Polymorphs of pyrimidine derivatives and their pharmaceutically acceptable salts and uses thereof

Abstract

Provided are polymorphs of a pyrimidine derivative and pharmaceutically acceptable salts thereof and applications. The pyrimidine derivative is a kind of A 2A / A 2B Dual receptor antagonist, chemical name is 3-(4-amino-5-fluoro-6-(1-((6-(2-hydroxypropane-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-2-yl)-2-methylbenzonitrile and its pharmaceutically acceptable salt polymorphs and applications.

Description

[0001] Related applications

[0002] This application claims priority to Chinese Patent Application No. CN202111079644.0, filed on September 15, 2021, entitled “Pyrimidine Derivatives and Pharmaceutically Acceptable Salts Thereof Polymorphs and Applications thereof,” the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the field of pharmaceutical technology, and particularly to a pyrimidine derivative and its pharmaceutically acceptable salt polymorphs and applications, specifically to a 3-(4-amino-5-fluoro-6-(1-((6-(2-hydroxypropane-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-2-yl)-2-methylbenzonitrile and its pharmaceutically acceptable salt polymorphs and applications. Background Technology

[0004] Adenosine is an endogenous nucleoside found throughout human cells, composed of adenine and ribose, and widely distributed both intracellularly and extracellularly. Adenosine participates in various physiological and biochemical functions in the body. For example, adenosine can directly enter the myocardium, where it is phosphorylated to adenosine triphosphate (ATP), participating in myocardial energy metabolism. In the central nervous system (CNS), adenosine controls the release of neurotransmitters and postsynaptic neuronal responses, playing a role in regulating movement, protecting neurons, and influencing sleep and wakefulness—essential life processes. Under pathological conditions, extracellular adenosine concentrations significantly increase under tumor or hypoxic conditions. Adenosine plays an important role in tumor immunosuppression by promoting tumor angiogenesis, proliferation, development, and migration.

[0005] The adenosine receptor (AR) belongs to the G protein-coupled receptor (GPCR) family, and its endogenous ligand is adenosine. Currently known adenosine receptors include A1 and A2. A A2 B It is composed of four subtypes of receptors, A1 and A3. Adenosine binding to A1 or A3 receptors can inhibit the production of cyclic adenosine monophosphate (cAMP); while binding to A2... A Or A2 B Receptor binding can activate adenosine activator enzyme, thereby upregulating cAMP levels and exerting further physiological regulatory effects.

[0006] A1 and A3 receptors are mainly expressed in the central nervous system, while A2 receptors are expressed in the central nervous system.A and A2 B Both adenosine receptors are expressed in the central nervous system and peripheral systems. Within the tumor microenvironment, A2... A and A2 B Both adenosine receptors are widely expressed in immune cells and have strong immunosuppressive functions. Therefore, developing drugs targeting these two receptors for the prevention or treatment of cancer or immune-related diseases is of great value.

[0007] To better meet market demand, further development of A2 A / A2 B Compounds with receptor antagonistic activity, their pharmaceutically acceptable salts, and their polymorphs are sought to contribute to further drug development. Summary of the Invention

[0008] The purpose of this application includes providing an A2 A / A 2B Receptor antagonists or their pharmaceutically acceptable salts, polymorphs, and applications.

[0009] In a first aspect of this application, a polymorph of a compound of formula X or a pharmaceutically acceptable salt of said compound X is provided; said compound X is a pyrimidine derivative having the structure shown in formula X.

[0010]

[0011] The first aspect of this application includes both polymorphs of the compound of formula X and polymorphs of pharmaceutically acceptable salts of the compound of formula X.

[0012] The pharmaceutically acceptable salts described herein are formed from a compound of formula X and an acid, and therefore include both the compound of formula X and the acid component.

[0013] In some embodiments, the pharmaceutically acceptable salt is an inorganic salt. Accordingly, the acid used for salt formation is an inorganic acid.

[0014] In some embodiments, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, and hydrobromide. Accordingly, the acid used for salt formation is selected from hydrochloric acid, sulfuric acid, and hydrobromic acid.

[0015] In some embodiments, the polymorphs of the compound of formula X and the polymorphs of pharmaceutically acceptable salts of the compound of formula X are each independently in anhydrous, hydrated, or solvate form.

[0016] In some implementations, Cu-Kα radiation is used to obtain X-ray powder diffraction patterns.

[0017] Each of the X-ray powder diffraction patterns mentioned in this application can be obtained independently using Cu-Kα radiation.

[0018] In some embodiments, the polymorph is a type I crystal of compound X, i.e., free alkali crystal type I, whose X-ray powder diffraction pattern has peaks at diffraction angles 2θ (°) in the lower group: 18.08±0.2, 21.41±0.2 and 24.83±0.2.

[0019] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form I further includes at least one peak selected from the group consisting of the following peaks at a diffraction angle of 2θ (°): 12.90±0.2, 15.26±0.2, 16.47±0.2, 17.81±0.2, and 19.57±0.2.

[0020] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form I further includes at least one peak selected from the group consisting of 2θ (°) at a diffraction angle of 22.01 ± 0.2 and 25.43 ± 0.2.

[0021] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form I has peaks at diffraction angles of 2θ (°) in the following group: 18.08±0.2, 21.41±0.2, and 24.83±0.2, and also includes two or more peaks selected from the following group at diffraction angles of 2θ (°): 12.90±0.2, 15.26±0.2, 16.47±0.2, 17.81±0.2, 19.57±0.2, 22.01±0.2, and 25.43±0.2.

[0022] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form I further includes two or more peaks selected from the group consisting of the following: 9.50±0.2, 10.13±0.2, 12.53±0.2, 18.89±0.2, 19.94±0.2 and 20.33±0.2.

[0023] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form I further includes two or more peaks selected from the group consisting of 7.73±0.2, 13.94±0.2 and 16.94±0.2 at a diffraction angle of 2θ (°): 16.94±0.2.

[0024] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form I further includes two or more peaks selected from the group consisting of: 27.84±0.2, 28.49±0.2, 29.27±0.2, 30.38±0.2, 30.86±0.2 and 32.03±0.2.

[0025] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form I has a diffraction peak at 2θ (°) as shown in Table 1, and the relative intensities of each diffraction peak are shown in Table 1.

[0026] Table 1. Positions and relative intensities of the main diffraction peaks in an X-ray powder diffraction pattern of free alkali crystal form I.

[0027] 7.73 W 17.81 S 25.43 S 9.50 M 18.08 VS 27.84 M 10.13 M 18.89 M 28.49 M 12.53 M 19.57 S 29.27 M 12.90 S 19.94 M 30.38 M 13.94 W 20.33 M 30.86 M 15.26 S 21.41 VS 32.03 M 16.47 S 22.01 S 16.94 W 24.83 VS

[0028] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form I is substantially as follows: Figure 1 What it represents.

[0029] In one embodiment, the X-ray powder diffraction pattern of the free alkali crystal form I is as follows: Figure 1 What it represents.

[0030] In some implementations, the free alkali crystal form I is in anhydrous form.

[0031] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form I has an endothermic peak at 190.15℃±3℃, and the heat of fusion is approximately 100.48J / g.

[0032] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form I has an endothermic peak at 190.15℃±1℃.

[0033] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form I has an endothermic peak at 190.15℃±0.5℃.

[0034] In some embodiments, the TGA spectrum of the free alkali crystal form I shows almost no weight loss before 150°C, and a weight loss of 0.123% between 150°C and 210°C.

[0035] In some embodiments, the free alkali crystal form I has substantially the following characteristics: Figure 2 The TGA-DSC spectrum is shown.

[0036] In one embodiment, the free alkali crystal form I has as follows Figure 2 The TGA-DSC spectrum is shown.

[0037] In some embodiments, the free alkali crystal form I exhibits a weight change of less than 0.2% due to adsorption during a relative humidity change of 0% to 80% RH at 25°C, and is almost non-hygroscopic; the percentage of weight change "%" is a weight percentage.

[0038] In some embodiments, the free alkali crystal form I has substantially the following characteristics: Figure 3 The dynamic water adsorption spectrum (DVS spectrum) is shown.

[0039] In one embodiment, the free alkali crystal form I has as follows Figure 3 The DVS diagram shown.

[0040] In some embodiments, the infrared spectrum of the free alkali crystal form I is at approximately 3490 cm⁻¹ -1 Approximately 3280cm -1 Approximately 3132cm -1 Approximately 2972cm -1 Approximately 2931cm -1 Approximately 2210cm -1 Approximately 1636–1451 cm -1 Approximately 1399cm -1 Approximately 1366cm -1 Approximately 855cm -1 Approximately 799cm -1 Approximately 769cm -1 An absorption peak exists at this location. The "approximately" here can be independently ±5 cm⁻¹. -1 ±3cm -1 or ±1cm -1 .

[0041] In some embodiments, the infrared spectrum of the free alkali crystal form I is essentially as follows: Figure 20 What it represents.

[0042] In some embodiments, the free alkali crystal form I has the following characteristics: Figure 20 The infrared spectrum that is characterized.

[0043] In some embodiments, the free alkali crystal form I has one or more features selected from the group consisting of:

[0044] (1) Its TGA-DSC spectrum is basically as follows Figure 2 What it represents;

[0045] (2) Its DVS map is basically as follows Figure 3 What is characterized; and

[0046] (3) Its infrared spectrum is basically as follows Figure 20 What it represents.

[0047] In some embodiments, the polymorph is a type IV crystal of compound X, i.e., free alkali type IV, whose X-ray powder diffraction pattern has peaks at diffraction angles of 2θ (°) in the lower group: 13.04±0.2, 15.80±0.2, 16.46±0.2 and 23.89±0.2.

[0048] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form IV further includes at least one peak at a diffraction angle of 2θ (°) selected from the group consisting of: 6.32±0.2, 9.08±0.2, 9.58±0.2, and 14.12±0.2.

[0049] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form IV further includes at least one peak at a diffraction angle of 2θ (°) selected from the group consisting of: 20.14±0.2, 20.59±0.2, 23.89±0.2, and 27.53±0.2.

[0050] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form IV has peaks at diffraction angles of 2θ (°) in the following group: 13.04±0.2, 15.80±0.2, 16.46±0.2, and 23.89±0.2, and also includes two or more peaks selected from the following group at diffraction angles of 2θ (°): 6.32±0.2, 9.08±0.2, 9.58±0.2, 14.12±0.2, 20.14±0.2, 20.59±0.2, 23.89±0.2, and 27.53±0.2.

[0051] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form IV has peaks at diffraction angles of 2θ (°) in the following group: 13.04±0.2, 15.80±0.2, 16.46±0.2, and 23.89±0.2, and also includes two or more peaks selected from the following group at diffraction angles of 2θ (°): 6.32±0.2, 9.08±0.2, 9.58±0.2, 14.12±0.2, 20.14±0.2, 20.59±0.2, 23.89±0.2, 27.53±0.2, and 37.76±0.2.

[0052] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form IV also includes one or two peaks selected from the group consisting of 7.64±0.2 and 8.34±0.2 at a diffraction angle of 2θ (°).

[0053] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form IV has a peak at 2θ (°) as shown in Table 2, and the relative intensities of each peak are shown in Table 2.

[0054] Table 2. Positions and relative intensities of the main diffraction peaks in an X-ray powder diffraction pattern of free alkali crystal form IV.

[0055] 6.32 S 13.04 VS 20.59 S 7.64 M 14.12 S 23.89 VS 8.34 M 15.80 VS 27.53 S 9.08 S 16.46 VS 37.76 S 9.58 S 20.14 S

[0056] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form IV is substantially as follows: Figure 4 What it represents.

[0057] In one embodiment, the X-ray powder diffraction pattern of the free alkali crystal form IV is as follows: Figure 4 What it represents.

[0058] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form IV has an endothermic peak at 189.64℃±3℃.

[0059] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form IV has an endothermic peak at 189.64℃±1℃.

[0060] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form IV has an endothermic peak at 189.64℃±0.5℃.

[0061] In some embodiments, the free alkali crystal form IV has substantially the following characteristics: Figure 5 The differential scanning calorimetry curve shown is shown.

[0062] In one embodiment, the free alkali crystal form IV has as follows Figure 5 The differential scanning calorimetry curve shown is shown.

[0063] In some embodiments, the polymorph is a V-type crystal of compound X, i.e., free alkali crystal V, whose X-ray powder diffraction pattern has peaks at diffraction angles of 2θ (°) in the lower group: 6.17±0.2, 9.37±0.2, 10.39±0.2, 11.65±0.2, 14.35±0.2, 15.74±0.2 and 17.21±0.2.

[0064] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form V further includes two or more peaks selected from the group consisting of the following peaks at a diffraction angle of 2θ (°): 21.65±0.2, 22.31±0.2, 24.55±±0.2, 24.86±0.2, 25.70±0.2, 26.08±0.2, and 27.31±0.2.

[0065] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form V also has a peak at the following diffraction angle 2θ (°): 38.71 ± 0.2.

[0066] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form V includes one or two peaks selected from the following groups at a diffraction angle of 2θ (°): 38.71±0.2 and 43.60±0.2.

[0067] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form V further includes two or more peaks selected from the group consisting of the following peaks at a diffraction angle of 2θ (°): 6.91±0.2, 8.08±0.2, 8.70±0.2, 12.77±0.2, and 13.25±0.2.

[0068] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form V further includes two or more peaks selected from the group consisting of: 19.01±0.2, 19.43±0.2, 21.35±0.2, 23.15±0.2, 29.38±0.2, 32.03±0.2, 32.29±0.2, 35.08±0.2, 39.80±0.2, and 40.19±0.2.

[0069] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form V includes two or more peaks selected from the group consisting of: 19.01±0.2, 19.43±0.2, 21.35±0.2, 23.15±0.2, 29.38±0.2, 32.03±0.2, 32.29±0.2, 35.08±0.2, 37.43±0.2, 39.80±0.2, and 40.19±0.2.

[0070] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form V has a peak at 2θ (°) as shown in Table 3, and the relative intensities of each peak are shown in Table 3.

[0071] Table 3. Positions and relative intensities of the main diffraction peaks in an X-ray powder diffraction pattern of free alkali crystal form V.

[0072] 6.17 S 17.21 S 27.31 S 6.91 M 19.01 M 29.38 M 8.08 M 19.43 M 32.03 M 8.70 M 21.35 M 32.29 M 9.37 S 21.65 S 35.08 M 10.39 S 22.31 S 37.43 M 11.65 S 23.15 M 38.71 S 12.77 M 24.55 S 39.80 M 13.25 M 24.86 S 40.19 M 14.35 VS 25.70 S 43.60 S 15.74 S 26.08 S

[0073] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form V is substantially as follows: Figure 6 What it represents.

[0074] In one embodiment, the X-ray powder diffraction pattern of the free alkali crystal form V is as follows: Figure 6 What it represents.

[0075] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form V has an endothermic peak at 189.94℃±3℃.

[0076] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form V has an endothermic peak at 189.94℃±1℃.

[0077] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form V has an endothermic peak at 189.94℃±0.5℃.

[0078] In some embodiments, the free alkali crystal form V has substantially the following characteristics: Figure 7 The differential scanning calorimetry curve shown is shown.

[0079] In one embodiment, the free alkali crystal form V has as follows Figure 7 The differential scanning calorimetry curve shown is shown.

[0080] In some embodiments, the polymorph is a type VI crystal of compound X, i.e., free alkali crystal type VI, whose X-ray powder diffraction pattern has peaks at diffraction angles of 2θ (°) in the lower group: 12.55±0.2, 14.86±0.2, 16.15±0.2, 17.69±0.2, 21.08±0.2, 21.58±0.2, 24.53±0.2 and 25.01±0.2.

[0081] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form VI further includes two or more peaks selected from the group consisting of the following: 9.04±0.2, 9.68±0.2, 13.37±0.2, 18.53±0.2, 19.19±0.2, 19.64±0.2 and 19.97±0.2.

[0082] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form VI further includes two or more peaks selected from the group consisting of the following: 2θ (°) at diffraction angles: 23.69±0.2, 27.55±0.2, 30.34±0.2 and 31.46±0.2.

[0083] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form VI further includes two or more peaks selected from the group consisting of the following: 9.04±0.2, 9.68±0.2, 13.37±0.2, 18.53±0.2, 19.19±0.2, 19.64±0.2, 19.97±0.2, 23.69±0.2, 27.55±0.2, 30.34±0.2, 31.46±0.2, and 37.42±0.2.

[0084] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form VI further includes one or two peaks selected from the following group at a diffraction angle of 2θ (°): 7.24±0.2 and 12.07±0.2.

[0085] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form VI has a peak at 2θ (°) as shown in Table 4, and the relative intensities of each peak are shown in Table 4.

[0086] Table 4. Positions and relative intensities of the main diffraction peaks in an X-ray powder diffraction pattern of free alkali crystal form VI.

[0087] 7.24 M 17.69 VS 24.53 VS 9.04 S 18.53 S 25.01 VS 9.68 S 19.19 S 27.55 S 12.07 M 19.64 S 30.34 S 12.55 VS 19.97 S 31.46 S 13.37 S 21.08 VS 37.42 S 14.86 VS 21.58 VS 16.15 VS 23.69 S

[0088] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form VI is substantially as follows: Figure 8 What it represents.

[0089] In one embodiment, the X-ray powder diffraction pattern of the free alkali crystal form VI is as follows: Figure 8 What it represents.

[0090] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form VI has an endothermic peak at 189.33℃±3℃.

[0091] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form VI has an endothermic peak at 189.33℃±1℃.

[0092] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form VI has an endothermic peak at 189.33℃±0.5℃.

[0093] In some embodiments, the free alkali crystal form VI has substantially the following characteristics: Figure 9 The differential scanning calorimetry curve shown is shown.

[0094] In one embodiment, the free alkali crystal form VI has as follows Figure 9 The differential scanning calorimetry curve shown is shown.

[0095] In some embodiments, the polymorph is a type VII crystal of compound X, i.e., free alkali crystal type VII, whose X-ray powder diffraction pattern has peaks at diffraction angle 2θ (°) in the lower group: 14.92±0.2, 16.13±0.2, 17.59±0.2, 20.87±0.2, 21.20±0.2, 21.71±0.2, 24.12±0.2, 24.62±0.2 and 25.12±0.2.

[0096] In some embodiments, the polymorph is a type VII crystal of compound X, i.e., free alkali crystal type VII, whose X-ray powder diffraction pattern has peaks at a diffraction angle of 2θ (°) in the lower group: 14.92±0.2, 16.13±0.2, 17.59±0.2, 20.87±0.2, 21.20±0.2, 21.71±0.2, 24.12±0.2, 24.62±0.2, 25.12±0.2, 37.40±0.2 and 43.55±0.2.

[0097] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form VII further includes two or more peaks selected from the group consisting of the following peaks at a diffraction angle of 2θ (°): 6.17±0.2, 9.07±0.2, 9.67±0.2, 10.37±0.2, 12.61±0.2, 14.39±0.2, 19.21±0.2, 19.73±0.2, and 20.05±0.2.

[0098] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form VII further includes two or more peaks selected from the group consisting of the following peaks at a diffraction angle of 2θ (°): 27.25±0.2, 27.39±0.2, 27.76±0.2, 28.97±0.2, 30.36±0.2, 31.25±0.2, and 31.67±0.2.

[0099] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form VII further includes two or more peaks selected from the group consisting of the following peaks at a diffraction angle of 2θ (°): 5.00±0.2, 6.91±0.2, 7.19±0.2, 11.58±0.2, 13.46±0.2, 33.47±0.2, and 34.98±0.2.

[0100] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form VII has a peak at 2θ (°) as shown in Table 5, and the relative intensities of each peak are shown in Table 5.

[0101] Table 5. Positions and relative intensities of the main diffraction peaks in an X-ray powder diffraction pattern of free alkali crystal form VII.

[0102] 5.00 M 16.13 VS 27.39 S 6.17 S 17.59 VS 27.76 S 6.91 M 19.21 S 28.97 S 7.19 M 19.73 S 30.36 S 9.07 S 20.05 S 31.25 S 9.67 S 20.87 VS 31.67 S 10.37 S 21.20 VS 33.47 M 11.58 M 21.71 VS 34.98 M 12.61 S 24.12 VS 37.40 VS 13.46 M 24.62 VS 43.55 VS 14.39 S 25.12 VS 14.92 VS 27.25 S

[0103] In some embodiments, the X-ray powder diffraction pattern of the free alkali crystal form VII is substantially as follows: Figure 10 What it represents.

[0104] In one embodiment, the X-ray powder diffraction pattern of the free alkali crystal form VII is as follows: Figure 10 What it represents.

[0105] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form VII has an endothermic peak at 189.36℃±3℃.

[0106] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form VII has an endothermic peak at 189.36℃±1℃.

[0107] In some embodiments, the differential scanning calorimetry curve of the free alkali crystal form VII has an endothermic peak at 189.36℃±0.5℃.

[0108] In some embodiments, the free alkali crystal form VII has substantially the following characteristics: Figure 11 The differential scanning calorimetry curve shown is shown.

[0109] In one embodiment, the free alkali crystal form VII has as follows Figure 11 The differential scanning calorimetry curve shown is shown.

[0110] In some embodiments, the free base polymorph is a type I crystal of the hydrochloride of compound X, i.e., hydrochloride crystal form I, whose X-ray powder diffraction pattern has peaks at diffraction angles of 2θ (°) in the lower group: 13.12±0.2, 13.91±0.2, 17.62±0.2, 22.58±0.2 and 26.51±0.2.

[0111] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form I further includes two or more peaks selected from the group consisting of the following peaks at a diffraction angle of 2θ (°): 8.39±0.2, 10.18±0.2, 15.25±0.2, 18.64±0.2, 20.96±0.2, 25.52±0.2, 27.01±0.2, and 29.48±0.2.

[0112] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form I further includes two or more peaks selected from the group consisting of the following peaks at a diffraction angle of 2θ (°): 11.44±0.2, 12.63±0.2, 17.27±0.2, 18.97±0.2, 20.12±0.2, 21.61±0.2, 23.29±0.2, and 29.15±0.2.

[0113] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form I has a peak at 2θ (°) as shown in Table 6, and the relative intensities of each peak are shown in Table 6.

[0114] Table 6. Positions and relative intensities of the main diffraction peaks in an X-ray powder diffraction pattern of hydrochloride crystal form I.

[0115] 8.39 M 17.27 M 22.58 VS 10.18 M 17.62 S 23.29 M 11.44 M 18.64 M 25.52 M 12.63 M 18.97 M 26.51 S 13.12 S 20.12 M 27.01 M 13.91 S 20.96 M 29.15 M 15.25 M 21.61 M 29.48 M

[0116] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form I is substantially as follows: Figure 13 What it represents.

[0117] In one embodiment, the X-ray powder diffraction pattern of the hydrochloride crystal form I is as follows: Figure 13 What it represents.

[0118] In some embodiments, the differential scanning calorimetry curve of the hydrochloride crystal form I has an endothermic peak at 225.37℃±3℃.

[0119] In some embodiments, the differential scanning calorimetry curve of the hydrochloride crystal form I has an endothermic peak at 225.37℃±1℃.

[0120] In some embodiments, the differential scanning calorimetry curve of the hydrochloride crystal form I has an endothermic peak at 225.37℃±0.5℃.

[0121] In some embodiments, the hydrochloride crystal form I has substantially the following characteristics: Figure 14 The differential scanning calorimetry curve shown is shown.

[0122] In one embodiment, the hydrochloride crystal form I has as follows Figure 14 The differential scanning calorimetry curve shown is shown.

[0123] In some embodiments, the polymorph is a type I crystal of the sulfate of compound X, i.e., sulfate crystal form I, whose X-ray powder diffraction pattern has peaks at diffraction angles 2θ (°) in the lower group: 15.13±0.2, 19.64±0.2 and 23.48±0.2.

[0124] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I further includes two or more peaks selected from the group consisting of the following peaks at a diffraction angle of 2θ (°): 11.62±0.2, 12.77±0.2, 13.13±0.2, 22.25±0.2, 24.80±0.2 and 26.09±0.2.

[0125] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I further includes two or more peaks selected from the group consisting of 12.19±0.2, 16.45±0.2 and 21.71±0.2 at a diffraction angle of 2θ (°): 12.19±0.2, 16.45±0.2 and 21.71±0.2.

[0126] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I has a peak at 2θ (°) as shown in Table 7, and the relative intensities of each peak are shown in Table 7.

[0127] Table 7. Positions and relative intensities of the main diffraction peaks in an X-ray powder diffraction pattern of sulfate crystal form I.

[0128] 11.62 S 15.13 VS 22.25 S 12.19 M 16.45 M 23.48 VS 12.77 S 19.64 VS 24.80 S 13.13 S 21.71 M 26.09 S

[0129] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I is substantially as follows: Figure 15 What it represents.

[0130] In one embodiment, the X-ray powder diffraction pattern of sulfate crystal form I is as follows: Figure 15 What it represents.

[0131] In some embodiments, the differential scanning calorimetry curve of the sulfate crystal form I has an endothermic peak at 205.20℃±3℃.

[0132] In some embodiments, the differential scanning calorimetry curve of the sulfate crystal form I has an endothermic peak at 205.20℃±1℃.

[0133] In some embodiments, the differential scanning calorimetry curve of the sulfate crystal form I has an endothermic peak at 205.20℃±0.5℃.

[0134] In some embodiments, the sulfate crystal form I has substantially the following characteristics: Figure 16 The differential scanning calorimetry curve shown is shown.

[0135] In one embodiment, the sulfate crystal form I has as follows Figure 16 The differential scanning calorimetry curve shown is shown.

[0136] In some embodiments, the polymorph is a type I crystal of the hydrobromide of formula X, i.e., hydrobromide crystal form I, whose X-ray powder diffraction pattern has peaks at diffraction angles of 2θ (°) in the lower group: 16.70±0.2, 23.51±0.2 and 23.96±0.2.

[0137] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystal form I further includes two or more peaks selected from the group consisting of: 11.84±0.2, 12.79±0.2, 19.34±0.2, 20.23±0.2, 23.09±0.2, 24.34±0.2, 25.37±0.2, 26.21±0.2, 26.99±0.2, 28.04±0.2, 33.22±0.2, and 35.96±0.2.

[0138] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystal form I further includes two or more peaks selected from the group consisting of: 11.48±0.2, 13.64±0.2, 15.46±0.2, 15.96±0.2, 17.66±0.2, 18.71±0.2, 20.99±0.2, 21.51±0.2, 31.60±0.2, 31.90±0.2, 35.52±0.2, 36.98±0.2, 37.81±0.2, 39.29±0.2, and 39.73±0.2.

[0139] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystal form I has a peak at 2θ (°) as shown in Table 8, and the relative intensities of each peak are shown in Table 8.

[0140] Table 8. Positions and relative intensities of the main diffraction peaks in an X-ray powder diffraction pattern of hydrobromide crystal form I.

[0141] 11.48 M 20.23 S 28.04 S 11.84 S 20.99 M 31.60 M 12.79 S 21.51 M 31.90 M 13.64 M 23.09 S 33.22 S 15.46 M 23.51 VS 35.52 M 15.96 M 23.96 VS 35.96 S 16.70 VS 24.34 S 36.98 M 17.66 M 25.37 S 37.81 M 18.71 M 26.21 S 39.29 M 19.34 S 26.99 S 39.73 M

[0142] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystal form I is substantially as follows: Figure 17 What it represents.

[0143] In one embodiment, the X-ray powder diffraction pattern of the hydrobromide crystal form I is as follows: Figure 17 What it represents.

[0144] In a second aspect of this application, a method for preparing polymorphs of the compound of formula X and its pharmaceutically acceptable salts is provided, which can be used to prepare the polymorphs of the first aspect.

[0145] In a second aspect of this application, the structure of compound X is consistent with that described above.

[0146] In a second aspect of this application, a method for preparing a polymorph of the compound of formula X is provided, comprising the following steps:

[0147] (a0) Dissolve the compound of formula X in a solvent to form a solution;

[0148] (b0) The solution is subjected to crystallization treatment to prepare a polymorph of the compound of formula X.

[0149] In this study, to achieve "clear dissolution," the amount of solvent should be appropriately controlled to ensure complete dissolution of compound X. If the amount is too low, a clear solution cannot be obtained; if the amount is too high, crystals may not precipitate during crystallization.

[0150] In some embodiments, in step (a0), the solvent is selected from acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, 50% (v / v) ethanol / water mixed solvent, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, and mixtures thereof.

[0151] In some implementations, the crystallization process in step (b0) can be selected from cooling crystallization, evaporation crystallization, or antisolvent crystallization.

[0152] In this article, the key step of cooling crystallization is cooling to allow crystals to precipitate.

[0153] In this article, the key step of the volatile crystallization is to evaporate the solvent to precipitate the crystals.

[0154] In this paper, the key step in antisolvent crystallization is "antisolvent addition," that is, adding an antisolvent, a poor solvent, or a combination of an antisolvent and a poor solvent to induce crystal precipitation. Adding an antisolvent is preferred.

[0155] In some embodiments, in step (b0), the crystallization process is performed by slow cooling, slow evaporation, or addition of an antisolvent.

[0156] In this article, examples of slow cooling include naturally cooling down to room temperature.

[0157] Examples of slow evaporation in this article include natural evaporation at room temperature.

[0158] In some embodiments, the prepared polymorph is the free alkali crystal form I, and the crystallization process is carried out by cooling crystallization, evaporation crystallization, or antisolvent crystallization.

[0159] In some embodiments, a method for preparing the free alkali crystal form I is provided, comprising the following steps:

[0160] (a1) Dissolve compound X in the presence of a solvent to form a solution;

[0161] (b1) The solution is subjected to crystallization treatment.

[0162] In some embodiments, in step (a1), the solvent is selected from acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, 50% ethanol (i.e., a 50% (v / v) ethanol / water mixture), dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, and mixtures thereof.

[0163] In some embodiments, in step (a1), the solvent is acetonitrile, isopropanol, ethanol, ethyl acetate, 50% ethanol, dimethyl sulfoxide, or N,N-dimethylacetamide.

[0164] In some embodiments, in step (a1), the compound of formula X is dissolved at a temperature T1. In some preferred embodiments, the temperature T1 is preferably above room temperature. For example, the compound of formula X is added to a solvent, heated to temperature T1, and held for a period of time to clarify the mixture (achieving the dissolution of the compound of formula X), and the resulting clarified system is the solution. The temperature T1 can be a constant temperature condition (maintained at a constant temperature) or a temperature range (maintained at a constant temperature range). In some embodiments, the "step of dissolving the compound of formula X" is performed at a temperature T1, which is selected from any of the following temperature ranges: 45°C–120°C, 50°C–100°C, 50°C–80°C, and 70°C–80°C. In some embodiments, the solution is heated to 45°C–120°C and held for a period of time to dissolve compound X; in some embodiments, the solution is heated to 50°C–100°C; in some embodiments, the solution is heated to 50°C–80°C; in some embodiments, the solution is heated to approximately 50°C (e.g., 50 ± 5°C); in some embodiments, the solution is heated to 70°C–80°C. In some embodiments, the temperature T1 is approximately any of the following temperatures: 48°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, and 80°C, and can be maintained at a constant temperature, or fluctuations are allowed within a certain range, such as ±1°C, ±2°C, ±3°C, ±4°C, ±5°C, etc. In some preferred embodiments, the temperature T1 is a constant temperature condition.

[0165] In some embodiments, in step (b1), the solution is crystallized by cooling, evaporation, or the addition of an antisolvent.

[0166] In some embodiments, in step (b1), the crystallization process is cooling crystallization, i.e., crystallization is performed using a cooling crystallization method. The cooling is relative to the temperature T1 in step (a1). In some embodiments, the solution is cooled to temperature T2 and held for a period of time to allow crystals to precipitate. Temperature T2 can be a constant temperature condition (maintained at a constant temperature) or a temperature range (maintained within a constant temperature range). In some embodiments, temperature T2 is selected from any of the following temperature ranges: -10°C to room temperature, 30°C to 20°C, 25°C to 15°C, 0°C to 5°C, 0°C to 4°C, below 0°C, and 0°C to -5°C. In some embodiments, temperature T2 is selected from any temperature within any of the following temperature ranges: -10°C to room temperature, 30°C to 20°C, 25°C to 15°C, 0°C to 5°C, 0°C to 4°C, below 0°C, and 0°C to -5°C. In some embodiments, the solution is cooled to any temperature within the range of -10°C to room temperature; in some embodiments, the solution is cooled to room temperature; in some embodiments, the solution is cooled to 30°C to 20°C; in some embodiments, the solution is cooled to 25°C to 15°C; in some embodiments, the solution is cooled to 0°C to 5°C; in some embodiments, the solution is cooled to 0°C or below; in some embodiments, the solution is cooled to 0°C to -5°C. In some embodiments, the temperature T2 is approximately any of the following temperatures: -5°C, -4°C, -2°C, 0°C, 5°C, 10°C, 15°C, 20°C, and 25°C, and can be maintained at a constant temperature at the listed temperatures, or fluctuations are allowed within a certain range, such as ±1°C, ±2°C, ±3°C, ±5°C, etc. In some preferred embodiments, the temperature T2 is a constant temperature condition.

[0167] In some embodiments, the free alkali crystal form I is prepared by any of the following methods:

[0168] (Ia) The solvent is acetonitrile, isopropanol, ethanol, ethyl acetate or a 50% (v / v) ethanol / water mixture, and the crystallization treatment is cooling crystallization;

[0169] (Ib) The solvent is a 50% (v / v) ethanol / water mixture, and the crystallization treatment is evaporative crystallization; or

[0170] (Ic) The solvent is dimethyl sulfoxide or N,N-dimethylacetamide, and the crystallization process is antisolvent crystallization.

[0171] In some embodiments, the compound of formula X is dissolved in acetonitrile, isopropanol, ethanol, ethyl acetate or 50% ethanol, and then crystallized by cooling crystallization to obtain the free alkali crystal form I of this application.

[0172] In some embodiments, the preparation method of the free base crystal form I includes the following steps: dissolving the compound of formula X in isopropanol, ethanol, ethyl acetate, or a 50% (v / v) ethanol / water mixed solvent at 50±5°C to form the solution; cooling the solution to 0°C to 4°C and maintaining it for a period of time to allow crystals to precipitate. In some preferred embodiments, the solution is naturally cooled to room temperature and then placed at 0°C to 4°C to allow solid precipitation.

[0173] In some embodiments, the preparation method of the free alkali crystal form I includes the following steps: dissolving the compound of formula X in ethanol at 75±5℃ to form the solution; cooling the solution to room temperature to precipitate crystals.

[0174] In some embodiments, the preparation method of the free alkali crystal form I includes the following steps: dissolving the compound of formula X in ethanol at 70±5℃ to form the solution; cooling the solution to room temperature to allow crystals to precipitate. In some preferred embodiments, the solution is cooled to room temperature by natural cooling.

[0175] In some embodiments, the preparation method of the free alkali crystal form I includes the following steps: dissolving the compound of formula X in acetonitrile at 75±5℃ to form the solution; cooling the solution to room temperature to allow crystals to precipitate. In some preferred embodiments, the solution is cooled to room temperature by natural cooling.

[0176] In some embodiments, the compound of formula X is dissolved in 50% ethanol and crystallized by volatilization to obtain free alkali crystal form I.

[0177] In some embodiments, the preparation method of the free alkali crystal form I includes the following steps: dissolving the compound of formula X in a 50% (v / v) ethanol / water mixed solvent to form the solution; and evaporating and crystallizing the solution at room temperature. In some preferred embodiments, the solution is evaporated and crystallized by natural evaporation at room temperature.

[0178] In some embodiments, the preparation method of the free alkali crystal form I includes the following steps: dissolving the compound of formula X in dimethyl sulfoxide or N,N-dimethylacetamide to form a solution; adding n-heptane to the solution to precipitate crystals.

[0179] In some embodiments, compound X is dissolved in dimethyl sulfoxide or N,N-dimethylacetamide and crystallized by antisolvent crystallization (or by antisolvent addition) to obtain free basal crystalline form I. In some of these embodiments, the antisolvent used in the antisolvent addition is n-heptane.

[0180] In some embodiments, the polymorph of the compound of formula X is the free alkali form IV, and the crystallization process is carried out by evaporation or the addition of an antisolvent.

[0181] The free alkali crystal form I obtained in the preparation method of the second aspect preferably conforms to any of the characterization methods described herein, including but not limited to X-ray powder diffraction patterns, characteristic peak combinations of diffraction angle 2θ (°) of X-ray powder diffraction patterns, differential scanning calorimetry curves, endothermic peaks of differential scanning calorimetry curves, and TGA-DSC diagrams.

[0182] In some embodiments, a method for preparing free alkali crystal form IV is provided, the method comprising the steps of:

[0183] (a2) Dissolve compound X in the presence of a solvent to form a solution;

[0184] (b2) The solution is crystallized by evaporation or by adding an antisolvent.

[0185] In some embodiments, in step (a2), the solvent is selected from acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, and mixtures thereof. In some embodiments, the solvent is acetone, acetonitrile, ethanol, and mixtures thereof.

[0186] In some embodiments, the compound of formula X is dissolved in acetone and crystallized by evaporation crystallization (e.g., slow evaporation) to obtain free alkali crystal form IV.

[0187] In some embodiments, compound X is dissolved in ethanol or acetonitrile, followed by crystallization with the addition of an antisolvent to obtain free basic form IV. In some of these embodiments, the antisolvent used is n-heptane.

[0188] In some embodiments, in step (b2), the solution is crystallized by slow evaporation or the addition of an antisolvent.

[0189] In some embodiments, the polymorph of the compound of formula X is the free alkali crystal form V, and the crystallization process is carried out by volatilization. In some embodiments, the crystallization process is carried out by slow volatilization.

[0190] In some embodiments, a method for preparing free alkali crystal form V is provided, the method comprising the steps of:

[0191] (a3) Dissolve compound X in the presence of a solvent to form a solution;

[0192] (b3) The solution is crystallized by evaporation.

[0193] In some implementations, the solvent in step (a3) ​​is ethanol.

[0194] In some embodiments, in step (b3), the solution is crystallized by slow evaporation.

[0195] In some embodiments, the polymorph of the compound of formula X is the free alkali crystalline form VI, and the crystallization process is carried out by volatilization.

[0196] In some embodiments, a method for preparing crystal form VI is provided, the method comprising the steps of:

[0197] (a4) Dissolve compound X in the presence of a solvent to form a solution;

[0198] (b4) The solution is crystallized by evaporation.

[0199] In some embodiments, in step (a4), the solvent is acetonitrile, tetrahydrofuran, dimethyl sulfoxide, or N,N-dimethylacetamide.

[0200] In some embodiments, in step (b4), the solution is crystallized by slow evaporation.

[0201] In some embodiments, the polymorph of the compound of formula X is the free alkali crystalline form VII, and the crystallization process is carried out by adding an antisolvent.

[0202] In some embodiments, a method for preparing free alkali crystal form VII is provided, the method comprising the steps of:

[0203] (a5) Dissolve compound X in the presence of a solvent to form a solution;

[0204] (b5) The solution is crystallized by adding an antisolvent.

[0205] In some implementations, the solvent in step (a5) is methanol.

[0206] In some embodiments, in step (b5), the antisolvent used in the antisolvent addition is n-heptane.

[0207] In a second aspect of this application, a method for preparing a polymorph of a pharmaceutically acceptable salt of compound X is also provided, comprising the following steps:

[0208] (a′0) In a solvent, the compound of formula X is mixed with an acid to form a solution;

[0209] (b′0) The solution is subjected to crystallization treatment.

[0210] The type of acid is selected based on the pharmaceutically acceptable type of salt, for use in the salt formation of compound X.

[0211] The molar ratio of pharmaceutically acceptable salt compound X to acid is controlled based on the amount of acid used. It is preferable to use an excess of acid.

[0212] In some embodiments, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and hydrobromic acid.

[0213] In some embodiments, a monobasic acid is used, and the molar ratio of the monobasic acid to the compound of formula X is 1.2:1.

[0214] In some embodiments, a dicarboxylic acid is used, and the molar ratio of the dicarboxylic acid to the compound of formula X is 0.6:1.

[0215] In some embodiments, the polymorph of a pharmaceutically acceptable salt of the compound of formula X is the hydrochloride crystal form I, the acid is hydrochloric acid, and the crystallization process is carried out by cooling, evaporation, or the addition of an antisolvent.

[0216] In some embodiments, the polymorph of the pharmaceutically acceptable salt of the compound of formula X is the hydrochloride crystal form I, the acid is hydrochloric acid, and the crystallization process is carried out by slow cooling, slow evaporation, or the addition of an antisolvent.

[0217] In some embodiments, a method for preparing hydrochloride crystal form I is provided, the method comprising the steps of:

[0218] (a6) In the presence of a solvent, the compound of formula X is mixed with a dilute hydrochloric acid solution (e.g., a 1M aqueous hydrochloric acid solution) to form a solution;

[0219] (b6) The solution is subjected to crystallization treatment by cooling, evaporation or addition of an antisolvent.

[0220] In some embodiments, in step (a6), the solvent is selected from acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof. In some embodiments, the solvent is isopropanol or acetone.

[0221] In some embodiments, in step (a6), the acid is 1M hydrochloric acid.

[0222] In some embodiments, in step (a6), the acid is a 1M aqueous hydrochloric acid solution.

[0223] In some embodiments, in step (b6), the solution is crystallized by slow cooling, slow evaporation, or the addition of an antisolvent.

[0224] In some embodiments, in step (b6), crystallization is performed by adding an antisolvent, the antisolvent being n-heptane.

[0225] In some embodiments, the polymorph of the pharmaceutically acceptable salt of the compound of formula X is the sulfate polymorph I, the acid is sulfuric acid, and the crystallization process is carried out by cooling (preferably slow cooling) or by adding an antisolvent.

[0226] In some embodiments, a method for preparing sulfate crystal form I is provided, the method comprising the steps of:

[0227] (a7) A solution is formed by mixing a compound of formula X with a dilute sulfuric acid solution (e.g., a 0.5 M aqueous sulfuric acid solution) in the presence of a solvent;

[0228] (b7) The solution is subjected to crystallization treatment by cooling or adding an antisolvent.

[0229] In some embodiments, in step (a7), the solvent is selected from acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof. In some embodiments, the solvent is selected from ethanol, isopropanol, acetone, ethyl acetate, and mixtures thereof.

[0230] In some embodiments, in step (a7), the acid is 0.5M sulfuric acid.

[0231] In some embodiments, in step (a7), the acid is a 0.5M aqueous sulfuric acid solution.

[0232] In some embodiments, in step (b7), the solution is crystallized by slow cooling or by adding an antisolvent.

[0233] In some embodiments, in step (b7), the crystallization process is carried out by adding an antisolvent, and the antisolvent used is n-heptane.

[0234] In some embodiments, the polymorph of the pharmaceutically acceptable salt of the compound of formula X is the hydrobromide polymorph I, the acid is hydrobromic acid, and the crystallization process is carried out by cooling (preferably slow cooling).

[0235] In some embodiments, a method for preparing hydrobromide crystal form I is provided, the method comprising the steps of:

[0236] (a8) In the presence of a solvent, the compound of formula X and hydrobromic acid are mixed to form a solution;

[0237] (b8) The solution is subjected to crystallization by slow cooling.

[0238] In some embodiments, in step (a8), the solvent is selected from acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof. In some embodiments, the solvent is selected from ethanol, isopropanol, acetone, ethyl acetate, and mixtures thereof.

[0239] In some implementations, in step (b8), the solution is crystallized by slow cooling.

[0240] In some embodiments, the method for preparing the polymorph further includes the following steps for preparing the compound of formula X:

[0241]

[0242] Compound X is generated by reacting compounds 1-5 and compound V2 in an organic solvent.

[0243] Examples of the organic solvents include, but are not limited to, tetrahydrofuran (THF).

[0244] In some embodiments, the method for preparing the polymorphs further includes the following steps for preparing compounds 1-5:

[0245]

[0246] Compounds 1-4 are generated by reacting compounds 1-3 with compound V1, and then TIPS are removed to generate compounds 1-5; wherein the TIPS are triisopropylsilyl.

[0247] Those skilled in the art know how to remove TIPS, so I will not go into details here.

[0248] A third aspect of this application provides a pharmaceutical composition comprising:

[0249] (a) any of the polymorphs described in the first aspect of this application (a polymorph of the compound of formula X or a pharmaceutically acceptable salt thereof); and (b) a pharmaceutically acceptable carrier.

[0250] The fourth aspect of this application provides for the preparation of polymorphs (polymorphs of compound X or pharmaceutically acceptable salts thereof) as described in the first aspect of this application, or pharmaceutical compositions as described in the third aspect of this application, in the preparation of adenosine A for prevention, treatment or prevention of adenosine A. 2A Receptor-mediated, adenosine A 2B Receptor-mediated or adenosine A 2A Receptor and adenosine A 2B Application in drugs that co-mediate diseases.

[0251] In some embodiments, compound X is used as component A. 2A / A 2B Receptor antagonists.

[0252] In some implementations, the disease is a tumor or an immune-related disease.

[0253] In some embodiments, the disease is a tumor. In this application, a tumor includes, but is not limited to, cancer.

[0254] In some implementations, the disease is cancer.

[0255] In some embodiments, the tumor is selected from prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, gastric cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, melanoma, basal carcinoma, mesothelial carcinoma, leukemia, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer, non-small cell lung cancer, adrenal cancer, thyroid cancer, kidney cancer, and bone cancer; it may also be selected from malignant glioma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, basal cell carcinoma of the skin, and seminoma of the testis.

[0256] In some implementations, the disease is an immune-related disease.

[0257] In some implementations, the immune-related diseases are selected from rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, anemic fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, Crohn's disease, ulcerative colitis, allergic contact dermatitis and other eczemas, systemic sclerosis, and multiple sclerosis.

[0258] The fifth aspect of this application provides a method for preventing, treating, or preventing adenosine A. 2A Receptor-mediated, adenosine A 2B Receptor-mediated or adenosine A 2A Receptor and adenosine A 2B Methods for co-mediated related diseases include administering a therapeutically effective amount of the polymorph of the first aspect of this application (a polymorph of compound X or a pharmaceutically acceptable salt of compound X) or the pharmaceutical composition of the third aspect of this application to the patient in need.

[0259] It should be understood that, within the scope of this application, the above-described technical features and those described below (including but not limited to the embodiments) can be combined with each other in any suitable manner to constitute new or preferred technical solutions, as long as they can be used to implement this application. Due to space limitations, they will not be described in detail here. The compound of formula X in this application has good related pharmacological activities.

[0260] Within the tumor microenvironment, A 2A and A 2B Two adenosine receptors are widely expressed in immune cells and possess strong immunosuppressive functions. Increased extracellular adenosine concentration is one of the important mechanisms for tumor cell immune escape; its concentration level is jointly determined by ATP levels and the expression levels of CD39 and CD73. Increased extracellular adenosine concentration is associated with cell death or hypoxia in the tumor microenvironment, releasing large amounts of ATP, and its concentration can reach 10–20 times that of normal tissues. Adenosine binds to adenosine receptors in the tumor microenvironment, which can inhibit anti-tumor responses, such as suppressing the function of CD8+ T cells, enhancing the function of immunosuppressive regulatory T cells, and inhibiting the function of antigen-presenting cells through dendritic cells. Some studies have shown that... 2A Receptor binding can also inhibit the tumor-killing activity of natural killer cells. Further studies have shown that A 2A Adenosine receptor antagonists can enhance the activity and killing ability of dendritic antigen-presenting cells, T cells, and natural killer cells, while inhibiting the function of regulatory T cells (T-regs), bone marrow-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), eliminating tumor immune tolerance, promoting tumor immune responses, thereby suppressing tumor growth and prolonging the survival of mice. Furthermore, A 2B The receptor has also been reported to promote tumor migration in mouse melanoma and triple-negative breast cancer models, therefore A 2B Receptor antagonists are also effective targets for tumor therapy. Therefore, blocking the activation of the adenosine signaling pathway to reduce or relieve immunosuppression and enhance the anti-tumor function of immune cells (especially T cells) is considered one of the effective means of tumor treatment.

[0261] The polymorphs of the compound of formula X and its pharmaceutically acceptable salts (i.e., the polymorphs of the compound of formula X and the polymorphs of its pharmaceutically acceptable salts) have good stability and therefore have the potential to be further developed into drugs. Attached Figure Description

[0262] Figure 1The image shows an X-ray powder diffraction (XRPD) pattern of free alkali crystal form I in one embodiment of this application, using Cu-Kα radiation. The horizontal axis represents the angle 2θ (°), the vertical axis represents the intensity, and the unit of the vertical axis is counts.

[0263] Figure 2 The image shows a TGA-DSC (thermogravimetric analysis-differential scanning calorimetry) spectrum of free alkali crystal form I in one embodiment of this application. The horizontal axis represents temperature (°C), the left vertical axis represents weight change (%), and the right vertical axis represents heat flow (Normalized) Q (W / g).

[0264] Figure 3 The image shows the dynamic moisture adsorption (DVS) spectrum of free alkali crystal form I in one embodiment of this application. The horizontal axis represents relative humidity (%) (Target RH (%)) and the vertical axis represents sample weight change (%) (Change In mass (%) - Ref).

[0265] Figure 4 The image shows an X-ray powder diffraction (XRPD) pattern of free alkali crystal form IV in one embodiment of this application, using Cu-Kα radiation. The horizontal axis represents the angle 2θ (°), the vertical axis represents the intensity, and the unit of the vertical axis is counts.

[0266] Figure 5 This is a differential scanning calorimetry (DSC) spectrum of free alkali crystal form IV in one embodiment of this application. The horizontal axis represents temperature (°C), and the vertical axis represents heat flow rate (Normalized) Q (W / g).

[0267] Figure 6 The image shows an X-ray powder diffraction (XRPD) pattern of free alkali crystal form V in one embodiment of this application, using Cu-Kα radiation. The horizontal axis represents the angle 2θ (°), the vertical axis represents the intensity, and the unit of the vertical axis is counts.

[0268] Figure 7 This is a differential scanning calorimetry (DSC) spectrum of free alkali crystal form V in one embodiment of this application. The horizontal axis represents temperature (°C), and the vertical axis represents heat flow (Normalized) Q (W / g).

[0269] Figure 8The image shows an X-ray powder diffraction (XRPD) pattern of free alkali crystal form VI in one embodiment of this application, using Cu-Kα radiation. The horizontal axis represents the angle 2θ (°), the vertical axis represents the intensity, and the unit of the vertical axis is counts.

[0270] Figure 9 This is a differential scanning calorimetry (DSC) spectrum of free alkali crystal form VI in one embodiment of this application. The horizontal axis represents temperature (°C), and the vertical axis represents heat flow (Normalized) Q (W / g).

[0271] Figure 10 The image shows an X-ray powder diffraction (XRPD) pattern of free alkali crystal form VII in one embodiment of this application, using Cu-Kα radiation. The horizontal axis represents the angle 2θ (°), the vertical axis represents the intensity, and the unit of the vertical axis is counts.

[0272] Figure 11 This is a differential scanning calorimetry (DSC) spectrum of free alkali crystal form VII in one embodiment of this application. The horizontal axis represents temperature (°C), and the vertical axis represents heat flow (Normalized) Q (W / g).

[0273] Figure 12 For comparison of XRPD spectra of free alkali crystal form I under 40℃ / 75% RH conditions in one embodiment of this application, the horizontal axis is the angle 2θ (°), the vertical axis is the intensity, and the unit of the vertical axis is counts.

[0274] Figure 13 The image shows an X-ray powder diffraction (XRPD) pattern of hydrochloride crystal form I in one embodiment of this application, using Cu-Kα radiation. The horizontal axis represents the angle 2θ (°), the vertical axis represents the intensity, and the unit of the vertical axis is counts.

[0275] Figure 14 This is a differential scanning calorimetry (DSC) spectrum of hydrochloride crystal form I in one embodiment of this application. The horizontal axis represents temperature (°C), and the vertical axis represents heat flow rate (Normalized) Q (W / g).

[0276] Figure 15 The image shows an X-ray powder diffraction (XRPD) pattern of sulfate crystal form I in one embodiment of this application, using Cu-Kα radiation. The horizontal axis represents the angle 2θ (°), the vertical axis represents the intensity, and the unit of the vertical axis is counts.

[0277] Figure 16 This is a differential scanning calorimetry (DSC) spectrum of sulfate crystal form I in one embodiment of this application. The horizontal axis represents temperature (°C), and the vertical axis represents heat flow (Normalized) Q (W / g).

[0278] Figure 17 The image shows an X-ray powder diffraction (XRPD) pattern of hydrobromide crystal form I in one embodiment of this application, using Cu-Kα radiation. The horizontal axis represents the angle 2θ (°), the vertical axis represents the intensity, and the unit of the vertical axis is counts.

[0279] Figure 18 For one embodiment of this application, the XRPD spectra of hydrochloride crystal form I are compared at 60°C and 40°C / 75% RH. The horizontal axis is Two-Theta (2θ), and the unit of the horizontal axis is deg (°). The vertical axis is intensity, and the unit of the vertical axis is counts.

[0280] Figure 19 For the comparison of XRPD spectra of sulfate crystal form I under 60°C and 40°C / 75% RH conditions in one embodiment of this application, the horizontal axis is Two-Theta (2θ), and the horizontal axis unit is deg (°); the vertical axis is intensity, and the vertical axis unit is counts; where "HY80****" is the sample number of the sulfate compound;

[0281] Figure 20 This is an infrared spectrum of free alkali crystal form I in one embodiment of this application, with the horizontal axis representing the wavenumber (em). -1 The vertical axis represents transmittance. Detailed Implementation

[0282] The present application will be further described in detail below with reference to some accompanying drawings, embodiments, and examples. It should be understood that these embodiments and examples are for illustrative purposes only and are not intended to limit the scope of the present application. The purpose of providing these embodiments and examples is to enable a more thorough and comprehensive understanding of the disclosure of the present application. It should also be understood that the present application can be implemented in many different forms and is not limited to the embodiments and examples described herein. Those skilled in the art can make various modifications or alterations without departing from the spirit of the present application, and the equivalent forms obtained also fall within the protection scope of the present application. Furthermore, numerous details are set forth in the following description to provide a fuller understanding of the present application. It should be understood that the present application can be implemented without one or more of these details.

[0283] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the specification of this application is for descriptive purposes only and is not intended to be limiting of the application.

[0284] the term

[0285] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings:

[0286] In this application, the selection range of "and / or", "or / and", and "and / or" includes any one of two or more related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions connected by "logical AND", and also undoubtedly includes technical solutions connected by "logical OR". For example, "A and / or B" includes three parallel solutions: A, B, and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, a technical solution that is connected by "logical OR"), as well as any and all combinations of A, B, C, and D, that is, combinations of any two or three of A, B, C, and D, and also combinations of all four of A, B, C, and D (that is, a technical solution that is connected by "logical AND").

[0287] In this application, "combinations thereof", "any combination thereof", "any combination thereof", etc., include all suitable combinations of any two or more items listed.

[0288] In this application, the term "suitable" as used in "suitable combination", "suitable method", "any suitable method", etc., refers to the ability to implement the technical solution of this application, solve the technical problem of this application, and achieve the expected technical effect of this application.

[0289] In this application, terms such as "preferred," "better," "more suitable," and "ideal" are merely used to describe implementation methods or embodiments that achieve better results, and should be understood not to limit the scope of protection of this application.

[0290] In this application, "optionally," "optionally," and "optional" mean that something is optional, that is, it means that it is selected from either "with" or "without." If there are multiple "optional" entries in a technical solution, unless otherwise specified, and there are no contradictions or mutual constraints, each "optional" entry shall be independent.

[0291] In this application, the terms "first aspect," "second aspect," "third aspect," "fourth aspect," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first," "second," "third," "fourth," etc., serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on quantity.

[0292] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0293] In this application, numerical intervals (i.e., numerical ranges) are involved. Unless otherwise specified, optional numerical distributions within the aforementioned numerical intervals are considered continuous and include the two endpoints (i.e., the minimum and maximum values) of the numerical range, as well as every value between these two endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints. Furthermore, when multiple ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0294] In this application, "M", "nM", "μM" and "mM" represent concentrations that, unless otherwise specified, are equivalent to mol / L, nmol / L, μmol / L and mmol / L, respectively.

[0295] In this application, "have" is open-ended. For example, "have peaks at certain locations in the spectrum" means that peaks exist at these locations in the spectrum, but does not exclude the possibility that peaks also exist at other locations in the spectrum.

[0296] Through extensive and in-depth research, the inventors discovered compound X, and found that it affects adenosine A. 2A Receptor, adenosine A 2BThe receptor, or both of these receptors, exhibit high inhibitory activity. Based on this, further research unexpectedly led to the discovery of a series of polymorphs of compound X and its pharmaceutically acceptable salts. These polymorphs not only possess good stability but also exhibit good in vivo and in vitro pharmacological activities, thus showing potential for further development into drugs.

[0297] The compounds of this application

[0298] In this application, compound X is 3-(4-amino-5-fluoro-6-(1-((6-(2-hydroxypropane-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-2-yl)-2-methylbenzonitrile, having the structure shown in formula (X).

[0299]

[0300] The compound of formula X is structurally a pyrimidine derivative. This compound of formula X is an A... 2A / A 2B Dual receptor antagonists can simultaneously block A 2A and A 2B Activation of these two receptors affects adenosine A. 2A Receptor, adenosine A 2B These receptors, or both, possess high inhibitory activity. Mechanistically, they regulate different immune cell populations, comprehensively blocking the immunosuppressive effects of adenosine in the microenvironment. This has profound clinical application value for tumor treatment and can be used to treat tumor-related diseases, immune-related diseases, or both.

[0301] In this application, "A" 2A / A 2B "Receptor antagonist" means both A 2A Receptor antagonists, also known as A receptor antagonists 2B Receptor antagonists can block A 2A Activation of receptors can also block A 2B Receptor activation.

[0302] This application also includes polymorphs of compounds of formula X and pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts are not particularly limited, but are preferably selected from hydrochloride, sulfate and hydrobromide.

[0303] In this application, polymorphs include, but are not limited to, polymorphs of free bases and polymorphs of pharmaceutically acceptable salts.

[0304] In this application, unless otherwise specified, the polymorphs of the compound of formula X refer to the polymorphs of the free base of the compound of formula X, including but not limited to free base polymorphs I, IV, V, VI and VII in this application.

[0305] In this application, the polymorphs of the compound of formula X and its pharmaceutically acceptable salts include, but are not limited to, free base polymorphs I, IV, V, VI, VII, hydrochloride polymorph I, sulfate polymorph I, and hydrobromide polymorph I of the compound of formula X.

[0306] In this application, the terms "type I crystal of formula X" and "free alkali crystal form I of formula X" have the same meaning and can be used interchangeably. Unless otherwise specified, "free alkali crystal form I" in this application refers to crystal form I of formula X.

[0307] In this application, the terms "type IV crystal of formula X" and "free base crystal form IV of formula X" have the same meaning and can be used interchangeably. Unless otherwise specified, "free base crystal form IV" in this application refers to crystal form IV of formula X.

[0308] In this application, the V-type crystal of compound X and the V-type free base crystal of compound X have the same meaning and can be used interchangeably. Unless otherwise specified, the V-type free base crystal in this application refers to the V-type crystal of compound X.

[0309] In this application, the VI-type crystal of compound X and the free alkali crystal form VI of compound X have the same meaning and can be used interchangeably. Unless otherwise specified, the free alkali crystal form VI in this application refers to crystal form VI of compound X.

[0310] In this application, the VII-type crystal of compound X and the free base crystal form VII of compound X have the same meaning and can be used interchangeably. Unless otherwise specified, the free base crystal form VII in this application refers to crystal form VII of compound X.

[0311] In this application, the terms "Type I crystal of hydrochloride of Formula X" and "Crystal form I of hydrochloride of Formula X" have the same meaning and can be used interchangeably. Unless otherwise specified, "Crystal form I of hydrochloride" in this application refers to "Crystal form I of hydrochloride of Formula X".

[0312] In this application, the terms "type I crystal of sulfate of formula X" and "sulfate crystal form I of formula X" have the same meaning and can be used interchangeably. Unless otherwise specified, sulfate crystal form I in this application refers to sulfate crystal form I of formula X.

[0313] In this application, the terms "type I crystal of hydrobromide of formula X" and "crystal form I of hydrobromide of formula X" have the same meaning and can be used interchangeably. Unless otherwise specified, crystal form I of hydrobromide in this application refers to crystal form I of hydrobromide of formula X.

[0314] As used herein, "drug" includes any agent, compound, composition, or mixture that provides physiological, pharmacological, or physiological and pharmacological effects in vivo or in vitro, and often provides beneficial effects. There is no particular limitation on the extent to which a "drug" produces physiological, pharmacological, or physiological and pharmacological effects in vivo; it may have systemic effects or produce effects only locally. There is no particular limitation on the activity of a "drug"; it may be an active substance that can interact with other substances or an inert substance that does not interact with other substances.

[0315] As used herein, "therapeutic effective amount" means the amount of the compound of this application that will elicit a biological or medical response in an individual, such as the amount of the compound of this application that brings about a physiological, pharmacological, or physiological and pharmacological positive effect in an individual, including but not limited to reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0316] As used in this article, "pharmaceutically acceptable" means that, within the bounds of reasonable medical judgment, it is suitable for use on patients and is commensurate with a reasonable benefit / risk ratio, and is applicable to pharmaceutical ligands, materials, compositions, or dosage forms.

[0317] As used herein, a “pharmaceuticalally acceptable carrier” should, in principle, be non-toxic and inert. The form of a “pharmaceuticalally acceptable carrier” is not particularly limited, and may include, but is not limited to, solid, semi-solid, and liquid states. The pharmaceutically acceptable carrier should be compatible with the patient, preferably a mammal, and more preferably a human. One function of the pharmaceutically acceptable carrier is to facilitate the delivery of an active agent to the target site without terminating the agent's activity. As used herein, the term “pharmaceuticalally acceptable carrier” includes buffers compatible with drug administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, and the like. Each carrier must be “pharmaceutically acceptable” in the sense of compatibility with other components in the formulation and harmlessness to the patient.

[0318] As used herein, "pharmaceutically acceptable salt" refers to a salt formed by any compound of the indicated structure with an acid or base that is suitable for use as a drug. In this context, it primarily refers to a salt formed by compound X with an acid that is suitable for use as a drug.

[0319] As used in this article, "patient" refers to an animal, preferably a mammal, and more preferably a human. The term "mammal" primarily refers to warm-blooded vertebrate mammals, including but not limited to: cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, cattle, sheep, horses, and humans.

[0320] In this application, there are no particular limitations on the manner of administration of compounds, polymorphs, pharmaceutical compositions, or agents. Representative methods of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous) injection, and local administration.

[0321] As used in this article, “treatment” means to reduce, slow the progression of, diminish, prevent, or maintain an existing disease or condition (such as cancer). Treatment also includes curing, preventing the development of, or reducing to some extent one or more symptoms of a disease or condition.

[0322] In this application, "prevention and / or treatment" means prevention, treatment, or control. "Control" indicates that it possesses both preventative and therapeutic effects.

[0323] In this application, "using Cu-Kα radiation" means that the corresponding spectrum was obtained by detecting Kα rays from a Cu target. When other methods are used for detection, the deviations of each diffraction peak may exist within the acceptable range in the art and should not be construed as a limitation of this application.

[0324] Polymorphs

[0325] Solids exist in amorphous, crystalline, or semi-crystalline forms. For small molecule (preferably with a molecular weight not exceeding 1000 Da) organic compounds, they primarily exist in amorphous or crystalline forms. In the crystalline form, the molecules are located within three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it can crystallize with different spatial lattice arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms, which are called "polymorphs." Different polymorphs of a given substance can differ from each other in one or more physical properties (such as solubility, dissolution rate, true specific gravity, crystal form, packing order, fluidity, and solid-state stability).

[0326] crystallization

[0327] Production-scale crystallization can be achieved by manipulating the solution to exceed the solubility limit of the compound of interest. This can be accomplished in various ways, such as dissolving the compound at a relatively high temperature and then cooling the solution below the saturation limit; or by reducing the liquid volume through boiling, evaporation at atmospheric pressure, vacuum drying, or other methods; the solubility of the compound of interest can be reduced by adding an antisolvent, or a poor solvent in which the compound has low solubility, or a mixture of such antisolvents or poor solvents. Another alternative method is to adjust the pH value to reduce solubility. For a detailed description of crystallization, see Crystallization, 3rd Edition, J.W. Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

[0328] Identification and properties of crystal forms

[0329] In this application, the crystal form of compound X was prepared, and its properties were studied using various methods and instruments, including but not limited to the following.

[0330] X-ray powder diffraction (XRPD)

[0331] X-ray powder diffraction (XRPD) methods for determining crystal form are known in the art. XRPD can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions in an XRPD spectrum mainly depend on the structure of the crystal form. The measurement of 2θ (Two-Theta) in XRPD spectra may vary slightly between different instruments; therefore, the 2θ values ​​of characteristic peaks in an XRPD spectrum cannot be considered absolute. Depending on the instruments used in the experiments of this application, a certain error (e.g., ±0.2°) is permissible in the diffraction peaks. It is understood that the error range is not absolute for different testing instruments and testing conditions. The crystal form of compound X in this application has a specific morphology and specific characteristic peaks in the XRPD spectrum.

[0332] Differential scanning calorimetry (DSC)

[0333] Also known as differential scanning calorimetry (DSC), it is a technique that measures the relationship between the energy difference between the analyte and a reference material and temperature during heating. The peak positions, shapes, and numbers on the DSC spectrum are related to the properties of the substance, and therefore can be used qualitatively to identify the substance. This method is commonly used in the field to detect various parameters such as phase transition temperature, glass transition temperature, and heat of reaction. The peak positions of DSC spectra may vary slightly between different instruments; therefore, the values ​​of the peak positions of the endothermic peaks in the DSC spectrum cannot be considered absolute. Depending on the instrument used in the experiments of this application, the experimental error or difference is also not absolute and may be less than or equal to 5℃, or less than or equal to 4℃, or less than or equal to 3℃, or less than or equal to 2℃, or less than or equal to 1℃.

[0334] Thermogravimetric analysis (TGA)

[0335] TGA is a technique used under programmed control to determine the mass change of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the process of sample sublimation and decomposition, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments. Based on the instrument used in the experiments of this application, the error in mass change is not absolute and a certain error (e.g., ±0.1%) is permissible.

[0336] In this application, the phrase "the X-ray powder diffraction pattern has a peak at a specific diffraction angle 2θ (°)" refers to a diffraction peak. The preceding statement indicates that the peak value is within the indicated numerical range, the indicated numerical point, the vicinity of the indicated numerical range, or the vicinity of the indicated numerical point. Due to differences in measuring instruments and conditions, the position of a peak or peaks in the actual obtained X-ray powder diffraction pattern may slightly deviate, meaning there may be slight differences from the characteristic peak combinations or X-ray powder diffraction patterns indicated in this application. However, it is understood that those skilled in the art can generally determine whether slightly different characteristic peak combinations or X-ray powder diffraction patterns can be substantially considered consistent with the crystal form described in this application. Therefore, those substantially considered consistent with the crystal form of the invention should be considered within the scope of protection of this application. For example, the statement "The X-ray powder diffraction pattern shows a peak at a diffraction angle of 16.63° ± 0.2°" means that the peak value can be located within or near the range of 16.63° ± 0.2°, as long as it does not affect the overall identification of the crystal form. Furthermore, "± 0.2°" here only indicates the error in the position of the peak value at the diffraction angle and is unrelated to other factors such as the peak shape and width.

[0337] In this application, the word "basically" in "X-ray powder diffraction pattern is basically as characterized by a specific pattern" should also be interpreted similarly. As long as it can be determined from the whole that a certain X-ray powder diffraction pattern is substantially consistent with the X-ray powder diffraction pattern described in this application, it should be considered to fall within the protection scope of this application.

[0338] It is understood that the differential scanning calorimetry (DSC) curves and the positions of the endothermic peaks shown therein in this application should also be interpreted similarly. Slight discrepancies with a certain value, a certain range of values, or a certain spectrum disclosed in this application are permissible. However, as long as it can be determined from the whole that some or all of the endothermic peak positions in the differential scanning calorimetry curve, or the entire curve is substantially consistent with this application, it should be considered to fall within the protection scope of this application.

[0339] Understandably, a similar interpretation can be made for other spectra that characterize crystal types (such as infrared spectra).

[0340] The term "dissolution" as used in this application refers to the complete dissolution of compound X or its pharmaceutically acceptable salt in a solvent.

[0341] The phrase "in the presence of a solvent" as used in this application refers to a system used to dissolve a compound or its salt, which includes a solvent and may also include non-solvent soluble components, insoluble components, or a combination of soluble and insoluble components. The phrase "in the presence of a solvent" as used in this application at least includes technical solutions "in a solvent." Furthermore, "in a solvent" is an open-ended description, including both closed-ended scenarios where dissolution is performed using only a solvent and open-ended scenarios where a co-solvent is also present in the solvent.

[0342] The “cooling” described in this application refers to a method of dissolving a compound of formula X or its pharmaceutically acceptable salt in a solvent at a relatively high temperature, and then cooling it at a certain temperature to obtain crystals.

[0343] The term "evaporation" as used in this application refers to a method of evaporating the solvent from a solution containing a compound of formula X or a pharmaceutically acceptable salt thereof at a certain temperature to obtain crystals.

[0344] The "antisolvent addition" described in this application refers to a method of adding another suitable solvent to a solution containing a compound of formula X or a pharmaceutically acceptable salt thereof, resulting in the precipitation of crystals. The suitable solvent can be an antisolvent, a poor solvent, or a combination thereof. In some embodiments, an antisolvent is preferred.

[0345] If it is desired that salt formation and crystallization occur simultaneously, and if the salt is less soluble than the reactants in the reaction medium, then adding an appropriate acid or base can lead to the direct crystallization of the desired salt. Similarly, in a medium where the final desired form is less soluble than the reactants, the completion of the synthesis reaction can allow the final product to crystallize directly.

[0346] Optimization of crystallization may include seeding the crystals in the desired form into the crystallization medium. Additionally, many crystallization methods can utilize combinations of the strategies described above. One embodiment involves dissolving the compound of interest in a solvent at a high temperature, followed by the controlled addition of an appropriate volume of antisolvent to bring the system just below saturation. At this point, seed crystals in the desired form can be added (while maintaining the integrity of the seed crystals), and the system is cooled to complete crystallization.

[0347] As used herein, the term "room temperature" generally refers to 4°C to 30°C, and may further refer to 20°C ± 5°C. In some embodiments of this application, room temperature refers to 20°C to 30°C.

[0348] Unless otherwise specified, the temperature parameters in this application are permitted to be either constant-temperature treatment or vary within a certain temperature range. It should be understood that the constant-temperature treatment allows temperature fluctuations within the precision range controlled by the instrument.

[0349] In this application, the term "mixture thereof" may be used to refer to a mixture formed from two or more of the listed substances. For example, "mixture thereof" in "the solvent is selected from acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, 50% (v / v) ethanol / water mixed solvent, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, and mixtures thereof" means a mixed solvent formed by the aforementioned solvents in any suitable manner. First, the mixture formed should still be usable as a solvent. Second, it is understood that this refers only to achievable mixed solvents.

[0350] In this application, "% (v / v)" means volume percentage. For example, "50% (v / v) ethanol / water mixed solvent" means a mixture of ethanol and water in a 1:1 volume ratio.

[0351] In this application, 50% ethanol, unless otherwise specified, refers to a mixed solvent formed by anhydrous ethanol and water in a volume ratio of 1:1, and can also be abbreviated as 50% (v / v) ethanol / water mixed solvent.

[0352] Identification and properties of polymorphs

[0353] After preparing polymorphs of compound X, this application investigated their properties using various methods and instruments, including but not limited to the following.

[0354] X-ray powder diffraction

[0355] The pharmaceutically acceptable salt polymorph of compound X of this application has a specific crystal morphology and exhibits specific characteristic peaks in its X-ray powder diffraction (XPRD) pattern. As one embodiment, in some embodiments of this application, the XPRD spectra were acquired on an Equinox 3000S / NX X-ray powder diffractometer, and the XPRD parameters are shown in Table 9.

[0356] Table 9. XPRD test parameters in some embodiments of this application.

[0357] X-ray source Cu K (λ=1.54056Angstrom) Light tube settings 40 kV, 30 mA detector PSD Scan range (2Theta) 0°～120° Scan step size (2Theta) 0.03° Scan rate 1 second / step

[0358] 2Theta, also known as 2θ, is expressed in degrees (°) and can also be written as deg.

[0359] In X-ray powder diffraction patterns, the positions of each peak are determined by 2θ (°). It is understood that different instruments, different conditions, or different instruments and conditions may result in slightly different data, and the positions and relative intensities of each peak may vary. Those skilled in the art should understand that when determining crystal form based on XRPD patterns, the peaks at low diffraction angles, their intensity, and peak shape integrity are relatively more meaningful. In this application, the applicant, through further research, discovered that when testing XRPD patterns using the aforementioned instruments, strong background peaks of the blank metal disk may appear near the 2θ (°) values ​​of 37.4° and 43.6° at high diffraction angles. For example, Figure 4 The peak near 37° is presumed to be generated by the blank metal disk (such as the peak at 37.76° in Table 2). Figure 6 The peaks near 37° and 43° are presumed to be generated by the blank metal disk (such as the peaks at 37.43° and 43.60° in Table 3). Figure 8 The peak near 37° is presumed to be generated by the blank metal disk (such as the peak at 37.42° in Table 4). Figure 10The peaks near 37° and 43° are presumed to be generated by the blank metal disk (such as the peaks at 37.40° and 43.55° in Table 5). The intensity division of the peaks only reflects the approximate size of the peaks at each position. In this application, when analyzing the diffraction peaks of each crystal form, the diffraction peak with the highest peak height in the XRPD spectrum obtained by the aforementioned method is taken as the base peak, and its relative intensity is defined as 100%, as I0 (for example, in some embodiments of this application, the peak with a 2θ (°) value of 21.41 in the XRPD spectrum of free alkali crystal form I is the base peak, the peak with a 2θ (°) value of 16.46 in the XRPD spectrum of free alkali crystal form IV is the base peak, the peak with a 2θ (°) value of 14.35 in the XRPD spectrum of free alkali crystal form V is the base peak, and the peak with a 2θ (°) value of 14.35 in the XRPD spectrum of free alkali crystal form VI is the base peak). The peak with a 2θ (°) value of 24.53 in the XRPD spectrum is the base peak; the peak with a 2θ (°) value of 37.40 in the XRPD spectrum of free alkali crystal form VII is the base peak; the peak with a 2θ (°) value of 22.58 in the XRPD spectrum of hydrochloride crystal form I is the base peak; the peak with a 2θ (°) value of 23.48 in the XRPD spectrum of sulfate crystal form I is the base peak; and the peak with a 2θ (°) value of 23.51 in the XRPD spectrum of hydrobromide crystal form I is the base peak. The relative intensity I / I0 of each other peak is defined as the ratio of its peak height to the base peak height. The definitions of the relative intensities of each peak in this application are shown in Table 10.

[0360] Table 10. Definition of the relative intensity of each peak in the XPRD spectrum in this application.

[0361] 50～100 VS (Very strong) 25～50 S (Strong) 10～25 M (Medium) 1～10 W(weak)

[0362] Differential Scanning Calorimetry (DSC)

[0363] As one of the implementation methods, in some embodiments of this application, the DSC spectrum is acquired on a DISCOVERY DSC25 differential scanning calorimeter, and the test parameters are shown in Table 11.

[0364] Table 11. DSC test parameters in some embodiments of this application.

[0365] method linear heating Sample tray Aluminum disc, pressure cap Temperature range 25℃～300℃ Scan rate (°C / min) 10 Protective gas Nitrogen

[0366] Thermogravimetric analysis (TGA)

[0367] As one of the implementation methods, in some embodiments of this application, the TGA spectra are acquired on a DISCOVERY TGA550 thermogravimetric analyzer, and the test parameters are shown in Table 12.

[0368] Table 12. TGA test parameters in some embodiments of this application.

[0369] method linear heating Sample tray Platinum crucible Scan range RT-400 degrees Scan rate (°C / min) 10 Protective gas Nitrogen

[0370] Infrared spectroscopy (IR) analysis

[0371] The tests were performed using an Agilent Cary 630 FTIR spectrometer with the solid potassium bromide (KBr) pellet method.

[0372] It is understood that other values ​​may be obtained when using other types of instruments that have the same function as the instruments described above or when using test conditions different from those used in this application. Therefore, the values ​​cited should not be regarded as absolute values.

[0373] Due to instrument errors or differences in operators, those skilled in the art will understand that the parameters used to characterize the physical properties of crystals may have slight differences. Therefore, the above parameters are only used to assist in characterizing the polymorphs provided in this application and should not be regarded as a limitation on the polymorphs of this application.

[0374] Some further examples are provided below.

[0375] The present application is further illustrated below with reference to some embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. For experimental methods in the following embodiments where details of conditions are not specified, please refer to the guidelines given in this application, or follow experimental manuals or conventional conditions in the art, or other experimental methods known in the art, or follow the conditions recommended by the manufacturer.

[0376] Unless otherwise specified, the percentage content mentioned in this application refers to volume percentage for gas-gas mixtures, mass percentage (wt%) for solid-solid mixtures, volume percentage (% (v / v)) for liquid-liquid mixtures, and mass percentage (wt%) or solid-liquid percentage (% (w / v)) for solid-liquid mixtures.

[0377] In the following examples, 50% ethanol refers to a 50% (v / v) ethanol / water mixed solvent.

[0378] Reagents and Instruments

[0379] In this application, the structure and purity of the compound were determined by nuclear magnetic resonance (NMR). 1 It can be determined by ¹H NMR and / or liquid chromatography-mass spectrometry (LC-MS). 1 ¹H NMR: Bruker AVANCE-400 NMR spectrometer, internal standard: tetramethylsilane (TMS). LC-MS: Agilent 1200 HPLC System / 6140 MS LC-MS / MS spectrometer (manufacturer: Agilent), Waters X-Bridge column, 150 mm × 4.6 mm, 3.5 μm.

[0380] The XPRD test uses the parameters shown in Table 9.

[0381] The DSC test uses the parameters shown in Table 11.

[0382] The starting materials known in this application can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCRGmbH&Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc., and Darui Chemicals.

[0383] As used herein, DCM represents dichloromethane, DMF represents dimethylformamide, DMSO represents dimethyl sulfoxide, THF represents tetrahydrofuran, EA represents ethyl acetate, PE represents petroleum ether, Et3N represents triethylamine, NH4F represents ammonium fluoride, t-BuOH represents tert-butanol, Pd(dppf)Cl2 represents [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride, CuI represents cuprous iodide, Pd(PPh3)2Cl2 represents bis(triphenylphosphine)palladium(II) chloride, DPPA represents diphenyl azidophosphate, and DBU represents 1,8-diazabicycloundec-7-ene.

[0384] As used in this article, Captisol represents sulfobutyl cyclodextrin.

[0385] In the following examples, hydrochloric acid solution, sulfuric acid solution, and hydrobromic acid solution all refer to aqueous solutions.

[0386] Preparation of intermediate V1

[0387]

[0388] 2-Methyl-3-bromobenzonitrile (15 g), bis-pinacol borate (23.32 g), potassium acetate (15.02 g), and Pd(dppf)Cl2 (2.80 g) were dissolved in a mixed solution of DMSO (20 mL) and dioxane (100 mL). The mixture was stirred at 100 °C for 3.5 h under nitrogen protection. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain a solid product, which was then separated by column chromatography (EA:PE = 15%–40%, v / v) to give compound V1 (21.05 g). MS (ESI): 244.1 [M+H] + .

[0389] Preparation of intermediate V2

[0390]

[0391] Step 1: Dissolve methyl 6-(hydroxymethyl)pyridinecarboxylate (50g) in THF (800mL) and add it dropwise to methyl magnesium bromide (3.0M, 398.82mL) under argon protection. Control the temperature at 0℃~15℃. A large amount of gas is released, and the mixture is stirred overnight at room temperature. Slowly add the reaction solution to solid ice, then add saturated ammonium chloride solution. Extract with DCM (300mL×10), dry to anhydrous sodium sulfate, concentrate under reduced pressure to dryness, and purify by silica gel column chromatography (EA∶PE=0%~100%, v / v) to obtain a colorless oily substance 2-(6-(hydroxymethyl)pyridin-2-yl)prop-2-ol (30g), MS (ESI): 168.1 [M+H] + .

[0392] Step 2: 2-(6-(hydroxymethyl)pyridin-2-yl)prop-2-ol (30 g) was dissolved in DCM (100 mL). DPPA (54.31 g) was added under stirring at room temperature and argon protection. Then, DBU (40.17 mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was heated to 50 °C and stirred overnight. The reaction solution was added to 100 mL of water, dried over DCM (200 mL × 2) with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EA:PE = 0%–30%, v / v) to obtain compound V2 (30 g). MS (ESI): 193 [M+H] + .

[0393] Example 1. Preparation of compound X (i.e., compound X)

[0394]

[0395] Step 1: Compound 1-1 (2,4,6-trichloro-5-fluoropyrimidine, 40 g) and triisopropylsilylacetylene (38.03 g) were dissolved in THF (400 mL). Under argon protection, the solution was cooled to 0 °C, and CuI (3.78 g) and Pd(PPh3)2Cl2 (6.97 g) were added sequentially. Then, Et3N (60.17 g, 595.79 mmol) was slowly added dropwise. After the addition was complete, the solution was stirred at 0 °C for 2 hours, then heated to room temperature and stirred for another 6 hours. The solution was then cooled to 0 °C, and NH3 / H2O (ammonia solution, 120 g, 80% concentration) was added dropwise. The solution was then stirred overnight at room temperature. LC-MS analysis confirmed the reaction was complete, yielding compound 1-2. MS (ESI): 347 [M+H] + .

[0396] Step 2: Add a large amount of water to the reaction solution obtained in Step 1, extract with DCM (200 mL × 3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, a large amount of solid precipitates out, add 60 mL of petroleum ether while stirring, filter to obtain compound 1-3 (31 g), the remaining mother liquor is purified by silica gel column chromatography (DCM:PE = 30%–80%, v / v) to obtain compound 1-3 (43 g), MS (ESI): 328.1 [M + H] + .

[0397] Step 3: Compounds 1-3 (41 g) and compound V1 (42.56 g) were dissolved in a mixed solvent of dioxane (400 mL) and water (60 mL). Under argon protection and stirring at room temperature, Na2CO3 (26.51 g) and Pd(dppf)2Cl (4.57 g) were added sequentially. The mixture was then heated to 100 °C and stirred for 24 hours. The reaction solution was poured into ice water, extracted with DCM (300 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compounds 1-4 (44 g). MS (ESI): 409.2 [M + H] + .

[0398] Step 4: Compounds 1-4 (44 g) were added to methanol (400 mL), and NH4F (47.60 g) was added with stirring at room temperature. The mixture was heated to 70 °C and stirred for 8 hours under argon protection. A large amount of water was added to the reaction solution while stirring, resulting in the washing out of a large amount of solid. The mixture was filtered to obtain brown compound 1-5 (27 g). MS (ESI): 253.1 [M+H] + .

[0399] Step 5: Compounds 1-5 (27g) and intermediate V2 (22g) were dissolved in a mixed solvent of THF (200mL) and t-BuOH (200mL). The mixture was stirred at room temperature under argon protection. An aqueous solution of Cu2SO4·5H2O (2.87g) was added sequentially (200mL of water), followed by sodium ascorbate (4.56g). The mixture was then heated to 60℃ and stirred for 24 hours. The reaction solution was poured into water, saturated sodium carbonate was added, and the mixture was extracted with DCM (300mL×3). The extract was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (DCM (containing 2% triethylamine):EA = 0-10%, v / v) to obtain 30g of compound X. 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.78 (s, 1H), 7.92 (d, J = 7.8Hz, 1H), 7.83 (dd, J = 7.7, 1.2Hz, 1H), 7.76 (t, J = 7.8Hz, 1H) , 7.60-7.48 (m, 3H), 7.45 (t, J=7.5Hz, 1H), 7.10 (d, J=6.9Hz, 1H), 5.77 (s, 2H), 5.18 (s, 1H), 2.63 (s, 3H), 1.34 (s, 6H). MS(ESI):445.2[M+H] + The obtained solid compound X was sent for XRPD analysis, and no characteristic peaks were shown in its X-ray powder diffraction pattern. Therefore, the compound X obtained in this example is in an amorphous form.

[0400] Example 2. Preparation of Free Alkali Crystal Form I

[0401] 2.1. Method 1

[0402] Approximately 20 mg of compound X (amorphous) was weighed into a glass vial. An appropriate amount of isopropanol, ethanol, ethyl acetate, or 50% ethanol was added. The mixture was heated at approximately 50°C until completely dissolved. The vial was then removed and allowed to cool to room temperature. After reaching room temperature, it was placed in a refrigerator to cool to 0°C–4°C until the solid precipitated. The solid was centrifuged, and the supernatant was discarded. The solid was then dried in an oven and subjected to XPRD analysis. The XPRD plot of the obtained solid product is shown below. Figure 1 As shown, this is defined in this application as free alkali crystal form I. The DSC spectrum of free alkali crystal form I is as follows. Figure 2 As shown, the endothermic peak is at 190.36℃. The DVS spectrum of free alkali crystal form I is shown below. Figure 3 As shown, the free alkali crystal form I exhibits a weight change of less than 0.2% due to adsorption during the relative humidity change from 0% to 80% at 25℃, indicating almost no hygroscopicity.

[0403] 2.2. Method Two

[0404] Approximately 30 g of compound X (amorphous) was weighed into a glass vial, and 150 ml of acetonitrile or ethanol was added. The mixture was heated to reflux. Upon cooling to room temperature, a solid precipitated out. The solid product was obtained by filtration. The obtained solid was subjected to XPRD analysis, yielding a free alkali crystal form I.

[0405] 2.3. Method Three

[0406] Weigh approximately 20 mg of compound X (amorphous) into a glass vial, add an appropriate amount of 50% ethanol to dissolve it, and allow the solution to evaporate slowly at room temperature. Take the solid obtained from the evaporation and perform XPRD analysis to obtain free alkali crystal form I.

[0407] 2.4. Method Four

[0408] 20 mg of compound X (amorphous) was weighed into a glass vial and dissolved in dimethyl sulfoxide or N,N-dimethylacetamide. The antisolvent n-heptane was then added to the solution, resulting in the precipitation of solid particles. XPRD analysis of the obtained solid revealed free alkali crystal form I.

[0409] Example 3. Preparation of free alkali crystal form IV

[0410] 3.1. Method 1

[0411] 20 mg of compound X (amorphous) was weighed into a glass vial, and an appropriate amount of acetone was added to dissolve it completely. The solution was then allowed to evaporate slowly at room temperature to obtain a solid. The XPRD spectrum of the obtained solid product is shown below. Figure 4 As shown, this is defined in this application as free alkali crystal form IV. The differential scanning calorimetry (DSC) spectrum of free alkali crystal form IV is shown below. Figure 5 As shown, free alkali crystal form IV has an exothermic peak at 156.16℃ and an endothermic peak at 189.64℃ (the endothermic peak position is similar to that of free alkali crystal form I), indicating that free alkali crystal form IV is a metastable crystal form and may transform into free alkali crystal form I during the heating process.

[0412] 3.2. Method Two

[0413] Weigh 20 mg of compound X (amorphous) into a glass vial, add an appropriate amount of ethanol or acetonitrile to dissolve it, add the antisolvent n-heptane after dissolution, and solid particles precipitate out. The obtained solid is subjected to XPRD analysis and is free alkali crystal form IV.

[0414] Example 4. Preparation of free alkali crystal form V

[0415] Weigh approximately 20 mg of compound X (amorphous) into a glass vial, add an appropriate amount of ethanol to dissolve it completely, and allow the solution to evaporate slowly at room temperature. Take the solid obtained from the evaporation and perform XPRD analysis. The XPRD spectrum of the obtained solid product is shown below. Figure 6 As shown, this is defined in this application as free alkali crystal form V. The DSC spectrum of free alkali crystal form V is as follows. Figure 7 As shown, the free alkali crystal form V has an exothermic peak at 128.28℃ (possibly due to incomplete drying of the crystal and the presence of some water of crystallization), a crystallization exothermic peak at 164.51℃, and an endothermic peak at 189.94℃ (the position of the endothermic peak is similar to that of the free alkali crystal form I). This indicates that the free alkali crystal form V is a metastable crystal form and may transform into the free alkali crystal form I during the heating process.

[0416] Example 5. Preparation of Free Alkali Crystal Form VI

[0417] Approximately 20 mg of compound X (amorphous) was weighed into separate glass vials. Acetonitrile, tetrahydrofuran, dimethyl sulfoxide, or N,N-dimethylacetamide were added to dissolve the compounds completely. The solutions were then allowed to slowly evaporate at room temperature. The resulting solids were collected and subjected to XPRD analysis. The XPRD spectrum of the solid product is shown below. Figure 8 As shown, this is defined in this application as free alkali crystal form VI. The DSC spectrum of free alkali crystal form VI is shown below. Figure 9 As shown, free alkali crystal form VI has an exothermic crystallization peak at 159.40℃ and an endothermic peak at 189.33℃ (the endothermic peak position is similar to that of free alkali crystal form I), indicating that free alkali crystal form VI is a metastable crystal form and may transform into free alkali crystal form I during the heating process.

[0418] Example 6. Preparation of free alkali crystal form VII

[0419] 20 mg of compound X (amorphous) was weighed into a glass vial and dissolved in methanol. Then, heptane, the antisolvent, was added, resulting in the precipitation of solid particles. The obtained solid was analyzed by XPRD. The X-ray powder diffraction pattern of the obtained solid product is shown below. Figure 10 As shown, this is defined in this application as free alkali crystal form VII. The differential scanning calorimetry (DSC) spectrum of free alkali crystal form VII is shown below. Figure 11 As shown, the free alkali crystal form VII has an endothermic peak at 189.36℃ (the position of the endothermic peak is similar to that of the free alkali crystal form I), indicating that the free alkali crystal form VII is a metastable crystal form and may transform into the free alkali crystal form I during the heating process.

[0420] Example 7. Suspension Vibration

[0421] Approximately 20 mg of compound X (free base crystal form I) was weighed into a glass vial. For each of the experimental groups, 1 ml of one of the solvents listed in the table below was added. After suspending and shaking the vials at room temperature for 24 hours, the supernatant was discarded after centrifugation. The solid was then dried in an oven and subjected to XPRD analysis. The experimental results for each group are shown in Table 13. The crystal form of free base crystal form I remained unchanged after suspension and shaking in the seven solvents listed.

[0422] Table 13. Screening Results of Polycrystalline Suspension Shaking

[0423]

[0424]

[0425] Example 8. Crystal form competition experiment

[0426] To determine the most stable crystalline form of compound X, a crystalline form competition experiment was conducted. 10 mg of each of the free base crystalline forms I, IV, V, VI, and VII were weighed out and thoroughly mixed. 20 mg of the resulting mixture was then weighed into glass vials, and 1 ml of each of the solvents listed in Table 14 was added. After suspension and shaking at room temperature for 24 hours, the precipitates were centrifuged, dried, and their XPRD values ​​were measured. The XPRD results showed that after mixing and shaking in different solvents for 24 hours, all the mixed crystalline forms converted to free base crystalline form I. Therefore, free base crystalline form I was determined to be the stable crystalline form.

[0427] Table 14. Results of Polycrystalline Screening Using Mixed Shaking

[0428] 1 ethanol I 2 Isopropanol I 3 Ethyl acetate I 4 water I 5 acetone I

[0429] Example 9: Stability test of free alkali crystal form I

[0430] Approximately 20 mg of free alkali crystal form I was weighed into glass sample vials and left uncapped under accelerated conditions (40°C, 75% RH). Samples were collected at 1 week, 2 weeks, 1 month, 2 months, and 4 months for XPRD analysis. Figure 12 It can be seen that the free alkali crystal form I has good physical stability, and the XPRD spectra obtained at different sampling times are highly consistent.

[0431] Example 10. Hydrochloride crystal form I

[0432] 10.1. Method 1

[0433] Weigh 20 mg of compound X (amorphous), add 1 M hydrochloric acid solution at a molar ratio of acid to compound X of 1.2:1, then add 2 M acetone or isopropanol, heat and sonicate to dissolve, maintain the reaction temperature at 50 °C for 4 h, then slowly cool to precipitate a solid, collect the solid by centrifugation. After evaporating the solvent, use the obtained solid for XRPD testing. Its X-ray powder diffraction pattern is shown below. Figure 13 As shown, this is defined as hydrochloride crystal form I in this application. The differential scanning calorimetry (DSC) spectrum of hydrochloride crystal form I is shown below. Figure 14 As shown, it has an endothermic peak at 225.37℃.

[0434] 10.2. Method Two

[0435] Weigh 20 mg of compound X (amorphous), add 1 M hydrochloric acid solution at a molar ratio of acid to compound X of 1.2:1, then add 2 M acetone or isopropanol, heat and sonicate to clarify, keep the reaction at 50 °C for 4 h, cool to room temperature, add the antisolvent n-heptane to precipitate the solid, centrifuge to collect the solid, evaporate the solvent from the obtained solid to obtain hydrochloride crystal form I.

[0436] Example 11. Sulfate crystal form I

[0437] 11.1. Method 1

[0438] Weigh 20 mg of compound X and add it to a 0.5 M sulfuric acid solution at a molar ratio of acid to compound X of 0.6:1. Then add 2 M of isopropanol, ethanol, or acetone, heat and sonicate to clarify, and maintain the reaction at 50 °C for 4 h. Afterward, slowly cool to precipitate a solid, and collect the solid by centrifugation. After evaporating the solvent, the obtained solid is used for XRPD testing. Its X-ray powder diffraction pattern is shown below. Figure 15 As shown, this is defined as sulfate crystal form I in this application. The differential scanning calorimetry (DSC) spectrum of sulfate crystal form I is shown below. Figure 16 As shown, sulfate crystal form I has an endothermic peak at 205.20℃.

[0439] 11.2. Method Two

[0440] Weigh 20 mg of compound X and add 0.5 M sulfuric acid solution according to the molar ratio of acid to compound X of 0.6:1. Then add 2 M ethyl acetate, heat and sonicate to clarify, keep the reaction at 50 °C for 4 h, and cool the clarified solution to room temperature. Add the antisolvent n-heptane to obtain sulfate crystal form I.

[0441] 11.3. Method Three

[0442] Weigh 300 mg of compound X (amorphous) into a small beaker, add 5 ml of acetone, and sonicate to dissolve. At 50°C, slowly add 900 ml of 0.5 M sulfuric acid solution while stirring, and maintain the reaction temperature for 4 hours until the solution becomes turbid. Centrifuge to discard the supernatant, separate the solid, and wash with acetone 3–5 times. Dry under vacuum overnight at 40°C to obtain sulfate crystal form I.

[0443] Example 12. Hydrobromide crystal form I

[0444] Weigh 20 mg of compound X, add 1 mol / L hydrobromic acid at a molar ratio of acid to compound X of 1.2:1, then add 1-3 ml of isopropanol, ethanol, acetone, or ethyl acetate. Heat and sonicate to clarify, maintain the reaction temperature at 50°C for 4 hours, then slowly cool to precipitate a solid. Collect the solid by centrifugation. After evaporating the solvent, use the obtained solid for XRPD testing. Its X-ray powder diffraction pattern is shown below. Figure 17 As shown, it is defined as hydrobromide crystal form I in this application.

[0445] Example 13. Stability test of hydrochloride crystal form I and sulfate crystal form I.

[0446] Appropriate amounts of hydrochloride crystal form I and sulfate crystal form I samples were weighed separately and placed under accelerated (40℃ / 75% RH) conditions with the lid open and under high-temperature (60℃) conditions with the lid closed. XPRD analysis was performed at 9, 14, and 28 days. Results are as follows: Figure 18 and Figure 19 As shown. From Figure 18 and Figure 19 It can be seen that hydrochloride crystal form I and sulfate crystal form I have good crystal form stability. Figure 18 and Figure 19 In the study, the XPRD spectra obtained at different sampling times were highly consistent.

[0447] Biological testing

[0448] In the test examples below, the sample used was compound X, and compound D1 was used as a control.

[0449] Test Example 1: Inhibitory activity against A2A and A2B receptors

[0450] CHO-K1 / ADORA2A / Gα15 (GenScript, M00246) and CHO-K1 / ADORA2B / Gα15 (GenScript, M00329) cells were cultured in Ham's F-12 (Gibco, 31765092) medium. The medium conditions were either 10% FBS, 200 μg / mL Zeocin, and 100 μg / mL Hygromycin B, or 10% FBS, 400 μg / mL G418, and 100 μg / mL Hygromycin B. For detailed culture conditions, please refer to the corresponding instruction manual. The screening steps are as follows:

[0451] 1. Adjust the cell density to 6 × 10⁶ cells / year using serum-free culture medium. 5 pcs / Ml.

[0452] In a 2.384-well plate (Greiner Bio-One, 784075), 5 μL of cell culture, 2.5 μL of NECA (Sigma, 119140-10 mg), and 2.5 μL of the compound solution were added to each well. The final concentration of NECA was 50 Nm (CHO-K1 / ADORA2A) or 10 Nm (CHO-K1 / ADORA2B). The final concentration of the compound was 3 μM, which was initially diluted three-fold downwards.

[0453] 3. Place in a 37℃ incubator and incubate for 30 minutes.

[0454] 4. Add 5 ml of Camp-d2 and 5 ml of Camp-ab (Cisbio, 62AM4PEB) in sequence.

[0455] 5.384-well plate was placed in the dark at room temperature for 1 hour.

[0456] 6. Read the plate data (Victor X5, PerkinElmer), use Xlfit nonlinear regression analysis, and calculate the IC50 of the compound. 50 The results are shown in Table 15.

[0457] Table 15. Effects of compound A 2A Receptors and A 2B Receptor inhibitory activity

[0458] X 0.001 0.003

[0459] As shown in Table 14, compound X of this application is effective against A. 2A Receptors and A 2B The receptors all exhibit high inhibitory activity.

[0460] Test Example 2: Inhibitory activity against A2A and A2B receptors

[0461] CHO-K1 / ADORA2A / Gα15 (GenScript, M00246) and CHO-K1 / ADORA2B / Gα15 (GenScript, M00329) cells were cultured in Ham's F-12 (Gibco, 31765092) medium containing 10% FBS, 200 μg / mL Zeocin, and 100 μg / mL Hygromycin B, or 10% FBS, 400 μg / mL G418, and 100 μg / mL Hygromycin B. For detailed culture conditions, please refer to the corresponding instruction manual. The screening steps are as follows:

[0462] 1. Adjust the cell density to 6 × 10⁶ cells / year using serum-free culture medium. 5 pcs / Ml.

[0463] 2. In each well of a 384-well plate (Greiner Bio-One, 784075), add 5 μL of cell culture, 2.5 μL of NECA (Sigma, 119140-10MG), and 2.5 μL of the compound solution. The final concentration of NECA was 1 μM (CHO-K1 / ADORA2A) or 0.1 μM (CHO-K1 / ADORA2B). The final concentration of the compound was 3 μM, which was initially down-diluted 3-fold.

[0464] 3. Place in a 37℃ incubator and incubate for 30 minutes.

[0465] 4. Add 5 μL of cAMP-d2 and 5 μL of cAMP-ab (Cisbio, 62AM4PEB) sequentially.

[0466] 5.384-well plate was placed in the dark at room temperature for 1 hour.

[0467] 6. Read the plate data (Victor X5, PerkinElmer), perform nonlinear regression analysis using XLfit, and calculate the IC50 of the compound. 50 The results are shown in Table 16.

[0468] Table 16. Effects of compound A 2A Receptors and A 2B Receptor inhibitory activity

[0469] X 0.024 0.062 D1 0.065 0.075

[0470] The structure of compound D1 is shown below, CAS number 2239273-34-6. Supplier: Suzhou Chukai Pharmaceutical Co., Ltd.; Batch number: 2009010AHP07.

[0471]

[0472] Test Example 3: In vivo pharmacokinetic study

[0473] The plasma concentrations of compound X in mice at different time points after intravenous injection and oral gavage administration were determined using LC / MS / MS to study the pharmacokinetic behavior of compound X in mice and evaluate its pharmacokinetic characteristics.

[0474] Experimental plan:

[0475] Experimental animals: Healthy adult male ICR mice (weighing 25g-40g, 12 mice; the intravenous injection group had free access to water and food, while the gavage group was fasted overnight and given free access to water and food 4 hours after administration), provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0476] Administration method and dosage: Select animals that meet the experimental requirements before administration, weigh and mark them. ICR mice were administered via tail vein (2 mg / kg, 5% DMSO, pH 4.5 20% Captisol) and by gavage (10 mg / kg, 5% DMSO, pH 4.5 20% Captisol).

[0477] Blood sampling: Before blood sampling, mice were tethered, and blood was collected from each drug-treated mouse at predetermined time points (for intravenous administration: blood was collected at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 7.5h, and 24h post-administration, for a total of 9 time points; for gavage administration: blood was collected at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 7.5h, and 24h post-administration, for a total of 9 time points), approximately 100 μL of blood was collected via the jugular vein. The blood was transferred to 1.5 mL tubes pre-filled with K2EDTA, centrifuged for 4 min (8000 rpm, 4℃), and the plasma was separated. The entire process was completed within 15 min after blood collection. All samples were stored at -20℃ until analysis. Drug concentration was determined using LC / MS / MS.

[0478] The pharmacokinetic properties of compound X in mice via intravenous administration are shown in Table 17.

[0479] Table 17. Pharmacokinetic parameters under intravenous administration

[0480] Compound X 14.7 2252 D1 19.0 1646

[0481] The pharmacokinetic properties of compound X in mice administered by gavage are shown in Table 18.

[0482] Table 18. Pharmacokinetic parameters under gastric administration route

[0483] Compound X 8730 10446 D1 5957 10291

[0484] Test Example 4: In vivo efficacy experiment of compound X of this application

[0485] Experimental protocol: This test case investigated the in vivo efficacy of compound X of the present application against mice with subcutaneous xenografts of the MC38(#22)-hpd-L1 colon cancer cell line. The compound X was administered orally to the mice bearing the MC38(#22)-hpd-L1 colon cancer cell line.

[0486] Experimental materials: C57BL / 6mice mice (female); mouse colon cancer MC38(#22)-hpd-L1 cells (Shanghai Jiao Tong University Cell Bank), cultured in vitro in a monolayer using RPMI-1640 medium containing 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Cells were passaged after routine digestion with trypsin-EDTA. Cells were harvested and counted when they reached the exponential growth phase and confluence reached 80%–90%.

[0487] Compound preparation: Measure the compound and add it to the solvent (40% Captisol acetate buffer, pH 3.8) to prepare a 10 mg / mL sample. Take 75 μL of Tecentriq solution (60 mg / mL) and add it to 8.925 mL of phosphate buffer (PBS) to prepare a 0.5 mg / mL phosphate solution (phosphate buffer).

[0488] Experimental procedure: Resuspend cells in phosphate buffer at a density of 5 × 10⁻⁶. 6 Cells / mL. Add 0.1 mL of PBS (containing 5 × 10⁶ cells / mL). 5 One MC38(#22)-hpd-L1 cell was subcutaneously injected into the right posterior back of each mouse. On the day of injection, mice were randomly divided into groups of 10 mice each according to their body weight. Drug administration began and continued twice daily for 22 days. Throughout the experiment, the animals were weighed and their health monitored daily. Tumor diameter was measured twice weekly using calipers.

[0489] The formula for calculating tumor volume V is: V = 0.5 × a × b 2 , where a and b represent the long and short diameters of the tumor, respectively.

[0490] The antitumor efficacy of the compounds was evaluated using the relative tumor proliferation rate (T / C%). The relative tumor proliferation rate (T / C%) was calculated as: T / C = Vt / Vc × 100% (Vt: mean tumor volume in the treatment group; Vc: mean tumor volume in the negative control group). Data for Vt and Vc were collected from the same day. The results are shown in Table 19.

[0491] Table 19. Relative tumor proliferation rate obtained from Test Example 4

[0492]

[0493] All references to documents mentioned in this application are incorporated herein by reference as if each document were individually incorporated herein by reference. Unless they conflict with the inventive purpose or technical solution of this application, all cited documents are incorporated herein by reference in their entirety and for all purposes. When citing documents in this application, the definitions of relevant technical features, terms, nouns, phrases, etc., are also incorporated herein by reference. When citing documents in this application, examples and preferred embodiments of the cited technical features may also be incorporated herein by reference, but only to the extent that they enable the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, this application shall prevail or modifications shall be made adaptably to the description in this application.

[0494] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0495] The embodiments described above are merely illustrative of several implementation methods of this application, intended to facilitate a detailed understanding of the technical solutions of this application, but should not be construed as limiting the scope of protection of this application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. Furthermore, it should be understood that after reading the above teachings of this application, those skilled in the art can make various alterations or modifications to this application, and the equivalent forms obtained also fall within the scope of protection of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent application should be determined by the content of the appended claims, and the specification and drawings can be used to interpret the content of the claims.

Claims

1. A polymorph of a compound of formula X, wherein, ； The polymorphs of compound X are selected from any one of the following groups: The free alkali crystal form I of the compound of formula X has the following peaks in its X-ray powder diffraction pattern at a diffraction angle of 2θ (°): 12.90±0.2, 15.26±0.2, 18.08±0.2, 21.41±0.2, 22.01±0.2 and 24.83±0.2; The free alkali crystal form IV of the compound of formula X has the following peaks in its X-ray powder diffraction pattern at a diffraction angle of 2θ (°): 6.32±0.2, 9.58±0.2, 13.04±0.2, 15.80±0.2, 16.46±0.2 and 23.89±0.2; The free alkali crystal form V of the compound of formula X has the following peaks in its X-ray powder diffraction pattern at a diffraction angle of 2θ (°): 6.17±0.2, 9.37±0.2, 10.39±0.2, 11.65±0.2, 14.35±0.2, 15.74±0.2 and 17.21±0.2; The free alkali crystal form VI of the compound of formula X has the following peaks in its X-ray powder diffraction pattern at a diffraction angle of 2θ (°): 12.55±0.2, 14.86±0.2, 16.15±0.2, 17.69±0.2, 21.08±0.2, 21.58±0.2, 24.53±0.2 and 25.01±0.2; The free alkali crystal form VII of the compound of formula X has the following peaks in its X-ray powder diffraction pattern at a diffraction angle of 2θ (°): 14.92±0.2, 16.13±0.2, 17.59±0.2, 20.87±0.2, 21.20±0.2, 21.71±0.2, 24.12±0.2, 24.62±0.2 and 25.12±0.

2.

2. The polymorph as described in claim 1, wherein, The polymorphs of compound X are selected from any one of the following groups: The X-ray powder diffraction pattern of the free alkali crystal form I also includes two or more peaks selected from the following group at a diffraction angle of 2θ (°): 16.47±0.2, 17.81±0.2, 19.57±0.2 and 25.43±0.2; The X-ray powder diffraction pattern of the free alkali crystal form IV also includes two or more peaks selected from the following group at a diffraction angle of 2θ (°): 9.08±0.2, 14.12±0.2, 20.14±0.2, 20.59±0.2 and 27.53±0.2; The X-ray powder diffraction pattern of the free alkali crystal form V also includes two or more peaks selected from the following group at a diffraction angle of 2θ (°): 21.65±0.2, 22.31±0.2, 24.55±0.2, 24.86±0.2, 25.70±0.2, 26.08±0.2 and 27.31±0.2; The X-ray powder diffraction pattern of the free alkali crystal form VI also includes two or more peaks selected from the following group at a diffraction angle of 2θ (°): 9.04±0.2, 9.68±0.2, 13.37±0.2, 18.53±0.2, 19.19±0.2, 19.64±0.2, 19.97±0.2, 23.69±0.2, 27.55±0.2, 30.34±0.2 and 31.46±0.2; The X-ray powder diffraction pattern of the free alkali crystal form VII also includes two or more peaks selected from the following group at a diffraction angle of 2θ (°): 6.17±0.2, 9.07±0.2, 9.67±0.2, 10.37±0.2, 12.61±0.2, 14.39±0.2, 19.21±0.2, 19.73±0.2 and 20.05±0.

2.

3. The polymorph as described in claim 2, wherein, The polymorphs of compound X are selected from any one of the following groups: The X-ray powder diffraction pattern of the free alkali crystal form I also includes two or more peaks selected from the following group at a diffraction angle of 2θ (°): 9.50±0.2, 10.13±0.2, 12.53±0.2, 18.89±0.2, 19.94±0.2 and 20.33±0.2; The X-ray powder diffraction pattern of the free alkali crystal form IV also includes one or two peaks selected from the following groups at a diffraction angle of 2θ (°): 7.64±0.2 and 8.34±0.2; The X-ray powder diffraction pattern of the free alkali crystal form V also includes two or more peaks selected from the following group at a diffraction angle of 2θ (°): 6.91±0.2, 8.08±0.2, 8.70±0.2, 12.77±0.2 and 13.25±0.2; The X-ray powder diffraction pattern of the free alkali crystal form VI also includes one or two peaks selected from the following group at a diffraction angle of 2θ (°): 7.24±0.2 and 12.07±0.2; The X-ray powder diffraction pattern of the free alkali crystal form VII also includes two or more peaks selected from the following group at a diffraction angle of 2θ (°): 27.25±0.2, 27.39±0.2, 27.76±0.2, 28.97±0.2, 30.36±0.2, 31.25±0.2 and 31.67±0.

2.

4. The polymorph as described in any one of claims 1 to 3, wherein, The X-ray powder diffraction pattern of the free alkali crystal type I is basically characterized in Figure 1; The X-ray powder diffraction pattern of the free alkali crystal type IV is basically characterized in Figure 4; The X-ray powder diffraction pattern of the free alkali crystal type V is basically characterized as shown in Figure 6. The X-ray powder diffraction pattern of the free alkali crystal type VI is basically characterized in Figure 8; The X-ray powder diffraction pattern of the free alkali crystal type VII is basically characterized as shown in Figure 10.

5. The polymorph as described in any one of claims 1 to 3, wherein, X-ray powder diffraction patterns were obtained using Cu-Kα radiation.

6. The polymorph as described in any one of claims 1 to 3, wherein, The differential scanning calorimetry curve of the free alkali crystal form I has an endothermic peak at 190.15±3℃; The differential scanning calorimetry curve of the free alkali crystal form IV has an endothermic peak at 189.64±3℃; The differential scanning calorimetry curve of the free alkali crystal form V has an endothermic peak at 189.94±3℃; The differential scanning calorimetry curve of the free alkali crystal form VI has an endothermic peak at 189.33±3℃; The differential scanning calorimetry curve of the free alkali crystal form VII has an endothermic peak at 189.36±3℃.

7. The polymorph as described in any one of claims 1 to 3, wherein, The free alkali crystal form I has one or more characteristics selected from the group consisting of: (1) Its TGA-DSC spectrum is basically represented as shown in Figure 2; (2) Its DVS spectrum is basically represented as shown in Figure 3; and (3) Its infrared spectrum is basically characterized as shown in Figure 20.

8. A polymorph of a pharmaceutically acceptable salt of compound X, wherein, The structural formula of compound X is: ； The pharmaceutically acceptable salts of compound X are selected from any one of the following groups: The hydrochloride crystal form I of the compound of formula X has X-ray powder diffraction patterns with peaks at diffraction angles of 2θ (°) in the lower group: 13.12±0.2, 13.91±0.2, 17.62±0.2, 18.64±0.2, 22.58±0.2 and 26.51±0.2; The sulfate crystal form I of the compound of formula X has X-ray powder diffraction patterns with peaks at diffraction angles of 2θ (°) in the lower group: 11.62±0.2, 12.77±0.2, 15.13±0.2, 19.64±0.2, 22.25±0.2, and 23.48±0.2; The hydrobromide crystal form I of the compound of formula X has X-ray powder diffraction patterns with peaks at diffraction angles of 2θ (°) in the following group: 12.79±0.2, 16.70±0.2, 23.51±0.2, 23.96±0.2, 24.34±0.2 and 28.04±0.

2.

9. The polymorph as described in claim 8, wherein, The pharmaceutically acceptable salts of compound X are selected from any one of the following groups: The X-ray powder diffraction pattern of the hydrochloride crystal form I also includes two or more peaks selected from the following groups at a diffraction angle of 2θ (°): 8.39±0.2, 10.18±0.2, 15.25±0.2, 20.96±0.2, 25.52±0.2, 27.01±0.2 and 29.48±0.2; The X-ray powder diffraction pattern of the sulfate crystal form I also includes two or more peaks selected from the following group at a diffraction angle of 2θ (°): 13.13±0.2, 24.80±0.2 and 26.09±0.2; The X-ray powder diffraction pattern of the hydrobromide crystal form I also includes two or more peaks selected from the following groups at a diffraction angle of 2θ (°): 11.84±0.2, 19.34±0.2, 20.23±0.2, 23.09±0.2, 25.37±0.2, 26.21±0.2, 26.99±0.2, 33.22±0.2 and 35.96±0.

2.

10. The polymorph as described in claim 9, wherein, The pharmaceutically acceptable salts of compound X are selected from any one of the following groups: The X-ray powder diffraction pattern of the hydrochloride crystal form I also includes two or more peaks selected from the following groups at a diffraction angle of 2θ (°): 11.44±0.2, 12.63±0.2, 17.27±0.2, 18.97±0.2, 20.12±0.2, 21.61±0.2, 23.29±0.2 and 29.15±0.2; The X-ray powder diffraction pattern of the sulfate crystal form I also includes two or more peaks selected from the following group at a diffraction angle of 2θ (°): 12.19±0.2, 16.45±0.2 and 21.71±0.2; The X-ray powder diffraction pattern of the hydrobromide crystal form I also includes two or more peaks selected from the following groups at a diffraction angle of 2θ (°): 11.48±0.2, 13.64±0.2, 15.46±0.2, 15.96±0.2, 17.66±0.2, 18.71±0.2, 20.99±0.2, 21.51±0.2, 31.60±0.2, 31.90±0.2, 35.52±0.2, 36.98±0.2, 37.81±0.2, 39.29±0.2, and 39.73±0.

2.

11. The polymorph as described in any one of claims 8 to 10, wherein, The X-ray powder diffraction pattern of the hydrochloride crystal form I is basically characterized by Figure 13; The X-ray powder diffraction pattern of sulfate crystal form I is basically characterized as shown in Figure 15. The X-ray powder diffraction pattern of the hydrobromide crystal form I is basically characterized as shown in Figure 17.

12. The polymorph as described in any one of claims 8 to 10, wherein, X-ray powder diffraction patterns were obtained using Cu-Kα radiation.

13. The polymorph as described in any one of claims 8 to 10, wherein, The differential scanning calorimetry curve of the hydrochloride crystal form I has an endothermic peak at 225.37±3℃; The differential scanning calorimetry curve of the sulfate crystal form I has an endothermic peak at 205.20±3℃.

14. A method for preparing a polymorph of the compound of formula X as described in claim 1, wherein, The structure of compound X is shown in Formula X: ； The preparation method includes the following steps: The compound of formula X is dissolved in the presence of a solvent to form a solution; The solution is subjected to crystallization to prepare a polymorph of compound X.

15. The method for preparing a polymorph as described in claim 14, wherein, The polymorph of compound X is free alkali crystal form I.

16. The method for preparing a polymorph as described in claim 14 or 15, wherein, The solvent is selected from acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, a 50% v / v ethanol / water mixture, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, and mixtures thereof.

17. The method for preparing a polymorph as described in claim 14 or 15, wherein, The preparation method is selected from any one of the following groups: (Ia) The solvent is acetonitrile, isopropanol, ethanol, ethyl acetate or a 50% v / v ethanol / water mixture, and the crystallization treatment is cooling crystallization; (Ib) The solvent is a 50% (v / v) ethanol / water mixture, and the crystallization treatment is evaporative crystallization; (Ic) The solvent is dimethyl sulfoxide or N,N-dimethylacetamide, and the crystallization treatment is anti-solvent crystallization.

18. The method for preparing a polymorph as described in claim 14 or 15, wherein, The preparation method includes the following steps: The compound of formula X is dissolved in isopropanol, ethanol, ethyl acetate, or a 50% v / v ethanol / water mixture at 50±5°C to form the solution. The solution is cooled to 0°C to 4°C to allow crystals to precipitate.

19. The method for preparing a polymorph as described in claim 14 or 15, wherein, The preparation method includes the following steps: The compound of formula X is dissolved in acetonitrile at 75±5°C to form the solution; or the compound of formula X is dissolved in ethanol at 70±5°C to form the solution. The solution is cooled to room temperature to allow crystals to precipitate.

20. A pharmaceutical composition, wherein, The pharmaceutical composition comprises: (a) The polymorph according to any one of claims 1 to 13, or the polymorph prepared by the preparation method according to any one of claims 14 to 19; and (b) Pharmaceutically acceptable carrier.

21. The polymorph according to any one of claims 1 to 13, or the polymorph prepared by the preparation method according to any one of claims 14 to 19, or the pharmaceutical composition according to claim 20, in the preparation of a drug for the prevention, treatment or prevention of adenosine A 2A Receptor-mediated, adenosine A 2B Receptor-mediated or adenosine A 2A Receptor and adenosine A 2B Application in drugs that co-mediate tumor or immune-related diseases, among which, Compound X is a component of A 2A / A 2B Receptor antagonists.

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