Polymorphs of pyrimidine derivatives and pharma-ceutically acceptable salts thereof and uses thereof

Abstract

The present invention provides polymorphs of pyrimidine derivatives and pharma- ceutically acceptable salts thereof, as well as uses thereof. 2A / A 2B The present invention provides polymorphs of the pyrimidine derivative, which is a receptor dual antagonist and has the chemical name 3-(4-amino-5-fluoro-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-2-yl)-2-methylbenzonitrile, and pharma- ceutically acceptable salts thereof, as well as uses thereof.

Description

[Technical field]

[0001] This application claims priority to a Chinese patent application filed on September 15, 2021, bearing application number CN202111079644.0 and titled "Polymorphs and Uses of Pyrimidine Derivatives and Pharmaceutically Acceptable Salts Thereof," the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of pharmaceutical technology, in particular to polymorphs and uses of pyrimidine derivatives and pharma- ceutically acceptable salts thereof, and to polymorphs and uses of 3-(4-amino-5-fluoro-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-2-yl)-2-methylbenzonitrile and pharma-ceutically acceptable salts thereof. [Background technology]

[0003] Adenosine is an endogenous nucleoside present throughout human cells, composed of adenine and ribose, and is widely distributed both intracellularly and extracellularly. Adenosine is involved in various physiological and biochemical functions in the body, for example, adenosine directly enters the myocardium and, by phosphorylation, generates adenosine triphosphate (ATP), which is involved in myocardial energy metabolism. In the central nervous system (CNS), adenosine plays a role in controlling the release of neurotransmitters and the response of postsynaptic neurons, influencing important life processes such as the regulation of movement, neuronal protection, and sleep and wakefulness. Under pathological conditions, extracellular adenosine concentrations are significantly increased in tumors or under hypoxic conditions. Adenosine plays an important role in tumor immunosuppression by promoting tumor angiogenesis, proliferation, development, and tumor metastasis.

[0004] Adenosine receptors (AR) belong to the G protein-coupled receptor (GPCR) family, and their endogenous ligand is adenosine. The currently known adenosine receptors are A1, A2 A , A2 B Adenosine is composed of four subtype receptors: A1 and A3. When adenosine binds to the A1 or A3 receptor, it inhibits the production of cyclic adenosine monophosphate (cAMP), but when it binds to the A2 receptor, it inhibits the production of cyclic adenosine monophosphate (cAMP). A or A2 B Upon binding to the receptor, adenosine-activating enzymes are activated, thereby increasing levels of cAMP and exerting further physiological regulatory effects.

[0005] Two types of receptors, A1 and A3, are expressed primarily in the central nervous system, whereas A2 A and A2 B Two types of adenosine receptors are expressed in both the central and peripheral nervous systems. In the tumor microenvironment, A2 A and A2 B These two types of adenosine receptors are widely expressed in immune cells and have strong immunosuppressive functions, so it is very valuable to develop drugs to prevent or treat tumors or immune-related diseases by focusing on these two targets.

[0006] To better meet market needs, 2A / A 2B Compounds having receptor antagonist activity, their pharma- ceutically acceptable salts, and their polymorphs are further developed to contribute to further drug development. Summary of the Invention

[0007] The object of the present invention is to A / A 2B The present invention includes providing polymorphs of the receptor antagonist or a pharma- ceutically acceptable salt thereof, as well as uses thereof.

[0008] In a first aspect of the present invention, there is provided a polymorph of a compound of formula X, or a pharma- ceutically acceptable salt of said compound of formula X, wherein said compound of formula X is a pyrimidine derivative and has the structure shown in formula X:

[0009] [ka] In the first aspect of the invention, polymorphs of the compound of formula X are also included, as are polymorphs of pharma- ceutically acceptable salts of the compound of formula X.

[0010] The pharma- ceutically acceptable salt comprises a compound of formula X and an acid moiety, since the salt is formed from the compound of formula X and an acid.

[0011] In some embodiments, the pharma- ceutically acceptable salt is an inorganic salt, and accordingly, the acid used to form the salt is an inorganic acid.

[0012] In some embodiments, the pharma- ceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, and hydrobromide salts, and accordingly, the acid used to form the salt is selected from the group consisting of hydrochloric acid, sulfuric acid, and hydrobromic acid.

[0013] In some embodiments, the polymorph of the compound of formula X and the polymorph of the pharma- ceutically acceptable salt of the compound of formula X are each independently anhydrous, hydrated or solvated.

[0014] In some embodiments, the powder X-ray diffraction spectrum is obtained using Cu-Kα radiation.

[0015] Each of the powder X-ray diffraction spectra according to the present invention can be independently obtained using Cu-Kα radiation.

[0016] In some embodiments, the polymorph is crystalline Form I of the compound of Formula X, i.e., free base crystalline Form I, whose powder X-ray diffraction spectrum has peaks at diffraction angles 2θ (°) of 18.08±0.2, 21.41±0.2, and 24.83±0.2.

[0017] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form I further comprises a peak at at least one diffraction angle 2θ (°) selected from the group consisting of 12.90±0.2, 15.26±0.2, 16.47±0.2, 17.81±0.2, and 19.57±0.2.

[0018] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form I further comprises at least one peak at a diffraction angle 2θ (°) selected from the group consisting of 22.01±0.2 and 25.43±0.2.

[0019] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form I has peaks at diffraction angles 2θ (°) of 18.08±0.2, 21.41±0.2, and 24.83±0.2, and further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0020] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form I further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0021] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form I further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 7.73±0.2, 13.94±0.2, and 16.94±0.2.

[0022] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form I further comprises peaks at two or more diffraction angles 2θ (°) 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.

[0023] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form I has diffraction peaks at the angles 2θ (°) shown in Table 1, with the relative intensities of each diffraction peak shown in Table 1.

[0024] [Table 1]

[0025] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form I is essentially as represented in FIG.

[0026] In one embodiment, the powder X-ray diffraction spectrum of the free base crystalline Form I is depicted in FIG.

[0027] In some embodiments, the free base crystalline Form I is an anhydrous form.

[0028] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form I has an endothermic peak at 190.15° C.±3° C. and a heat of fusion of about 100.48 J / g.

[0029] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form I has an endothermic peak at 190.15°C ± 1°C.

[0030] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form I has an endothermic peak at 190.15°C ± 0.5°C.

[0031] In some embodiments, the TGA spectrum of the free base crystalline Form I shows little weight loss up to 150°C, and a weight loss of 0.123% from 150°C to 210°C.

[0032] In some embodiments, the free base crystalline Form I has a TGA-DSC spectrum essentially as shown in FIG.

[0033] In one embodiment, the free base crystalline Form I has the TGA-DSC spectrum shown in FIG.

[0034] In some embodiments, the free base crystalline form I exhibits almost no hygroscopicity, with a weight change due to adsorption of less than 0.2% during a relative humidity change process from 0% to 80% Rh under conditions of 25°C, and the percentage of weight change (%) is a weight percentage.

[0035] In some embodiments, the free base crystalline Form I has a dynamic moisture sorption spectrum (DVS spectrum) essentially as shown in FIG.

[0036] In one embodiment, the free base crystalline Form I has the DVS spectrum shown in FIG.

[0037] In some embodiments, the infrared spectrum of the free base crystalline Form I has a peak at about 3490 cm -1 , approx. 3280cm -1 , approx. 3132cm -1 , approx. 2972cm -1 , approx. 2931cm -1 , about 2210cm -1 , approx. 1636~1451cm -1 , about 1399cm -1 , approx. 1366cm -1 , about 855cm -1 , about 799cm -1 and about 769 cm -1 The absorption peak exists at 100 nm. Here, "approximately" is ±5 cm. -1 , ±3cm -1 or ±1cm -1may be also possible.

[0038] In some embodiments, the infrared spectrum of the free base crystalline Form I is essentially represented in FIG.

[0039] In some embodiments, the free base crystalline Form I has an infrared spectrum represented in FIG.

[0040] In some embodiments, the free base crystalline form I is (1) The TGA-DSC spectrum is basically shown in Figure 2. (2) The DVS spectrum is basically shown in Figure 3. (3) The infrared spectrum is basically as shown in Figure 20. The present invention has one or more characteristics selected from the group consisting of:

[0041] In some embodiments, the polymorph is Form IV of the compound of Formula X, i.e., free base Form IV, whose powder X-ray diffraction spectrum has peaks at diffraction angles 2θ (°) of 13.04±0.2, 15.80±0.2, 16.46±0.2, and 23.89±0.2.

[0042] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form IV further comprises a peak at at least one diffraction angle 2θ (°) selected from the group consisting of 6.32±0.2, 9.08±0.2, 9.58±0.2, and 14.12±0.2.

[0043] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form IV further comprises a peak at at least one diffraction angle 2θ (°) selected from the group consisting of 20.14±0.2, 20.59±0.2, 23.89±0.2, and 27.53±0.2.

[0044] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form IV has peaks at diffraction angles 2θ (°) of 13.04±0.2, 15.80±0.2, 16.46±0.2, and 23.89±0.2, and further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0045] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form IV has peaks at diffraction angles 2θ (°) of 13.04±0.2, 15.80±0.2, 16.46±0.2, and 23.89±0.2, and further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0046] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form IV further comprises peaks at one or two diffraction angles 2θ (°) selected from the group consisting of 7.64±0.2 and 8.34±0.2.

[0047] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form IV has peaks at the degrees 2θ shown in Table 2, with the relative intensities of each peak shown in Table 2.

[0048] [Table 2]

[0049] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form IV is essentially as represented in FIG.

[0050] In one embodiment, the powder X-ray diffraction spectrum of the free base crystalline Form IV is depicted in FIG.

[0051] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form IV has an endothermic peak at 189.64°C ± 3°C.

[0052] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form IV has an endothermic peak at 189.64°C ± 1°C.

[0053] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form IV has an endothermic peak at 189.64°C ± 0.5°C.

[0054] In some embodiments, the free base crystalline Form IV has a differential scanning calorimetry curve essentially as shown in FIG.

[0055] In one embodiment, the free base crystalline Form IV has a differential scanning calorimetry curve as shown in FIG.

[0056] In some embodiments, the polymorph is Form V of the compound of Formula X, i.e., free base crystalline Form V, having an X-ray powder diffraction spectrum with peaks at diffraction angles 2θ (°) of 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.

[0057] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline form V further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0058] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline form V has a peak at a diffraction angle 2θ (°) of 38.71±0.2.

[0059] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline form V comprises peaks at one or two diffraction angles 2θ (°) selected from the group consisting of 38.71±0.2 and 43.60±0.2.

[0060] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline form V further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 6.91±0.2, 8.08±0.2, 8.70±0.2, 12.77±0.2, and 13.25±0.2.

[0061] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form V further comprises peaks at two or more diffraction angles 2θ (°) 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.

[0062] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form V comprises peaks at two or more diffraction angles 2θ (°) 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.

[0063] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form V has peaks at the degrees 2θ shown in Table 3, with the relative intensities of each peak shown in Table 3.

[0064] [Table 3]

[0065] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form V is essentially as represented in FIG.

[0066] In one embodiment, the powder X-ray diffraction spectrum of the free base crystalline form V is depicted in FIG.

[0067] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form V has an endothermic peak at 189.94°C ± 3°C.

[0068] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form V has an endothermic peak at 189.94°C ± 1°C.

[0069] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form V has an endothermic peak at 189.94°C ± 0.5°C.

[0070] In some embodiments, the free base crystalline form V has a differential scanning calorimetry curve essentially as shown in FIG.

[0071] In one embodiment, the free base crystalline form V has a differential scanning calorimetry curve as shown in FIG.

[0072] In some embodiments, the polymorph is Form VI of the compound of Formula X, i.e., free base Form VI, having an X-ray powder diffraction spectrum with peaks at diffraction angles 2θ (°) of 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.

[0073] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form VI further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0074] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form VI further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 23.69±0.2, 27.55±0.2, 30.34±0.2, and 31.46±0.2.

[0075] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form VI further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0076] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form VI further comprises peaks at one or two diffraction angles 2θ (°) selected from the group consisting of 7.24±0.2 and 12.07±0.2.

[0077] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form VI has peaks at the degrees 2θ (°) set forth in Table 4, with the relative intensities of each peak set forth in Table 4.

[0078] [Table 4]

[0079] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form VI is essentially as represented in FIG.

[0080] In one embodiment, the powder X-ray diffraction spectrum of the free base crystalline Form VI is depicted in FIG.

[0081] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form VI has an endothermic peak at 189.33°C ± 3°C.

[0082] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form VI has an endothermic peak at 189.33°C ± 1°C.

[0083] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form VI has an endothermic peak at 189.33°C ± 0.5°C.

[0084] In some embodiments, the free base crystalline Form VI has a differential scanning calorimetry curve essentially as shown in FIG.

[0085] In one embodiment, the free base crystalline Form VI has a differential scanning calorimetry curve as shown in FIG.

[0086] In some embodiments, the polymorph is crystalline Form VII of the compound of Formula X, i.e., free base crystalline Form VII, having an X-ray powder diffraction spectrum with peaks at diffraction angles 2θ (°) of 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.

[0087] In some embodiments, the polymorph is crystalline Form VII of the compound of Formula X, i.e., free base crystalline Form VII, having an X-ray powder diffraction spectrum with peaks at diffraction angles 2θ (°) of 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.

[0088] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form VII further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0089] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form VII further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0090] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form VII further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0091] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form VII has peaks at the degrees 2θ shown in Table 5, with the relative intensities of each peak shown in Table 5.

[0092] [Table 5]

[0093] In some embodiments, the powder X-ray diffraction spectrum of the free base crystalline Form VII is essentially as represented in FIG.

[0094] In one embodiment, the powder X-ray diffraction spectrum of the free base crystalline Form VII is depicted in FIG.

[0095] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form VII has an endothermic peak at 189.36°C ± 3°C.

[0096] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form VII has an endothermic peak at 189.36°C ± 1°C.

[0097] In some embodiments, the differential scanning calorimetry curve for the free base crystalline Form VII has an endothermic peak at 189.36°C ± 0.5°C.

[0098] In some embodiments, the free base crystalline Form VII has a differential scanning calorimetry curve essentially as shown in FIG.

[0099] In one embodiment, the free base crystalline Form VII has a differential scanning calorimetry curve as shown in FIG.

[0100] In some embodiments, the free base polymorph is crystalline Form I of the hydrochloride salt of compound of Formula X, i.e., hydrochloride crystalline Form I, having an X-ray powder diffraction spectrum with peaks at diffraction angles 2θ (°) of 13.12±0.2, 13.91±0.2, 17.62±0.2, 22.58±0.2, and 26.51±0.2.

[0101] In some embodiments, the powder X-ray diffraction spectrum of the hydrochloride salt crystalline Form I further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0102] In some embodiments, the powder X-ray diffraction spectrum of the hydrochloride salt crystalline Form I further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0103] In some embodiments, the X-ray powder diffraction spectrum of the hydrochloride salt crystalline Form I has peaks at the degrees 2θ shown in Table 6, with the relative intensities of each peak shown in Table 6.

[0104] [Table 6]

[0105] In some embodiments, the powder X-ray diffraction spectrum of the hydrochloride salt crystalline Form I is essentially as represented in FIG.

[0106] In one embodiment, the powder X-ray diffraction spectrum of the hydrochloride salt crystalline form I is depicted in FIG.

[0107] In some embodiments, the differential scanning calorimetry curve for the hydrochloride salt crystalline Form I has an endothermic peak at 225.37°C ± 3°C.

[0108] In some embodiments, the differential scanning calorimetry curve for the hydrochloride salt crystalline Form I has an endothermic peak at 225.37°C ± 1°C.

[0109] In some embodiments, the differential scanning calorimetry curve for the hydrochloride salt crystalline Form I has an endothermic peak at 225.37°C ± 0.5°C.

[0110] In some embodiments, the hydrochloride salt crystalline Form I has a differential scanning calorimetry curve essentially as shown in FIG.

[0111] In one embodiment, the hydrochloride salt crystalline Form I has a differential scanning calorimetry curve as shown in FIG.

[0112] In some embodiments, the polymorph is Form I of the sulfate salt of the compound of Formula X, i.e., sulfate salt crystalline Form I, whose powder X-ray diffraction spectrum has peaks at diffraction angles 2θ (°) of 15.13±0.2, 19.64±0.2, and 23.48±0.2.

[0113] In some embodiments, the powder X-ray diffraction spectrum of the Sulfate Salt crystalline Form I further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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.

[0114] In some embodiments, the powder X-ray diffraction spectrum of the Sulfate Salt crystalline Form I further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 12.19±0.2, 16.45±0.2, and 21.71±0.2.

[0115] In some embodiments, the powder X-ray diffraction spectrum of the Sulfate Salt, Form I, has peaks at the degrees 2θ shown in Table 7, with the relative intensities of each peak shown in Table 7.

[0116] [Table 7]

[0117] In some embodiments, the powder X-ray diffraction spectrum of the Sulfate Salt, Form I, is essentially that represented in FIG.

[0118] In one embodiment, the powder X-ray diffraction spectrum of the Sulfate Salt Crystalline Form I is presented in FIG.

[0119] In some embodiments, the differential scanning calorimetry curve for the Sulfate Salt crystalline Form I has an endothermic peak at 205.20°C ± 3°C.

[0120] In some embodiments, the differential scanning calorimetry curve for the Sulfate Salt crystalline Form I has an endothermic peak at 205.20°C ± 1°C.

[0121] In some embodiments, the differential scanning calorimetry curve for the Sulfate Salt crystalline Form I has an endothermic peak at 205.20°C ± 0.5°C.

[0122] In some embodiments, the Sulfate Salt Crystal Form I has a differential scanning calorimetry curve essentially as shown in FIG.

[0123] In one embodiment, the Sulfate Salt Crystal Form I has a differential scanning calorimetry curve as shown in FIG.

[0124] In some embodiments, the polymorph is Form I of the hydrobromide salt of the compound of Formula X, i.e., hydrobromide salt Form I, whose powder X-ray diffraction spectrum has peaks at diffraction angles 2θ (°) of 16.70±0.2, 23.51±0.2, and 23.96±0.2.

[0125] In some embodiments, the powder X-ray diffraction spectrum of the hydrobromide salt crystalline Form I further comprises peaks at two or more diffraction angles 2θ (°) 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.

[0126] In some embodiments, the powder X-ray diffraction spectrum of the hydrobromide salt crystalline Form I further comprises peaks at two or more diffraction angles 2θ (°) 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.

[0127] In some embodiments, the powder X-ray diffraction spectrum of the hydrobromide salt crystalline Form I has peaks at the degrees 2θ shown in Table 8, with the relative intensities of each peak shown in Table 8.

[0128] [Table 8]

[0129] In some embodiments, the powder X-ray diffraction spectrum of the hydrobromide salt crystalline Form I is essentially as represented in FIG.

[0130] In one embodiment, the powder X-ray diffraction spectrum of the hydrobromide salt crystalline form I is depicted in FIG.

[0131] In a second aspect of the present invention, there is provided a process for the preparation of polymorphs of the compound of formula X and its pharma-ceutically acceptable salts, which can be used to prepare the polymorphs described in the first aspect.

[0132] In a second aspect of the invention, the structure of the compound of formula X corresponds to that shown above.

[0133] In a second aspect of the present invention, (a0) dissolving the compound of formula X in a solvent until a clear solution is formed; (b0) subjecting the solution to a crystallization process to prepare a polymorph of the compound of formula X; The present invention provides a process for preparing the polymorph of the compound of formula X, comprising:

[0134] In this specification, in order to realize "dissolving until transparent", it is necessary to properly control the amount of the corresponding solvent so as to completely dissolve the compound represented by formula X. If the amount is too low, a transparent solution cannot be obtained, and if the amount is too high, crystals may not be precipitated during crystallization treatment.

[0135] In some embodiments, in step (a0), the solvent is selected from the group consisting of acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, a 50% (v / v) ethanol / water mixture, dimethylsulfoxide, N,N-dimethylacetamide, tetrahydrofuran, and mixtures thereof.

[0136] In some embodiments, in step (b0), the method of the crystallization treatment is selected from the group consisting of crystallization by temperature reduction, crystallization by volatilization, and crystallization by antisolvent.

[0137] In this specification, the important step in the crystallization by temperature reduction is to precipitate crystals by decreasing the temperature.

[0138] In this specification, the important step in the crystallization by evaporation is to evaporate the solvent and precipitate the crystals.

[0139] As used herein, the key step in the antisolvent crystallization is the "addition of an antisolvent", i.e., the addition of an antisolvent, an antisolvent, or a combination of an antisolvent and an antisolvent to precipitate crystals. Preferably, an antisolvent is added.

[0140] In some embodiments, in step (b0), the method of crystallization is slow cooling, slow evaporation, or addition of an anti-solvent.

[0141] In this specification, an example of slowly decreasing the temperature is allowing the temperature to naturally decrease to room temperature.

[0142] As used herein, an example of slow evaporation is natural evaporation at room temperature.

[0143] In some embodiments, the polymorph prepared is said free base crystalline Form I, and said crystallization process is carried out by reduced temperature crystallization, volatilization crystallization, or antisolvent crystallization.

[0144] In some embodiments, (a1) dissolving a compound of formula X in the presence of a solvent until a clear solution is formed; (b1) subjecting the solution to a crystallization treatment; The present invention provides a process for preparing the free base crystalline form I, comprising:

[0145] In some embodiments, in step (a1), the solvent is selected from the group consisting of acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, 50% ethanol (i.e., a 50% (v / v) ethanol / water mixture), dimethylsulfoxide, N,N-dimethylacetamide, tetrahydrofuran, and mixtures thereof.

[0146] In some embodiments, in step (a1), the solvent is acetonitrile, isopropanol, ethanol, ethyl acetate, 50% ethanol, dimethylsulfoxide, or N,N-dimethylacetamide.

[0147] In some embodiments, in the step (a1), the compound represented by formula X is dissolved until it becomes transparent under the condition of temperature T1. In some preferred embodiments, the temperature T1 is preferably higher than room temperature. For example, the compound represented by formula X is put into a solvent, heated to temperature T1, and then maintained for a certain time to clarify the mixed system (realizing dissolving the compound represented by formula X until it becomes transparent), and the obtained clear system is the solution. The temperature T1 may be a constant temperature condition (maintained at a constant temperature) or may be a temperature range (maintained at a constant temperature range). In some embodiments, the "step of dissolving the compound represented by formula X until it becomes transparent" is performed under the condition of temperature T1, and the temperature T1 is any one selected from the group consisting of a temperature range of 45°C to 120°C, 50°C to 100°C, 50°C to 80°C, and 70°C to 80°C. In some examples, the solution is heated to 45°C to 120°C, and then maintained for a certain time to dissolve the compound represented by formula X until it becomes transparent. In some embodiments, the solution is heated to 50°C to 100°C. In some embodiments, the solution is heated to 50°C to 80°C. In some embodiments, the solution is heated to around 50°C (e.g., 50±5°C). In some embodiments, the solution is heated to 70°C to 80°C. In some embodiments, the temperature T1 is about any one of 48°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, and 80°C, and may be maintained at a constant temperature at the recited temperature or may vary within a range, for example, ±1°C, ±2°C, ±3°C, ±4°C, ±5°C, etc. In some preferred embodiments, the temperature T1 is a constant temperature condition.

[0148] In some embodiments, in step (b1), the solution is subjected to a crystallization treatment by lowering the temperature, volatilization, or addition of an anti-solvent.

[0149] In some embodiments, in the step (b1), the crystallization method is crystallization by temperature drop, that is, the crystallization method is performed by temperature drop. The temperature drop is based on the temperature T1 in the step (a1). In some embodiments, the solution is cooled to a temperature T2, and then maintained for a certain period of time to precipitate crystals. The temperature T2 may be a constant temperature condition (maintained at a constant temperature) or may be within a temperature range (maintained within a certain temperature range). In some embodiments, the temperature T2 is any one selected from the group consisting of -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, 0°C or lower, and 0°C to -5°C. In some embodiments, the temperature T2 is selected from any temperature within the temperature range of -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, 0°C or lower, 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 0°C, in some embodiments, the solution is cooled to 0°C to -5°C. In some embodiments, the temperature T2 is about any one of -5°C, -4°C, -2°C, 0°C, 5°C, 10°C, 15°C, 20°C, and 25°C, and may be maintained at a constant temperature at the mentioned temperature, or may vary within a certain range, for example, ±1°C, ±2°C, ±3°C, ±5°C, etc. In some preferred embodiments, the temperature T2 is a constant temperature condition.

[0150] In some embodiments, (Ia) the solvent is acetonitrile, isopropanol, ethanol, ethyl acetate, or a mixed solvent of 50% (v / v) ethanol / water, and the crystallization method is crystallization by cooling; (Ib) the solvent is a mixed solvent of 50% (v / v) ethanol / water, and the crystallization method is crystallization by evaporation; (Ic) the solvent is dimethylsulfoxide or N,N-dimethylacetamide, and the crystallization method is antisolvent crystallization; The free base crystalline form I is prepared by any of the methods described above.

[0151] In some embodiments, the compound of formula X is dissolved in acetonitrile, isopropanol, ethanol, ethyl acetate or 50% ethanol until it becomes transparent, and then crystallized by cooling to obtain the free base crystalline form I of the present invention.

[0152] In some embodiments, the method for preparing the free base crystalline Form I includes dissolving the compound of formula X in isopropanol, ethanol, ethyl acetate or a mixed solvent of 50% (v / v) ethanol / water at 50±5° C. until the solution becomes transparent, and then cooling the solution to 0° C. to 4° C. and maintaining the solution for a certain period of time to precipitate crystals. In some preferred embodiments, the solution is naturally cooled to room temperature and placed at 0° C. to 4° C. to precipitate a solid.

[0153] In some embodiments, the method for preparing the free base crystalline Form I includes dissolving the compound of formula X in ethanol at 75±5° C. until a clear solution is formed, and cooling the solution to room temperature to precipitate crystals.

[0154] In some embodiments, the method for preparing the free base crystalline Form I includes dissolving the compound of formula X in ethanol at 70±5° C. until the solution becomes clear, and cooling the solution to room temperature to precipitate crystals. In some preferred embodiments, the solution is cooled to room temperature by natural cooling.

[0155] In some embodiments, the method for preparing the free base crystalline Form I includes dissolving the compound of Formula X in acetonitrile at 75±5° C. until a clear solution is formed, and cooling the solution to room temperature to precipitate crystals. In some preferred embodiments, the solution is cooled to room temperature by natural cooling.

[0156] In some embodiments, the compound of formula X is dissolved in 50% ethanol until clear, and the free base crystalline Form I is obtained by crystallization using the method of crystallization by evaporation.

[0157] In some embodiments, the method for preparing the free base crystalline Form I includes dissolving the compound of formula X in a 50% (v / v) ethanol / water mixture until a clear solution is formed, and subjecting the solution to evaporative crystallization at room temperature. In some preferred embodiments, the solution is subject to evaporative crystallization by natural evaporation at room temperature.

[0158] In some embodiments, the method for preparing the free base crystalline Form I comprises dissolving the compound of formula X in dimethylsulfoxide or N,N-dimethylacetamide until a clear solution is formed, and adding n-heptane to the solution to precipitate crystals.

[0159] In some embodiments, the compound of formula X is dissolved in dimethylsulfoxide or N,N-dimethylacetamide until clear, and then crystallized by anti-solvent crystallization (or anti-solvent addition) to obtain the free base crystalline Form I. In some embodiments thereof, the anti-solvent used in the anti-solvent addition is n-heptane.

[0160] In some embodiments, the polymorph of the compound of formula X is the free base crystalline Form IV, and the crystallization is accomplished by evaporation or addition of an anti-solvent.

[0161] The free base crystalline form I obtained by the preparation method of the second embodiment preferably complies with any of the characterization methods herein, including, but not limited to, powder X-ray diffraction spectrum, a combination of characteristic peaks at diffraction angles 2θ (°) in the powder X-ray diffraction spectrum, a differential scanning calorimetry curve, an endothermic peak in the differential scanning calorimetry curve, and a TGA-DSC diagram.

[0162] In some embodiments, a method for preparing free base crystalline Form IV is provided, the method comprising: (a2) dissolving a compound of formula X in the presence of a solvent until a clear solution is formed; (b2) subjecting the solution to a crystallization treatment by evaporation or addition of an antisolvent; Includes.

[0163] In some embodiments, in step (a2), the solvent is selected from the group consisting of acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, and mixtures thereof, hi some embodiments, the solvent is selected from the group consisting of acetone, acetonitrile, ethanol, and mixtures thereof.

[0164] In some embodiments, the compound of formula X is dissolved in acetone until clear, and the crystallization process is carried out by a method of crystallization by evaporation (e.g., slow evaporation) to obtain the free base crystalline Form IV.

[0165] In some embodiments, the compound of formula X is dissolved in ethanol or acetonitrile until clear, and then subjected to a crystallization process by addition of an anti-solvent to obtain the free base crystalline form IV, in some of these embodiments, the anti-solvent used is n-heptane.

[0166] In some embodiments, in step (b2), the solution is subjected to a crystallization treatment by slow evaporation or addition of an anti-solvent.

[0167] In some embodiments, the polymorph of the compound of formula X is the free base crystalline form V, and the crystallization process is carried out by evaporation. In some embodiments, the crystallization process is carried out by slow evaporation.

[0168] In some embodiments, a method for preparing free base crystalline form V is provided, the method comprising: (a3) dissolving the compound of formula X in the presence of a solvent until a clear solution is formed; (b3) subjecting the solution to a crystallization treatment by evaporation; Includes.

[0169] In some embodiments, in step (a3), the solvent is ethanol.

[0170] In some embodiments, in the step (b3), the solution is subjected to a crystallization treatment by slowly evaporating it.

[0171] In some embodiments, the polymorph of the compound of formula X is the free base crystalline Form VI, and the crystallization process is performed by volatilization.

[0172] In some embodiments, a method for preparing crystalline Form VI is provided, the method comprising the steps of: (a4) dissolving the compound of formula X in the presence of a solvent until a clear solution is formed; (b4) subjecting the solution to a crystallization treatment by evaporation; Includes.

[0173] In some embodiments, in step (a4), the solvent is acetonitrile, tetrahydrofuran, dimethylsulfoxide, or N,N-dimethylacetamide.

[0174] In some embodiments, in the step (b4), the solution is subjected to a crystallization treatment by slowly evaporating it.

[0175] In some embodiments, the polymorph of the compound of formula X is the free base crystalline Form VII, and the crystallization is carried out by addition of an anti-solvent.

[0176] In some embodiments, a method for preparing free base crystalline Form VII is provided, the method comprising: (a5) dissolving the compound of formula X in the presence of a solvent until a clear solution is formed; (b5) subjecting the solution to a crystallization treatment by addition of an antisolvent; Includes.

[0177] In some embodiments, in step (a5), the solvent is methanol.

[0178] In some embodiments, in step (b5), the anti-solvent used in the addition of the anti-solvent is n-heptane.

[0179] In a second aspect of the present invention, (a′0) mixing the compound represented by formula X with an acid in a solvent to form a solution; (b'0) subjecting the solution to a crystallization treatment; The present invention further provides a process for preparing a polymorph of a pharma- ceutically acceptable salt of a compound of formula X, comprising:

[0180] The type of the acid is selected according to the type of pharma- ceutically acceptable salt and is used to form a salt with the compound of formula X.

[0181] The amount of acid controls the molar ratio of the compound of formula X to the acid component in the pharma- ceutically acceptable salt. Preferably, an excess of acid is used.

[0182] In some embodiments, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and hydrobromic acid.

[0183] In some embodiments, a monobasic acid is used and the molar ratio of monobasic acid to the compound of formula X is 1.2:1.

[0184] In some embodiments, a diacid is used and the molar ratio of diacid to the compound of formula X is 0.6:1.

[0185] In some embodiments, the polymorph of the pharma- ceutically acceptable salt of compound of formula X is the hydrochloride salt crystalline Form I, the acid is hydrochloric acid, and the crystallization is by lowering the temperature, volatilization, or addition of an anti-solvent.

[0186] In some embodiments, the polymorph of the pharma- ceutically acceptable salt of compound of formula X is the hydrochloride salt crystalline Form I, the acid is hydrochloric acid, and the crystallization is carried out by slow cooling, slow evaporation, or addition of an anti-solvent.

[0187] In some embodiments, a method for preparing the hydrochloride salt crystalline Form I is provided, the method comprising: (a6) mixing a compound of formula X and a dilute hydrochloric acid solution (e.g., 1 M aqueous hydrochloric acid) in the presence of a solvent to form a solution; (b6) subjecting the solution to a crystallization treatment by lowering the temperature, volatilization, or addition of an antisolvent; Includes.

[0188] In some embodiments, in step (a6), the solvent is selected from the group consisting of 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.

[0189] In some embodiments, in step (a6), the acid is 1 M hydrochloric acid.

[0190] In some embodiments, in step (a6), the acid is a 1 M aqueous hydrochloric acid solution.

[0191] In some embodiments, in step (b6), the solution is subjected to a crystallization treatment by slowly lowering the temperature, slowly volatilizing, or adding an anti-solvent.

[0192] In some embodiments, in step (b6), the crystallization process is carried out by addition of an anti-solvent, and the anti-solvent used is n-heptane.

[0193] In some embodiments, the polymorph of the pharma- ceutically acceptable salt of compound of formula X is the sulfate salt Form I, the acid is sulfuric acid, and the crystallization is carried out by lowering the temperature (preferably slowly lowering the temperature) or by adding an anti-solvent.

[0194] In some embodiments, a method for preparing crystalline Form I of the Sulfate Salt is provided, the method comprising: (a7) mixing a compound of formula X and a dilute sulfuric acid solution (e.g., 0.5 M aqueous sulfuric acid) in the presence of a solvent to form a solution; (b7) subjecting the solution to a crystallization treatment by lowering the temperature or adding an antisolvent; Includes.

[0195] In some embodiments, in step (a7), the solvent is selected from the group consisting of acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof. In some embodiments, the solvent is selected from the group consisting of ethanol, isopropanol, acetone, ethyl acetate, and mixtures thereof.

[0196] In some embodiments, in step (a7), the acid is 0.5 M sulfuric acid.

[0197] In some embodiments, in step (a7), the acid is 0.5 M aqueous sulfuric acid.

[0198] In some embodiments, in step (b7), the solution is subjected to a crystallization treatment by slowly lowering the temperature or adding an anti-solvent.

[0199] In some embodiments, in step (b7), the crystallization is carried out by addition of an anti-solvent, and the anti-solvent used is n-heptane.

[0200] In some embodiments, the polymorph of the pharma- ceutically acceptable salt of compound of formula X is the hydrobromide salt Form I, the acid is hydrobromic acid, and the crystallization is performed by decreasing the temperature (preferably slowly decreasing the temperature).

[0201] In some embodiments, a method for preparing crystalline Form I of the hydrobromide salt is provided, the method comprising: (a8) mixing a compound of formula X and hydrobromic acid in the presence of a solvent to form a solution; (b8) performing a crystallization treatment on the solution by slowly lowering the temperature; Includes.

[0202] In some embodiments, in step (a8), the solvent is selected from the group consisting of acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof. In some embodiments, the solvent is selected from the group consisting of ethanol, isopropanol, acetone, ethyl acetate, and mixtures thereof.

[0203] In some embodiments, in the step (b8), the solution is subjected to a crystallization treatment by slowly lowering the temperature.

[0204] In some embodiments, the method for preparing the polymorph further comprises the steps of preparing the compound of formula X: [ka]

[0205] The compound of formula X is produced by reacting compound 1-5 with compound V2 in an organic solvent.

[0206] Examples of such organic solvents include, but are not limited to, tetrahydrofuran (THF).

[0207] In some embodiments, the method for preparing the polymorph further comprises the steps of preparing compound 1-5: [ka]

[0208] Reaction of compound 1-3 with compound V1 produces compound 1-4, and removal of the TIPS produces compound 1-5, where the TIPS is a triisopropylsilyl group.

[0209] Those skilled in the art know how to remove TIPS, so we won't go into detail here.

[0210] In a third aspect of the present invention, there is provided a pharmaceutical composition, the pharmaceutical composition comprising: The compound of the present invention comprises (a) any polymorph of the first aspect of the present invention (a polymorph of the compound of formula X or a pharma- ceutically acceptable salt thereof) and (b) a pharma- ceutically acceptable carrier.

[0211] In a fourth aspect of the present invention, adenosine A 2A Mediated by adenosine A 2BReceptor-mediated or adenosine A 2A Adenosine A and its receptors 2B The present invention provides the use of a polymorph according to the first aspect of the invention (a polymorph of the compound of formula X or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition according to the third aspect of the invention, in the preparation of a medicament for the prevention and / or treatment of a disease mediated by both of these receptors.

[0212] In some embodiments, the compound of formula X is 2A / A 2B Used as a receptor antagonist.

[0213] In some embodiments, the disease is a tumor or an immune-related disease.

[0214] In some embodiments, the disease is a tumor. In the present invention, tumors include, but are not limited to, cancer.

[0215] In some embodiments, the disease is cancer.

[0216] 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 lining cancer, white blood cell cancer, 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, and may be selected from glioma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, basal cell carcinoma of the skin, and testicular seminoma.

[0217] In some embodiments, the disease is an immune-related disease.

[0218] In some embodiments, the immune-related disease is 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.

[0219] In a fifth aspect of the invention, adenosine A 2A Mediated by adenosine A 2B Receptor-mediated or adenosine A 2A Adenosine A and its receptors 2B The present invention provides a method for preventing and / or treating an associated disease mediated by both of these receptors, comprising administering to a patient in need thereof a therapeutically effective amount of a polymorph according to the first aspect of the invention (a polymorph of the compound of formula X or a polymorph of a pharma- ceutically acceptable salt of the compound of formula X), or a pharmaceutical composition according to the third aspect of the invention.

[0220] It should be understood that, within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described below (including but not limited to the examples) can be combined with each other in any suitable manner to form a new or preferred technical solution, as long as the present invention can be implemented. For the sake of space, no detailed description is required. The compound of formula X of the present invention has good relevant pharmacological activity.

[0221] In the tumor microenvironment, A 2A and A 2BThe two types of adenosine receptors are widely expressed in immune cells and have strong immunosuppressive functions. An increase in the extracellular adenosine concentration is one of the important mechanisms of immune escape of tumor cells, and its concentration level is determined jointly by the ATP level and the expression levels of CD39 and CD73. An increase in the extracellular adenosine concentration is associated with a large amount of ATP release due to cell death or hypoxia in the tumor microenvironment, and its concentration can reach 10-20 times that of normal tissues. Adenosine can bind to adenosine receptors in the tumor microenvironment and inhibit antitumor responses, such as inhibiting the function of CD8+ T cells, enhancing the function of regulatory T cells that suppress immune responses, and inhibiting the function of antigen-presenting cells by dendritic cells. Some studies have shown that binding to the A2A receptor may also inhibit the tumor-killing effect of natural killer cells. Further studies have shown that A2A adenosine receptor antagonists enhance the activity and killing ability of dendritic antigen-presenting cells, T cells, and natural killer cells, inhibit the function of regulatory T cells (T-reg), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAM), eliminate tumor immune tolerance, and promote the development of tumor immune responses, which in turn inhibits tumor growth and extends mouse survival. It has also been reported that A2B receptors promote tumor migration in mouse melanoma and triple-negative breast cancer models, so A2B receptor antagonists are also effective tumor therapeutic targets. Therefore, blocking the activation of the adenosine signal pathway to reduce or eliminate immune suppression and enhance the antitumor function of immune cells (especially T cells) is considered to be one of the effective means of tumor treatment.

[0222] The polymorphs of the compound of formula X and its pharma- ceutically acceptable salts of the present invention (i.e., the polymorphs of the compound of formula X and the polymorphs of the pharma- ceutically acceptable salts of the compound of formula X) have good stability and therefore have the potential to be further developed into drugs. [Brief description of the drawings]

[0223] [Figure 1]FIG. 1 is a powder X-ray diffraction (XRPD) spectrum of the free base crystalline form I in one embodiment of the present invention, using Cu-Kα radiation, the abscissa is the angle 2θ (°), the ordinate is the intensity, and the ordinate unit is the number of counts. [Diagram 2] FIG. 2 is a TGA-DSC (thermogravimetric analysis-differential scanning calorimetry) spectrum of the free base crystalline Form I in one embodiment of the present invention, where the abscissa is temperature (° C.), the left ordinate is weight change (%), and the right ordinate is heat flow (Normalized) Q (W / g). [Diagram 3] FIG. 3 is a dynamic moisture sorption (DVS) spectrum of the free base crystalline Form I in one embodiment of the present invention, where the abscissa is relative humidity (%) (Target RH (%)) and the ordinate is sample weight change (%) (Change In mass (%)-Ref). [Figure 4] FIG. 4 is an X-ray powder diffraction (XRPD) spectrum of the free base crystalline Form IV in one embodiment of the present invention, using Cu-Kα radiation, the abscissa is the angle 2θ (°), the ordinate is the intensity, and the ordinate unit is the number of counts. [Diagram 5] FIG. 5 is a differential scanning calorimetry (DSC) spectrum of the free base crystalline Form IV in one embodiment of the present invention, where the abscissa is temperature (° C.) and the ordinate is heat flow (Normalized) Q (W / g). [Figure 6] FIG. 6 is an X-ray powder diffraction (XRPD) spectrum of the free base crystalline form V in one embodiment of the present invention, using Cu-Kα radiation, the abscissa is the angle 2θ (°), the ordinate is the intensity, and the ordinate unit is the number of counts. [Figure 7] FIG. 7 is a differential scanning calorimetry (DSC) spectrum of the free base crystalline form V in one embodiment of the present invention, where the abscissa is temperature (° C.) and the ordinate is heat flow (Normalized) Q (W / g). [Figure 8]FIG. 8 is an X-ray powder diffraction (XRPD) spectrum of the free base crystalline Form VI in one embodiment of the present invention, using Cu-Kα radiation, the abscissa is the angle 2θ (°), the ordinate is the intensity, and the ordinate unit is the number of counts. [Figure 9] FIG. 9 is a differential scanning calorimetry (DSC) spectrum of the free base crystalline Form VI in one embodiment of the present invention, where the abscissa is temperature (° C.) and the ordinate is heat flow (Normalized) Q (W / g). [Figure 10] FIG. 10 is an X-ray powder diffraction (XRPD) spectrum of the free base crystalline Form VII in one embodiment of the present invention, using Cu-Kα radiation, the abscissa is the angle 2θ (°), the ordinate is the intensity, and the ordinate unit is the number of counts. [Figure 11] FIG. 11 is a differential scanning calorimetry (DSC) spectrum of the free base crystalline Form VII in one embodiment of the present invention, where the abscissa is temperature (° C.) and the ordinate is heat flow (Normalized) Q (W / g). [Figure 12] FIG. 12 is a comparison of XRPD spectra of free base crystalline Form I in one embodiment of the present invention under 40° C. / 75% RH conditions, where the abscissa is the angle 2θ (°), the ordinate is intensity, and the ordinate unit is the number of counts. [Figure 13] FIG. 13 is a powder X-ray diffraction (XRPD) spectrum of the hydrochloride crystalline form I in one embodiment of the present invention, using Cu-Kα radiation, the abscissa is the angle 2θ (°), the ordinate is the intensity, and the unit of the ordinate is the number of counts. [Figure 14] FIG. 14 is a differential scanning calorimetry (DSC) spectrum of the hydrochloride salt crystalline form I in one embodiment of the present invention, where the abscissa is temperature (° C.) and the ordinate is heat flow (Normalized) Q (W / g). [Figure 15]FIG. 15 is a powder X-ray diffraction (XRPD) spectrum of the Sulfate Crystal Form I in one embodiment of the present invention, using Cu-Kα radiation, the abscissa is the angle 2θ (°), the ordinate is the intensity, and the ordinate unit is the number of counts. [Figure 16] FIG. 16 is a differential scanning calorimetry (DSC) spectrum of the Sulfate Salt Crystal Form I in one embodiment of the present invention, where the abscissa is temperature (° C.) and the ordinate is heat flow (Normalized) Q (W / g). [Figure 17] FIG. 17 is a powder X-ray diffraction (XRPD) spectrum of the hydrobromide salt crystalline form I in one embodiment of the present invention, using Cu-Kα radiation, the abscissa is the angle 2θ (°), the ordinate is the intensity, and the ordinate unit is the number of counts. [Figure 18] FIG. 18 is a comparison of XRPD spectra of the hydrochloride crystalline form I in one embodiment of the present invention, measured at 60° C. and 40° C. / 75% RH, respectively. The abscissa is Two-Theta (2θ), the unit of the abscissa is angle (°), the ordinate is intensity, and the unit of the ordinate is counts. [Figure 19] FIG. 19 is a comparison of XRPD spectra of the sulfate salt crystalline form I in one embodiment of the present invention under conditions of 60° C. and 40° C. / 75% RH, where the abscissa is Two-Theta (2θ), the abscissa unit is angle (°), the ordinate is intensity, and the ordinate unit is counts, where “HY80****” is the sample number of the sulfate salt compound. [Figure 20] FIG. 20 is an infrared spectrum of the free base crystalline form I in one embodiment of the present invention, where the abscissa is wavenumber (cm −1 ) and the ordinate is transmittance. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0224] The present invention will be described in more detail below with reference to some figures, embodiments and examples. It should be understood that these embodiments and examples are for the purpose of illustrating the present invention, and are not intended to limit the scope of the present invention, and the purpose of providing these embodiments and examples is to allow the contents disclosed in the present invention to be fully and in detail understood. It should be further understood that the present invention can be realized in various forms and is not limited to the embodiments and examples described herein, and those skilled in the art can make various changes and modifications within the scope of the present application, and the obtained equivalent forms are also included in the protection scope of the present invention. It should also be understood that in the following description, a large amount of details are given to make the present invention more fully understandable, but the present invention can be practiced without one or more of these details.

[0225] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. In the present invention, the terms used herein are for the convenience of describing the embodiments and examples, and are not intended to limit the present invention.

[0226] term Unless otherwise stated or contradictory, terms or phrases used herein have the following meanings:

[0227] In the present invention, the selection scope of "and / or", "or / and", "and / or" includes any one of two or more related items, and also includes any and all combinations of related items, and the any and all combinations include any combination of two related items, any combination of more than two related items, or all combinations of related items. It should be understood that when at least three items are connected by a combination of at least two conjunctions selected from the group consisting of "and / or", "or / and", and "and / or", in the present invention, the technical solution obviously includes technical solutions all connected by "logical AND", and more obviously includes technical solutions all connected by "logical OR". For example, "A and / or B" includes three parallel technical solutions, A, B, and A+B. As another example, a technical proposal of "A, and / or, B, and / or, C, and / or D" includes any one of A, B, C, and D (i.e., technical proposals all connected by "logical OR"), includes any and all combinations of A, B, C, and D, i.e., includes any combination of two or three of A, B, C, and D, and includes four combinations of A, B, C, and D (i.e., technical proposals all connected by "logical AND").

[0228] As used herein, "combinations thereof," "any combination thereof," "any way of combining thereof," and the like, include all suitable ways of combining any two or more of the listed items.

[0229] In the present invention, the term "appropriate" in the phrases "appropriate combining method", "appropriate method", "any appropriate method", etc., refers to the ability to implement the technical solution of the present invention, solve the technical problems of the present invention, and achieve the technical effects expected of the present invention.

[0230] It should be understood that in the present invention, the terms "preferable", "better", "superior" and "suitable" are used only to describe embodiments or examples having better effects, and are not intended to limit the scope of protection of the present invention.

[0231] In the present invention, "optionally", "optional", and "optional" refer to something that may or may not be present, that is, to one of two parallel technical solutions, "present" and "absent". Unless otherwise specified and unless there is a contradictory or mutually restrictive relationship, when there are multiple "options" in one technical solution, each "option" is independent of each other.

[0232] In the present invention, the terms "first", "second", "third", "fourth", etc. in "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are for descriptive purposes only and cannot be understood to indicate or imply relative importance or quantity, and cannot be understood to imply the importance or quantity of the technical features indicated. And it should be understood that "first", "second", "third", "fourth", etc. are for non-exhaustive enumeration and descriptive purposes only, and do not constitute closed-form limitations on the quantities.

[0233] In the present invention, technical features described in an open form include closed technical solutions consisting of the recited features, and open technical solutions including the recited features.

[0234] In the present invention, unless otherwise specified, for a numerical interval (i.e., a numerical range), the distribution of selectable numerical values ​​is considered to be continuous within the numerical interval, and includes the two numerical endpoints (i.e., the minimum and maximum values) of the numerical range, and all values ​​between the two numerical endpoints. Unless otherwise specified, when a numerical interval refers only to integers within the numerical interval, the integers at the two endpoints of the numerical range and each integer between the two endpoints are included. In addition, when multiple ranges are provided to describe a function or characteristic, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any subranges contained therein.

[0235] In the present invention, unless otherwise specified, when "M", "nM", "μM" and "mM" indicate concentrations, they correspond to mol / L, nmol / L, μmol / L and mmol / L, respectively.

[0236] In the present invention, "have" is an open-ended statement: for example, "having peaks at particular positions in the spectrum" means having peaks at those positions in the spectrum and does not exclude the presence of peaks at other positions in the spectrum.

[0237] After extensive and detailed research, the inventors have discovered a compound represented by formula X, which is adenosine A 2A Receptor, Adenosine A 2B It has been found that the compound represented by formula X has high inhibitory activity against either one of the two receptors, or against both of the two receptors. Based on this, through further research, it has been unexpectedly found that a series of polymorphs of the compound represented by formula X and its pharma- ceutical acceptable salts are not only more stable, but also have better in vivo and in vitro related pharmacological activities, and therefore have the prospect of being further developed into drugs.

[0238] Compounds of the Invention In the present invention, the compound represented by formula X is 3-(4-amino-5-fluoro-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-2-yl)-2-methylbenzonitrile, and has the structure represented by formula (X).

[0239] [ka]

[0240] The compound represented by formula X is a pyrimidine derivative from the viewpoint of structure. 2A / A 2B A dual receptor antagonist 2A and A2B It can simultaneously block the activation of two types of receptors, adenosine A 2A Receptor, Adenosine A 2B It has high inhibitory activity against the adenosine receptor or the two receptors. Mechanistically speaking, it can regulate various immune cell populations, comprehensively block the immunosuppressive effect of adenosine in the microenvironment, and has extensive clinical application value in tumor therapy, and can be used to treat tumor-related diseases, immune-related diseases, or tumor-immune-related diseases.

[0241] In the present invention, "A 2A / A 2B Receptor antagonists" are 2A It is also a receptor antagonist, A 2B It is also a receptor antagonist, A 2A Blocks receptor activation and A 2B Receptor activation can be blocked.

[0242] The present invention further includes polymorphs of the compound of formula X and its pharma- ceutically acceptable salts, where the pharma- ceutically acceptable salts are not particularly limited and are preferably selected from hydrochloride, sulfate, and hydrobromide salts.

[0243] In the present invention, polymorphs include, but are not limited to, polymorphs of the free base and polymorphs of pharma- ceutically acceptable salts.

[0244] In the present invention, unless otherwise specified, the polymorph of the compound represented by formula X refers to a polymorph of the free base of the compound represented by formula X, including, but not limited to, free base crystalline form I, free base crystalline form IV, free base crystalline form V, free base crystalline form VI and free base crystalline form VII in the present invention.

[0245] In the present invention, polymorphs of the compound of formula X and its pharma- ceutically acceptable salts include, but are not limited to, free base crystalline Form I, free base crystalline Form IV, free base crystalline Form V, free base crystalline Form VI, free base crystalline Form VII, hydrochloride crystalline Form I, sulfate crystalline Form I, and hydrobromide crystalline Form I of the compound of formula X.

[0246] In the present invention, the I-type crystal of the compound represented by formula X and the free base crystalline form I of the compound represented by formula X have the same meaning and can be used interchangeably. Unless otherwise specified, the free base crystalline form I in the present invention refers to the crystalline form I of the compound represented by formula X.

[0247] In the present invention, the IV type crystal of the compound represented by formula X and the free base crystalline form IV of the compound represented by formula X have the same meaning and can be used interchangeably. Unless otherwise specified, the free base crystalline form IV in the present invention refers to the crystalline form IV of the compound represented by formula X.

[0248] In the present invention, the V-type crystal of the compound represented by formula X and the free base crystalline form V of the compound represented by formula X have the same meaning and can be used interchangeably. Unless otherwise specified, the free base crystalline form V in the present invention refers to the crystalline form V of the compound represented by formula X.

[0249] In the present invention, the VI type crystal of the compound represented by formula X and the free base crystalline form VI of the compound represented by formula X have the same meaning and can be used interchangeably. Unless otherwise specified, the free base crystalline form VI in the present invention refers to the crystalline form VI of the compound represented by formula X.

[0250] In the present invention, the VII type crystal of the compound represented by formula X and the free base crystalline form VII of the compound represented by formula X have the same meaning and can be used interchangeably. Unless otherwise specified, the free base crystalline form VII in the present invention refers to the crystalline form VII of the compound represented by formula X.

[0251] In the present invention, the I-type crystal of the hydrochloride of the compound represented by formula X and the hydrochloride crystal form I of the compound represented by formula X have the same meaning and can be used interchangeably. Unless otherwise specified, the hydrochloride crystal form I in the present invention refers to the hydrochloride crystal form I of the compound represented by formula X.

[0252] In the present invention, the I-type crystal of the sulfate of the compound represented by formula X and the sulfate crystal form I of the compound represented by formula X have the same meaning and can be used interchangeably. Unless otherwise specified, the sulfate crystal form I in the present invention refers to the sulfate crystal form I of the compound represented by formula X.

[0253] In the present invention, the hydrobromide form I crystal of the compound represented by formula X and the hydrobromide form I crystal of the compound represented by formula X have the same meaning and can be used interchangeably. Unless otherwise specified, the hydrobromide form I crystal of the compound represented by formula X in the present invention refers to the hydrobromide form I crystal of the compound represented by formula X.

[0254] As used herein, a "drug" includes any agent, compound, composition, or mixture that produces a physiological effect, a pharmacological effect, or a physiological and pharmacological effect in vivo or in vitro, and usually produces a beneficial effect. The extent to which the "drug" finds its physiological effect, pharmacological effect, or a physiological and pharmacological effect in vivo is not particularly limited, and it may have a systemic effect or a local effect. The activity of the "drug" is not particularly limited, and it may be an active substance that interacts with other substances, or an inactive substance that does not interact with other substances.

[0255] As used herein, a "therapeutically effective amount" refers to an amount of a compound of the invention that elicits a biological or medical response in an individual, e.g., an amount that provides a positive physiological, pharmacological, or physiological and pharmacological effect to an individual, including, but not limited to, reducing or inhibiting an enzyme or protein activity, ameliorating symptoms, alleviating a disease symptom, slowing or retarding the progression of a disease, or preventing a disease.

[0256] As used herein, "pharmaceutical acceptable" refers to something that is suitable for administration to a patient, within the scope of sound medical judgment, and consistent with a reasonable benefit / risk ratio, and is applicable to a pharmaceutical ligand, material, composition or dosage form.

[0257] As used herein, a "pharmaceutically acceptable carrier" should be non-toxic and inert in principle. The form of the "pharmaceutically acceptable carrier" is not particularly limited, and includes, but is not limited to, solid, semi-solid, liquid, etc. The pharmaceutically acceptable carrier must be compatible with the patient, and the patient is preferably a mammal, more preferably a human. One of the functions of the pharmaceutically acceptable carrier is that it is suitable for delivering the active agent to the intended target without terminating the activity of the active agent. As used herein, the term "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., that are compatible with drug administration. Each carrier must be "pharmaceutically acceptable" in terms of being compatible with other ingredients of the formulation and harmless to the patient.

[0258] As used herein, "pharmaceutically acceptable salt" refers to a salt formed with an acid or base with any compound of the structure shown, suitable for use as a drug. In this specification, it primarily refers to a salt formed with an acid with a compound of formula X, suitable for use as a drug.

[0259] As used herein, a "patient" is an animal, preferably a mammal, and more preferably a human. The term "mammal" refers primarily to warm-blooded vertebrate animals, including, but not limited to, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, cows, sheep, horses, and humans.

[0260] In the present invention, there is no particular limitation on the method of administration of the compound, polymorph, pharmaceutical composition, or drug, etc. Representative administration methods include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous) injection, and local administration.

[0261] As used herein, "treatment" refers to alleviating, slowing the progression of, reducing, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment further includes curing, preventing the progression of, or alleviating to some extent one or more symptoms of the disease or condition.

[0262] In the present invention, "prevention and / or treatment" refers to prevention, treatment, or prevention and treatment. Here, "prevention and treatment" refers to having the effects of prevention and treatment at the same time.

[0263] In the present invention, "using Cu-Kα radiation" means that the corresponding spectrum is detected by Kα radiation of a Cu target, and when measured by other methods, each diffraction peak may have deviations within the range accepted in the art, and should not be understood as a limitation of the present invention.

[0264] polymorph Solids exist in amorphous, crystalline, or semi-crystalline forms. Low molecular weight (preferably with a molecular weight of 1000 Da or less) organic compounds exist primarily in amorphous or crystalline forms. In crystalline forms, the molecules are arranged in three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements (a property known as "polymorphism") to form crystals of different crystalline forms, which are called "polymorphs." Different polymorphs of a given substance may differ from each other in one or more physical properties (e.g., one or more of solubility, dissolution rate, true specific gravity, crystal shape, packing pattern, flowability, and solid-state stability).

[0265] crystal Production-scale crystallization can be achieved by manipulating the solution to exceed the solubility limit of the compound of interest. This can be achieved, for example, by dissolving the compound at a relatively high temperature and then cooling the solution below the saturation limit, by boiling, evaporating at atmospheric pressure, vacuum drying, or otherwise reducing the volume of the liquid, or by reducing the solubility of the compound of interest by adding an antisolvent, an antisolvent in which the compound is less soluble, or a mixture of such antisolvents or antisolvents. Another option is to adjust the pH to reduce the solubility. For a detailed description of crystallization, see Crystallization, Third Edition, JW Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

[0266] Identification and characterization of crystal forms In the present invention, crystalline forms of the compound of formula X have been prepared and their properties have been further investigated by several methods and apparatus, including but not limited to the following:

[0267] X-ray Powder Diffraction (XRPD) Methods for measuring X-ray powder diffraction of crystalline forms are known in the art. XRPD can measure information such as changes in crystalline form, crystallinity, and crystalline structure state, and is a common method for identifying crystalline forms. The peak positions in the XRPD spectrum mainly depend on the structure of the crystalline form. Measurement of 2θ (Two-Theta) in the XRPD spectrum may vary slightly between different instruments, so the 2θ values ​​of characteristic peaks in the XRPD spectrum are not considered absolute. Depending on the conditions of the instrument used in the test of the present invention, the diffraction peaks are allowed to have some error (e.g., ±0.2°). As can be understood, when the measurement instruments and measurement conditions are different, the error range is not absolute. The crystalline form of the compound represented by formula X of the present invention has a specific crystalline form and has a specific characteristic peak in the XRPD spectrum.

[0268] Differential Scanning Calorimetry (DSC) Also called "differential calorimetric scanning analysis", it is a technique for measuring the relationship between the energy difference between a measured substance and a reference substance during the heating process and the temperature. The position, shape and number of peaks in a DSC spectrum are related to the properties of the substance, and can therefore be used to qualitatively identify the substance. In the art, this method is commonly used to detect various parameters such as the phase transition temperature, glass transition temperature and heat of reaction of a substance. The position of the peak in a DSC spectrum may be slightly different between different instruments, so the value of the peak position of the DSC endothermic peak in a DSC spectrum is not considered absolute. Depending on the conditions of the instrument used in the test of the present invention, the numerical value of the experimental error or difference is also not absolute, and the numerical value may be 5°C or less, 4°C or less, 3°C or less, 2°C or less, or 1°C or less.

[0269] Thermogravimetric analysis (TGA) TGA is a technique that measures the mass change of a substance according to temperature by program control, and is suitable for confirming the reduction of the solvent in the crystal or the process of sublimation and decomposition of the sample, and can estimate the state of the crystal water or the solvent contained in the crystal. The mass change shown in the TGA curve depends on many factors such as the preparation of the sample and the instrument, and the mass change measured by TGA is slightly different between different instruments. Depending on the conditions of the instrument used in the test of the present invention, the error of the mass change is not absolute, and a certain degree of error (e.g., ±0.1%) is allowed.

[0270] Regarding "the powder X-ray diffraction spectrum has a peak at a specific diffraction angle 2θ (°)" described in the present invention, the peak refers to a diffraction peak, and the above description means that the peak value of the peak is within the indicated numerical range, at the indicated numerical point, near the indicated numerical range, or near the indicated numerical point. Due to differences in measurement factors such as the measurement device and measurement conditions, the position of a certain peak or the position of some peak values ​​in the actually obtained powder X-ray diffraction spectrum may be slightly different, that is, it may be slightly different from the characteristic peak combination or powder X-ray diffraction spectrum shown in the present invention. However, as can be understood, a person skilled in the art can confirm whether a characteristic peak combination or powder X-ray diffraction spectrum with slight differences as a whole substantially corresponds to the crystalline form described in the present invention. Therefore, those that are confirmed to substantially correspond to the crystalline form of the present invention should be recognized as being within the protection scope of the present invention. For example, "the powder X-ray diffraction spectrum has a peak at a diffraction angle of 16.63°±0.2°" indicates that the peak value of the peak may be within the range of 16.63°±0.2° and in the vicinity of the range as long as it does not interfere with the identification of the crystalline form as a whole. Moreover, "±0.2°" here simply represents an error in the diffraction angle position of the peak value, and is unrelated to other elements such as the peak shape and peak width of the peak.

[0271] In the present invention, the term "essentially" in "the powder X-ray diffraction spectrum is essentially as shown in a particular drawing" should be understood in the same manner, and as long as it can be determined that a certain powder X-ray diffraction spectrum substantially coincides with the powder X-ray diffraction spectrum described in the present invention, it should be determined that the certain powder X-ray diffraction spectrum is within the scope of protection of the present invention.

[0272] As can be understood, the differential scanning calorimetry (DSC) curves and the positions of endothermic peaks shown therein in the present invention should be understood similarly, and slight differences between certain numerical values ​​or certain numerical ranges or certain spectra disclosed in the present invention are allowed, and as long as it can be determined that the positions of some or all of the endothermic peaks in the differential scanning calorimetry curves or the entire curve are substantially in accordance with the present invention, it should be determined that they are within the protection scope of the present invention.

[0273] As can be appreciated, spectra characterizing other crystalline forms (eg, infrared spectra) should be understood similarly.

[0274] "Dissolving until clear" according to the present invention refers to completely dissolving the compound of formula X or a pharma- ceutically acceptable salt thereof using a solvent.

[0275] "In the presence of a solvent" according to the present invention means that the system in which the compound or its salt is dissolved until it becomes transparent contains a solvent, and furthermore, the presence of non-solvent soluble components, insoluble components, or soluble and insoluble components is allowed. "In the presence of a solvent" according to the present invention includes at least the technical solution "in a solvent". And, the description "in a solvent" is also an open form description, includes a closed form in which the compound or its salt is dissolved until it becomes transparent using only a "solvent", and includes the open form in which a dissolution aid component is further present in the "solvent".

[0276] The "cooling down" described in the present invention refers to a method in which the compound represented by formula X or a pharma- ceutical acceptable salt thereof is dissolved in a solvent at a relatively high temperature until it becomes transparent, and then cooled at a certain temperature to obtain crystals.

[0277] The "volatilization" according to the present invention refers to a method in which a solution containing the compound represented by formula X or a pharma- ceutical acceptable salt thereof is placed at a certain temperature to volatilize the solvent and obtain crystals.

[0278] The "addition of an anti-solvent" according to the present invention refers to a method of adding another suitable solvent to a solution containing the compound of formula X or a pharma- ceutically acceptable salt thereof to precipitate crystals. The suitable solvent may be an anti-solvent, an anti-solvent, or a combination thereof. In some embodiments, an anti-solvent is preferred.

[0279] When it is desired that salt formation occur concomitant with crystallization, the addition of an appropriate acid or base can result in the direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting materials. Similarly, completion of a synthetic reaction can result in the direct crystallization of the final product if the final desired form is less soluble than the reactants.

[0280] Crystallization optimization involves seeding the crystallization medium with crystals of the desired morphology. However, many crystallization methods can use a combination of the above measures. One example is dissolving the compound of interest in a solvent at high temperature, then adding an appropriate volume of antisolvent in a controlled manner to bring the system just to the saturation level. Now, seed crystals of the desired morphology are introduced (preserving the integrity of the seed crystals), and the system is cooled to complete the crystallization.

[0281] As used herein, the term "room temperature" generally refers to 4° C. to 30° C., and may also refer to 20° C.±5° C. In some embodiments of the present invention, room temperature refers to 20° C. to 30° C.

[0282] Unless otherwise specified, the temperature parameters in the present invention may be constant temperature processes or may be allowed to vary within a certain temperature range. It should be understood that the constant temperature processes allow the temperature to vary within the range of accuracy controlled by the device.

[0283] In the present invention, it is acceptable to use "mixtures thereof" to refer to mixtures of two or more of the listed substances. For example, "the solvent is selected from the group consisting of acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, 50% (v / v) ethanol / water mixed solvent, dimethylsulfoxide, N,N-dimethylacetamide, tetrahydrofuran, and mixtures thereof" refers to the mixed solvents of the listed solvents formed by any suitable method, and the formed mixture must still be usable as a solvent, and as can be understood, only the mixed solvents that can be realized.

[0284] In the present invention, "% (v / v)" means volume percentage. For example, "50% (v / v) ethanol / water mixed solvent" means a mixture of ethanol and water in a volume ratio of 1:1.

[0285] In the present invention, unless otherwise specified, 50% ethanol refers to a mixed solvent formed by absolute ethanol and water in a volume ratio of 1:1, and may be abbreviated as 50% (v / v) ethanol / water mixed solvent.

[0286] Polymorphic Identification and Characterization In the present invention, polymorphs of the compound of formula X were prepared and then their properties were investigated by several methods and apparatus, including but not limited to the following:

[0287] Powder X-ray diffraction The polymorphs of the pharma- ceutically acceptable salts of the compound of formula X of the present invention have specific crystalline forms and have specific characteristic peaks in the X-ray powder diffraction spectrum (XPRD). In one embodiment, in some examples of the present invention, the XPRD spectrum was collected on an Equinox3000S / N X-ray powder diffraction analyzer, and the XPRD parameters are shown in Table 9.

[0288] [Table 9]

[0289] 2Theta is 2θ, " o " may be used as the unit of measurement, and the unit may be expressed as "deg".

[0290] In the powder X-ray diffraction spectrum, the peak positions are 2θ( o ) is determined. As can be understood, different instruments, different conditions, or different instruments and conditions may cause the data obtained to be slightly different, and the position and relative intensity of each peak may change. Those skilled in the art should understand that when determining a crystal form by XRPD spectrum, factors such as the peak at low diffraction angles and its intensity, the completeness of the peak shape, etc., are relatively important for reference. In the present invention, as a result of further research, the applicant has found that when measuring XRPD spectrum with the above-mentioned instrument, a strong background peak due to a blank metal pan may appear near two points where the 2θ(°) values ​​at high diffraction angles are 37.4° and 43.6°. For example, in FIG. 4, the peak near 37° is presumed to be due to a blank metal pan (e.g., the 37.76° peak in Table 2), in FIG. 6, the peak near 37° and the peak near 43° are presumed to be due to a blank metal pan (e.g., the 37.43° and 43.60° peaks in Table 3), in FIG. 8, the peak near 37° is presumed to be due to a blank metal pan (e.g., the 37.42° peak in Table 4), and in FIG. 10, the peak near 37° and the peak near 43° are presumed to be due to a blank metal pan (e.g., the 37.40° and 43.55° peaks in Table 5). The peak intensity classification reflects only the approximate magnitude of the peak at each position. In the present invention, when analyzing the diffraction peaks of each crystalline form, the diffraction peak having the highest peak height in the XRPD spectrum obtained by the above-mentioned method is defined as the base peak, and its relative intensity is defined as 100%, and I0 (for example, in some embodiments of the present invention, 2θ( o The peak with a 2θ( oThe peak with a 2θ( o The peak with a 2θ( o The peak with a 2θ( o The peak with a 2θ( o The peak with a 2θ( o The peak with a 2θ( o The peak with a value of 23.51 is defined as the base peak, and the ratio of the peak height to the base peak height of each of the other peaks is defined as the relative intensity I / I0. In the present invention, the definition of the relative intensity range of each peak is shown in Table 10.

[0291] [Table 10]

[0292] Differential Scanning Calorimetry (DSC) In one embodiment, in some examples of the present invention, DSC spectra were collected on a DISCOVERY DSC25 Differential Scanning Calorimeter, and the measurement parameters are shown in Table 11.

[0293] [Table 11]

[0294] Thermogravimetric analysis (TGA) In one embodiment, in some examples of the present invention, TGA spectra were collected on a DISCOVERY TGA550 Thermogravimetric Analyzer, and the measurement parameters are shown in Table 12.

[0295] [Table 12]

[0296] Infrared spectrum (IR) analysis Measurements are carried out using an Agilent Cary 630 FTIR infrared spectrophotometer using the solid potassium bromide (KBr) pellet method.

[0297] As can be understood, when using other types of equipment with the same functionality as the above-mentioned equipment, or when using measurement conditions different from those of the present invention, different values ​​may be obtained, so the quoted values ​​should not be considered as absolute values.

[0298] As one skilled in the art can appreciate, there may be slight differences in the parameters used to characterize the physical properties of crystals due to instrumental error or operator differences, and the above parameters are used only to aid in characterizing the polymorphs provided in the present invention and should not be considered as limitations on the polymorphs of the present invention.

[0299] Some further examples are provided below.

[0300] The present invention will be further described below with reference to some examples.It should be understood that these examples are used to describe the present invention and do not limit the scope of the present invention.For the experimental method that does not specify detailed conditions in the following examples, the guidelines described in this specification take precedence, but can also follow the experimental manual in the field, conventional conditions, can refer to other experimental methods known in the field, or can follow the conditions recommended by the manufacturer.

[0301] Unless otherwise stated, the percentage contents according to the present invention refer to volume percentages for gas-gas mixtures, mass percentages (wt%) for solid-solid mixtures, volume percentages (v / v) for liquid-liquid mixtures, mass percentages (wt%) or solid-liquid percentages (w / v) for solid-liquid mixtures.

[0302] In the following examples, 50% ethanol refers to a mixed solvent of 50% (v / v) ethanol / water.

[0303] Reagents and equipment In the present invention, the structure and purity of the compound can be confirmed by nuclear magnetic resonance ( 1 1 H NMR) and / or liquid chromatography / mass spectrometry (LC-MS). 1 H NMR: Bruker AVANCE-400 nuclear magnetic resonance instrument, internal standard was tetramethylsilane (TMS). LC-MS: Agilent 1200 HPLC System / 6140 MS liquid chromatography / mass spectrometry instrument (manufacturer: Agilent Technologies), column: Waters X-Bridge, 150 mm × 4.6 mm, 3.5 μm.

[0304] The XPRD measurement uses the parameters shown in Table 9.

[0305] The DSC measurements use the parameters shown in Table 11.

[0306] In the present invention, known starting materials can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemical.

[0307] As used herein, DCM refers to dichloromethane, DMF refers to dimethylformamide, DMSO refers to dimethylsulfoxide, THF refers to tetrahydrofuran, EA refers to ethyl acetate, PE refers to petroleum ether, Et3N refers to triethylamine, NHF refers to ammonium fluoride, t-BuOH refers to tert-butyl alcohol, Pd(dppf)Cl2 refers to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), CuI refers to cuprous iodide, Pd(PPh3)2Cl2 refers to bis(triphenylphosphine)palladium(II) dichloride, DPPA refers to diphenylphosphoryl azide, and DBU refers to 1,8-diazabicycloundec-7-ene.

[0308] As used herein, Captisol refers to sulfobutyl ether-β-cyclodextrin.

[0309] In the following examples, the hydrochloric acid solution, the sulfuric acid solution and the hydrobromic acid solution all refer to aqueous solutions.

[0310] Preparation of intermediate V1 [ka]

[0311] 2-Methyl-3-bromobenzonitrile (15 g), bis(pinacolato)diboron (23.32 g), potassium acetate (15.02 g) and Pd(dppf)Cl2 (2.80 g) were dissolved in a mixture of DMSO (20 mL) and dioxane (100 mL) and stirred at 100 °C for 3.5 h under nitrogen gas protection. After complete reaction, the solvent was evaporated to dryness under reduced pressure to obtain a solid product, which was separated by column chromatography (EA:PE = 15% ~ 40%, volume ratio) to obtain compound V1 (21.05 g). MS (ESI): 244.1 [M + H] + .

[0312] Preparation of intermediate V2 [ka]

[0313] Step 1: 6-(hydroxymethyl)methylpicolinate (50 g) was dissolved in THF (800 mL) and added dropwise to methylmagnesium bromide (3.0 M, 398.82 mL) under argon gas protection, the temperature was controlled at 0°C to 15°C, a large amount of gas was generated, and the mixture was stirred at room temperature overnight. The reaction solution was slowly poured into solid ice, and then saturated ammonium chloride solution was added, extracted with DCM (300 mL x 10), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by silica gel column (EA:PE = 0% to 100%, volume ratio) to obtain colorless oily 2-(6-(hydroxymethyl)pyridin-2-yl)propan-2-ol (30 g). MS (ESI): 168.1 [M + H] + .

[0314] Step 2: Compound 2-(6-(hydroxymethyl)pyridin-2-yl)propan-2-ol (30 g) was dissolved in DCM (100 mL), and DPPA (54.31 g) was added while stirring at room temperature under argon gas protection, and DBU (40.17 mL) was slowly added dropwise under ice bath conditions, and after the addition was completed, the temperature was raised to 50 ° C and stirred overnight. The above reaction solution was added to 100 mL of water, dried with DCM (200 mL × 2) and anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by silica gel column separation (EA:PE = 0% ~ 30%, volume ratio) to obtain compound V2 (30 g). MS (ESI): 193 [M + H] + .

[0315] Example 1. Preparation of a compound represented by formula X (i.e., compound X) [ka]

[0316] Step 1: Compound 1-1 (2,4,6-trichloro-5-fluoropyrimidine, 40 g), triisopropylsilylacetylene (38.03 g) were dissolved in THF (400 mL), cooled to 0° C. under argon gas protection, CuI (3.78 g) and Pd(PPh3)2Cl2 (6.97 g) were added in this order, and Et3N (60.17 g, 595.79 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred at 0° C. for 2 hours, warmed to room temperature, stirred for 6 hours, and cooled to 0° C., NH3 / H2O (aqueous ammonia solution, 120 g, concentration 80%) was added dropwise, and stirred at room temperature overnight. The reaction was detected to be complete by LC-MS, and compound 1-2 was obtained. MS (ESI): 347 [M+H] + .

[0317] Step 2: Add a large amount of water to the reaction solution finally obtained in step 1, extract with DCM (200mL x 3), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. A large amount of solid precipitates. Add 60mL of petroleum ether while stirring, filter, and obtain compound 1-3 (31g). The remaining mother liquor is separated and purified with a silica gel column (DCM:PE = 30% to 80%, volume ratio) to obtain compound 1-3 (43g). MS (ESI): 328.1 [M + H] + .

[0318] Step 3: Compound 1-3 (41 g) and compound V1 (42.56 g) were dissolved in a mixed solvent of dioxane (400 mL) and water (60 mL), and under argon gas protection, Na2CO3 (26.51 g) and Pd(dppf)2Cl (4.57 g) were added in this order while stirring at room temperature, and the temperature was raised 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 to dryness under reduced pressure, and separated and purified with a silica gel column to obtain compound 1-4 (44 g). MS (ESI): 409.2 [M + H] + .

[0319] Step 4: Compound 1-4 (44 g) was added to methanol (400 mL), and while stirring at room temperature, NHF (47.60 g) was added, and the mixture was heated to 70° C. under argon gas protection and stirred for 8 hours. A large amount of water was added to the reaction solution while stirring, and a large amount of solid precipitated. The solid was filtered to obtain brown compound 1-5 (27 g). MS (ESI): 253.1 [M+H] + .

[0320] Step 5: Compound 1-5 (27 g) and intermediate V2 (22 g) were dissolved in a mixed solvent of THF (200 mL) and t-BuOH (200 mL), and stirred at room temperature under argon gas protection. An aqueous solution of Cu2SO4·5H2O (2.87 g) (200 mL water) and sodium ascorbate (4.56 g) were added in that order, and the mixture was heated to 60°C and stirred for 24 hours. The reaction solution was poured into water, saturated sodium carbonate was added, and the mixture was extracted with DCM (300 mL x 3), dried over anhydrous sodium sulfate, and purified by silica gel column separation (DCM (containing 2% triethylamine): EA = 0-10%, volume ratio) to obtain 30 g of compound X. 1 H 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 subjected to XRPD measurement, and since there was no characteristic peak in the powder X-ray diffraction spectrum, the compound X obtained in this example was in an amorphous form.

[0321] Example 2. Preparation of free base crystalline form I 2.1.Method 1 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, and the mixture was heated to dissolve until it became transparent under conditions of about 50°C. The glass vial was taken out, cooled to room temperature, cooled to room temperature, and then placed in a refrigerator and cooled to 0°C to 4°C. After a solid precipitated, the mixture was centrifuged, the supernatant was discarded, and the solid was dried in an oven and subjected to XPRD measurement. The XPRD spectrum of the obtained solid product is shown in Figure 1, and in this invention, it is defined as free base crystalline form I. The DSC spectrum of free base crystalline form I is shown in Figure 2, in which the endothermic peak was 190.36°C. The DVS spectrum of free base crystalline form I is shown in Figure 3, in which the weight change due to adsorption during the change process of 25°C and relative humidity 0% to 80%RH was less than 0.2%, and the free base crystalline form I had almost no hygroscopicity.

[0322] 2.2.Method 2 Approximately 30 g of compound X (amorphous) was weighed into a glass vial, 150 mL of acetonitrile or ethanol was added, and the mixture was heated to reflux. The temperature was lowered to room temperature, and a solid precipitated. The solid was filtered to obtain a solid product. The solid was subjected to XPRD measurement, and free base crystalline form I was obtained.

[0323] 2.3.Method 3 Approximately 20 mg of compound X (amorphous) was weighed into a glass vial, and an appropriate amount of 50% ethanol was added to dissolve the compound until it became transparent. The solution was then placed at room temperature and slowly evaporated. The solid obtained by the evaporation was subjected to XPRD measurement, and free base crystalline form I was obtained.

[0324] 2.4.Method 4 20 mg of compound X (amorphous) was weighed into a glass vial, dissolved in dimethyl sulfoxide or N,N-dimethylacetamide until transparent, and the solution was added with n-heptane as an antisolvent to precipitate solid particles. The solid was subjected to XPRD measurement, and free base crystalline form I was identified.

[0325] Example 3. Preparation of Free Base Crystalline Form IV 3.1.Method 1 20 mg of compound X (amorphous) was weighed into a glass vial, and an appropriate amount of acetone was added to dissolve until it became transparent. The solution was placed at room temperature and slowly evaporated to obtain a solid. The XPRD spectrum of the obtained solid product is shown in FIG. 4, which is defined as free base crystalline form IV in the present invention. The differential scanning calorimetry spectrum of free base crystalline form IV is shown in FIG. 5, and free base crystalline form IV has an exothermic peak at 156.16°C and an endothermic peak at 189.64°C (the position of the endothermic peak is similar to that of free base crystalline form I), which indicates that free base crystalline form IV is a metastable crystalline form and may change to free base crystalline form I during the process of heating.

[0326] 3.2.Method 2 20 mg of compound X (amorphous) was weighed into a glass vial, and dissolved in an appropriate amount of ethanol or acetonitrile until it became transparent. After dissolution, an antisolvent, n-heptane, was added, and solid particles were precipitated. The solid obtained was subjected to XPRD measurement, and was found to be free base crystalline form IV.

[0327] Example 4. Preparation of Free Base Crystalline Form V About 20 mg of compound X (amorphous) was weighed into a glass vial, and an appropriate amount of ethanol was added to dissolve until it became transparent. The solution was placed at room temperature and slowly evaporated. The solid obtained by evaporation was subjected to XPRD measurement. The XPRD spectrum of the solid product obtained is shown in Figure 6, and in this invention, it is defined as free base crystalline form V. The DSC spectrum of free base crystalline form V is shown in Figure 7, and free base crystalline form V has one exothermic peak at 128.28 ° C (the crystals are not completely dried, and there may be crystal water remaining), one exothermic peak at 164.51 ° C, and one endothermic peak at 189.94 ° C (the position of the endothermic peak is similar to that of free base crystalline form I), which indicates that free base crystalline form V is a metastable crystalline form and may change to free base crystalline form I during the heating process.

[0328] Example 5. Preparation of free base crystalline form VI About 20 mg of compound X (amorphous) was weighed into a glass vial, and dissolved in acetonitrile, tetrahydrofuran, dimethyl sulfoxide, or N,N-dimethylacetamide until it became transparent. The solution was placed at room temperature and slowly evaporated. The solid obtained by evaporation was collected and subjected to XPRD measurement. The XPRD spectrum of the solid product obtained is shown in FIG. 8, and in the present invention, it is defined as free base crystalline form VI. The DSC spectrum of free base crystalline form VI is shown in FIG. 9, and free base crystalline form VI has one crystallization exothermic peak at 159.40°C and an endothermic peak at 189.33°C (the position of the endothermic peak is similar to that of free base crystalline form I), which indicates that free base crystalline form VI is a metastable crystalline form and may change to free base crystalline form I during the process of heating.

[0329] Example 6. Preparation of Free Base Crystalline Form VII 20 mg of compound X (amorphous) was weighed into a glass vial, added with methanol, dissolved until transparent, and added with n-heptane as an antisolvent, and solid particles were precipitated. XPRD measurement was performed on the obtained solid. The powder X-ray diffraction spectrum of the obtained solid product is shown in FIG. 10, and is defined as free base crystalline form VII in the present invention. The differential scanning calorimetry spectrum of free base crystalline form VII is shown in FIG. 11, and free base crystalline form VII has an endothermic peak at 189.36° C. (the position of the endothermic peak is similar to that of free base crystalline form I), which indicates that free base crystalline form VII is a metastable crystalline form and may change to free base crystalline form I during the process of heating.

[0330] Example 7. Suspension and shaking Approximately 20 mg of compound X (free base crystalline form I) was weighed into a glass vial, and 1 mL of the solvent in the table below was added to each experimental group. The glass vial was suspended and shaken at room temperature for 24 hours, then centrifuged, the supernatant was discarded, the solid was dried in an oven, and XPRD measurement was performed. The experimental results for each experimental group are shown in Table 13, and the free base crystalline form I did not change crystal form after being suspended and shaken in the seven solvents shown.

[0331] [Table 13]

[0332] Example 8. Competition experiment of crystal forms In order to determine the most stable crystalline form of compound X, a crystalline form competition experiment was conducted. 10 mg each of free base crystalline form I, free base crystalline form IV, free base crystalline form V, free base crystalline form VI, and free base crystalline form VII were weighed out and mixed thoroughly, and 20 mg of the mixed crystalline form was weighed into a glass vial, and 1 mL of the solvent in Table 14 was added, and the mixture was suspended and shaken at room temperature for 24 hours, then centrifuged, the precipitate was collected, dried, and then subjected to XPRD measurement. According to the XPRD results, after mixing and shaking in different solvents for 24 hours, all the mixed crystalline forms were converted to free base crystalline form I, so it was determined that free base crystalline form I was the stable crystalline form.

[0333] [Table 14]

[0334] Example 9. Stability Study of Free Base Crystalline Form I Approximately 20 mg of free base crystalline Form I was weighed into a glass vial and left uncapped under accelerated conditions (40°C, 75% RH), and samples were taken after 1 week, 2 weeks, 1 month, 2 months, and 4 months, respectively, for XPRD measurement. As can be seen from Figure 12, free base crystalline Form I had good physical stability, and the XPRD spectra obtained at different sampling times were highly consistent.

[0335] Example 10. Hydrochloride Crystalline Form I 10.1.Method 1 20 mg of compound X (amorphous) was weighed out, 1 M hydrochloric acid solution was added so that the molar ratio of acid to compound X was 1.2:1, and 2 Ml of acetone or isopropanol was added, and the mixture was dissolved by heating and ultrasonication until it became transparent, and the mixture was reacted for 4 hours at 50°C, and then the temperature was slowly lowered to precipitate a solid, and the solid was centrifuged and collected. The solid obtained was subjected to XRPD measurement after removing the solvent, and the powder X-ray diffraction spectrum is shown in Figure 13, and in the present invention, it is defined as hydrochloride crystalline form I. The differential scanning calorimetry spectrum of hydrochloride crystalline form I is shown in Figure 14, and has an endothermic peak at 225.37°C.

[0336] 10.2.Method 2 20 mg of compound X (amorphous) was weighed out, and 1 M hydrochloric acid solution was added so that the molar ratio of acid to compound X was 1.2:1. Then, 2 Ml of acetone or isopropanol was added, and the mixture was clarified by heating and ultrasonication, and the mixture was kept at 50°C and reacted for 4 hours. The temperature was then lowered to room temperature, and the anti-solvent n-heptane was added to precipitate a solid. The mixture was centrifuged, the solid was collected, and the solvent of the resulting solid was removed to obtain hydrochloride crystalline form I.

[0337] Example 11. Sulfate Crystal Form I 11.1.Method 1 20 mg of compound X was weighed out, and 0.5 M sulfuric acid solution was added so that the molar ratio of acid to compound X was 0.6:1. Then, 2 Ml of isopropanol, ethanol or acetone was added, and the mixture was clarified by heating and ultrasonication, and reacted at 50°C for 4 hours. The temperature was slowly lowered to precipitate a solid, and the solid was centrifuged and collected. The solid obtained was subjected to XRPD measurement after removing the solvent, and the powder X-ray diffraction spectrum is shown in Figure 15. In the present invention, the solid is defined as sulfate crystalline form I. The differential scanning calorimetry spectrum of sulfate crystalline form I is shown in Figure 16, and sulfate crystalline form I has an endothermic peak at 205.20°C.

[0338] 11.2.Method 2 20 mg of compound X was weighed out, and 0.5 M sulfuric acid solution was added so that the molar ratio of acid to compound X was 0.6:1. Then, 2 Ml of ethyl acetate was added, and the mixture was clarified by heating and ultrasonication, and the temperature was kept at 50°C for 4 hours. The mixture was then cooled to room temperature, and n-heptane, an anti-solvent, was added to obtain sulfate crystal form I from the transparent solution.

[0339] 11.3.Method 3 300 mg of compound X (amorphous) was weighed into a small beaker, 5 mL of acetone was added, and the mixture was dissolved by ultrasonic waves. 900 mL of 0.5 M sulfuric acid solution was slowly added dropwise under stirring at 50°C, and the reaction was carried out for 4 hours while maintaining the temperature, and the solution became cloudy. The mixture was centrifuged, the supernatant was discarded, and the solid was separated and washed with acetone 3 to 5 times. The mixture was dried in vacuum overnight at 40°C, and sulfate crystal form I was obtained.

[0340] Example 12. Hydrobromide Crystal Form I 20 mg of compound X was weighed out, 1 mol / L of hydrobromic acid was added so that the molar ratio of acid to compound X was 1.2:1, and 1 Ml to 3 Ml of isopropanol, ethanol, acetone or ethyl acetate was added, and the mixture was clarified by heating and ultrasonic waves, and reacted for 4 hours at 50°C. The temperature was then slowly lowered to precipitate a solid, which was then centrifuged and collected. The obtained solid was subjected to XRPD measurement after removing the solvent. The powder X-ray diffraction spectrum is shown in FIG. 17, and in the present invention, it is defined as hydrobromide salt crystal form I.

[0341] Example 13. Stability experiment of hydrochloride crystalline form I and sulfate crystalline form I Appropriate amounts of hydrochloride crystalline form I and sulfate crystalline form I samples were weighed out and stored under accelerated (40°C / 75%RH) open condition and high temperature (60°C) sealed condition for 9 days, 14 days and 28 days, respectively, and XPRD measurements were performed. The results are shown in Figures 18 and 19. As can be seen from Figures 18 and 19, hydrochloride crystalline form I and sulfate crystalline form I have good crystal form stability, and in Figures 18 and 19, the XPRD spectra obtained at different sampling times are all highly consistent.

[0342] biometrics In the following test examples, the sample used was compound X, and further compound D1 was used as a control.

[0343] Test Example 1: Inhibitory activity against A2A and A2B receptors 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 10% FBS, 200 μg / Ml Zeocin (bleomycin) and 100 μg / Ml Hygromycin B (hygromycin B), or 10% FBS, 400 μg / Ml G418 and 100 μg / Ml Hygromycin B. For details of the culture conditions, please refer to the corresponding manual. The selection steps are as follows.

[0344] 1. Using serum-free medium, increase the cell density to 6 x 10 5 Adjusted to pieces / ml.

[0345] 2. Each well of a 384-well plate (Greiner Bio-One, 784075) contained 5 mL of cell solution, 2.5 mL of NECA (Sigma, 119140-10MG) and 2.5 mL of compound solution, with the final concentration of NECA being 50 Nm (CHO-K1 / ADORA2A) or 10 Nm (CHO-K1 / ADORA2B) and the final concentration of compound being obtained by 3-fold dilution from a starting concentration of 3 μM.

[0346] 3. Place in a 37°C incubator and leave to stand for 30 minutes to culture.

[0347] 4.5 Ml of Camp-d2 and 5 Ml of Camp-ab (Cisbio, 62AM4PEB) were added in this order.

[0348] 5. The 384-well plate was left in the dark at room temperature for 1 hour.

[0349] 6. Read the plate (Victor X5, PerkinElmer) and perform Xlfit nonlinear regression analysis on the data to determine the IC values ​​of compounds. 50 The results are shown in Table 15.

[0350] [Table 15]

[0351] As can be seen from Table 15, the compound X of the present invention is A 2A Receptor and A 2B Both have high inhibitory activity against the receptor.

[0352] Test Example 2: Inhibitory activity against A2A and A2B receptors 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 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 details of the culture conditions, please refer to the corresponding manual. The selection steps are as follows:

[0353] 1. Using serum-free medium, increase the cell density to 6 x 10 5 Adjusted to pieces / ml.

[0354] 2. Each well of a 384-well plate (Greiner Bio-One, 784075) was loaded with 5 μL of cell solution, 2.5 μL of NECA (Sigma, 119140-10MG) and 2.5 μL of compound solution, with the final concentration of NECA being 1 μM (CHO-K1 / ADORA2A) or 0.1 μM (CHO-K1 / ADORA2B) and the final concentration of compound being obtained by 3-fold dilution from the starting concentration of 3 μM.

[0355] 3. Place in a 37°C incubator and leave to stand for 30 minutes to culture.

[0356] 4.5 μL of cAMP-d2 and 5 μL of cAMP-ab (Cisbio, 62AM4PEB) were added in this order.

[0357] 5. The 384-well plate was left in the dark at room temperature for 1 hour.

[0358] 6. Read the plate (Victor X5, PerkinElmer) and perform XLfit nonlinear regression analysis on the data to determine the IC values ​​of compounds. 50 The results are shown in Table 16.

[0359] [Table 16]

[0360] The structure of compound D1, CAS number 2239273-34-6, is shown below: Supplier: Suzhou Chukai Pharmaceutical Co., Ltd., Batch number: 2009010AHP07.

[0361] [ka]

[0362] Test Example 3: In vivo pharmacokinetics test Compound X of the present invention was administered to mice by intravenous injection and forced oral administration, and the plasma drug concentrations were measured at different times using LC / MS / MS to study the pharmacokinetic behavior of compound X of the present invention in mice and evaluate its pharmacokinetic characteristics.

[0363] Test plan: Test animals: Healthy adult male ICR mice (body weight 25-40 g, 12 mice; the intravenous injection group had free access to water and food, and the oral gavage group had free access to water and food 4 hours after administration) were provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0364] Administration method and dosage: Animals that meet the experimental requirements were selected, weighed, and marked before administration. ICR mice were administered the drug via the tail vein (2 mg / kg, 5% DMSO, pH 4.5, 20% Captisol) or orally (10 mg / kg, 5% DMSO, pH 4.5, 20% Captisol).

[0365] Blood collection: Mice were restrained before blood collection, and approximately 100 μL of blood was collected from the jugular vein at the designated time points from each administered mouse (intravenous administration: blood was collected at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 7.5 hours, and 24 hours after administration, respectively, for a total of 9 time points; oral gavage administration: blood was collected at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 7.5 hours, and 24 hours after administration, respectively, for a total of 9 time points). The blood was transferred to a 1.5 mL test tube containing pre-added K2EDTA, centrifuged (8000 rpm, 4 °C) for 4 minutes, and the entire process of separating plasma was completed within 15 minutes after blood collection. All samples had to be stored in a refrigerator at -20 °C until analysis. Drug concentrations were measured by LC / MS / MS method.

[0366] The pharmacokinetic parameters of compound X of the present invention in vivo in mice following intravenous administration are shown in Table 17.

[0367] [Table 17]

[0368] The pharmacokinetic parameters of compound X of the present invention in mice administered orally by forced administration are shown in Table 18.

[0369] [Table 18]

[0370] Test Example 4: In vivo efficacy test of compound X of the present invention Experimental plan: This test example considers the following: Compound X of the present invention was orally administered to tumor-bearing mice subcutaneously transplanted with mouse colon cancer cell line MC38(#22)-hpd-L1, and then the in vivo pharmacological effect of Compound X in the colon cancer MC38(#22)-hpd-L1 tumor-bearing mice was measured.

[0371] Experimental materials: C57BL / 6 mice (female); mouse colon cancer MC38 (#22)-hpd-L1 cells (Shanghai Jiao Tong University Cell Library) were cultured in monolayer in vitro, using RPMI-1640 medium containing 10% fetal bovine serum, in an incubator at 37°C and 5% CO2. Pancreatic enzyme-EDTA was used for general digestion and subculture. When the cells were in the exponential growth phase and reached 80%-90% saturation, they were harvested and counted.

[0372] Preparation of compounds: Compounds were weighed out and added to a solvent (40% captisol acetate buffer, pH 3.8) to prepare 10 mg / mL samples. 75 μL of Tecentriq solution (60 mg / mL) was added to 8.925 mL of phosphate buffer (PBS) to prepare 0.5 mg / mL phosphate solution (phosphate buffer).

[0373] Experimental operation: 5×10 6 The cells were resuspended in phosphate buffer at a density of 10 cells / mL. 5 Mice were subcutaneously inoculated with 10 MC38(#22)-hpd-L1 cells (containing 10 MC38(#22)-hpd-L1 cells) into the right back of each mouse, and randomly divided into groups of 10 mice per group according to their body weight on the day of inoculation. Treatment was started twice daily for 22 days. Animal health was monitored throughout the experiment by daily weight measurement. Tumor diameters were measured twice weekly with a caliper.

[0374] The formula for calculating tumor volume V is: V = 0.5 × a × b 2 , a and b represent the long and short diameters of the tumor, respectively.

[0375] The antitumor effect of the compound was evaluated by the relative tumor growth rate T / C (%). Relative tumor growth rate T / C (%) = Vt / Vc x 100% (Vt: average tumor volume of the treatment group; Vc: average tumor volume of the negative control group). Vt and Vc were obtained from data on the same day. The results are shown in Table 19.

[0376] [Table 19]

[0377] All documents mentioned in this invention are incorporated herein by reference as if each individual document were incorporated by reference alone. The cited documents of the present invention are incorporated herein by reference in their entirety for all purposes, unless they are inconsistent with the purpose or technical solution of the present invention. When a cited document is cited in this invention, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited document are also cited. When a cited document is cited in this invention, examples of relevant technical features, preferred embodiments thereof may also be incorporated into the present invention by reference only to the extent feasible. It should be understood that when the cited content is inconsistent with the description of the present invention, the present invention shall prevail or the description of the present invention shall appropriately correct it.

[0378] The technical features of the above-mentioned embodiments and examples can be arbitrarily combined. In order to simplify the description, all possible combinations of the technical features of the above-mentioned embodiments and examples are not described, but as long as there is no contradiction in the combination of technical features, they should be considered to be within the scope described in this specification.

[0379] The above examples only describe some embodiments of the present invention for a detailed understanding of the present invention, and should not be construed as limiting the scope of protection of the present invention. It should be pointed out that those skilled in the art can make some modifications and improvements without departing from the concept of the present invention, all of which are included in the scope of protection of the present invention. It should also be understood that after reading the above description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and the resulting equivalent forms are also included in the scope of protection of the present invention. It should also be understood that all technical solutions obtained by those skilled in the art through logical analysis, reasoning, or limited testing based on the technical solutions provided in the present invention are within the scope of protection of the claims attached to the present invention. Therefore, the scope of protection of the present invention patent is based on the content of the attached 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 or a polymorph of a pharma- ceutically acceptable salt of said compound of formula X, 【Chemistry 1】 The pharma- ceutically acceptable salt is an inorganic salt, polymorph.

2. 2. The polymorph of claim 1, wherein the pharma- ceutically acceptable salt is any one selected from the group consisting of hydrochloride, sulfate, and hydrobromide.

3. The polymorph of the compound of formula X is A free base crystalline form I of the compound represented by formula X has peaks in a powder X-ray diffraction spectrum at diffraction angles 2θ (°) of 18.08±0.2, 21.41±0.2, 22.01±0.2 and 24.83±0.2; A free base crystalline form IV of the compound of formula X having a powder X-ray diffraction spectrum with peaks at diffraction angles 2θ (°) of 13.04±0.2, 15.80±0.2, 16.46±0.2 and 23.89±0.2; The free base crystalline form V of the compound of formula X has peaks at diffraction angles 2θ (°) of 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 in its powder X-ray diffraction spectrum. and, a free base crystalline form VI of the compound of formula X having an X-ray powder diffraction spectrum with peaks at diffraction angles 2θ (°) of 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; a free base crystalline form VII of the compound of formula X having an X-ray powder diffraction spectrum with peaks at diffraction angles 2θ (°) of 6.17±0.2, 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 of claim 1, which is any one selected from the group consisting of:

4. The polymorph of the compound of formula X is the free base crystalline form I, whose powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 12.90±0.2, 15.26±0.2, 16.47±0.2, 17.81±0.2, 19.57±0.2, and 25.43±0.2; the free base crystalline form IV, whose powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 6.32±0.2, 9.08±0.2, 9.58±0.2, 14.12±0.2, 20.14±0.2, 20.59±0.2 and 27.53±0.2; the free base crystalline form V, whose powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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 free base crystalline Form VI, wherein the powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 9.04±0.2, 9.68±0.2, 13.37±0.2, 18.53±0.2, 19.19±0.2, 19.19±0.2, 19.97±0.2, 23.69±0.2, 27.55±0.2, 30.34±0.2 and 31.46±0.2; the free base crystalline Form VII, wherein the powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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; 4. The polymorph of claim 3, which is any one selected from the group consisting of:

5. The polymorph of the compound of formula X is the free base crystalline form I, whose powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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 free base crystalline form IV, whose powder X-ray diffraction spectrum further comprises peaks at one or two diffraction angles 2θ (°) selected from the group consisting of 7.64±0.2 and 8.34±0.2; the free base crystalline form V, whose powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 6.91±0.2, 8.08±0.2, 8.70±0.2, 12.77±0.2 and 13.25±0.2; the free base crystalline form VI, whose powder X-ray diffraction spectrum further comprises peaks at one or two diffraction angles 2θ (°) selected from the group consisting of 7.24±0.2 and 12.07±0.2; the free base crystalline Form VII, wherein the powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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; 5. The polymorph of claim 4, which is any one selected from the group consisting of:

6. The powder X-ray diffraction spectrum of the free base crystalline form I is shown in FIG. [Figure 1] The powder X-ray diffraction spectrum of the free base crystalline form IV is shown in FIG. [Figure 4] The powder X-ray diffraction spectrum of the free base crystalline form V is shown in FIG. [Figure 6] The powder X-ray diffraction spectrum of the free base crystalline form VI is shown in FIG. [Figure 8] The powder X-ray diffraction spectrum of the free base crystalline form VII is shown in FIG. [Figure 10] The polymorph of claim 3.

7. 4. The polymorph of claim 3, wherein each powder X-ray diffraction spectrum is obtained using Cu-Kα radiation.

8. The differential scanning calorimetry curve of the free base crystalline form I has an endothermic peak at 190.15±3° C.; The differential scanning calorimetry curve of the free base crystalline form IV has an endothermic peak at 189.64±3° C.; The differential scanning calorimetry curve of the free base crystalline form V has an endothermic peak at 189.94±3° C.; The differential scanning calorimetry curve of the free base crystalline form VI has an endothermic peak at 189.33±3° C.; The differential scanning calorimetry curve of the free base crystalline form VII has an endothermic peak at 189.36±3° C. R, The polymorph of claim 3.

9. The free base crystalline form I is (1) The TGA-DSC spectrum is shown in FIG. 2 below; [Figure 2] (2) The DVS spectrum is shown in FIG. 3 below. [Figure 3] (3) The infrared spectrum is shown in FIG. 20 below; [Figure 20] 4. The polymorph of claim 3, having one or more characteristics selected from the group consisting of:

10. The polymorphs of the pharma- ceutically acceptable salts of the compound of formula X are The hydrochloride crystalline form I of the compound represented by formula X has peaks in a powder X-ray diffraction spectrum at diffraction angles 2θ (°) of 13.12±0.2, 13.91±0.2, 17.62±0.2, 22.58±0.2 and 26.51±0.2; A sulfate crystalline form I of the compound represented by formula X has peaks at diffraction angles 2θ (°) of 15.13±0.2, 19.64±0.2 and 23.48±0.2 in a powder X-ray diffraction spectrum; A crystalline form I of the hydrobromide salt of the compound represented by formula X has peaks in a powder X-ray diffraction spectrum at diffraction angles 2θ (°) of 16.70±0.2, 23.51±0.2 and 23.96±0.2; 2. The polymorph of claim 1, which is any one selected from the group consisting of:

11. The polymorphs of the pharma- ceutically acceptable salts of the compound of formula X are Powder X-ray diffraction spectra were 8.39±0.2, 10.18±0.2, and 15.25±0. the hydrochloride salt crystalline form I further comprising peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 2, 18.64±0.2, 20.96±0.2, 25.52±0.2, 27.01±0.2 and 29.48±0.2; the Sulfate Salt Crystalline Form I, whose powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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; and the hydrobromide salt crystalline Form I, wherein the powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) 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.

11. The polymorph of claim 10, which is any one selected from the group consisting of:

12. The polymorphs of the pharma- ceutically acceptable salts of the compound of formula X are the hydrochloride salt crystalline form I, whose powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 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 Sulfate Salt Crystalline Form I, whose powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) selected from the group consisting of 12.19±0.2, 16.45±0.2 and 21.71±0.2; and said hydrobromide salt crystalline Form I, wherein the powder X-ray diffraction spectrum further comprises peaks at two or more diffraction angles 2θ (°) 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.

12. The polymorph of claim 11, which is any one selected from the group consisting of:

13. The powder X-ray diffraction spectrum of the hydrochloride crystalline form I is shown in FIG. [Figure 13] The powder X-ray diffraction spectrum of the sulfate crystalline form I is shown in FIG. [Figure 15] The powder X-ray diffraction spectrum of the hydrobromide salt crystalline form I is shown in FIG. [Figure 17] 11. The polymorph of claim 10.

14. 11. The polymorph of claim 10, wherein each powder X-ray diffraction spectrum is obtained using Cu-Kα radiation.

15. The differential scanning calorimetry curve of the hydrochloride crystalline form I has an endothermic peak at 225.37±3° C.; 11. The polymorph of claim 10, wherein the differential scanning calorimetry curve for the Sulfate Salt crystalline Form I has an endothermic peak at 205.20±3° C.

16. A method for preparing a polymorph of a compound of formula X, the structure of said compound of formula X being shown in formula X: 【Chemistry 2】 The preparation method comprises the steps of: dissolving the compound of formula X in the presence of a solvent until a clear solution is formed; subjecting the solution to a crystallization process to prepare a polymorph of the compound of formula X; A method for preparing a polymorph comprising:

17. 17. The process for preparing the polymorph of the compound of formula X according to claim 16, wherein the polymorph is free base crystalline Form I.

18. 17. The process for preparing the polymorph of claim 16, wherein the solvent is selected from acetonitrile, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, a 50% (v / v) ethanol / water mixture, dimethylsulfoxide, N,N-dimethylacetamide, tetrahydrofuran, and mixtures thereof.

19. (Ia) the solvent is acetonitrile, isopropanol, ethanol, ethyl acetate, or a mixed solvent of 50% (v / v) ethanol / water, and the crystallization method is crystallization by cooling; (Ib) the solvent is a mixed solvent of 50% (v / v) ethanol / water, and the crystallization method is crystallization by evaporation; (Ic) the solvent is dimethylsulfoxide or N,N-dimethylacetamide, and the crystallization method is antisolvent crystallization; 17. A method for preparing the polymorph of claim 16, which is any one selected from the group consisting of:

20. dissolving the compound of formula X in isopropanol, ethanol, ethyl acetate or a 50% (v / v) ethanol / water mixture at 50±5° C. until the solution becomes clear; A step of lowering the temperature of the solution to 0°C to 4°C to precipitate crystals; 17. A process for preparing the polymorph of claim 16 comprising:

21. dissolving the compound of formula X in acetonitrile at 75±5° C. until clear to form the solution; or dissolving the compound of formula X in ethanol at 70±5° C. until clear to form the solution; A step of lowering the temperature of the solution to room temperature and precipitating crystals; 17. A process for preparing the polymorph of claim 16 comprising:

22. (a) a polymorph according to any one of claims 1 to 15; (b) a pharma- ceutically acceptable carrier; and 13. A pharmaceutical composition comprising:

23. Adenosine A ２Ａ Mediated by adenosine A ２Ｂ Receptor-mediated or adenosine A ２Ａ Adenosine A receptors ２Ｂ 16. Use of the polymorph according to any one of claims 1 to 15 in the preparation of a medicament for the prevention and / or treatment of a tumor or an immune-related disease mediated by both of the receptors.

24. Adenosine A ２Ａ Mediated by adenosine A ２Ｂ Receptor-mediated or adenosine A ２Ａ Adenosine A receptors ２Ｂ 23. Use of the pharmaceutical composition of claim 22 in the preparation of a medicament for the prevention and / or treatment of a tumor or an immune-related disease mediated by both of the receptors.

25. The compound represented by formula X is A ２Ａ / A ２Ｂ 24. The use according to claim 23 as a receptor antagonist.

Images