 24.26±0.2°, 24.76±0.2°, 25.79±0.2°, 26.75±0.2°, 27.47±0.2°, 28.19±0.2°, 29.38±0.2°, and 29.91±0.2°.

[0040] In some preferred embodiments, the DSC pattern of crystalline form A is substantially as shown in Figure 2-2.

[0041] In some preferred embodiments, the TGA pattern of crystalline form A is substantially as shown in Figures 2-3.

[0042] In some more preferred embodiments, the XRPD pattern of crystalline form A comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 2-1, and even more preferably, the XRPD pattern of crystalline form A is as shown in Figure 2-1.

[0043] The TGA weight loss of crystalline form A is small, as shown in Figure 2-4. 1 The H NMR spectrum shows no appreciable residual solvent. In some embodiments, crystalline form A is not a solvate. More preferably, crystalline form A is anhydrous.

[0044] In some embodiments, crystalline form A has a melting point greater than about 170°C.

[0045] In some embodiments, no change in crystalline form is observed after drying crystalline form A at about 50° C. for 3 hours.

[0046] Crystalline form A has good solid-state stability, high temperature stability, high humidity stability, pressure stability and low hygroscopicity.

[0047] In another aspect, the present invention provides a method for preparing crystalline form A, comprising stirring amorphous Compound I in acetone:HO (e.g., about 1:4, v:v) at an elevated temperature to obtain crystalline form A as a solid precipitate.

[0048] In some embodiments, the elevated temperature is a temperature of about 40-70°C, for example, about 45-65°C or about 50-60°C, preferably about 50°C.

[0049] In some embodiments, stirring can be carried out for a suitable period of time, for example, about 1 to 2 days.

[0050] ii. Crystalline form G The present invention also provides crystalline form G of compound I, wherein the XRPD pattern of crystalline form G comprises diffraction peaks at diffraction angles (2θ) of about 4.99±0.2°, 10.05±0.2°, 16.99±0.2°, 19.21±0.2°, and 20.28±0.2°.

[0051] Alternatively or additionally, crystalline form G has any one, two or all of the following properties: (1) The DSC pattern of crystalline form G has one endothermic peak at about 188.3°C ± 3.0°C; and (2) Form G has a weight loss of about 0.494% as measured by TGA during heating to about 180°C ± 3°C.

[0052] In some preferred embodiments, the XRPD pattern of crystalline form G further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 12.33±0.2°, 15.84±0.2°, 17.34±0.2°, 17.59±0.2°, 20.67±0.2°, 21.68±0.2°, and 26.59±0.2°.

[0053] In some preferred embodiments, the XRPD pattern of crystalline form G further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 12.62±0.2°, 15.00±0.2°, 18.30±0.2°, 23.88±0.2°, 24.72±0.2°, 29.12±0.2°, and 33.76±0.2°.

[0054] In some preferred embodiments, the DSC pattern of crystalline form G is substantially as shown in Figure 3-2.

[0055] In some preferred embodiments, the TGA pattern of crystalline form G is substantially as shown in Figure 3-3.

[0056] In some more preferred embodiments, the XRPD pattern of crystalline form G comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 3-1, and even more preferably, the XRPD pattern of crystalline form G is as shown in Figure 3-1.

[0057] The TGA weight loss of crystalline form G is small. 1 No significant residual solvent was observed by H NMR analysis. In some embodiments, crystalline form G is not a solvate. More preferably, crystalline form G is anhydrous.

[0058] In some embodiments, crystalline form G has a melting point greater than about 170°C.

[0059] Form G is the thermodynamically more stable form at room temperature and 50°C. In a suspension competition test of Form A and Form G in ethanol (EtOH) or methanol (MeOH) / water mixtures at room temperature and 50°C, Form A was confirmed to transform into Form G, indicating that Form G is thermodynamically more stable.

[0060] In some embodiments, no change in crystalline form is observed after drying crystalline form G for 3 hours at 50° C. Crystalline form G also has good solid-state stability, high temperature stability, high humidity stability, pressure stability, and low hygroscopicity.

[0061] In another aspect, the present invention also provides a method for preparing crystalline form G, comprising the steps of: (1) providing a clear solution of Compound I in acetonitrile (ACN) at a first elevated temperature; and (2) allowing the solution to cool to room temperature to obtain crystalline form G as a solid precipitate; The present invention provides a method comprising:

[0062] In some embodiments, the first elevated temperature is a temperature of about 50-70°C, for example, about 55-65°C or about 60-65°C, preferably about 60°C.

[0063] In some embodiments, the method comprises stirring a suspension of Compound I in acetonitrile at a second elevated temperature and then heating the suspension to a first elevated temperature to obtain a clear solution.

[0064] In some embodiments, the second elevated temperature is a temperature of about 40-60°C, for example, about 45-55°C or about 50-55°C, preferably about 50°C.

[0065] iii.Crystal form C The present invention also provides crystalline form C of compound I, wherein the XRPD pattern of crystalline form C is characterized by comprising diffraction peaks at diffraction angles (2θ) of about 7.28±0.2°, 10.87±0.2°, 18.39±0.2°, 22.12±0.2°, and 23.24±0.2°.

[0066] Alternatively or additionally, crystalline form C has any one, two or all of the following properties: (1) The DSC pattern of crystalline form C has one endothermic peak at approximately 109.0°C ± 3.0°C; (2) Form C has a weight loss of about 7.81% as measured by TGA during heating to about 120°C ± 3°C; and (3) Crystal form C 1 1 H NMR spectrum substantially as shown in Figure 4-4.

[0067] In some preferred embodiments, the XRPD pattern of crystalline form C further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 11.37±0.2°, 14.67±0.2°, 15.73±0.2°, 18.67±0.2°, 19.39±0.2°, 19.79±0.2°, 20.01±0.2°, 21.66±0.2°, and 23.80±0.2°.

[0068] In some preferred embodiments, the XRPD pattern of crystalline form C further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 11.79±0.2°, 17.09±0.2°, 18.96±0.2°, 21.43±0.2°, 22.68±0.2°, 25.01±0.2°, and 28.17±0.2°.

[0069] In some preferred embodiments, the DSC pattern of crystalline form C is substantially as shown in Figure 4-2.

[0070] In some preferred embodiments, the TGA pattern of crystalline form C is substantially as shown in Figure 4-3.

[0071] In some more preferred embodiments, the XRPD pattern of crystalline form C comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 4-1, and even more preferably, the XRPD pattern of crystalline form C is as shown in Figure 4-1.

[0072] In some embodiments, crystalline form C is a solvate, more specifically a solvate with tetrahydrofuran (THF), wherein the stoichiometric ratio of compound I to THF is preferably about 1:0.72.

[0073] In DSC tests, crystalline form C changes to an amorphous form upon heating at 110° C. for 5 minutes.

[0074] In another aspect, the present invention also provides a method for preparing crystalline form C, comprising the steps of: (1) providing a clear solution of Compound I in THF; (2) adding an anti-solvent to the clear solution under stirring to obtain crystalline form C as a solid precipitate; The present invention provides a method comprising:

[0075] In some embodiments, the anti-solvent is water.

[0076] iv.Crystal form D The present invention also provides crystalline form D of compound I, wherein the XRPD pattern of crystalline form D is characterized by comprising diffraction peaks at diffraction angles (2θ) of about 7.17±0.2°, 10.77±0.2°, 11.36±0.2°, 18.10±0.2°, 19.29±0.2°, and 2.95±0.2°.

[0077] Alternatively or additionally, crystalline form D has any one, two or all of the following properties: (1) The DSC pattern of crystalline form D has one endothermic peak at about 104.1°C ± 3.0°C; (2) Form D has a weight loss of about 11.75% as measured by TGA during heating to about 180°C ± 3°C; and (3) Crystalline form D 1 1 H NMR spectrum substantially as shown in Figure 5-4.

[0078] In some preferred embodiments, the XRPD pattern of crystalline form D further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 3.54±0.2°, 11.78±0.2°, 15.62±0.2°, 18.45±0.2°, and 21.78±0.2°.

[0079] In some preferred embodiments, the XRPD pattern of crystalline form D further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 14.44±0.2°, 16.93±0.2°, 19.85±0.2°, 22.44±0.2°, and 4.39±0.2°.

[0080] In some preferred embodiments, the DSC pattern of crystalline form D is substantially as shown in Figure 5-2.

[0081] In some preferred embodiments, the TGA pattern of crystalline form D is substantially as shown in Figure 5-3.

[0082] In some more preferred embodiments, the XRPD pattern of crystalline form D comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 5-1, and even more preferably, the XRPD pattern of crystalline form D is as shown in Figure 5-1.

[0083] In some embodiments, crystalline form D is a solvate, more specifically a solvate with 2-methyltetrahydrofuran (2-MeTHF), wherein the stoichiometric ratio of compound I to 2-MeTHF is preferably about 1:0.79.

[0084] In DSC tests, crystalline form D transforms into an amorphous form upon heating at 120° C. for 10 minutes.

[0085] In another aspect, the present invention also provides a method for preparing crystalline form D, comprising the steps of: (1) providing a clear solution of Compound I in 2-MeTHF; (2) adding anti-solvent to the clear solution under stirring to obtain crystalline form D as a solid precipitate; The present invention provides a method comprising:

[0086] In some embodiments, the anti-solvent is heptane (HEP).

[0087] v.Crystal form E The present invention also provides crystalline form E of compound I, wherein the XRPD pattern of crystalline form E comprises diffraction peaks at diffraction angles (2θ) of about 7.29±0.2°, 10.52±0.2°, 11.43±0.2°, 11.87±0.2°, and 8.37±0.2°.

[0088] Alternatively or additionally, crystalline form E has any one, two or all of the following properties: (1) The DSC pattern of crystalline form E has one endothermic peak at about 105.6°C ± 3.0°C; (2) Form E has a weight loss of about 11.46% as measured by TGA during heating to about 140°C ± 3°C; and (3) Crystal form E 1 1 H NMR spectrum substantially as shown in Figure 6-4.

[0089] In some preferred embodiments, the XRPD pattern of crystalline form E further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 13.55±0.2°, 14.67±0.2°, 15.78±0.2°, 17.13±0.2°, 19.28±0.2°, 20.05±0.2°, 21.20±0.2°, 22.08±0.2°, and 24.55±0.2°.

[0090] In some preferred embodiments, the DSC pattern of crystalline form E is substantially as shown in Figure 6-2.

[0091] In some preferred embodiments, the TGA pattern of crystalline form E is substantially as shown in Figure 6-3.

[0092] In some more preferred embodiments, the XRPD pattern of crystalline form E comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 6-1, and even more preferably, the XRPD pattern of crystalline form E is as shown in Figure 6-1.

[0093] In some embodiments, crystalline form E is a solvate, more specifically a solvate with methyl tert-butyl ether (MTBE), wherein the stoichiometric ratio of compound I to MTBE is preferably about 1:0.74.

[0094] In DSC tests, crystalline form E transforms into an amorphous form upon heating at 120° C. for 10 minutes.

[0095] In another aspect, the present invention also provides a method for preparing crystalline form E, comprising the steps of: suspending the amorphous form of Compound I in MTBE and stirring the resulting suspension at a suitable temperature to obtain crystalline Form E as a solid precipitate; The present invention provides a method comprising:

[0096] In some embodiments, the appropriate temperature is, for example, about 40 to 70°C, such as about 45 to 65°C or about 50 to 60°C, preferably about 50°C.

[0097] In some embodiments, stirring can be carried out for a suitable period of time, for example, about 1 to 2 days.

[0098] vi. Crystal form Ix The present invention also provides crystalline form Ix of compound I, wherein the XRPD pattern of crystalline form Ix is characterized by comprising diffraction peaks at diffraction angles (2θ) of about 3.70±0.2°, 7.47±0.2°, 11.24±0.2°, 11.46±0.2°, 15.02±0.2°, 18.82±0.2°, 19.68±0.2°, 22.64±0.2°, and 8.24±0.2°.

[0099] Alternatively or additionally, crystalline form Ix has any one, two or all of the following properties: (1) The DSC pattern of crystalline form Ix has one endothermic peak at approximately 113.2°C ± 3.0°C; (2) Form Ix has a weight loss of about 8.68% as measured by TGA during heating to about 130°C ± 3°C; and (3) Crystalline Form Ix 1 1 H NMR spectrum substantially as shown in Figure 7-4.

[0100] In some preferred embodiments, the DSC pattern of crystalline form Ix is substantially as shown in Figure 7-2.

[0101] In some preferred embodiments, the TGA pattern of crystalline form Ix is substantially as shown in Figure 7-3.

[0102] In some more preferred embodiments, the XRPD pattern of crystalline form Ix comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 7-1, and even more preferably, the XRPD pattern of crystalline form Ix is as shown in Figure 7-1.

[0103] In some embodiments, crystalline form Ix is a solvate, more particularly a solvate with acetone, wherein the stoichiometric ratio of compound I to acetone is preferably about 1:0.78.

[0104] In DSC tests, crystalline form Ix transforms into an amorphous form upon heating at 120° C. for 10 minutes.

[0105] In another aspect, the present invention also provides a method for preparing crystalline form Ix of compound I, comprising the steps of: (1) providing a clear solution of Compound I in acetone; and (2) slowly evaporating the solution at room temperature under conditions that allow for slow evaporation to obtain crystalline Form Ix as a solid precipitate; The present invention provides a method comprising:

[0106] In some embodiments, the slow evaporation can be carried out for a suitable period of time, for example, about 3 days.

[0107] vii.Crystal form J The present invention also provides crystalline form J of compound I, wherein the XRPD pattern of crystalline form J is characterized by comprising diffraction peaks at diffraction angles (2θ) of about 7.42±0.2°, 18.10±0.2°, 18.74±0.2°, 19.03±0.2°, and 22.13±0.2°.

[0108] Alternatively or additionally, crystalline form J has any one, two or all of the following properties: (1) The DSC pattern of crystalline form J has one endothermic peak at approximately 107.7°C ± 3.0°C; (2) Form J has a weight loss of about 10.35% as measured by TGA during heating to about 130°C ± 3°C; and (3) Crystal form J 1 The 1 H NMR spectrum is substantially as shown in Figure 8-4.

[0109] In some preferred embodiments, the XRPD pattern of crystalline form J further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 3.68±0.2°, 10.58±0.2°, 10.77±0.2°, 11.01±0.2°, 14.95±0.2°, 22.56±0.2°, 24.54±0.2°, and 27.27±0.2°.

[0110] In some preferred embodiments, the XRPD pattern of crystalline form J further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 11.67±0.2°, 13.62±0.2°, 16.32±0.2°, 17.59±0.2°, 20.53±0.2°, 25.09±0.2°, and 26.05±0.2°.

[0111] In some preferred embodiments, the DSC pattern of crystalline form J is substantially as shown in Figure 8-2.

[0112] In some preferred embodiments, the TGA pattern of crystalline form J is substantially as shown in Figure 8-3.

[0113] In some more preferred embodiments, the XRPD pattern of crystalline form J comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 8-1, and even more preferably, the XRPD pattern of crystalline form J is as shown in Figure 8-1.

[0114] In some embodiments, crystalline form J is a solvate, more particularly a solvate with MTBE, wherein the stoichiometric ratio of compound I to MTBE is preferably about 1:0.77.

[0115] In DSC tests, crystalline form J changes to an amorphous form when heated at 120° C. for 10 minutes.

[0116] In another aspect, the present invention also provides a method for preparing crystalline form J, comprising the steps of: (1) providing a hot, clear solution of Compound I in a mixture of EtOH:MTBE (e.g., about 1:3, v:v); and (2) allowing the solution to cool to room temperature to obtain crystalline form J as a solid precipitate; The present invention provides a method comprising:

[0117] In some embodiments, the elevated temperature is a temperature of about 40 to 60°C, for example, about 45 to 55°C or about 50 to 55°C, preferably about 50°C.

[0118] In some embodiments, the method comprises stirring a suspension of Compound I in a mixture of EtOH:MTBE and then heating the suspension to an elevated temperature to dissolve Compound I and form a solution.

[0119] viii. Crystal form K The present invention also provides crystalline form K of compound I, wherein the XRPD pattern of crystalline form K comprises diffraction peaks at diffraction angles (2θ) of about 3.70±0.2°, 7.44±0.2°, 18.74±0.2°, 19.40±0.2°, and 22.38±0.2°.

[0120] Alternatively or additionally, crystalline form K has any one, two or all of the following properties: (1) The DSC pattern of crystalline form K has one endothermic peak at approximately 103.8°C ± 3.0°C; (2) Form K has a weight loss of about 8.47% as measured by TGA during heating to about 110°C ± 3°C; and (3) Crystal form K 1 The 1 H NMR spectrum is substantially as shown in Figure 9-4.

[0121] In some preferred embodiments, the XRPD pattern of crystalline form K further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 11.20±0.2°, 11.81±0.2°, 14.94±0.2°, 24.73±0.2°, 26.15±0.2°, and 27.45±0.2°.

[0122] In some preferred embodiments, the XRPD pattern of crystalline form K further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 13.76±0.2°, 15.82±0.2°, 16.44±0.2°, 17.65±0.2°, 21.14±0.2°, 23.92±0.2°, and 25.29±0.2°.

[0123] In some preferred embodiments, the DSC pattern of crystalline form K is substantially as shown in Figure 9-2.

[0124] In some preferred embodiments, the TGA pattern of crystalline form K is substantially as shown in Figure 9-3.

[0125] In some more preferred embodiments, the XRPD pattern of crystalline form K comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 9-1, and even more preferably, the XRPD pattern of crystalline form K is as shown in Figure 9-1.

[0126] In some embodiments, crystalline form K is a solvate, more specifically a solvate with MTBE, wherein the stoichiometric ratio of compound I to MTBE is preferably about 1:0.47.

[0127] In DSC tests, crystalline form K changes to an amorphous form upon heating at 110° C. for 10 minutes.

[0128] In another aspect, the present invention also provides a method for preparing crystalline form K, comprising the steps of: (1) providing a hot, clear solution of Compound I in a mixture of CH2Cl2:MTBE (e.g., about 1:3, v:v); and (2) allowing the solution to cool to room temperature to obtain crystalline form K as a solid precipitate; The present invention provides a method comprising:

[0129] In some embodiments, the elevated temperature is a temperature of about 40-60°C, for example, about 45-55°C or about 50-55°C, preferably about 50°C.

[0130] In some embodiments, the method includes stirring a suspension of Compound I in a mixture of CH2Cl2:MTBE, and then heating the suspension to an elevated temperature to dissolve Compound I and form a solution.

[0131] ix.Crystal form L The present invention also provides crystalline form L of compound I, wherein the XRPD pattern of crystalline form L comprises diffraction peaks at diffraction angles (2θ) of about 7.41±0.2°, 11.18±0.2°, 18.72±0.2°, 19.75±0.2°, and 22.42±0.2°.

[0132] Alternatively or additionally, crystalline form L has any one, two or all of the following properties: (1) The DSC pattern of crystalline form L has one endothermic peak at about 98.1°C ± 3.0°C; (2) crystalline form L has a weight loss of about 7.62% as measured by TGA during heating to about 110°C ± 3°C; and (3) Crystal form L 1 1 H NMR spectrum substantially as shown in Figure 10-4.

[0133] In some preferred embodiments, the XRPD pattern of crystalline form L further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 10.97±0.2°, 11.76±0.2°, 24.73±0.2°, 26.34±0.2°, and 27.32±0.2°.

[0134] In some preferred embodiments, the DSC pattern of crystalline form L is substantially as shown in Figure 10-2.

[0135] In some preferred embodiments, the TGA pattern of crystalline form L is substantially as shown in Figure 10-3.

[0136] In some more preferred embodiments, the XRPD pattern of crystalline form L comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 10-1, and even more preferably, the XRPD pattern of crystalline form L is as shown in Figure 10-1.

[0137] In some embodiments, crystalline form L is a solvate, more particularly a solvate with THF, wherein the stoichiometric ratio of compound I to THF is preferably about 1:0.75.

[0138] In DSC tests, crystalline form L changes to an amorphous form upon heating at 120° C. for 10 minutes.

[0139] In another aspect, the present invention also provides a method for preparing crystalline form L, comprising the steps of: (1) providing a hot, clear solution of Compound I in a mixture of THF:HO (e.g., about 1:2, v:v); and (2) allowing the solution to cool to room temperature to obtain crystalline form L as a solid precipitate; The present invention provides a method comprising:

[0140] In some embodiments, the elevated temperature is a temperature of about 40 to 60°C, for example, about 45 to 55°C or about 50 to 55°C, preferably about 50°C.

[0141] In some embodiments, the method comprises stirring a suspension of Compound I in a mixture of THF:H2O, and then heating the suspension to an elevated temperature to dissolve Compound I and form a solution.

[0142] x.Crystal form M The present invention also provides crystalline form M of compound I, wherein the XRPD pattern of crystalline form M is characterized by comprising diffraction peaks at diffraction angles (2θ) of about 3.51±0.2°, 7.11±0.2°, 14.28±0.2°, 17.93±0.2°, 21.58±0.2°, and 25.25±0.2°.

[0143] Alternatively or additionally, crystalline form M has any one, two or all of the following properties: (1) The DSC pattern of crystalline form M has two endothermic peaks at about 95.8°C ± 3.0°C and about 109.2°C ± 3.0°C, respectively; (2) Form M has a weight loss of about 15.55% as measured by TGA during heating to about 230°C ± 3°C; and (3) Crystal form M 1 1 H NMR spectrum substantially as shown in Figure 11-4.

[0144] In some preferred embodiments, the DSC pattern of crystalline form M is substantially as shown in Figure 11-2.

[0145] In some preferred embodiments, the TGA pattern of crystalline form M is substantially as shown in Figure 11-3.

[0146] In some more preferred embodiments, the XRPD pattern of crystalline form M comprises diffraction peaks at diffraction angles (2θ) substantially the same as those shown in Figure 11-1, and even more preferably, the XRPD pattern of crystalline form M is as shown in Figure 11-1.

[0147] In some embodiments, crystalline form M is a solvate, more particularly a solvate with anisole, wherein the stoichiometric ratio of compound I to anisole is preferably about 1:1.

[0148] In DSC tests, crystalline form M changes to an amorphous form upon heating at 105° C. for 10 minutes.

[0149] In another aspect, the present invention also provides a method for preparing crystalline form M, comprising the steps of: (1) providing a hot, clear solution of Compound I in a mixture of anisole:HEP (e.g., about 9:1, v:v); and (2) allowing the solution to cool to room temperature to obtain crystalline form M as a solid precipitate; The present invention provides a method comprising:

[0150] In some embodiments, the elevated temperature is a temperature of about 40 to 60°C, for example, about 45 to 55°C or about 50 to 55°C, preferably about 50°C.

[0151] In some embodiments, the method comprises stirring a suspension of Compound I in a mixture of anisole:HEP, and then heating the suspension to an elevated temperature to dissolve Compound I and form a solution.

[0152] xi.Crystal form N The present invention further provides crystalline form N of compound I, wherein the XRPD pattern of crystalline form N is characterized by comprising diffraction peaks at diffraction angles (2θ) of about 3.57±0.2°, 7.23±0.2°, 14.57±0.2°, 18.26±0.2°, and 21.96±0.2°.

[0153] Alternatively or additionally, crystalline form N has any one, two or all of the following properties: (1) The DSC pattern of crystalline form N exhibits one endothermic peak at approximately 106.8°C ± 3.0°C; (2) Form N has a weight loss of about 11.80% as measured by TGA during heating to about 180°C ± 3°C; and (3) Crystal form N 1 1 H NMR spectrum substantially as shown in Figure 12-4.

[0154] In some preferred embodiments, the XRPD pattern of crystalline form N further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 10.91±0.2°, 22.95±0.2°, 23.88±0.2°, and 37.08±0.2°.

[0155] In some preferred embodiments, the DSC pattern of crystalline form N is substantially as shown in Figure 12-2.

[0156] In some preferred embodiments, the TGA pattern of crystalline form N is substantially as shown in Figure 12-3.

[0157] In some more preferred embodiments, the XRPD pattern of crystalline form N comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 12-1, and even more preferably, the XRPD pattern of crystalline form N is as shown in Figure 12-1.

[0158] In some embodiments, crystalline form N is a solvate, more specifically a solvate with isopropyl alcohol (IPA), wherein the stoichiometric ratio of compound I to IPA is preferably about 1:0.82.

[0159] In DSC tests, crystalline form N changes to an amorphous form upon heating at 120° C. for 10 minutes.

[0160] In another aspect, the present invention also provides a method for preparing crystalline form N of compound I, comprising the steps of: (1) providing a solution of Compound I in a mixture of IPA:HO (e.g., about 4:1, v:v); and (2) slowly evaporating the solution at room temperature under conditions that allow for slow evaporation to obtain crystalline form N as a solid precipitate; The present invention provides a method comprising:

[0161] In some embodiments, the slow evaporation can be carried out for a suitable period of time, for example, about 6-10 days or about 8-9 days.

[0162] xii. Crystal form O The present invention further provides crystalline form O of compound I, wherein the XRPD pattern of crystalline form O is characterized by comprising diffraction peaks at diffraction angles (2θ) of about 7.54±0.2°, 10.95±0.2°, 18.88±0.2°, 19.79±0.2°, and 22.62±0.2°.

[0163] Alternatively or additionally, crystalline form O has any one, two or all of the following properties: (1) The DSC pattern of crystalline form O has one endothermic peak at approximately 95.5°C ± 3.0°C; (2) Form O has a weight loss of about 5.38% as measured by TGA during heating to about 110°C ± 3°C. (3) Crystal form O 1 The 1 H NMR spectrum is substantially as shown in Figure 13-4.

[0164] In some preferred embodiments, the XRPD pattern of crystalline form O further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 11.44±0.2°, 11.88±0.2°, 13.75±0.2°, and 21.19±0.2°.

[0165] In some preferred embodiments, the XRPD pattern of crystalline form O further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 15.05±0.2°, 15.87±0.2°, 16.17±0.2°, 24.95±0.2°, 26.44±0.2°, and 27.66±0.2°.

[0166] In some preferred embodiments, the XRPD pattern of crystalline form O further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 17.45±0.2°, 21.86±0.2°, 23.85±0.2°, and 25.72±0.2°.

[0167] In some preferred embodiments, the DSC pattern of crystalline form O is substantially as shown in Figure 13-2.

[0168] In some preferred embodiments, the TGA pattern of crystalline form O is substantially as shown in Figure 13-3.

[0169] In some more preferred embodiments, the XRPD pattern of crystalline form O comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 13-1, and even more preferably, the XRPD pattern of crystalline form O is as shown in Figure 13-1.

[0170] In some embodiments, crystalline form O is a solvate, more particularly a solvate with acetone, wherein the stoichiometric ratio of compound I to acetone is preferably about 1:0.5.

[0171] In DSC tests, crystalline form O changes to an amorphous form upon heating at 120° C. for 10 minutes.

[0172] In another aspect, the present invention also provides a method for preparing crystalline form O of compound I, comprising the steps of: The method comprises contacting the amorphous form of Compound I with acetone vapor in a closed vessel for a suitable period of time to obtain crystalline Form O.

[0173] In some embodiments, a suitable period of time is, for example, about 9 to 10 days.

[0174] xiii. Other crystalline forms The present invention also provides metastable crystalline forms of Compound I, including: (1) Crystalline form B having an XRPD pattern substantially as shown in Figure 14, which converts to an amorphous form upon drying at about 50°C for 3 hours. (2) Crystalline form H, having an XRPD pattern substantially as shown in Figure 15, which transforms into a weakly crystalline state upon drying at about 50°C for 2 hours. (3) Crystalline form F having an XRPD pattern substantially as shown in Figure 16, which transforms into crystalline form D upon storage at room temperature under closed conditions for 21 days. (4) Crystalline form P, having an XRPD pattern substantially as shown in Figure 17, which converts to an amorphous form upon drying at about 50°C for 3.5 hours.

[0175] II. Pharmaceutical Compositions In another aspect, the present invention provides a pharmaceutical composition comprising a crystalline form of compound I of the present invention, wherein the crystalline form of compound I is selected from crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form Ix, crystalline form J, crystalline form K, crystalline form L, crystalline form M, crystalline form N, crystalline form O and crystalline form P described herein. Preferably, the crystalline form of compound I is selected from crystalline form A, crystalline form C, crystalline form D, crystalline form E, crystalline form G, crystalline form Ix, crystalline form J, crystalline form K, crystalline form L, crystalline form M, crystalline form N and crystalline form O. More preferably, the crystalline form of compound I is selected from crystalline form A or crystalline form G, and even more preferably, crystalline form G.

[0176] The present invention also provides pharmaceutical compositions as described above, further comprising one, two or more other therapeutically active ingredients.

[0177] The pharmaceutical compositions of the present invention may also include a pharmaceutically acceptable carrier.

[0178] As used herein, "pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered that is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0179] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils (including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like). Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerol, propylene glycol, water, ethanol, and the like. If desired, the compositions may also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0180] The pharmaceutical compositions of the present invention can act systemically and / or locally. To this end, they can be administered by any suitable route, such as injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration, or they can be administered orally, bucally, intranasally, transmucosally, topically, in the form of ophthalmic preparations or by inhalation.

[0181] The pharmaceutical composition of the present invention can be administered in dosage forms suitable for these administration routes.

[0182] Dosage forms include, but are not limited to, liquid preparations, semi-solid preparations, and solid preparations.Solid or semi-solid preparations include, but are not limited to, capsules, tablets, pills, lozenges, sugar-coated tablets, granules, powders, ointments, and creams.Liquid preparations include, but are not limited to, elixirs, syrups, emulsions, dispersions, suspensions, solutions, sprays, and drops.

[0183] As used herein, the term "therapeutically effective amount" means that amount of a compound that, when administered, will relieve to some extent one or more of the symptoms of the disease or disorder being treated.

[0184] Dosage regimen can be adjusted to obtain optimal desired response.For example, a single bolus can be administered, or several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.It is worth noting that dosage varies according to the type and severity of the condition to be alleviated, and can include single or multiple administrations.In addition, it should be understood that for a specific subject, specific dosing schedule needs to be adjusted over time according to the needs of the subject and the professional judgment of the person administering or supervising the administration of the composition.

[0185] The amount of the compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose will be about 0.0001 to about 50 mg / kg of body weight per day, e.g., about 0.01 to about 10 mg / kg per day (as a single or divided dose). For a 70 kg person, this corresponds to about 0.007 mg / day to about 3500 mg / day, e.g., about 0.7 mg / day to about 700 mg / day. In some cases, dosage levels not exceeding the lower end of the aforementioned ranges may be sufficient, while in other cases, larger doses may still be used without causing adverse side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0186] The content or amount of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg.

[0187] As used herein, the term "treatment" means reversing, alleviating, or inhibiting the progression of the disease or disorder to which the term applies, or one or more symptoms of the disease or disorder. As used herein, the term "prevention" means preventing or arresting the onset or appearance of one or more symptoms of the disease or disorder to which the term applies.

[0188] As used herein, a "subject" includes a human or a non-human animal. Exemplary human embodiments include a human subject (referred to as a patient) suffering from a disease, e.g., a disease described herein, or a normal subject. "Non-human animals" in the present invention include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, domestic animals and / or farm animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0189] III. Methods of Use and Treatment The crystalline form of Compound I of the present invention has excellent GLP-1 receptor agonist activity and can treat and / or prevent GLP-1 receptor-mediated diseases and related disorders.

[0190] Thus, in one aspect, the present invention provides a method for treating and / or preventing a GLP-1 receptor-mediated disease or related disorder, comprising administering an effective amount of a crystalline form of Compound I of the present invention or a pharmaceutical composition of the present invention to a subject in need thereof.

[0191] In another aspect, the present invention provides a crystalline form of Compound I of the present invention or a pharmaceutical composition of the present invention for use in the treatment and / or prevention of GLP-1 receptor-mediated diseases and related disorders.

[0192] In another aspect, the present invention provides the use of a crystalline form of Compound I of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for treating and / or preventing a GLP-1 receptor-mediated disease or related disorder.

[0193] In another aspect, the present invention provides a method for treating and / or preventing a metabolic-related disease or disorder, comprising administering an effective amount of a crystalline form of Compound I of the present invention or a pharmaceutical composition of the present invention to a subject in need thereof.

[0194] In another aspect, the present invention provides a crystalline form of Compound I of the present invention or a pharmaceutical composition of the present invention for use in the treatment and / or prevention of a metabolic-related disease or disorder.

[0195] In another aspect, the present invention provides the use of a crystalline form of Compound I of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for treating and / or preventing a metabolic-related disease or disorder.

[0196] In some embodiments, the metabolic-related disease or disorder comprises GLP-1 receptor-mediated diseases and related disorders.

[0197] In some embodiments, the GLP-1 receptor mediated disease or related disorder is selected from diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, non-alcoholic fatty liver disease, dyslipidemia, and hyperinsulinemia.

[0198] In some embodiments, the diabetes is selected from T1D and / or T2DM, idiopathic T1D, early-onset T2DM, latent autoimmune diabetes, atypical diabetes of the juvenile and gestational diabetes.

[0199] In some embodiments, the GLP-1 receptor mediated disease or related disorder is obesity.

[0200] In some embodiments, the GLP-1 receptor mediated disease or related disorder is T2DM.

[0201] In some embodiments, the GLP-1 receptor mediated disease or related disorder is non-alcoholic fatty liver disease.

[0202] In some embodiments, the crystalline form of compound I is selected from crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form Ix, crystalline form J, crystalline form K, crystalline form L, crystalline form M, crystalline form N, crystalline form O, and crystalline form P. Preferably, the crystalline form of compound I is selected from crystalline form A, crystalline form C, crystalline form D, crystalline form E, crystalline form G, crystalline form Ix, crystalline form J, crystalline form K, crystalline form L, crystalline form M, crystalline form N, and crystalline form O. More preferably, the crystalline form of compound I is crystalline form A or crystalline form G, and even more preferably, crystalline form G.

[0203] Beneficial effects The crystalline forms of Compound I of the present invention, preferably Form A and Form G, have good physicochemical properties, such as low hygroscopicity, and good physicochemical stability (solid-state stability, high temperature resistance, high humidity resistance, and / or high pressure resistance). Form G has high thermodynamic stability in the temperature range from room temperature to 50°C. Form G also has high pressure stability. The crystalline forms of Compound I may have good druggability and / or bioavailability. [Example]

[0204] The present invention will be further described in detail through the following examples. The examples of the present invention are only used 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 insubstantial improvements and adjustments, which still fall within the protection scope of the present invention.

[0205] All solvents used in the examples are commercially available and can be used without further purification.

[0206] The abbreviations used in this application have the following meanings: rt denotes room temperature; H2O denotes water; CH2Cl2 denotes dichloromethane; THF denotes tetrahydrofuran; IPA denotes isopropyl alcohol; 2-MeTHF denotes 2-methyltetrahydrofuran; NMP denotes N-methylpyrrolidone; DME denotes dimethoxyethane; DCM denotes dichloromethane; Xphos denotes 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; EtOAc denotes ethyl acetate; MeOH denotes methanol; 2-Me-THF denotes 2-methyltetrahydrofuran; DAST denotes diethylaminosulfur trifluoride. TFE indicates tetrafluoroethylene; ACN indicates acetonitrile; CPME indicates cyclopentyl methyl ether; DMSO indicates dimethyl sulfoxide; EtOH indicates ethanol; TFA indicates trifluoroacetic acid; TsOH indicates p-toluenesulfonic acid; MIBK indicates methyl isobutyl ketone; HEP indicates n-heptane; IPAc indicates isopropyl acetate; EtOAc indicates ethyl acetate; DMF indicates N,N-dimethylformamide; MTBE indicates methyl tert-butyl ether; MEK indicates methyl ethyl ketone; CHCl3 indicates chloroform; and MCH indicates methylcyclohexane.

[0207] Compounds are named manually or by ChemDraw® software, and commercially available compounds adopt names from supplier catalogs.

[0208] The equipment and parameters used herein are as follows: 1. X-ray powder diffractometer (XRPD) [Table 1] 2. Thermogravimetric analyzer (TGA) and differential scanning calorimeter (DSC) [Table 2] 3. High-Performance Liquid Chromatography (HPLC) [Table 3] 4. Dynamic Vapor Sorption (DVS) Measurements [Table 4] 5. Proton nuclear magnetic resonance ( 1 H NMR) [Table 5]

[0209] Example 1: Preparation of Compound 1 [ka]

[0210] [ka]

[0211] Preparation method Compound 1-2: To a solution of compound 1-1 (20.0 g, 98.0 mmol) in MeCN (500 mL), imidazole (10.0 g, 147.0 mmol) was added, followed by TBSCl (16.3 g, 107.8 mmol). The mixture was stirred at room temperature for 5 hours. H2O (500 mL) was added. The reaction solution was extracted with EtOAc (3 x 500 mL). The organic phases were combined, washed with brine (500 mL), dried (Na2SO4), filtered, concentrated, and subjected to flash chromatography (SiO2, hexane) to give 31 g of compound 1-2. Yield: 99.6%. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (m, 3H), 4.62 (s, 2H), 0.81 (s, 9H), 0.00 (s, 6H).

[0212] Compound 1-3: To a solution of compound 1-2 (20.0 g, 62.8 mmol) in anhydrous THF (200 mL) was added N-BuLi (2.5 M in THF, 27.6 mL, 69.1 mmol) dropwise at −78 °C under N. The mixture was stirred at this temperature for 0.5 h, and oxetan-3-one (4.5 g, 62.8 mmol) was added. The mixture was then stirred at room temperature under N for 2.5 h. The reaction solution was quenched with water (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layers were combined, washed with brine (100 mL), dried (NaSO), filtered, concentrated, and subjected to flash chromatography (SiO, 25% EtOAc-hexane) to give 14 g of compound 1-3. Yield: 71.0%. 1 H NMR (400 MHz, DMSO-d6) δ 7.42 - 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).

[0213] Compound 1-4: To a solution of compound 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. The mixture was stirred at room temperature for 2 h, and then CS (3.6 g, 89.7 mmol) and MeI (6.4 g, 44.8 mmol) were added at 0 °C under N. The mixture was then stirred at 0 °C under N for 0.5 h. The reaction solution was quenched with saturated NH Cl solution (100 mL) and extracted with EtOAc (3 × 200 mL). The organic phases were combined, washed with brine (200 mL), dried (Na SO ), filtered, and concentrated to give 14 g of compound 1-4. The product was used directly in the next step without further purification.

[0214] Compound 1-5: To a solution of compound 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). The mixture was stirred at 125 °C under a N2 atmosphere for 0.5 h. The reaction solution was concentrated and purified by flash chromatography (SiO2, 20% EtOAc-hexane) to give 8 g of compound 1-5. Yield for two steps: 60.6%. 1 H NMR (400 MHz, DMSO-d6) δ 7.41 (t, J = 8.0 Hz, 1H), 7.23 - 7.16 (m, 2H), 4.91 (dd, J = 8.3, 5.9 Hz, 2H), 4.72 (s, 2H), 4.59 (t, J = 6.3 Hz, 2H), 4.30 - 4.18 (m, 1H), 0.88 (s, 9H), 0.07 (s, 6H).

[0215] Compound 1-6: To a solution of compound 1-5 (8.0 g, 43.0 mmol) in THF (200 mL) was added EtN HF (13.9 g, 86.0 mmol). The reaction solution was stirred at room temperature under a N atmosphere for 16 hours. The reaction solution was concentrated and purified by flash chromatography (SiO, EtOAc-hexane) to give 5 g of compound 1-6. Yield: 99.9%. 1 H NMR (400 MHz, DMSO-d6) δ 7.44 (t, J = 7.8 Hz, 1H), 7.20 (t, J = 9.1 Hz, 2H), 5.22 (t, J = 5.7 Hz, 1H), 4.92 (dd, J = 8.0, 6.1 Hz, 2H), 4.59 (t, J = 6.3 Hz, 2H), 4.52 (d, J = 5.6 Hz, 2H), 4.30 - 4.18 (m, 1H).

[0216] Compound 1-7: To a solution of compound 1-6 (4.8 g, 26.3 mmol) in DCM (100 mL) was added NBS (5.2 g, 29.0 mmol), followed by PPh (7.7 g, 29.0 mmol) at 0 °C. The mixture was stirred at room temperature under a N atmosphere for 5 h. H2O (100 mL) was added. The reaction solution was extracted with DCM (3 × 100 mL). The organic phases were combined, washed with brine (100 mL), dried (Na2SO4), filtered, concentrated, and purified by flash chromatography (SiO2, EtOAc-hexane) to give 2 g of compound 1-7. Yield: 30.7%. 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (t, J = 8.0 Hz, 1H), 7.33 - 7.20 (m, 2H), 4.92 (dd, J = 8.3, 6.0 Hz, 2H), 4.70 (s, 2H), 4.60 (t, J = 6.3 Hz, 2H), 4.34 - 4.20 (m, 1H).

[0217] Compound 1-8: Compound 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 the solvent DMF (50 mL). Then, CsCO (2.4 g, 7.37 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. H0 (50 mL) was added. The reaction solution was extracted with EtOAc (3 x 50 mL). The organic phases were combined, washed with brine (50 mL), dried (NaSO), filtered, concentrated, and purified by flash chromatography (SiO, EtOAc-hexane) to give 500 mg of compound 1-8. Yield: 45.9%. 1H NMR (400 MHz, CDCl3) δ 7.60 (t, J = 7.7 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.17 (s, 1H), 7.13 (d, J = 11.4 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 5.43 (d, J = 7.5 Hz, 3H), 5.33 (s, 1H), 4.45 (s, 2H), 4.14 (d, J = 14.0 Hz, 2H), 3.03 (t, J = 12.8 Hz, 1H), 2.80 (t, J = 12.9 Hz, 2H), 1.85 (d, J = 12.5 Hz, 2H), 1.57-1.61 (m 3H), 1.42 (s, 9H). / LC-MS (ESI) m / z: 443.2 [M + H] + .

[0218] Compound 1-9: To a solution of compound 1-8 (210 mg, 0.49 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated to give 250 mg of compound 1-9. LC-MS: MC20-1128-086C (ESI) m / z: 343.1 [M + H] + .

[0219] Compound 1-10: Compound 1-9 (200 mg, 0.58 mmol) and (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (172 mg, 0.58 mmol) were added to the solvent dioxane (20 mL) and MeCN (12 mL), and then KCO (162 mg, 1.16 mmol) was added. The reaction solution was stirred at 65 °C for 3 hours. HO (20 mL) was added. The reaction solution was extracted with EtOAc (3 × 20 mL). The organic phases were combined, washed with brine (20 mL), dried (NaSO), filtered, concentrated, and purified by flash chromatography (SiO, EtOAc-hexane) to give 60 mg of compound 1-10. Yield: 22.0%. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 1.1 Hz, 1H), 7.82 (dd, J = 8.5, 1.6 Hz, 1H), 7.70 - 7.59 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 11.3 Hz, 1H), 7.21 (d, J = 9.5 Hz, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.38 (s, 2H), 5.35 - 5.30 (m, 1H), 5.12 (qd, J = 7.0, 2.5 Hz, 1H), 4.90 (dd, J = 8.3, 6.0 Hz, 2H), 4.80-4.84 (m 1H), 4.65-4.71 (m, 1H), 4.58 (t, J = 6.4 Hz, 2H), 4.47 (dt, J = 8.3, 6.5 Hz, 1H), 4.37 (dt, J = 9.1, 5.9 Hz, 1H), 4.21-4.28 (m,1H), 3.94-4.02 (m,1H), 3.87 (s, 3H), 3.78 (d, J = 13.6 Hz, 1H), 3.01 (d, J = 9.4 Hz, 1H), 2.85 (d, J = 13.5 Hz, 1H), 2.73 - 2.59 (m, 2H), 2.27 (d, J = 10.0 Hz, 1H), 2.17 (d, J = 11.6 Hz, 1H), 1.76 (m, 4H). / LC-MS (ESI) m / z: 601.4 [M + H] + .

[0220] Compound 1: To a solution of compound 1-10 (60 mg, 0.1 mmol) in MeOH (1 mL) and THF (5 mL) was added 1M LiOH (2 mL). The reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated and purified by preparative HPLC to give 10.95 mg of compound 1 as a white solid. Yield: 18.6%. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.79 (dd, J1= 4.0 Hz, , J2= 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 12.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.38 (s, 2H), 5.12 (m, 1H), 4.90 (dd, J = 8.0 Hz, 2H), 4.77 (dd, J1= 4.0 Hz, J2= 16.0 Hz, 1H), 4.64 (d, J = 4.0 Hz, 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 = 12.0 Hz, 1H), 3.77 (d, J = 12.0 Hz, 1H), 3.00 (d, J = 12.0 Hz, 1H), 2.86 (d, J = 12.0 Hz, 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).

[0221] Compound I was in amorphous form with an XRPD pattern as determined by XRPD as shown in FIG.

[0222] Example 2 - Assay of GLP-1R Agonist Activity of Compound I (1) Test equipment and reagents [Table 6]

[0223] (2) GLP-1R Kit GLP-1R-mediated agonist activity was measured by a cell-based assay using a homogeneous time-resolved fluorescence (i.e., HTRF)-based cAMP detection kit to measure cAMP levels in cells. The method was a competitive immunoassay, which allowed for the direct pharmacological characterization of compounds acting on Gs-coupled receptors in adherent or suspension cells.

[0224] A standard curve of native cAMP or unlabeled cAMP produced by cells competed with the d2-labeled cAMP red receptor to bind to the monoclonal anti-cAMP Eu3+ cryptate donor, and the specific signal was inversely proportional to the cAMP concentration in the standard or test sample.

[0225] The human GLP-1R coding sequence (NCBI Reference Sequence NP_2053.3) was subcloned into pEGFP-N1 (tsingke), and cell lines stably expressing the receptor were isolated. GLP-1R expression density was confirmed by GFP expression under a fluorescence microscope.

[0226] (3) GLP-1R-GFP-293A cell culture 293A GFP-GLP-1R cells were cultured in DMEM growth medium (containing 10% heat-inactivated fetal bovine serum (GEMINI Cat 900-108) and 1% Pen-3Trep (Sangom Biotech Cat E607011-0100)) in a humidified atmosphere, 5% CO2, 37°C incubator.

[0227] (4) cAMP level test method Test compounds (in DMSO) were diluted 1:5 with distilled water in stimulation buffer at different concentrations, followed by the addition of 500 μM 3-isobutyl-1-methylxanthine (IBMX; Meilunbiocat MB5226) to obtain a 2X compound working solution. Five μL of compound was then added to a white 384-well assay plate (Corning 3824) using a multichannel pipette. The final DMSO concentration in the buffer was 1‰.

[0228] 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 IC 1000 counter to determine cell viability and cell count per mL. The remaining cell suspension was then adjusted with stimulation buffer and 2000 viable cells were delivered per well using a multichannel pipette. Five μL of the cell suspension was added to each well of the plate already containing compound. The plate was sealed and incubated at 37°C, 5% CO2 for 30 minutes.

[0229] 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 plate. The plate was then incubated at room temperature for 60 minutes, and the change in HTRF signal was read using a Tecan Spark reader: absorbance values ​​at 340 nm (excitation) / 615 nm and 665 nm (emission). Raw data were converted to nM cAMP by interpolation from the cAMP standard curve, and the effect was calculated as a percentage relative to the saturating concentration of the full agonist GLP-37 (400 nM) included on each plate. EC50 determinations were based on agonist dose-response curves and analyzed using a four-parameter logistic dose-response equation with a curve-fitting program.

[0230] This study demonstrated that Compound I activates GLP-1R signaling via the cAMP pathway, thus acting as a GLP-1R agonist. The study data were expressed as geometric means (EC 50 The results are shown in the form of s).

[0231] Experimental results: Compound I exhibited strong agonistic activity against GLP-1R. [Table 7]

[0232] Example 3: Preparation of crystalline forms of Compound I A total of 111 polymorph screening tests were conducted using the amorphous form as the starting material, resulting in the identification of 16 crystalline forms. The screening methods included slow evaporation, crystallization slurries at 4-8°C, crystallization slurries at room temperature, crystallization slurries at 50°C, addition of antisolvents, addition of anti-antisolvents, cooling crystallization, gas-liquid diffusion, gas-solid diffusion, water vapor stress, polymer induction, grinding, repeated heating and cooling, and rotary evaporation. Among these, 12 crystalline forms, as described in Example 3, were stable, including the anhydrous forms A and G, and the remaining forms were the corresponding solvated forms.

[0233] 1. Crystalline form A 200.49 mg of amorphous Compound I was suspended in 5 mL of a mixture of acetone / HO (1 / 4, v / v). After magnetic stirring of the suspension at 50°C for about 1 day, the solid was isolated to obtain crystalline Form A, which has the XRPD pattern shown in Figure 2-1.

[0234] 2. Crystal form G 199.87 mg of amorphous Compound I was suspended in 18 mL of ACN. The suspension was stirred at 50°C, then heated to 60°C to dissolve, and then filtered. The clear solution was allowed to cool to room temperature, and the solid was isolated. The solid was crystalline form G, having the XRPD pattern shown in Figure 3-1.

[0235] 3. Crystal form C 19.94 mg of Compound I was dissolved in 0.5 mL of THF and filtered. Then, 1.0 mL of HO was added to the clear solution under magnetic stirring. A large amount of white precipitate formed, and a solid was separated. The solid was crystalline form C, having the XRPD pattern shown in Figure 4-1.

[0236] 4. Crystal form D 19.8 mg of compound I was dissolved in 0.5 mL of 2-MeTHF and filtered. Then, 1.0 mL of HEP was added to the clear solution under magnetic stirring. A large amount of precipitate formed, and a solid was separated. The solid was crystalline form D, which has the XRPD pattern shown in Figure 5-1.

[0237] 5. Crystal form E 100.18 mg of amorphous Compound I was added to a 20 mL vial, followed by the addition of 2.5 mL of MTBE. The resulting suspension was magnetically stirred at 50° C. for approximately 1 day, after which the solid was collected by centrifugation. The solid was identified as crystalline form E, having the XRPD pattern shown in FIG. 6-1.

[0238] 6. Crystalline form Ix 99.79 mg of amorphous Compound I was added to 4.0 mL of acetone and filtered. The vial containing the filtrate was sealed with parafilm, the parafilm was punctured, and the vial was left at room temperature to slowly evaporate for 3 days. The resulting solid was collected. This solid was identified as Form Ix, having the XRPD pattern shown in Figure 7-1.

[0239] 7. Crystal form J 20.05 mg of Compound I was suspended in 0.8 mL of a mixture of EtOH / MTBE (1 / 3 v / v). The suspension was clarified at 50°C and then filtered. The clear solution was allowed to cool to room temperature, and the solid was separated. The solid was crystalline form J, having the XRPD pattern shown in Figure 8-1.

[0240] 8. Crystal form K 20 mg of compound I was suspended in 1.2 mL of a mixture of CHCl / MTBE (1 / 3 v / v). The suspension was clarified at 50°C and then filtered. The clear solution was allowed to cool to room temperature, and the solid was separated. The solid was crystalline form K, having the XRPD pattern shown in Figure 9-1.

[0241] 9. Crystal form L 100.14 mg of compound I was suspended in 9.0 mL of a mixture of THF / HO (1 / 2 v / v). The suspension was clarified at 50°C and then filtered. The clear solution was allowed to cool to room temperature, and the solid was separated. The solid was crystalline form L, having the XRPD pattern shown in Figure 10-1.

[0242] 10. Crystal form M 99.83 mg of compound I was suspended in 10 mL of a mixture of anisole / HEP (9 / 1 v / v). The suspension was clarified at 50°C and then filtered. The clear solution was allowed to cool to room temperature, and the solid was separated. The solid was crystalline form M, having the XRPD pattern shown in Figure 11-1.

[0243] 11. Crystal form N 20.08 mg of Compound I was suspended in 1.0 mL of a mixture of IPA / HO (4 / 1 v / v) and filtered. The vial containing the filtrate was sealed with parafilm, the parafilm was punctured, and the vial was left at room temperature to slowly evaporate for 8 days. The resulting solid was collected. This solid was crystalline form N, having the XRPD pattern shown in Figure 12-1.

[0244] 12. Crystal form O 20.17 mg of amorphous Compound I was added to a 3 mL vial, which was then placed in a 20 mL vial containing 3 mL of acetone. The 20 mL vial was sealed with a cap and placed at room temperature to allow acetone vapor to interact with Compound I. After 10 days, the resulting solid was removed. The solid was crystalline form O, having the XRPD pattern shown in Figure 13-1.

[0245] Compared with the metastable crystalline form described in Example 4, the crystalline form described in Example 3 did not show any decrease in crystallinity or change in crystalline form under dry conditions (50°C).

[0246] Both anhydrous crystalline forms A and G have melting points above 170°C and exhibit excellent crystalline form properties in terms of equilibrium solubility, hygroscopicity, solid-state stability, pressure stability, and high humidity stability.

[0247] The solvates of crystalline forms C, O, E, Ix, J, K, L, M, N and D may be stable for a long period of time if evaporation of the solvent does not occur at high temperatures (e.g., temperatures above 100°C).

[0248] Example 4: Preparation of metastable crystalline forms of Compound I 1. Crystal form B 200.09 mg of amorphous Compound I was suspended in 5 mL of a mixed solvent of CHCl / HEP (1 / 2 v / v). The suspension was magnetically stirred at room temperature for about 1 day, and then the solid was isolated. This solid was crystalline form B, having the XRPD pattern shown in FIG. 14.

[0249] 2. Crystal form H 100.06 mg of compound I was suspended in 11 mL of a mixed solvent of EtOAc / HEP (2 / 1 v / v). The suspension was then heated to 50° C. and equilibrated for about 2 hours, after which it was filtered. The filtrate was slowly cooled to room temperature in a water bath. The resulting solid was isolated to obtain crystalline form H, which has the XRPD pattern shown in FIG. 15.

[0250] 3. Crystal form F 100.14 mg of Compound I was added to 9.0 mL of a mixed solvent of 2-MeTHF / HEP (8 / 1 v / v) and filtered. The vial containing the filtrate was sealed with parafilm, punctured, and placed at room temperature for slow evaporation for 3 days. The resulting solid was collected to give Form F, which has the XRPD pattern shown in Figure 16.

[0251] 4. Crystal form P 19.87 mg of Compound I was placed in a 5.0 mL vial, 1.0 mL of CHCl was added, and filtered to obtain a clear solution. This solution was added to a 20 mL vial containing 3 mL of HEP, and then the solid was separated to obtain crystalline form P, which has the XRPD pattern shown in FIG. 17.

[0252] The four metastable crystalline forms described in Example 4 were less stable than the respective crystalline forms described in Example 3. Crystalline form B changed to an amorphous form when dried at 50°C for 3 hours. Crystalline form H showed a weakly crystalline state when dried at 50°C for 2 hours. Crystalline form F changed to stable crystal form D under closed conditions for 21 days. Crystalline form P changed to an amorphous form when dried at 50°C for 3.5 hours.

[0253] Example 5: Determination of the equilibrium solubility of Compound I The equilibrium solubilities of Forms A and G of Compound I were measured in four media: HO (purified water), FaSSGF (fasted-state simulated gastric fluid), FaSSIF (fasted-state simulated intestinal fluid), and FeSSIF (fed-state simulated intestinal fluid) at 37°C for 24 hours.

[0254] 10 mg of each of Form A and Form G was added to 1 mL of the corresponding medium and magnetically stirred at a constant temperature of 37 ± 2°C. After 24 hours, samples were taken and separated by centrifugation. The resulting solid was examined by XRPD, and the supernatant was filtered and subjected to solubility testing.

[0255] The results shown in Table E-1 indicate that after 24 hours of stirring in different media, no change in crystalline form was observed between Form A and Form G in HO, FeSSIF, and FaSSIF. On the other hand, the hydrochloride salt was produced in FaSSGF. The equilibrium solubilities of Form A and Form G in water were both less than 0.1 mg / mL.

[0256] [Table 8]

[0257] Form A has significantly increased solubility in both FeSSIF and FaSSGF compared to water, making it beneficial for oral administration before or after meals. Form G has significantly increased solubility in FeSSIF compared to water, making it beneficial for oral administration after meals. Form A may be more advantageous than Form G for oral administration before meals.

[0258] Example 6: Determination of the hygroscopicity of crystalline forms A and G of Compound I DVS studies were performed on Form A and Form G of Compound I to assess the risk of sample stability changes at 25°C and humidity. The test results are summarized in Table E-2. The DVS pattern of Form A is shown in Figures 2-5, and the DVS pattern of Form G is shown in Figures 3-5.

[0259] [Table 9]

[0260] The results showed that under 80% RH, crystalline form A absorbed 0.89% water, and crystalline form G absorbed 0.73% water, indicating that both are slightly hygroscopic. No change in crystalline form was observed before and after the DVS test. Both crystalline forms A and G have good low hygroscopicity.

[0261] Example 7: Determination of the solid-state stability of crystalline forms A and G of Compound I Form A and Form G of Compound I were subjected to long-term (25°C / 60% RH) and accelerated (40°C / 75% RH) conditions for 10 days, respectively, to determine the HPLC purity and crystalline form changes. The test results are shown in Table E-3.

[0262] [Table 10] The results showed that no change in crystalline form was observed before and after the test for crystalline forms A and G. The purity of crystalline form A decreased by approximately 0.6% under long-term conditions and by approximately 0.8% under accelerated conditions. The purity of crystalline form G decreased by approximately 0.4% under both long-term and accelerated conditions. Crystalline forms A and G showed good solid-state stability under both long-term and accelerated conditions, with no significant difference observed between the two. However, crystalline form G tended to be less affected by the test conditions.

[0263] Example 8: Determination of the high temperature stability of crystalline forms A and G of compound I Form A and Form G of Compound I were tested for HPLC purity and morphological change after being stored at 60° C. for 1 day and 10 days, respectively. The test results are summarized in Table E-4.

[0264] [Table 11]

[0265] The results showed that the purity of crystalline form A decreased by approximately 0.1% after 1 day at high temperature and by approximately 1.1% after 10 days at high temperature, and the purity of crystalline form G decreased by approximately 0.3% after 1 day at high temperature and by approximately 1.2% after 10 days at high temperature. No change in crystalline form was observed in any samples. Both crystalline forms A and G showed good stability at high temperature, and no significant difference was observed between them.

[0266] Example 9: Evaluation of the high humidity stability of crystalline forms A and G of Compound I Form A and Form G of Compound I were subjected to high humidity (90% RH) conditions for 1 day and 10 days, respectively, and then tested for HPLC purity and crystalline form change. The test results are summarized in Table E-5.

[0267] [Table 12]

[0268] The results showed that the purity of crystalline form A decreased by approximately 0.3% after 1 day and approximately 1.0% after 10 days under high humidity, while the purity of crystalline form G decreased by approximately 0.1% after 1 day and approximately 1.3% after 10 days under high humidity. No change in crystalline form was observed in any of the samples. Both crystalline forms A and G showed good high humidity stability, and no significant difference was observed between them.

[0269] Example 10: Measurement of pressure stability of crystalline forms A and G of compound I Form A and Form G of Compound I were each pressurized at 1000 MPa for 5 minutes, and then tested for HPLC purity and crystalline form change. The test results are summarized in Table E-6.

[0270] [Table 13]

[0271] The examples described herein are intended to illustrate the principles and implementation methods of the present invention. These examples are provided as a reference for understanding the present invention and are not intended to limit the present invention. Note that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications are also within the scope of the claims of the present invention.

Claims

1. A crystalline form of compound I, i.e., (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.

2. The crystalline form is crystalline form A, wherein: the X-ray powder diffraction (XRPD) pattern of crystalline form A comprises diffraction peaks at diffraction angles (2θ) of about 4.97±0.2°, 11.74±0.2°, 13.27±0.2°, 21.04±0.2°, and 24.06±0.2°; and / or The differential scanning calorimetry (DSC) pattern of crystalline form A has one endothermic peak at about 177.8°C ± 3.0°C; and / or Form A loses about 0.037% weight upon heating to about 150°C ± 3°C as measured by thermogravimetric analysis (TGA); and / or Crystalline form A 1 H NMR spectra substantially as shown in Figures 2-4; Preferably, the XRPD pattern of crystalline form A further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 15.88±0.2°, 16.26±0.2°, 16.44±0.2°, 18.43±0.2°, 19.17±0.2°, 19.48±0.2°, 19.65±0.2°, 19.89±0.2°, 20.11±0.2°, 20.67±0.2°, 21.27±0.2°, 22.81±0.2°, and 23.4±0.2°; More preferably, the XRPD pattern of crystalline form A further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 9.99±0.2°, 17.65±0.2°, 20.32±0.2°, 24.26±0.2°, 24.76±0.2°, 25.79±0.2°, 26.75±0.2°, 27.47±0.2°, 28.19±0.2°, 29.38±0.2°, and 29.91±0.2°; and / or the DSC pattern of crystalline form A is substantially as shown in Figure 2-2; and / or The TGA pattern of crystalline form A is substantially as shown in Figures 2-3; More preferably, the XRPD pattern of crystalline form A comprises diffraction peaks at substantially the same diffraction angles (2θ) as those shown in Figure 2-1, and even more preferably, the XRPD pattern of crystalline form A is as shown in Figure 2-1; More preferably, crystalline form A is not a solvate, more preferably an anhydrate.

2. The crystalline form of claim 1.

3. The crystalline form is crystalline form G, wherein: the XRPD pattern of crystalline form G comprises diffraction peaks at diffraction angles (2θ) of about 4.99±0.2°, 10.05±0.2°, 16.99±0.2°, 19.21±0.2°, and 20.28±0.2°; and / or The DSC pattern of crystalline form G has one endothermic peak at about 188.3°C ± 3.0°C; and / or Form G had a weight loss of 0.494% during heating to about 180°C ± 3°C as measured by TGA; Preferably, the XRPD pattern of crystalline form G further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 12.33±0.2°, 15.84±0.2°, 17.34±0.2°, 17.59±0.2°, 20.67±0.2°, 21.68±0.2°, and 26.59±0.2°; More preferably, the XRPD pattern of crystalline form G further comprises diffraction peaks at any one or more or all of the following diffraction angles (2θ): about 12.62±0.2°, 15.00±0.2°, 18.30±0.2°, 23.88±0.2°, 24.72±0.2°, 29.12±0.2°, and 33.76±0.2°; and / or the DSC pattern of crystalline form G is substantially as shown in Figure 3-2; and / or The TGA pattern of crystalline form G is substantially as shown in Figure 3-3; More preferably, the XRPD pattern of crystalline form G comprises diffraction peaks at diffraction angles (2θ) substantially identical to the diffraction peaks at diffraction angles (2θ) shown in Figure 3-1, and even more preferably, the XRPD pattern of crystalline form G is as shown in Figure 3-1; More preferably, crystalline form G is not a solvate, more preferably an anhydrate.

2. The crystalline form of claim 1.

4. 4. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 3 and a pharmaceutically acceptable carrier, wherein the crystalline form is crystalline form A of claim 2 or crystalline form G of claim 3.

5. 10. The crystalline form or pharmaceutical composition according to any one of claims 1 to 3 or claim 4, wherein the crystalline form is preferably crystalline form A according to claim 2 or crystalline form G according to claim 3, for use in the treatment and / or prevention of GLP-1 receptor mediated diseases and related disorders.

6. Use of the crystalline form according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4 in the manufacture of a medicament for treating and / or preventing a GLP-1 receptor mediated disease or related disorder, wherein the crystalline form is preferably crystalline form A according to claim 2 or crystalline form G according to claim 3.

7. A method for treating and / or preventing a GLP-1 receptor mediated disease or related disorder, comprising administering to a subject in need thereof an effective amount of the crystalline form according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4, wherein the crystalline form is preferably crystalline form A according to claim 2 or crystalline form G according to claim 3.

8. the GLP-1 receptor-mediated disease or related disorder is selected from diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, non-alcoholic fatty liver disease, dyslipidemia, and hyperinsulinemia; The crystalline form or pharmaceutical composition of claim 5, the use of claim 6 or the method of claim 7, wherein the diabetes is preferably selected from T1D and / or T2DM, idiopathic T1D, early-onset T2D, latent autoimmune diabetes, atypical diabetes of juveniles and gestational diabetes.

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