Crystal form of compound HIF-117 as well as preparation method and application of crystal form

Abstract

The invention provides various new crystal forms of an HIF-117 compound as well as a preparation method and application thereof. The crystal forms are selected from any one or more of the following twelve crystal forms: a crystal form A, a crystal form B, a crystal form C, a crystal form D, a crystal form E, a crystal form F, a crystal form G, a crystal form H, a crystal form I, a crystal form J, a crystal form K and a crystal form L. The crystal form has good stability, and has very important value for drug development, preparation development and production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical crystal forms, in particular, relates to a plurality of new crystal forms of HIF-117 compound and a preparation method and application thereof. BACKGROUND

[0002] Hypoxia-inducible factor (HIF) is a transcription factor released by the body in response to cell hypoxia. It acts on the DNA of cells to regulate the expression of genes required for a series of hypoxia protection reactions. HIF can promote the secretion of EPO in the kidney and other non-renal organs (such as the liver), and up-regulate the level of EPO receptor (EPO-R) in the bone marrow. At the same time, HIF can also promote the absorption of iron in the intestine and mobilize the transport of iron to the bone marrow, thereby promoting the production of hemoglobin in the body.

[0003] Hypoxia-inducible factor (HIF) is the main mediator involved in the cellular hypoxic response, and its level in the body mainly depends on the degradation rate. Proline hydroxylase (PHD) is a rate-limiting enzyme for HIF degradation reaction, which can hydroxylate the proline residues of HIF, which are then combined with E3 ubiquitin ligase and then degraded by proteasome. Under hypoxic conditions, HIF degradation is reduced, thereby activating a series of hypoxia-related gene (including EPO) expression, allowing cells and tissues to adapt to the hypoxic environment. By pharmacologically inhibiting HIF degradation, it can become a new method for treating renal anemia, and PHD inhibitors (PHI, also known as HIF stabilizers) have thus emerged (Kautz L et al. Nat Genet, 2014, 46(7): 678-684).

[0004] The present application relates to a HIF-117 compound, whose chemical name is [(5-hydroxy-2-naphthalen-1-yl-[1,7]naphthyridine-6-carbonyl)-amino] acetic acid, which is a small molecule selective inhibitor of hypoxia-inducible factor proline hydroxylase, and its structural formula is:

[0005]

[0006] The compound No. 14 of Example 13 of Chinese Patent Authorized Publication No. CN106146491B reports the structure of the compound (free base), and does not make any research and report on the structure form polymorphism such as polymorphism of the above-mentioned compound.

[0007] Polymorphism refers to the phenomenon that the same element or compound has two or more different crystal structure due to different internal particle (atom, ion, molecule) structure or arrangement. It is well known that polymorphism phenomenon widely exists in drugs. The existence form and quantity of polymorphic compounds are unpredictable. Different crystal forms of the same drug can be significantly different in appearance, solubility, melting point, particle size, dissolution, density, hardness, etc., thereby affecting the stability, biological activity, efficacy and safety of the drug, especially oral solid preparations. Therefore, comprehensive and systematic polymorphic screening of the compound is needed in the process of new drug research and development, and selecting the crystal form suitable for drug preparation development has important clinical significance. SUMMARY

[0008] In view of the above-mentioned disadvantages of the prior art, the purpose of the present application is to provide a crystal form of compound HIF-117 and a preparation method thereof. The crystalline form of the present application has good stability, and has very important value for drug development, preparation development and production.

[0009] To achieve the above-mentioned purposes and other related purposes, the present application is realized by including the following technical solutions.

[0010] The present application provides a crystal form of a compound or a solvate thereof having a structural formula as shown in Formula I,

[0011]

[0012] The crystal form is selected from any one or more of the following twelve crystal forms: crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J, crystal form K, and crystal form L.

[0013] Among them, crystal form A, crystal form D, crystal form G, crystal form H and crystal form J are anhydrous substances, crystal form B and crystal form I are hydrates, crystal form C is a tetrahydrofuran solvate, crystal form E is a dimethyl sulfoxide solvate, crystal form F is an N-methyl pyrrolidone solvate, crystal form K is a 1,4-dioxane solvate, and crystal form L is an N,N-dimethylacetamide solvate.

[0014] For the anhydrous crystal form A of the compound of Formula I, further characteristic descriptions are as follows.

[0015] In one embodiment, for the anhydrous crystal form A of the compound of Formula I, the X-ray powder diffraction (XRPD) pattern has characteristic peaks at 2θ values of 14.56±0.2°, 18.45±0.2°, 18.81±0.2° and 21.81±0.2°.

[0016] In a preferred embodiment, the anhydrous crystal form A of the compound of formula I further has characteristic peaks at one or more of the following positions on its XRPD plot with 2θ values: 9.92±0.2°, 11.88±0.2°, 13.31±0.2°, 23.96±0.2°, 24.56±0.2°, 25.22±0.2°.

[0017] In a preferred embodiment, the anhydrous crystal form A of the compound of formula I has XRPD characteristic peaks at 2θ values ​​and d values ​​and relative intensities as shown in Table 1 below.

[0018] Table 1

[0019]

[0020]

[0021] In some preferred embodiments, the anhydrous crystal form A of the Formula I compound has substantially the following characteristics: Figure 1 The XRPD diagram shown.

[0022] In this invention, Cu-Kα radiation is used in the X-ray powder diffraction.

[0023] In some preferred embodiments, the anhydrous crystal form A of compound I further has one or more of the following characteristics:

[0024] 1) In the thermogravimetric analysis (TGA) chart, there is no significant weight loss when the temperature is raised to 200±5℃; preferably, there is a weight loss of no more than 0.5% by weight during the process of raising the temperature to 200±5℃, more preferably, there is a weight loss of no more than 0.3% by weight during the process of raising the temperature to 200±5℃.

[0025] 2) In the DSC plot, there is an endothermic peak at 222.0±5℃.

[0026] In some preferred embodiments, the anhydrous crystal form A of compound I further has one or more of the following characteristics:

[0027] 1) Basically as Figure 2 The TGA diagram shown;

[0028] 2) Basically as Figure 3 The DSC diagram shown.

[0029] For the hydrate crystal form B of compound of formula I, further characteristics are described below.

[0030] In one embodiment, for hydrate crystal form B of compound of formula I, its X-ray powder diffraction (XRPD) pattern has characteristic peaks at 2θ values ​​of 11.88±0.2°, 15.26±0.2°, 15.43±0.2°, 16.62±0.2° and 26.16±0.2°.

[0031] In a preferred embodiment, the XRPD plot of the hydrate crystal form B of Formula I compound has characteristic peaks at one or more of the following positions with a 2θ value: 17.93±0.2°, 20.20±0.2°, 22.50±0.2°, 23.40±0.2°, and 28.70±0.2°.

[0032] In a preferred embodiment, the hydrate crystal form B of compound I has XRPD characteristic peaks at 2θ values, as well as d values ​​and relative intensities, substantially as shown in Table 2. Table 2 is detailed below.

[0033] Table 2

[0034]

[0035]

[0036] In a more preferred embodiment, the hydrate crystal form B of compound I has substantially the following characteristics: Figure 4 The XRPD diagram shown.

[0037] In some preferred embodiments, the hydrate crystal form B of Formula I compound also has one or more of the following characteristics:

[0038] 1) In the TGA diagram, there is no significant weight loss when the temperature is raised to 90±5℃. Preferably, there is a weight loss of no more than 0.5% by weight when the temperature is raised to 90±5℃. More preferably, there is a weight loss of no more than 5% by weight when the temperature is raised to 200±5℃.

[0039] 2) In the differential scanning calorimetry (DSC) graph, there are endothermic peaks at 130.5±5℃, 138.0±5℃ and 222.5±5℃, and an exothermic peak at 135.5±5℃.

[0040] In a preferred embodiment, the molar ratio of water to HIF-117 in crystal form B is 1.

[0041] In some preferred embodiments, the hydrate crystal form B of Formula I compound also has one or more of the following characteristics:

[0042] 1) Basically as Figure 5 The TGA diagram shown;

[0043] 2) Basically as Figure 6 The DSC diagram shown.

[0044] Preferably, the molar ratio of water to HIF-117 in the hydrate Form B of the compound of Formula I is 1.

[0045] For the tetrahydrofuran (THF) solvate Form C of the compound of Formula I, further characteristics are described as follows.

[0046] In one embodiment, the THF solvate Form C of the compound of Formula I has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.26±0.2°, 12.81±0.2°, 15.30±0.2°, and 15.80±0.2° in terms of 2θ values.

[0047] In a preferred embodiment, the THF solvate Form C of the compound of Formula I has XRPD characteristic peaks at substantially the 2θ values and d values and relative intensities as shown in Table 3. Table 3 is shown below.

[0048] Table 3

[0049] Diffractogram angle 2 theta d-value Intensity % 5.26 16.80 100.00 6.09 14.52 12.74 12.81 6.91 76.14 15.30 5.79 68.59 15.80 5.61 78.64 18.65 4.76 2.03 20.07 4.43 6.17 23.32 3.82 14.75 23.87 3.73 14.16 24.13 3.69 15.06 26.26 3.39 11.82 27.14 3.29 4.65 27.86 3.20 5.08 29.92 2.99 3.62

[0050] In a more preferred embodiment, the Form C has an XRPD pattern substantially as shown in Figure 7

[0051] In some preferred embodiments, the THF solvate Form C of the compound of Formula I further has one or more of the following characteristics:

[0052] 1) In a TGA pattern, there is no more than 3.5% weight loss up to 100±5°C; in a TGA pattern, there is no more than 10% weight loss up to 200±5°C.

[0053] 2) In a DSC pattern, there are endothermic peaks at 137.4±5°C, 188.2±5°C, and 221.6±5°C, and an exothermic peak at 189.9±5°C.

[0054] In some preferred embodiments, the THF solvate Form C of the compound of Formula I further has one or more of the following characteristics:

[0055] 1) a TGA pattern substantially as shown in Figure 8

[0056] 2) a DSC pattern substantially as shown in Figure 9

[0057] Preferably, the molar ratio of tetrahydrofuran to HIF-117 in the THF solvate Form C of the compound of Formula I is 0.3.

[0058] For the anhydrous Form D of the compound of Formula I, further characteristics are described as follows.​​​

[0059] In one embodiment, the compound of Formula I anhydrate Form D has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 2-Theta values of 5.47 ± 0.2°, 12.97 ± 0.2°, 15.85 ± 0.2°, and 16.44 ± 0.2°.

[0060] In a preferred embodiment, the compound of Formula I anhydrate Form D has an XRPD pattern with characteristic peaks at substantially the 2-Theta values and d-values and relative intensities as shown in Table 4. Table 4 is shown below.

[0061] Table 4

[0062] Diffractogram angle 2 theta d-value Intensity % 5.47 16.16 100.00 10.95 8.08 4.99 12.06 7.34 3.28 12.97 6.83 17.83 13.53 6.54 2.20 15.85 5.59 10.43 16.44 5.39 75.50 19.71 4.50 2.34 20.96 4.24 0.56 23.08 3.85 2.08 23.58 3.77 0.61 24.31 3.66 4.81 24.54 3.63 4.12 26.39 3.38 3.86 27.14 3.29 0.97 28.34 3.15 0.66 29.97 2.98 0.50 30.81 2.90 0.63 33.23 2.70 2.91 38.89 2.32 0.63

[0063] In a preferred embodiment, the compound of Formula I anhydrate Form D has an XRPD pattern substantially as shown in Table 4. Figure 10

[0064] In some preferred embodiments, the compound of Formula I anhydrate Form D further has one or more of the following characteristics:

[0065] 1) In a TGA pattern, there is no more than 2% weight loss up to 150 ± 5°C, preferably, no more than 1.95% weight loss up to 150 ± 5°C.

[0066] 2) In a DSC pattern, there are endothermic peaks at 189.5 ± 5°C, 221.3 ± 5°C, and an exothermic peak at 191.6 ± 5°C.

[0067] In some preferred embodiments, the compound of Formula I anhydrate Form D further has one or more of the following characteristics:

[0068] 1) a TGA pattern substantially as shown in Table 5; Figure 11

[0069] 2) a DSC pattern substantially as shown in Table 6. Figure 12

[0070] Further characteristic descriptions for the compound of Formula I dimethyl sulfoxide (DMSO) solvate Form E are as follows.

[0071] In one embodiment, the compound of Formula I DMSO solvate Form E has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 2-Theta values of 4.34 ± 0.2°, 13.01 ± 0.2°, 15.29 ± 0.2°, 15.90 ± 0.2°, 16.62 ± 0.2°, 17.39 ± 0.2°, 20.13 ± 0.2°, and 25.06 ± 0.2°.

[0072] ​​​In a preferred embodiment, the DMSO solvate crystalline Form E of the compound of Formula I has XRPD characteristic peaks and d-values and relative intensities substantially as shown in Table 5. Table 5 is shown below.

[0073] Table 5

[0074] Diffractogram angle 2 theta d-value Intensity % 4.34 20.36 73.60 8.77 10.09 11.76 13.01 6.80 33.17 15.29 5.80 50.40 15.90 5.57 100.00 16.62 5.33 38.59 17.39 5.10 37.81 17.61 5.04 31.61 20.13 4.41 30.19 22.13 4.02 11.42 22.49 3.95 14.04 25.06 3.55 70.49 27.67 3.22 6.21 31.94 2.80 3.38

[0075] In some preferred embodiments, the DMSO solvate crystalline Form E of the compound of Formula I has an XRPD pattern substantially as shown in Figure 13

[0076] In some preferred embodiments, the DMSO solvate crystalline Form E of the compound of Formula I further has one or more of the following characteristics:

[0077] 1) in a TGA pattern, not more than 20.0 wt% weight loss upon heating to 200±5°C, preferably, not more than 19.8 wt% weight loss upon heating to 200±5°C;

[0078] 2) in a DSC pattern, endothermic peaks at 79.1±5°C, 100.5±5°C, preferably, further endothermic peaks at 161.5±5°C and / or 200.2±5°C.

[0079] In some preferred embodiments, the DMSO solvate crystalline Form E of the compound of Formula I further has one or more of the following characteristics:

[0080] 1) a TGA pattern substantially as shown in Figure 14

[0081] 2) a DSC pattern substantially as shown in Figure 15

[0082] Preferably, the molar ratio of dimethyl sulfoxide to HIF-117 in the DMSO solvate crystalline Form E of the compound of Formula I is 0.9.

[0083] For the N-methylpyrrolidone (NMP) solvate crystalline Form F of the compound of Formula I, further characteristic descriptions are as follows.

[0084] In one embodiment, the NMP solvate crystalline Form F of the compound of Formula I has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 2Θ values at the following positions: 3.99±0.2°, 11.92±0.2°, 14.53±0.2°, 15.06±0.2°, 17.62±0.2°, 23.30±0.2°, 25.86±0.2°, and 26.56±0.2°.

[0085] ​​​In a preferred embodiment, the compound of Formula I NMP solvate Form F has XRPD characteristic peaks and d-values and relative intensities substantially as shown in Table 6. Table 6 is shown below.

[0086] Table 6

[0087] Diffractogram angle 2 theta d-value Intensity % 3.99 22.12 73.41 7.52 11.75 13.02 8.27 10.69 10.00 9.39 9.42 24.12 9.89 8.94 3.58 11.92 7.42 58.06 12.32 7.19 9.62 13.32 6.65 5.26 13.95 6.35 12.94 14.53 6.10 100.00 15.06 5.88 84.53 15.91 5.57 21.40 16.56 5.35 10.72 17.62 5.03 60.05 18.43 4.81 16.72 18.80 4.72 10.27 19.34 4.59 3.13 20.16 4.41 19.28 21.82 4.07 21.98 22.12 4.02 28.30 22.60 3.94 22.00 23.30 3.82 45.37 23.52 3.78 28.45 24.65 3.61 17.24 25.55 3.49 31.21 25.86 3.44 70.47 26.56 3.36 38.05 28.14 3.17 10.69 28.63 3.12 9.51 31.69 2.82 4.56 33.01 2.71 4.41 34.59 2.59 2.82 37.44 2.40 2.83

[0088] In a more preferred embodiment, the compound of Formula I NMP solvate Form F has an XRPD pattern substantially as shown in Figure 16

[0089] In some preferred embodiments, the compound of Formula I NMP solvate Form F further has one or more of the following characteristics:

[0090] 1) in a TGA pattern, not more than 13.0 wt% weight loss on heating to 160±5°C, and not more than 7.5 wt% further weight loss between 160±5°C and 250±5°C. Preferably, in a TGA pattern, not more than 12.75 wt% weight loss on heating to 160±5°C, and not more than 7.1 wt% further weight loss between 160±5°C and 250±5°C;

[0091] 2) in a DSC pattern, endothermic peaks at 91.2±5°C and 211.2±5°C

[0092] In some preferred embodiments, the compound of Formula I NMP solvate Form F further has one or more of the following characteristics:

[0093] 1) a TGA pattern substantially as shown in Figure 17

[0094] 2) a DSC pattern substantially as shown in Figure 18

[0095] Preferably, the molar ratio of N-methyl pyrrolidone to HIF-117 in the compound of Formula I NMP solvate Form F is 0.7.

[0096] Further characteristic descriptions for the compound of Formula I anhydrous Form G are as follows.

[0097] In one embodiment, for the compound of Formula I anhydrous Form G, the X-ray powder diffraction (XRPD) pattern Figure 2 has characteristic peaks at 5.48±0.2°, 12.03±0.2°, 12.97±0.2°, 15.89±0.2°, and 16.47±0.2°.

[0098] ​​​In a preferred embodiment, the anhydrous crystal form G of the compound of formula I has XRPD characteristic peaks at 2θ values, as well as d values ​​and relative intensities, substantially as shown in Table 7. Table 7 is shown below.

[0099] Table 7

[0100] Diffractogram angle 2 theta d-value Intensity % 5.48 16.13 23.78 12.03 7.36 14.19 12.97 6.83 100.00 13.47 6.58 6.58 15.89 5.58 33.38 16.07 5.52 8.67 16.47 5.38 11.15 17.49 5.07 3.02 18.79 4.72 0.79 19.77 4.49 8.01 21.64 4.11 1.95 22.81 3.90 1.92 23.15 3.84 3.76 24.39 3.65 7.81 24.62 3.62 4.51 25.09 3.55 1.41 26.10 3.41 4.27 26.46 3.37 9.11 27.22 3.28 2.18 28.48 3.13 1.87 30.01 2.98 1.38 31.05 2.88 2.00

[0101] In some preferred embodiments, the anhydrous crystal form G of the compound of formula I has substantially the following characteristics: Figure 19 The XRPD diagram shown.

[0102] In some preferred embodiments, the anhydrous crystal form G of the compound of formula I also has one or more of the following characteristics:

[0103] 1) In the TGA diagram, the weight loss upon heating to 200±5℃ is no more than 2.5% by weight; preferably, the weight loss upon heating to 200±5℃ is no more than 2.2% by weight.

[0104] 2) In the DSC diagram, there is an endothermic peak at 222.6±5℃ and an exothermic peak at 187.9±5℃.

[0105] In some preferred embodiments, the anhydrous crystal form G of the compound of formula I also has one or more of the following characteristics:

[0106] 1) Basically as Figure 20 The TGA diagram shown;

[0107] 2) Basically as Figure 21 The DSC diagram shown.

[0108] For the anhydrous crystal form H of compound I, further characteristics are described below.

[0109] In one embodiment, the anhydrous crystal form H of the compound of formula I has characteristic peaks in its X-ray powder diffraction (XRPD) pattern at 2θ values ​​of 7.33±0.2°, 10.07±0.2°, 14.35±0.2°, and 14.72±0.2°.

[0110] In a preferred embodiment, the anhydrous crystal form H of the Formula I compound has XRPD characteristic peaks at 2θ values, d values, and relative intensities substantially as shown in Table 8. Table 8 is shown below.

[0111] Table 8

[0112] Diffractogram angle 2 theta d-value Intensity % 5.06 17.46 12.36 7.33 12.07 37.37 7.93 11.15 6.11 10.07 8.78 20.16 10.24 8.64 18.08 11.53 7.67 10.53 14.35 6.17 30.19 14.72 6.02 100.00 15.66 5.66 18.09 17.13 5.18 8.53 18.47 4.80 6.25 19.72 4.50 5.73 20.26 4.38 3.03 21.16 4.20 4.28 22.53 3.95 12.17 23.11 3.85 5.29 23.59 3.77 3.76 25.43 3.50 8.48 27.88 3.20 4.92 29.55 3.02 7.61

[0113] In some preferred embodiments, the anhydrous crystal form H of the compound of formula I has substantially the following properties: Figure 22 The XRPD diagram shown.

[0114] In some preferred embodiments, the compound of Formula I anhydrate Form H further has one or more of the following characteristics:

[0115] 1) has a weight loss of no more than 5.8% by weight in a TGA trace up to 200 ± 5 °C.

[0116] 2) has an endothermic peak at 219.0 ± 5 °C in a DSC trace.

[0117] In some preferred embodiments, the compound of Formula I anhydrate Form H further has one or more of the following characteristics:

[0118] 1) a TGA trace substantially as shown in Figure 23 ;

[0119] 2) a DSC trace substantially as shown in Figure 24 .

[0120] For the compound of Formula I hydrate Form I, further characteristic descriptions are as follows.

[0121] In one embodiment, for the compound of Formula I hydrate Form I, the X-ray powder diffraction (XRPD) pattern has characteristic peaks at the following positions in terms of 2Θ values: 5.48 ± 0.2°, 12.05 ± 0.2°, 12.85 ± 0.2°, 15.39 ± 0.2°, and 16.49 ± 0.2°.

[0122] In a preferred embodiment, the compound of Formula I hydrate Form I has XRPD characteristic peaks at 2Θ values and d values and relative intensities substantially as shown in Table 9. The data in Table 9 is shown below.

[0123] Table 9

[0124] Diffractogram angle 2 theta d-value Intensity % 5.31 16.65 20.62 5.48 16.13 43.00 10.95 8.08 1.32 11.82 7.49 8.63 12.05 7.35 29.78 12.64 7.00 45.74 12.85 6.89 100.00 13.63 6.50 10.40 15.39 5.76 37.62 15.67 5.65 19.03 15.92 5.57 10.56 16.49 5.38 20.10 19.23 4.61 3.92 19.57 4.54 1.98 20.46 4.34 1.62 21.27 4.18 1.44 23.72 3.75 6.83 24.25 3.67 5.46 24.70 3.60 2.78 25.43 3.50 1.64 25.94 3.43 2.55 33.28 2.69 0.98

[0125] In some preferred embodiments, the compound of Formula I hydrate Form I has an XRPD pattern substantially as shown in Figure 25 .

[0126] In some preferred embodiments, the compound of Formula I hydrate Form I further has one or more of the following characteristics:

[0127] 1) has a weight loss of no more than 3.1% by weight in a TGA trace up to 200 ± 5 °C.

[0128] 2) has endothermic peaks at 186.1 ± 5 °C and 220.5 ± 5 °C and an exothermic peak at 189.6 ± 5 °C in a DSC trace. Preferably, the differential scanning calorimetry trace of Form I also has an endothermic peak at 146.9 ± 5 °C.

[0129] In some preferred embodiments, the compound of formula I hydrate crystalline Form I further has one or more of the following characteristics:

[0130] 1) a TGA pattern substantially as shown in Figure 2; Figure 26

[0131] 2) a DSC pattern substantially as shown in Figure 3. Figure 27

[0132] Preferably, the molar ratio of water to HIF-117 in the compound of formula I hydrate crystalline Form I is 0.7.

[0133] For the compound of formula I anhydrous crystalline Form J, further characteristic descriptions are as follows.

[0134] In one embodiment, the compound of formula I anhydrous crystalline Form J has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following positions in terms of 2Θ values: 5.04±0.2°, 10.07±0.2°, 14.59±0.2°, 14.82±0.2°, 16.04±0.2°, and 18.79±0.2°.

[0135] In one preferred embodiment, the compound of formula I anhydrous crystalline Form J has XRPD characteristic peaks at substantially the 2Θ values and d values and relative intensities as shown in Table 10. The data in Table 10 are shown below.

[0136] Table 10

[0137] Diffractogram angle 2 theta d-value Intensity % 5.04 17.55 100.00 7.39 11.97 21.57 8.00 11.06 21.44 9.81 9.01 22.84 10.07 8.78 26.84 12.84 6.89 14.44 13.74 6.44 15.27 14.59 6.07 81.94 14.82 5.98 97.61 15.39 5.76 12.78 16.04 5.53 64.00 16.66 5.32 12.65 18.79 4.72 30.78 20.01 4.44 4.17 21.79 4.08 3.07 23.42 3.80 12.18 24.15 3.69 20.77 24.90 3.58 8.58 25.72 3.46 16.09 26.67 3.34 13.22 27.68 3.22 6.07 28.75 3.11 5.32 30.16 2.96 6.88 30.57 2.92 4.42 32.81 2.73 1.02 33.81 2.65 3.33

[0138] In some preferred embodiments, the compound of formula I anhydrous crystalline Form J has an XRPD pattern substantially as shown in Figure 6. Figure 28

[0139] In some preferred embodiments, the compound of formula I anhydrous crystalline Form J further has one or more of the following characteristics:

[0140] 1) in a TGA pattern, not more than 3.0% weight loss upon heating to 150±5°C; preferably, not more than 2.7% weight loss upon heating to 150±5°C;

[0141] 2) in a DSC pattern, endothermic peaks at 214.5±5°C and 220.4±5°C; preferably, also an endothermic peak at 84.0±5°C.

[0142] In some preferred embodiments, the compound of formula I anhydrous crystalline Form J further has one or more of the following characteristics:

[0143] 1) a TGA pattern substantially as shown in Figure 8; Figure 29 ​​​​

[0144] 2) a TGA pattern substantially as shown in Figure 6. Figure 30

[0145] Form K of the 1,4-Dioxane solvate of the compound of Formula I.

[0146] In one embodiment, Form K of the 1,4-Dioxane solvate of the compound of Formula I has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following positions in terms of 2Θ: 4.27 ± 0.2°, 12.80 ± 0.2°, 14.62 ± 0.2°, 14.71 ± 0.2°, 17.09 ± 0.2°, 17.75 ± 0.2°, 19.79 ± 0.2°, and 20.54 ± 0.2°.

[0147] In a preferred embodiment, Form K of the 1,4-Dioxane solvate of the compound of Formula I has XRPD characteristic peaks at 2Θ values and d values and relative intensities substantially as shown in Table 11. Table 11 is shown below.

[0148] Table 11

[0149] Diffractogram angle 2 theta d-value Intensity % 4.27 20.69 71.55 7.34 12.05 12.34 8.55 10.35 0.68 10.22 8.66 8.42 12.80 6.92 100.00 14.62 6.06 61.48 14.71 6.02 66.49 15.86 5.59 26.92 17.09 5.19 73.99 17.38 5.10 24.46 17.75 5.00 63.30 18.29 4.85 11.09 19.79 4.49 23.11 20.54 4.32 47.83 21.30 4.17 3.97 23.22 3.83 4.71 24.37 3.65 5.55 25.56 3.48 7.83 26.18 3.40 3.94 27.58 3.23 5.72 30.17 2.96 5.63 32.34 2.77 9.78 33.64 2.66 1.86

[0150] In some preferred embodiments, Form K of the 1,4-Dioxane solvate of the compound of Formula I has an XRPD pattern substantially as shown in Figure 6. Figure 31

[0151] In some preferred embodiments, Form K of the 1,4-Dioxane solvate of the compound of Formula I further has one or more of the following characteristics:

[0152] 1) in a TGA pattern, not more than 19% weight loss upon heating to 150 ± 5 °C, preferably, not more than 18.85% weight loss upon heating to 150 ± 5 °C;

[0153] 2) in a DSC pattern, endothermic peaks at 91.6 ± 5 °C, 216.9 ± 5 °C, and 220.9 ± 5 °C.

[0154] In some preferred embodiments, Form K of the 1,4-Dioxane solvate of the compound of Formula I further has one or more of the following characteristics:

[0155] 1) a TGA pattern substantially as shown in Figure 6. Figure 32

[0156] 2) a DSC pattern substantially as shown in Figure 6. Figure 33

[0157] ​​​​Preferably, in the 1,4-dioxane solvate Form K of the compound of Formula I, the molar ratio of 1,4-dioxane to HIF-1 17 is 0.9.

[0158] For the N,N-dimethylacetamide (DMAc) solvate Form L of the compound of Formula I.

[0159] In one embodiment, the form is the N,N-dimethylacetamide solvate Form L of the compound of Formula I having an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following positions in terms of 2Θ values: 4.84 ± 0.2°, 6.50 ± 0.2°, 14.54 ± 0.2° and 21.41 ± 0.2°.

[0160] In a preferred embodiment, the DMAc solvate Form L of the compound of Formula I has characteristic peaks in the XRPD pattern at one or more of the following positions in terms of 2Θ values: 8.65 ± 0.2°, 13.02 ± 0.2°, 16.78 ± 0.2°, 19.47 ± 0.2°.

[0161] In a preferred embodiment, the N,N-dimethylacetamide solvate Form L of the compound of Formula I has XRPD characteristic peaks at substantially the 2Θ values and d values and relative intensities as shown in Table 12, which is as follows.

[0162] Table 12

[0163] Diffractogram angle 2 theta d-value Intensity % 4.84 18.26 67.75 6.50 13.60 87.09 8.65 10.22 21.00 9.69 9.13 9.45 11.01 8.04 4.01 13.02 6.80 32.51 14.54 6.09 100.00 16.78 5.28 29.24 17.33 5.12 4.81 19.47 4.56 20.36 19.63 4.52 14.14 21.41 4.15 22.17 21.86 4.07 10.41 22.53 3.95 11.75 23.84 3.73 5.85 24.35 3.66 6.27 25.00 3.56 8.13 25.47 3.50 20.25 25.71 3.47 20.71 26.73 3.34 11.00 28.65 3.12 8.32 29.14 3.06 10.01 31.05 2.88 1.87 35.78 2.51 1.23

[0164] In some preferred embodiments, the Form L has an XRPD pattern substantially as shown in Table 12. Figure 34

[0165] In some preferred embodiments, the N,N-dimethylacetamide solvate Form L of the compound of Formula I further has one or more of the following characteristics:

[0166] 1) a weight loss of no more than 13.5% by weight upon heating to 150 ± 5 °C in the TGA pattern;

[0167] 2) an endothermic peak at 86.8 ± 5 °C, 207.0 ± 5 °C and 216.0 ± 5 °C and an exothermic peak at 95.1 ± 5 °C in the DSC pattern. Preferably, there is also an endothermic peak at 104.1 ± 5 °C.

[0168] In some preferred embodiments, the N,N-dimethylacetamide solvate Form L of the compound of Formula I further has one or more of the following characteristics:

[0169] 1) a TGA pattern substantially as shown in Table 13; Figure 35

[0170] 2) a DSC pattern substantially as shown in Table 14.​​Figure 36 DSC pattern.

[0171] Preferably, the molar ratio of N,N-dimethylacetamide to HIF-117 in the N,N-dimethylacetamide solvate crystal form L of the compound of formula I is 0.5.

[0172] The second aspect of the present application provides a preparation method of the crystal form according to any one of the above, which comprises contacting or reacting the compound of formula I with a solvent, and then preparing the corresponding crystalline form.

[0173] In a preferred embodiment, the preparation method is selected from any one of the suspension stirring method, the anti-solvent addition method, the rapid cooling method, the slow cooling method, the gas-liquid diffusion method, the temperature cycling method, and the grinding method.

[0174] In the preparation method, the suspension stirring method, the compound of formula I is added to the solvent, stirred, and then the solid is collected by centrifugation.

[0175] In the preparation method, the anti-solvent addition method, the compound of formula I is added to the solvent, dissolved, filtered, and then the solid is collected by centrifugation after adding the anti-solvent and stirring.

[0176] In the preparation method, the rapid cooling method, the compound of formula I is added to the solvent, stirred at high temperature, and a saturated clear solution is obtained, then the solid is collected by centrifugation after rapid cooling.

[0177] In the preparation method, the slow cooling method, the compound of formula I is added to the solvent, stirred at high temperature, and a saturated clear solution is obtained, then the solid is collected by centrifugation after slow cooling.

[0178] In the preparation method, the gas-liquid diffusion method, the compound of formula I is added to the solvent, dissolved to obtain a saturated clear solution, and then the solid is collected by centrifugation after standing at room temperature.

[0179] In the preparation method, the temperature cycling method, the compound of formula I is added to the solvent to obtain a suspension, and then the solid is collected by centrifugation after suspension stirring with temperature cycling.

[0180] In the preparation method, the grinding method, the compound of formula I is directly ground or ground with water, and then the solid is collected.

[0181] In the preparation method, the temperature of the reaction or crystallization can be a conventional temperature in the art.

[0182] In the preparation method, the time for crystallization is not particularly limited, and the crystal form can be precipitated.

[0183] In a preferred embodiment, the solvent is selected from one or more of water, alcohols, ketones, esters, alkanes, aromatic hydrocarbons, halogenated hydrocarbons, nitriles, ethers, aliphatic hydrocarbons; more preferably selected from one or more of water, methanol, ethanol, isopropanol, acetone, 1,4-dioxane, acetonitrile, dichloromethane, trichloromethane, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, n-heptane, dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone. The selection of specific solvent can be adjusted by those skilled in the art according to different preparation methods.

[0184] In a more preferred embodiment, the mass volume ratio of the compound of formula I to solvent is 100 mg: (1-50 mL), preferably 100 mg: (1.5-47 mL).

[0185] The third aspect of the present application provides a pharmaceutical composition comprising a crystalline form according to any one of the above.

[0186] The crystalline form of the compound of formula I or solvate thereof can be a therapeutically effective amount.

[0187] A "therapeutically effective amount" refers to the amount of a compound according to the present application, in the form thereof, which when administered to a patient in need thereof, is sufficient to effect treatment for the disease state, condition, or disorder for which the compound has utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is being sought by those of ordinary skill in the art.

[0188] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0189] The pharmaceutically acceptable excipient can be an excipient well known in the art, which in the case of solid formulations includes, but is not limited to, diluents, binders, disintegrants, lubricants, glidants, release rate controlling agents, plasticizers, preservatives, antioxidants, and the like.

[0190] The pharmaceutical composition can be in a dosage form suitable for human consumption, such as tablets, capsules, granules, powders, or pills, preferably tablets, capsules, granules, disintegrating tablets, sustained or controlled release tablets, sustained or controlled release capsules, and the like.

[0191] The fourth aspect of the present application also provides the use of a crystalline form according to any one of the above or the pharmaceutical composition described above in the preparation of a medicament for the prevention and / or treatment of anemia in dialysis patients with chronic kidney disease and non-dialysis anemia with chronic kidney disease.

[0192] The technical solution of the present application has the following beneficial effects:

[0193] 1. The prior art has not reported the crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J, crystal form K, crystal form L of [(5-hydroxy-2-naphthalen-1-yl-[1,7]naphthyridine-6-carbonyl)-amino] acetic acid, and this application first discovers the new crystal form of the compound. Through a large number of experiments and screening, the crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J, crystal form K, crystal form L are first prepared by the application; and the TGA and DSC test results show that the crystal form A, crystal form D, crystal form G, crystal form H, crystal form J are anhydrous substances, the hydrate crystal form B and the crystal form I are converted into the anhydrous crystal form A under heating, the solvent compound crystal form E, crystal form K, crystal form L are converted into the anhydrous crystal form J after heating, the solvent compound crystal form C is converted into the anhydrous crystal form D after heating, and the solvent compound crystal form F is converted into the anhydrous crystal form A after heating, indicating that the anhydrous crystal form has good thermal stability, and the crystal form A, crystal form D, crystal form G, crystal form H, crystal form J are taken as candidate objects.

[0194] 2. The application also provides a preparation method of the crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J, crystal form K and crystal form L, which is simple in operation, high in reproducibility, free from solvent residue, friendly to the environment and suitable for different scale production.

[0195] 3. The crystal form A, crystal form D, crystal form G, crystal form H and crystal form J prepared by the application have good stability, are convenient to store, can avoid the risk of crystal transformation in the process of drug development or production, avoid the change of bioavailability and drug efficacy, can be developed into a dosage form suitable for clinical use, and have strong economic value. BRIEF DESCRIPTION OF DRAWINGS

[0196] Figure 1 It is an XRPD pattern of the anhydrous crystal form A of the compound of formula I.

[0197] Figure 2 It is a TGA pattern of the anhydrous crystal form A of the compound of formula I.

[0198] Figure 3 It is a DSC pattern of the anhydrous crystal form A of the compound of formula I.

[0199] Figure 4 It is an XRPD pattern of the hydrate crystal form B of the compound of formula I.

[0200] Figure 5 It is a TGA pattern of the hydrate crystal form B of the compound of formula I.

[0201] Figure 6 It is a DSC pattern of the hydrate crystal form B of the compound of formula I.

[0202] Figure 7XRPD pattern for Form C THF solvate of the compound of Formula I.

[0203] Figure 8 TGA pattern for Form C THF solvate of the compound of Formula I.

[0204] Figure 9 DSC pattern for Form C THF solvate of the compound of Formula I.

[0205] Figure 10 XRPD pattern for Form D anhydrate of the compound of Formula I.

[0206] Figure 11 TGA pattern for Form D anhydrate of the compound of Formula I.

[0207] Figure 12 DSC pattern for Form D anhydrate of the compound of Formula I.

[0208] Figure 13 XRPD pattern for Form E DMSO solvate of the compound of Formula I.

[0209] Figure 14 TGA pattern for Form E DMSO solvate of the compound of Formula I.

[0210] Figure 15 DSC pattern for Form E DMSO solvate of the compound of Formula I.

[0211] Figure 16 XRPD pattern for Form F NMP solvate of the compound of Formula I.

[0212] Figure 17 TGA pattern for Form F NMP solvate of the compound of Formula I.

[0213] Figure 18 DSC pattern for Form F NMP solvate of the compound of Formula I.

[0214] Figure 19 XRPD pattern for Form G anhydrate of the compound of Formula I.

[0215] Figure 20 TGA pattern for Form G anhydrate of the compound of Formula I.

[0216] Figure 21 DSC pattern for Form G anhydrate of the compound of Formula I.

[0217] Figure 22 XRPD pattern for Form H anhydrate of the compound of Formula I.

[0218] Figure 23 TGA pattern for Form H anhydrate of the compound of Formula I.

[0219] Figure 24 DSC pattern of Form H anhydrous crystalline form of the compound of Formula I.

[0220] Figure 25 XRPD pattern of Form I hydrate crystalline form of the compound of Formula I.

[0221] Figure 26 TGA pattern of Form I hydrate crystalline form of the compound of Formula I.

[0222] Figure 27 DSC pattern of Form I hydrate crystalline form of the compound of Formula I.

[0223] Figure 28 XRPD pattern of Form J anhydrous crystalline form of the compound of Formula I.

[0224] Figure 29 TGA pattern of Form J anhydrous crystalline form of the compound of Formula I.

[0225] Figure 30 DSC pattern of Form J anhydrous crystalline form of the compound of Formula I.

[0226] Figure 31 XRPD pattern of Form K 1,4-Dioxane solvate crystalline form of the compound of Formula I.

[0227] Figure 32 TGA pattern of Form K 1,4-Dioxane solvate crystalline form of the compound of Formula I.

[0228] Figure 33 DSC pattern of Form K 1,4-Dioxane solvate crystalline form of the compound of Formula I.

[0229] Figure 34 XRPD pattern of Form L DMAc solvate crystalline form of the compound of Formula I.

[0230] Figure 35 TGA pattern of Form L DMAc solvate crystalline form of the compound of Formula I.

[0231] Figure 36 DSC pattern of Form L DMAc solvate crystalline form of the compound of Formula I. DETAILED DESCRIPTION

[0232] The present application will be further described in the following specific examples, but it is not intended to limit the scope of protection of the present application. Those skilled in the art can make improvements to the preparation method and use the instruments within the scope of the claims, and these improvements should also be considered as the scope of protection of the present application. Therefore, the scope of protection of the present application patent should be subject to the appended claims.

[0233] In the present application, "room temperature" generally refers to 14°C to 31°C, unless otherwise specified.

[0234] The abbreviations used in the present application are explained as follows:

[0235] XRPD: X-ray powder diffraction

[0236] DSC: differential scanning calorimetry

[0237] TGA: thermogravimetric analysis

[0238] Instruments and methods used to collect data:

[0239] The X-ray powder diffraction patterns described in the present application were collected on a PANalytical X'Pert3 X-ray powder diffractometer.

[0240] The method parameters for the PANalytical X'Pert3 X-ray powder diffraction are as follows:

[0241] X-ray type: Cu, Kα

[0242] 1.540598; 1.544426

[0243] Kα2 / Kα1 intensity ratio: 0.50

[0244] Voltage: 45 kilovolts (kV)

[0245] Current: 40 milliamps (mA)

[0246] Divergence slit: 1 / 16 degree

[0247] Scan mode: continuous

[0248] Scan range: from 3.0 to 40.0 degrees

[0249] Step scan time: 46.665 seconds

[0250] Step size: 0.0263 degrees.

[0251] The differential scanning calorimetry (DSC) data described in the present application were collected on a TA Instruments Discovery DSC 2500 differential scanning calorimeter with instrument control software TRIOS and analysis software Universal Analysis. Typically, 1-5 milligrams of sample was placed in an aluminum crucible with lid (unless otherwise noted) and the sample was heated from room temperature to 350 °C at a rate of 10 °C / min under a dry N2flow of 50 mL / min, while the TA software recorded the heat flow of the sample during the temperature ramp. In the present application, melting points are reported as onset temperatures.

[0252] The thermal gravimetric analysis (TGA) data described herein were obtained using a Discovery TGA 5500 thermal gravimetric analyzer, instrument control software is TRIOS, and analysis software is Universal Analysis. Typically, 2-5 mg of sample was placed in a platinum crucible, and the sample was heated from room temperature to 350 °C at a ramp rate of 10 °C / min under a dry N2flow of 50 mL / min, while the TA software recorded the weight change of the sample during the heating process.

[0253] Unless otherwise specified, the following examples were performed at room temperature.

[0254] Further, when referring to figures such as XRPD patterns, DSC patterns, TGA patterns, etc., the term "substantially as shown in" refers to figures that are not necessarily identical to those described herein, but which fall within the limits of experimental error or deviation when considered by one of ordinary skill in the art.

[0255] For example, for XRPD patterns, at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks of an XRPD pattern of a certain crystalline form are shown in the given XRPD pattern. At the same time, variations in representative peak positions (2 theta) and relative peak intensities are taken into account. Peak positions can show some variation between different instruments and different samples, typically up to 0.1° to 0.2°. In addition, relative peak intensities can also vary between instruments and also due to the degree of crystallinity, preferred orientation, prepared sample, and other factors known to those skilled in the art.

[0256] As used herein, "substantially in agreement with the figure" as described for DSC patterns or TGA patterns is also intended to encompass variations known to those skilled in the art in connection with these analytical techniques. For well-defined peaks in DSC patterns, variations of typically up to ± 0.5 °C, and even more for broad peaks (up to ± 1 °C, or up to ± 5 °C, or up to ± 8 °C). For mass loss in TGA patterns, depending on many factors such as sample preparation and instrument, there are slight differences in the mass loss detected by different instruments and different samples, typically up to ± 1 %, or up to ± 2 % variation.

[0257] The impurity content data described herein were obtained using a Shimadzu LC-20A (VWD) high performance liquid chromatograph, with the following method parameters:

[0258] Column: Agilent Eplicse XDB C18 (4.6 x 150 mm, 5 μm), or equivalent

[0259] Column temperature: 40 °C

[0260] Flow rate: 1.0 ml / min

[0261] Wavelength: 262 nm

[0262] Run time: 29 min

[0263] Test method: Take HIF-117, add 80 ml acetonitrile to dissolve to obtain a solution containing about 0.2 mg per 1 ml, as a test solution, inject into a liquid chromatograph, record the chromatogram and total impurity content.

[0264] As used herein, "anhydrous crystal form" means a crystal form that does not contain solvent and water.

[0265] Without departing from the common general knowledge, the above-mentioned preferred conditions can be combined in any manner to obtain preferred embodiments of the present application.

[0266] The reagents and raw materials used in the present application are commercially available.

[0267] Finally, the skilled person in the art will understand that in the preparation of each crystal form of the HIF-117 compound described in the present application, it is necessary to dissolve the solid HIF-117 compound of the starting material. The starting material can be a crude product, and the HIF-117 compound can exist in the crude product in the form of crystals and / or amorphous substance.

[0268] Examples 1 to 4: Preparation of crystalline Form A

[0269] Under room temperature conditions, take an appropriate amount of compound HIF-117 raw material solid and place it in a 20-milliliter glass vial, add a corresponding volume of a positive solvent to obtain a clear solution, and filter the sample using a 0.45-micron pore size polytetrafluoroethylene filter. Then, take an appropriate amount of solution into a 20-milliliter glass vial, and add a corresponding anti-solvent dropwise to it. If solid precipitates, centrifuge the resulting solid. If no solid precipitates after adding about 9 milliliters of anti-solvent, stop adding the anti-solvent, transfer the sample to a 5°C environment and magnetically stir for five days, and then transfer the sample to room temperature and evaporate.

[0270] The solid obtained in this example is crystal form A. The detailed test conditions involved in this example are shown in Table 13.

[0271] Table 13

[0272]

[0273] Examples 5 to 7: Preparation of crystalline Form A

[0274] HIF-117 solid was weighed into a 3ml glass vial, and the appropriate volume of solvent was added to dissolve the solid. The sample was filtered using a 0.45 micron pore size polytetrafluoroethylene filter. The sample was capped with a cap liner and four pinholes were punched into the cap liner. The sample was then allowed to slowly evaporate at room temperature until solid precipitated.

[0275] The solid obtained in this example was Form A. The detailed experimental conditions involved in this example are shown in Table 14.

[0276] Table 14

[0277]

[0278]

[0279] Example 8: Preparation of crystalline Form A

[0280] HIF-117 solid 3.2kg, ethyl acetate 172kg were added into a reactor, and the stirring was started. The temperature was raised to reflux until the solid was completely dissolved. After distilling out 84kg of ethyl acetate, the temperature was lowered to 5°C to obtain 2.24kg of HIF-117 Form A.

[0281] Examples 9 to 10: Preparation of crystalline Form A

[0282] HIF-117 solid was weighed into a 3ml glass vial, and the appropriate volume of solvent was added to obtain a suspension. The suspension was stirred at 50°C for two hours. The sample solution was filtered hot into a new 3ml glass vial using a 0.45 micron pore size polytetrafluoroethylene filter. The vial was capped and the temperature was lowered from 50°C to 5°C. The vial was then kept at 5°C for five days. If no solid precipitated, the sample was transferred to room temperature to evaporate until solid precipitated.

[0283] The solid obtained in this example was Form A. The detailed experimental conditions involved in this example are shown in Table 15.

[0284] Table 15

[0285]

[0286] Example 11 : Preparation of crystalline Form A

[0287] Weigh 100.0 mg of compound HIF-117 solid into a 20 mL glass vial at room temperature. Add 2.5 mL of 1,4-dioxane to dissolve the solid. Filter the sample solution using a 0.45 μm pore size polytetrafluoroethylene (PTFE) membrane. Transfer 0.5 mL of the solution to a new 3 mL glass vial and place the vial open into a 20 mL glass vial pre-filled with 4 mL of water. Seal the vial and allow it to undergo gas-liquid permeation at room temperature for 7 days. Transfer the vial to room temperature for evaporation to obtain HIF-117 crystal form A.

[0288] Examples 1 to 11 above are all specific methods for preparing crystal form A and their scale-up production methods. Those skilled in the art can clearly understand through the above experiments that crystal form A can be prepared by the crystal form preparation methods described above, and can also be scaled up to form a batch of crystal form A products.

[0289] The products of Examples 1 to 11 described above, as tested by XRPD, were all of crystal form A.

[0290] The crystal form A prepared in Example 8 was tested by XRPD. The XRPD data of this crystal form are shown in Table 1, and the XRPD plot is shown in the figure. Figure 1 As shown, the TGA diagram is as follows: Figure 2 As shown, the DSC diagram is as follows Figure 3 As shown. By Figure 2 It can be seen that when heated to approximately 200℃, there is no significant weight loss, only 0.28% by weight; Figure 3 It can be seen that there is an endothermic peak at approximately 222.0℃ (peak temperature).

[0291] Example 12: Preparation of crystalline Form B

[0292] 20.9 mg of solid HIF-117 was weighed at room temperature and placed in a 3 mL glass vial. 1.0 mL of tetrahydrofuran / water (volume ratio 1:1) was added to dissolve the solid. The solution was filtered through a 0.45 μm pore size polytetrafluoroethylene (PTFE) membrane. The sample was sealed with a sealing film, which was then punctured with four pinholes. The solution was then allowed to slowly evaporate at room temperature until solid precipitated, yielding HIF-117 crystal form B.

[0293] Examples 13 to 20: Preparation of crystalline Form B

[0294] Weigh an appropriate amount of solid HIF-117 crystal form A at room temperature and place it in an HPLC glass vial or container. Add an appropriate volume of solvent to obtain a suspension. Stir magnetically at room temperature, 50°C, or other temperatures, and collect the solid.

[0295] The solid obtained in this embodiment is crystal form B. The detailed experimental conditions involved in this embodiment are shown in Table 16.

[0296] Table 16

[0297]

[0298] The products of Examples 12-20 above were all of crystal form B as determined by XRPD testing. The XRPD data for crystal form B prepared in Example 20 are shown in Table 2, and the XRPD plots are shown below. Figure 4 As shown, the TGA diagram is as follows: Figure 5 As shown, the DSC diagram is as follows Figure 6 As shown. By Figure 5 It can be seen that when heated to approximately 90°C, there is a weight loss of 0.27% by weight; when heated from 90°C to approximately 200°C, there is a weight loss of 4.63% by weight. It is inferred that the molar ratio of water to HIF-117 is 1. Figure 6 It can be seen that there is an endothermic peak at approximately 130.5℃ (peak temperature), an endothermic peak at 138.0℃ (peak temperature), an endothermic peak at 222.5℃ (peak temperature), and an exothermic peak at 135.5℃ (peak temperature).

[0299] Examples 21 to 23: Preparation of crystalline Form C

[0300] Weigh an appropriate amount of the HIF-117 raw material solid at room temperature and place it in a 20 mL glass vial. Add the corresponding volume of positive solvent to obtain a clear solution. Filter any undissolved sample using a 0.45 μm PTFE filter membrane. Then, transfer an appropriate amount of solution to a 20 mL glass vial and add the corresponding antisolvent dropwise. If solid precipitates, centrifuge to separate the solid. If no solid precipitates after adding approximately 9 mL of antisolvent, stop adding the antisolvent, transfer the sample to a 5 °C environment, and magnetically stir for five days. Finally, allow the sample to evaporate at room temperature.

[0301] The solids obtained in this embodiment are all of crystal form C. The detailed experimental conditions involved in this embodiment are shown in Table 17.

[0302] Table 17

[0303]

[0304]

[0305] Example 24: Preparation of crystalline Form C

[0306] 20.9 mg of compound HIF-117 solid was weighed at room temperature and placed in a 3 mL glass vial. 0.5 mL of tetrahydrofuran was added to dissolve the solid. The sample was sealed with sealing film and four pinholes were punched in it. The sample was then allowed to evaporate slowly at room temperature until solid precipitated to obtain HIF-117 crystal form C.

[0307] The XRPD data of the product prepared in Example 23 in Form C is shown in Table 3, the XRPD pattern is shown in Figure 3, the TGA test result is shown in Figure 4, the DSC pattern is shown in Figure 5. It can be seen from Figure 4 that the weight loss starts at 29.4°C, and there is a weight loss of 3.22% when heated to 100°C, and there is a weight loss of 6.45% when heated from 100°C to about 200°C; it can be seen from Figure 5 that there is an endothermic peak at about 137.4°C (peak temperature), an endothermic peak at 188.2°C (peak temperature), an endothermic peak at 221.6°C (peak temperature), and an exothermic peak at 189.9°C (peak temperature). The molar ratio of tetrahydrofuran to HIF-117 is 0.3 by HNMR detection. To study the TGA weight loss of Form C, the Form C prepared in Example 23 was heated to 150°C and cooled to room temperature, and then the XRPD was tested. The results showed that the sample was converted to Form D; the sample was heated to 200°C and cooled to room temperature, and then the XRPD was tested. The results showed that the sample was converted to Form A. Figure 7 Figure 8 Figure 9 Figure 8 Figure 9

[0308] Examples 25 to 26: Preparation of crystalline Form D

[0309] An appropriate amount of solid compound HIF-117 raw material was weighed and placed in a 20-milliliter glass vial, and a corresponding volume of a positive solvent was added to obtain a clear solution. The sample that was not dissolved was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 microns. Then, an appropriate amount of solution was transferred to a 20-milliliter glass vial, and a corresponding amount of an anti-solvent was added dropwise. If solid precipitated, the resulting solid was centrifuged. If no solid precipitated after about 9 milliliters of anti-solvent was added, the addition of anti-solvent was stopped, and the sample was transferred to a 5°C environment and magnetically stirred for five days. If no solid precipitated, the sample was transferred to room temperature and the solid was collected by evaporation to obtain HIF-117 Form D.

[0310] The detailed test conditions involved in this example are shown in Table 18.

[0311] Table 18

[0312]

[0313] Example 27: Preparation of crystalline Form D

[0314] ​​​​​HIF-117 solid was weighed out in an amount of 82.3 mg in a 20 ml glass vial, 2 ml of 2-methyltetrahydrofuran was added to dissolve the solid, the sample solution was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 μm, and 0.5 ml of the solution was taken into a new 3 ml glass vial, which was then placed in a 20 ml glass bottle pre-filled with 4 ml of methanol. After sealing, the sample was subjected to gas-liquid penetration at room temperature for 7 days, and then transferred to a solid collection device at room temperature to obtain HIF-117 crystalline form D.

[0315] The products of Examples 25-27 were all crystalline form D as determined by XRPD. The XRPD data of the crystalline form D prepared in Example 27 are shown in Table 4, the XRPD pattern is shown in Figure 10 , the TGA pattern is shown in Figure 11 , and the DSC pattern is shown in Figure 12 . As shown in Figure 11 , only 1.92% weight loss occurred when the temperature was raised to about 150.0°C. As shown in Figure 12 , there was an endothermic peak at about 189.5°C (peak temperature), an endothermic peak at about 221.3°C (peak temperature), and an exothermic peak at about 191.6°C (peak temperature), indicating that it had stability.

[0316] Example 28: Preparation of crystalline Form E

[0317] HIF-117 solid was weighed out in an amount of 20.8 mg in a 3 ml glass vial, which was then placed in a 20 ml glass bottle pre-filled with 4 ml of dimethyl sulfoxide, and subjected to gas-solid penetration at room temperature for 7 days after sealing, and then the solid was collected to obtain HIF-117 crystalline form E.

[0318] Examples 29 to 30: Preparation of crystalline Form E

[0319] HIF-117 solid was weighed out in an amount of 20.8 mg in a 3 ml glass vial, which was then placed in a 20 ml glass bottle pre-filled with 4 ml of dimethyl sulfoxide, and subjected to gas-solid penetration at room temperature for 7 days after sealing, and then the solid was collected to obtain HIF-117 crystalline form E.

[0320] The detailed test conditions in this example are shown in Table 19.

[0321] Table 19

[0322]

[0323] Example 31 : Preparation of crystalline Form E

[0324] At room temperature, 20.8 mg of solid compound HIF-117 was weighed into a HPLC glass vial, and 0.3 mL of dimethyl sulfoxide / isopropyl acetate (1:9) was added to obtain a suspension. The mixture was stirred at room temperature, and the solid was collected to obtain HIF-117 Form E.

[0325] The product of Example 28-31 were tested by XRPD, all of which were Form E. The XRPD data of Form E prepared in Example 31 are shown in Table 5, the XRPD pattern is shown in Figure 13 , the TGA pattern is shown in Figure 14 , and the DSC pattern is shown in Figure 15 . As can be seen from Figure 14 , it has a weight loss of 19.77% when heated to about 200.0°C. As can be seen from Figure 15 , there is an endothermic peak at about 79.1°C (peak temperature), an endothermic peak at 100.5°C (peak temperature), an endothermic peak at 161.5°C (peak temperature), and an endothermic peak at 200.2°C (peak temperature). HNMR detection shows that the molar ratio of dimethyl sulfoxide to HIF-117 is 0.9. To study the TGA weight loss of Form E, the Form E prepared in Example 31 was heated to 120°C and cooled to room temperature, and then XRPD was tested. The results show that the sample is converted to Form J.

[0326] Example 32: Preparation of crystalline Form F

[0327] At room temperature, 19.6 mg of solid compound HIF-117 was weighed into a 3 mL glass vial, which was placed in a 20 mL glass bottle pre-filled with 4 mL of N-methyl pyrrolidone. After sealing, it was placed at room temperature for 7 days of gas-solid penetration, and the solid was collected to obtain HIF-117 Form F.

[0328] The XRPD data of Form F prepared in this example are shown in Table 6, the XRPD pattern is shown in Figure 16 , the TGA pattern is shown in Figure 17 , and the DSC pattern is shown in Figure 18 . As can be seen from Figure 17 , it has a weight loss of 12.71% when heated to about 160.0°C, and a weight loss of 7.08% when heated to about 250.0°C. As can be seen from Figure 18 , there is an endothermic peak at about 91.2°C (peak temperature), and an endothermic peak at 211.2°C (peak temperature). HNMR detection shows that the molar ratio of N-methyl pyrrolidone to HIF-117 is 0.7. To study the TGA weight loss, the Form F prepared in this example was heated to 150°C and cooled to room temperature, and then XRPD was tested. The results show that the sample is converted to Form A.

[0329] Example 33: Preparation of crystalline Form G

[0330] HIF-117 solid was weighed into a 20 mL glass vial at room temperature, 1,4-dioxane 3.0 mL was added to dissolve the solid, the sample solution was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 μm, and 0.5 mL of the solution was taken into a new 3 mL glass vial, which was left open in a 20 mL glass bottle pre-filled with 4 mL of acetonitrile. After sealing, it was left to vaporize at room temperature for 7 days, and then transferred to room temperature to collect the solid to obtain HIF-117 crystalline form G.

[0331] Example 34: Preparation of crystalline Form G

[0332] HIF-117 solid was weighed into a 20 mL glass vial at room temperature, 1,4-dioxane 3.0 mL was added to dissolve the solid, the sample solution was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 μm, and 0.5 mL of the solution was taken into a new 3 mL glass vial, which was left open in a 20 mL glass bottle pre-filled with 4 mL of acetonitrile. After sealing, it was left to vaporize at room temperature for 7 days, and then transferred to room temperature to collect the solid to obtain HIF-117 crystalline form G.

[0333] Examples 35 to 40: Preparation of crystalline Form G

[0334] HIF-117 solid was weighed into a 20 mL glass vial at room temperature, 1,4-dioxane 3.0 mL was added to dissolve the solid, the sample solution was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 μm, and 0.5 mL of the solution was taken into a new 3 mL glass vial, which was left open in a 20 mL glass bottle pre-filled with 4 mL of acetonitrile. After sealing, it was left to vaporize at room temperature for 7 days, and then transferred to room temperature to collect the solid to obtain HIF-117 crystalline form G.

[0335] The detailed test conditions involved in this example are shown in Table 20.

[0336] Table 20

[0337]

[0338]

[0339] The products of Examples 33-40 were tested by XRPD, and all were crystalline form G. The XRPD data of the crystalline form G prepared in Example 40 are shown in Table 7, the XRPD pattern is shown in Figure 19 , the TGA pattern is shown in Figure 20 , and the DSC pattern is shown in Figure 21 . As can be seen from Figure 20 , it has a weight loss of 2.19% when heated to about 200.0°C. As can be seen from Figure 21 , there is an exothermic peak at about 187.9°C (peak temperature), and an endothermic peak at 222.6°C (peak temperature).

[0340] Examples 41 to 42: Preparation of crystalline Form H

[0341] An appropriate amount of compound HIF-117 solid was weighed into a HPLC glass vial, and a corresponding volume of solvent was added to obtain a suspension. The suspension was stirred magnetically at room temperature, and the solid was collected to obtain HIF-117 Form H.

[0342] The detailed experimental conditions involved in this example are shown in Table 21.

[0343] Table 21

[0344]

[0345] The product of the above Examples 41-42 was tested by XRPD, and was Form H. The XRPD data of the Form H prepared in Example 41 are shown in Table 8, the XRPD pattern is shown in Figure 22 , the TGA pattern is shown in Figure 23 , and the DSC pattern is shown in Figure 24 . As can be seen from Figure 23 , there was a weight loss of 5.79% when heated to about 200.0°C. As can be seen from Figure 24 , there was an endothermic peak at about 219.0°C (peak temperature).

[0346] Example 43: Preparation of crystalline Form I

[0347] An appropriate amount of compound HIF-117 solid was weighed into a HPLC glass vial, and a corresponding volume of solvent was added to obtain a suspension. The suspension was stirred magnetically at room temperature, and the solid was collected to obtain HIF-117 Form H.

[0348] Examples 44 to 46: Preparation of crystalline Form I

[0349] An appropriate amount of compound HIF-117 solid was weighed into a HPLC glass vial, and a corresponding volume of solvent was added to obtain a suspension. The suspension was stirred magnetically at room temperature, and the solid was collected to obtain HIF-117 Form H.

[0350] Table 22

[0351]

[0352]

[0353] The products of the above Examples 43-46 were tested by XRPD, all of which were Form I. Among them, the XRPD data of Form I prepared in Example 45 are shown in Table 9, the XRPD pattern is shown in Figure 25 , the TGA pattern is shown in Figure 26 , and the DSC pattern is shown in Figure 27 . As can be seen from Figure 26 , it has a weight loss of 3.04% when heated to about 200.0°C, and the molar ratio of water to HIF-117 is 0.7. As can be seen from Figure 27 , there is an endothermic peak at about 186.1°C (peak temperature), an endothermic peak at about 220.5°C (peak temperature), and an exothermic peak at about 189.6°C. In addition, there is a small endothermic peak at about 146.9°C (peak temperature). The Form I prepared in Example 45 was tested by temperature-variable XRPD, and the results showed that the Form I did not change after being purged with nitrogen for 20 minutes, and partially changed to Form A after being heated to 120°C and 150°C in a nitrogen atmosphere, and completely changed to Form A after being heated to 200°C.

[0354] Example 47: Preparation of crystalline Form J

[0355] At room temperature, 82.3 mg of solid compound HIF-117 was weighed into a 20 mL glass vial, 2.0 mL of 2-methyltetrahydrofuran was added to dissolve the solid, the sample solution was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 μm, and 0.5 mL of the solution was taken into a new 3 mL glass vial, which was placed in a 20 mL glass bottle pre-filled with 4 mL of dichloromethane, and was sealed and placed at room temperature for evaporation until solid was precipitated to obtain Form J of HIF-117.

[0356] Example 48: Preparation of crystalline Form J

[0357] At room temperature, 20.3 mg of solid compound HIF-117 was weighed into a 3 mL glass vial, 0.5 mL of 2-methyltetrahydrofuran was added to dissolve the solid, the sample was sealed with a sealing film and four pinholes were punched on it, and then was placed at room temperature for slow evaporation until solid was precipitated to obtain Form J of HIF-117.

[0358] The products of the above Examples 47-48 were tested by XRPD, all of which were Form J. Among them, the XRPD data of Form J prepared in Example 48 are shown in Table 10, the XRPD pattern is shown in Figure 28 , the TGA pattern is shown in Figure 29 , and the DSC pattern is shown in Figure 30 . As can be seen fromFigure 29 It can be seen that when heated to approximately 150.0℃, it experiences a weight loss of 2.68% by weight. Figure 30 It can be seen that there is an endothermic peak at approximately 214.5℃ (peak temperature); there is an endothermic peak at approximately 220.4℃ (peak temperature); and there is a smaller endothermic peak at approximately 84℃ (peak temperature).

[0359] Examples 49 to 50: Preparation of crystalline Form K

[0360] Weigh an appropriate amount of solid HIF-117 compound into a 3 mL glass vial at room temperature, add an appropriate volume of solvent to dissolve the solid, seal the sample with sealing film and poke four pinholes in it, and then allow it to slowly evaporate at room temperature until the solid precipitates to obtain HIF-117 crystal form K. The detailed experimental conditions involved in this example are shown in Table 23.

[0361] Table 23

[0362]

[0363]

[0364] The products from Examples 49-50 were all XRPD tested and found to be crystal form K. The XRPD data for crystal form K prepared in Example 49 are shown in Table 11, and the XRPD plots are shown below. Figure 31 As shown, the TGA diagram is as follows: Figure 32 As shown, the DSC diagram is as follows Figure 33 As shown. By Figure 32 It can be seen that when heated to approximately 150.0℃, it experiences a weight loss of 18.81% by weight. Figure 33 It can be seen that there is an endothermic peak at approximately 91.6℃ (peak temperature), an endothermic peak at approximately 216.9℃ (peak temperature), and an endothermic peak at approximately 220.9℃ (peak temperature). HNMR analysis showed that the molar ratio of 1,4-dioxane to HIF-117 was 0.9. To study the DSC signal of crystal form K, crystal form K prepared in Example 49 was heated to 150°C and then cooled to room temperature before XRPD testing. The results showed that crystal form K transformed into crystal form J after heating.

[0365] Example 51 : Preparation of crystalline Form L

[0366] 86.2 mg of compound HIF-117 raw material solid was weighed at room temperature and placed in a 20 mL glass vial. 1.2 mL of N,N-dimethylacetamide was added to obtain a clear solution. Then, an appropriate amount of the solution was transferred to a 20 mL glass vial and 9 mL of acetonitrile was added dropwise. The sample was then transferred to room temperature to volatilize and obtain HIF-117 crystal form L.

[0367] The XRPD data for crystal form L of product 51 in this embodiment are shown in Table 12, and the XRPD plot is shown in... Figure 34 As shown, the TGA diagram is as follows: Figure 35 As shown, the DSC diagram is as follows Figure 36 As shown. By Figure 35 It can be seen that when heated to approximately 150.0℃, it experiences a weight loss of 13.47% by weight. Figure 36 As can be seen, there is an endothermic peak at approximately 86.8℃ (peak temperature), an endothermic peak at approximately 207.0℃ (peak temperature), an endothermic peak at approximately 216.0℃ (peak temperature), and an exothermic peak at approximately 95.1℃ (peak temperature). Additionally, there is an endothermic peak at approximately 104.1℃ (peak temperature). HNMR analysis showed that the molar ratio of N,N-dimethylacetamide to HIF-117 was 0.5. To study the DSC signal of crystal form L, the product of Example 51, crystal form L, was heated to 130℃ and then cooled to room temperature before XRPD testing. The results showed that crystal form L transformed into crystal form J after heating.

[0368] Example 52: Suspension competition experiment between crystalline Form A, crystalline Form D, crystalline Form G, crystalline Form H, crystalline Form J

[0369] 7.5 mg of HIF-117 was weighed into EtOAc and stirred for 3 hours at room temperature and 50°C, respectively, before filtration. The filtrate was transferred to an HPLC vial containing free crystal form A and crystal form G, and the suspension was further stirred at room temperature and 50°C. After 7 days of competitive suspension in the EtOAc system, crystal form J was added, followed by crystal form H after 11 days, and crystal forms D and I after 19 days.

[0370] Table 24

[0371]

[0372] XRPD results show that crystal form A is thermodynamically more stable at room temperature and 50°C.

[0373] Example 53: Hygroscopicity study of crystalline Form A

[0374] The crystal form A sample was subjected to a dynamic water adsorption (DVS) test under constant temperature conditions of 25°C and humidity variations of 0%RH-95%RH-0%RH. The conclusions are shown in Table 25.

[0375] Table 25

[0376] Name Moisture sorption (25°C / 80% RH) XRPD before and after DVS Crystalline Form A 0.069％ No change

[0377] This indicates that crystal form A sample does not easily absorb moisture during storage, is easy to preserve, and can have a long shelf life.

[0378] Example 54: Mechanical stability of crystalline Form A

[0379] The XRPD of the Form A tablet was tested after tabletting at different pressures of 2000 bar, 4000 bar, and 6000 bar, and showed that the crystal form did not change significantly.

[0380] Example 55: Stability test of crystalline Form A

[0381] An appropriate amount of Form A sample was placed in an open weighing bottle, spread into a 5 mm thick layer, and placed in a high temperature (60°C), high humidity (92.5% RH), and light (without packaging and with packaging, total illumination greater than 1.2 x 10 6 Lux.hr, total illumination greater than 3.6 x 10 6 Lux.hr, near ultraviolet energy ≥ 200 W.hr / m 2 The illumination time of the ultraviolet lamp was controlled to be 48 h), and samples were taken at 5, 10, and 30 days for testing (total impurities and XRPD). The results are shown in Table 26.

[0382] Table 26

[0383] Test conditions Total impurities (%) XRPD 0 days 0.44 Crystalline Form A 5 days, 60°C 0.38 Crystalline Form A 5 days, high humidity 0.39 Crystalline Form A 5 days, light 0.88 Crystalline Form A 5 days, light (protected from light with packaging) 0.41 Crystalline Form A 10 days, 60°C 0.40 Crystalline Form A 10 days, high humidity 0.40 Crystalline Form A 10 days, light 1.08 Crystalline Form A 10 days, light (darkness) 0.41 Form A 30 days, 60°C 0.38 Form A 30 days, high humidity 0.39 Form A 30 days, light 1.32 Form A 30 days, light (darkness) 0.40 Form A

[0384] The stability results show that the Form A crystal form is stable under high temperature, high humidity, and light-avoiding conditions, and does not change significantly. The impurities increase under light conditions, and the purity almost does not change under high temperature, high humidity, and light (light-avoiding) conditions. It exhibits good stability.

[0385] Example 56: Bioavailability of Form A

[0386] Sprague-Dawley rats were selected, with 6 rats in each group, and half male and half female. After the SD rats were administered HIF-117 (anhydrous Form E or Form A) at a dose of 3 mg / kg by intravenous injection (IV) and at a dose of 8, 20, and 40 mg / kg by oral gavage (IG), the concentration of HIF-117 in the plasma of the rats was determined, and the pharmacokinetic parameters of HIF-117 in the SD rats and the bioavailability after IG administration were calculated using the non-compartment model in Phoenxi WinNonlin 7.0.

[0387] The results show that after IG administration at doses of 8, 20, and 40 mg / kg, the average bioavailability was 65.4%, 74.1%, and 96.8%, respectively, indicating that HIF-117 (anhydrous Form E or Form A) has good in vivo absorption characteristics and good bioavailability in rats.

[0388] The above merely describes preferred embodiments of the present application, and is not intended to limit the present application in any form or in essence. It should be noted that those skilled in the art can make some improvements and supplements without departing from the method of the present application, and these improvements and supplements should also be considered as the protection scope of the present application. For those skilled in the art, some slight changes, modifications and equivalent changes made by using the disclosed technical content without departing from the spirit and scope of the present application are equivalent embodiments of the present application; meanwhile, any equivalent changes, modifications and evolution made according to the essential technology of the present application to the above embodiments are still within the scope of the technical solutions of the present application.

Claims

1. A crystal form of a compound or its solvate with the structural formula shown in Formula I, characterized in that, The crystal form is selected from any one or more of the following twelve: crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J, crystal form K, and crystal form L; Among them, crystal forms A, D, G, H and J are anhydrous, crystal forms B and I are hydrates, crystal form C is a tetrahydrofuran solvate, crystal form E is a dimethyl sulfoxide solvate, crystal form F is an N-methylpyrrolidone solvate, crystal form K is a 1,4-dioxane solvate, and crystal form L is an N,N-dimethylacetamide solvate.

2. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 14.56±0.2°, 18.45±0.2°, 18.81±0.2° and 21.81±0.2°; And / or, the X-ray powder diffraction pattern of the crystal form B has characteristic peaks at 2θ values ​​of 11.88±0.2°, 15.26±0.2°, 15.43±0.2°, 16.62±0.2° and 26.16±0.2°; And / or, the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2θ values ​​of 5.26±0.2°, 12.81±0.2°, 15.30±0.2° and 15.80±0.2°; And / or, the X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 2θ values ​​of 5.47±0.2°, 12.97±0.2°, 15.85±0.2° and 16.44±0.2°; And / or, the X-ray powder diffraction pattern of the crystal form E has characteristic peaks at 2θ values ​​of 4.34±0.2°, 13.01±0.2°, 15.29±0.2°, 15.90±0.2°, 16.62±0.2°, 17.39±0.2°, 20.13±0.2° and 25.06±0.2°; And / or, the X-ray powder diffraction pattern of the crystal form F has characteristic peaks at 2θ values ​​of 3.99±0.2°, 11.92±0.2°, 14.53±0.2°, 15.06±0.2°, 17.62±0.2°, 23.30±0.2°, 25.86±0.2° and 26.56±0.2°; And / or, the X-ray powder diffraction pattern of the crystal form G has characteristic peaks at 2θ values ​​of 5.48±0.2°, 12.03±0.2°, 12.97±0.2°, 15.89±0.2° and 16.47±0.2°; And / or, the X-ray powder diffraction pattern of the crystal form H has characteristic peaks at 2θ values ​​of 7.33±0.2°, 10.07±0.2°, 14.35±0.2° and 14.72±0.2°; And / or, the X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ values ​​of 5.48±0.2°, 12.05±0.2°, 12.85±0.2°, 15.39±0.2° and 16.49±0.2°; And / or, the X-ray powder diffraction pattern of the crystal form J has characteristic peaks at 2θ values ​​of 5.04±0.2°, 10.07±0.2°, 14.59±0.2°, 14.82±0.2°, 16.04±0.2° and 18.79±0.2°; And / or, the X-ray powder diffraction pattern of the crystal form K has characteristic peaks at 2θ values ​​of 4.27±0.2°, 12.80±0.2°, 14.62±0.2°, 14.71±0.2°, 17.09±0.2°, 17.75±0.2°, 19.79±0.2° and 20.54±0.2°; And / or, the X-ray powder diffraction pattern of the crystal form L has characteristic peaks at 2θ values ​​of 4.84±0.2°, 6.50±0.2°, 14.54±0.2° and 21.41±0.2°.

3. The crystal form according to claim 2, characterized in that, The X-ray powder diffraction pattern of crystal form A also has a characteristic peak at at least one of the following 2θ values: 9.92±0.2°, 11.88±0.2°, 13.31±0.2°, 23.96±0.2°, 24.56±0.2°, and 25.22±0.2°. And / or, the X-ray powder diffraction pattern of crystal form B also has a characteristic peak at at least one of the following 2θ values: 17.93±0.2°, 20.20±0.2°, 22.50±0.2°, 23.40±0.2°, and 28.70±0.2°; And / or, the X-ray powder diffraction pattern of crystal form C is shown in Table 3; more preferably, the X-ray powder diffraction pattern of crystal form C is shown in Figure 7; And / or, the X-ray powder diffraction pattern of the crystal form D is shown in Table 4; more preferably, the X-ray powder diffraction pattern of the crystal form D is shown in Figure 10; And / or, the X-ray powder diffraction pattern of the crystal form E is shown in Table 5; more preferably, the X-ray powder diffraction pattern of the crystal form E is shown in Figure 13; And / or, the X-ray powder diffraction pattern of the crystal form F is shown in Table 6; more preferably, the X-ray powder diffraction pattern of the crystal form F is shown in Figure 16; And / or, the X-ray powder diffraction pattern of the crystal form G is shown in Table 7; more preferably, the X-ray powder diffraction pattern of the crystal form F is shown in Figure 19; And / or, the X-ray powder diffraction pattern of the crystal form H is shown in Table 8; more preferably, the X-ray powder diffraction pattern of the crystal form H is shown in Figure 22; And / or, the X-ray powder diffraction pattern of crystal form I is shown in Table 9; more preferably, the X-ray powder diffraction pattern of crystal form I is shown in Figure 25; And / or, the X-ray powder diffraction pattern of crystal form J is shown in Table 10; more preferably, the X-ray powder diffraction pattern of crystal form J is shown in Figure 28; And / or, the X-ray powder diffraction pattern of the crystal form K is shown in Table 11; more preferably, the X-ray powder diffraction pattern of the crystal form K is shown in Figure 31; And / or, the X-ray powder diffraction pattern of the crystal form L also has a characteristic peak at at least one of the following 2θ values: 8.65±0.2°, 13.02±0.2°, 16.78±0.2°, and 19.47±0.2°.

4. The crystal form according to claim 3, characterized in that, The X-ray powder diffraction pattern of crystal form A has a characteristic peak at at least one of the following 2θ values: 8.45±0.2°, 8.76±0.2°, 14.76±0.2°, 16.97±0.2°, 17.73±0.2°, 20.66±0.2°, 22.00±0.2°, and 23.82±0.2°. Preferably, the X-ray powder diffraction pattern of crystal form A is shown in Table 1. More preferably, the X-ray powder diffraction pattern of crystal form A is shown in Figure 1. And / or, the X-ray powder diffraction pattern of crystal form B is shown in Table 2; more preferably, the X-ray powder diffraction pattern of crystal form B is shown in Figure 4; And / or, the X-ray powder diffraction pattern of the crystal form L is shown in Table 12; more preferably, the X-ray powder diffraction pattern of the crystal form L is shown in Figure 34.

5. The crystal form according to claim 1, characterized in that, In the thermogravimetric analysis diagram of crystal form A, there is no significant weight loss when the temperature is raised to 200±5℃. Preferably, in the thermogravimetric analysis diagram of crystal form A, there is a weight loss of no more than 0.5% by weight when the temperature is raised to 200±5℃. More preferably, the thermogravimetric analysis diagram of crystal form A is basically consistent with Figure 2. And / or, in the thermogravimetric analysis (TGA) diagram of crystal form B, there is no significant weight loss when the temperature is raised to 90±5℃; preferably, in the TGA diagram of crystal form B, there is a weight loss of no more than 0.5% by weight when the temperature is raised to 90±5℃; more preferably, in the TGA diagram of crystal form B, there is a weight loss of no more than 5% by weight when the temperature is raised to 200±5℃; even more preferably, the TGA diagram of crystal form B is substantially consistent with Figure 5. And / or, in the thermogravimetric analysis diagram of crystal form C, there is a weight loss of no more than 3.5% by weight when the temperature is raised to 100±5℃; preferably, in the thermogravimetric analysis diagram of crystal form C, there is a weight loss of no more than 10% by weight when the temperature is raised to 200±5℃; more preferably, the thermogravimetric analysis diagram of crystal form C is substantially consistent with Figure 8. And / or, in the thermogravimetric analysis diagram of crystal form D, the weight loss is no more than 2.0% by weight when the temperature is raised to 150±5℃; more preferably, the thermogravimetric analysis diagram of crystal form D is substantially consistent with that of Figure 11; And / or, in the thermogravimetric analysis diagram of crystal form E, the weight loss upon heating to 200±5℃ is no more than 20% by weight; preferably, in the thermogravimetric analysis diagram of crystal form E, the weight loss upon heating to 200±5℃ is no more than 19.8% by weight; more preferably, the thermogravimetric analysis diagram of crystal form E is substantially consistent with Figure 14; And / or, in the thermogravimetric analysis diagram of crystal form F, there is a weight loss of no more than 13.0% by weight when the temperature is raised to 160±5℃; preferably, in the thermogravimetric analysis diagram of crystal form F, there is a further weight loss of no more than 7.5% by weight between 160±5℃ and 250±5℃; more preferably, the thermogravimetric analysis diagram of crystal form F is substantially consistent with Figure 17. And / or, in the thermogravimetric analysis diagram of the crystal form G, the weight loss upon heating to 200±5℃ is no more than 2.5% by weight; preferably, in the thermogravimetric analysis diagram of the crystal form G, the weight loss upon heating to 200±5℃ is no more than 2.2% by weight; more preferably, the thermogravimetric analysis diagram of the crystal form G is substantially consistent with Figure 20; And / or, in the thermogravimetric analysis diagram of crystal form H, there is a weight loss of no more than 5.8% by weight when the temperature is raised to 200±5℃; more preferably, the thermogravimetric analysis diagram of crystal form H is substantially consistent with Figure 23; And / or, in the thermogravimetric analysis diagram of crystal form I, there is a weight loss of no more than 3.1% by weight when the temperature is raised to 200±5℃; more preferably, the thermogravimetric analysis diagram of crystal form I is substantially consistent with Figure 26; And / or, in the thermogravimetric analysis diagram of crystal form J, there is a weight loss of no more than 3.0% by weight when the temperature is raised to 150±5℃; more preferably, the thermogravimetric analysis diagram of crystal form J is substantially consistent with Figure 29; And / or, in the thermogravimetric analysis diagram of crystal form K, there is a weight loss of no more than 19% by weight when the temperature is raised to 150±5℃; more preferably, the thermogravimetric analysis diagram of crystal form K is substantially consistent with Figure 32; And / or, in the thermogravimetric analysis diagram of the crystal form L, there is a weight loss of no more than 13.5% by weight when the temperature is raised to 150±5℃; more preferably, the thermogravimetric analysis diagram of the crystal form L is substantially consistent with that of Figure 35.

6. The crystal form according to claim 1, characterized in that, The differential scanning calorimetry (DSC) curve of crystal form A shows an endothermic peak at 222.0 ± 5 °C. More preferably, the DSC curve of crystal form A is substantially the same as that in Figure 3. And / or, the differential scanning calorimetry plot of crystal form B has endothermic peaks at 130.5±5℃, 138.0±5℃ and 222.5±5℃, and an exothermic peak at 135.5±5℃; more preferably, the differential scanning calorimetry plot of crystal form B is substantially consistent with that of Figure 6. And / or, the differential scanning calorimetry plot of the crystal form C has endothermic peaks at 137.4±5℃, 188.2±5℃ and 221.6±5℃, and an exothermic peak at 189.9℃±5℃; more preferably, the differential scanning calorimetry plot of the crystal form C is substantially consistent with Figure 9. And / or, the differential scanning calorimetry plot of the crystal form D has endothermic peaks at 189.5±5℃ and 221.3±5℃, and an exothermic peak at 191.6±5℃; more preferably, the differential scanning calorimetry plot of the crystal form D is substantially consistent with Figure 12. And / or, the differential scanning calorimetry plot of crystal form E has endothermic peaks at 79.1±5℃ and 100.5±5℃; preferably, it further has endothermic peaks at 161.5±5℃ and / or 200.2±5℃; more preferably, the differential scanning calorimetry plot of crystal form E is substantially consistent with Figure 15; And / or, the differential scanning calorimetry plot of the crystal form F has endothermic peaks at 91.2±5℃ and 211.2±5℃; more preferably, the differential scanning calorimetry plot of the crystal form F is substantially consistent with Figure 18. And / or, the differential scanning calorimetry plot of the crystal form G has an endothermic peak at 222.6±5℃ and an exothermic peak at 187.9±5℃; more preferably, the differential scanning calorimetry plot of the crystal form G is substantially consistent with Figure 21. And / or, the differential scanning calorimetry plot of the crystal form H has an endothermic peak at 219.0±5℃; more preferably, the differential scanning calorimetry plot of the crystal form H is substantially consistent with Figure 24; And / or, the differential scanning calorimetry (DSC) plot of crystal form I has endothermic peaks at 186.1±5℃ and 220.5±5℃, and an exothermic peak at 189.6±5℃; preferably, the DSC plot of crystal form I also has an endothermic peak at 146.9±5℃; more preferably, the DSC plot of crystal form I is substantially consistent with Figure 27; And / or, the differential scanning calorimetry plot of crystal form J has endothermic peaks at 214.5±5℃ and 220.4±5℃, preferably, it also has an endothermic peak at 84.0±5℃; more preferably, the differential scanning calorimetry plot of crystal form J is substantially consistent with Figure 30. And / or, the differential scanning calorimetry plot of the crystal form K has endothermic peaks at 91.6±5℃, 216.9±5℃ and 220.9±5℃; more preferably, the differential scanning calorimetry plot of the crystal form K is substantially consistent with Figure 33. And / or, the differential scanning calorimetry (DSC) plot of crystal form L has endothermic peaks at 86.8±5℃, 207.0±5℃ and 216.0±5℃, and an exothermic peak at 95.1±5℃; preferably, the DSC plot of crystal form L also has an endothermic peak at 104.1±5℃; more preferably, the DSC plot of crystal form L is substantially consistent with Figure 36.

7. A method for preparing a crystal form according to any one of claims 1 to 6, characterized in that, The compound of formula I is contacted or reacted with a solvent, and then the corresponding crystalline form is prepared.

8. The preparation method according to claim 7, characterized in that, The solvent is selected from one or more of water, alcohols, ketones, esters, alkanes, aromatic hydrocarbons, halogenated hydrocarbons, nitriles, ethers, and aliphatic hydrocarbons; more preferably, it is selected from one or more of water, methanol, ethanol, isopropanol, acetone, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, n-heptane, dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, and N-methylpyrrolidone.

9. A pharmaceutical composition, characterized in that, It comprises the crystal form according to any one of claims 1 to 6; preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

10. Use of the crystal form according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for the prevention and / or treatment of anemia in dialysis patients with chronic kidney disease and in non-dialysis patients with chronic renal anemia.

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