Crystal forms of compound HIF-117, preparation method therefor and use thereof

Abstract

Provided are a plurality of novel crystal forms of a HIF-117 compound, a preparation method therefor and the use thereof. The crystal forms are any one or more selected from 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. The crystal forms have good stability and are of great significance for drug development, formulation development and production.

Description

Crystalline form of compound HIF-117 and preparation method and use thereof

[0001] The present application claims priority to patent application No. CN202411352997.7, filed on September 26, 2024, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to the technical field of drug crystal forms, in particular, to a plurality of new crystal forms of HIF-117 compound and a preparation method and use thereof. BACKGROUND

[0003] 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.

[0004] 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 then binds to E3 ubiquitin ligase and is subsequently 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).

[0005] 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:

[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 the 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 new drug development process, 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 first aspect of the present application provides a crystal form of a compound or a solvate thereof having a structural formula as shown in Formula I,

[0011] 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.

[0012] Among them, crystal form A, crystal form D, crystal form G, crystal form H and crystal form J are anhydrous, 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.

[0013] For the anhydrous crystal form A of the compound of Formula I, further characteristic descriptions are as follows.

[0014] 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°.

[0015] In a preferred embodiment, the anhydrate crystalline Form A of the compound of Formula I further has characteristic peaks in its XRPD pattern at one or more of the following positions: 9.92±0.2°, 11.88±0.2°, 13.31±0.2°, 23.96±0.2°, 24.56±0.2°, 25.22±0.2°.

[0016] In a preferred embodiment, the Form is anhydrate crystalline Form A 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 1, which is shown below.

[0017] Table 1

[0018] In some more preferred embodiments, the anhydrate crystalline Form A of the compound of Formula I has an XRPD pattern substantially as shown in Figure 1.

[0019] In the present application, Cu-Ka radiation is used in the X-ray powder diffraction.

[0020] In some preferred embodiments, the anhydrate crystalline Form A of the compound of Formula I further has one or more of the following characteristics:

[0021] 1) in a thermogravimetric analysis (TGA) pattern, there is no significant weight loss up to 200±5°C; preferably, there is no more than 0.5% weight loss up to 200±5°C, more preferably, there is no more than 0.3% weight loss up to 200±5°C;

[0022] 2) in a DSC pattern, there is an endothermic peak at 222.0±5°C.

[0023] In some preferred embodiments, the anhydrate crystalline Form A of the compound of Formula I further has one or more of the following characteristics:

[0024] 1) a TGA pattern substantially as shown in Figure 2;

[0025] 2) a DSC pattern substantially as shown in Figure 3.

[0026] For the hydrate crystalline Form B of the compound of Formula I, further characteristic descriptions are as follows.

[0027] In one embodiment, for the hydrate crystalline Form B of the 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°.

[0028] In a preferred embodiment, the XRPD pattern of the compound of formula I hydrate Form B has characteristic peaks at one or more of the following 2Θ values: 17.93 ± 0.2°, 20.20 ± 0.2°, 22.50 ± 0.2°, 23.40 ± 0.2°, 28.70 ± 0.2°.

[0029] In a preferred embodiment, the compound of formula I hydrate Form B has XRPD characteristic peaks at substantially the 2Θ values and d values and relative intensities shown in Table 2. Table 2 is as follows.

[0030] Table 2

[0031] In a more preferred embodiment, the compound of formula I hydrate Form B has an XRPD pattern substantially as shown in Figure 4.

[0032] In some preferred embodiments, the compound of formula I hydrate Form B further has one or more of the following characteristics:

[0033] 1) In a TGA pattern, there is no significant weight loss up to 90 ± 5°C, preferably there is no more than 0.5% weight loss up to 90 ± 5°C, more preferably there is no more than 5% weight loss up to 200 ± 5°C.

[0034] 2) In a differential scanning calorimetry (DSC) pattern, there are endothermic peaks at 130.5 ± 5°C, 138.0 ± 5°C and 222.5 ± 5°C, and an exothermic peak at 135.5 ± 5°C.

[0035] In a preferred embodiment, the molar ratio of water to HIF-117 in the Form B is 1.

[0036] In some preferred embodiments, the compound of formula I hydrate Form B further has one or more of the following characteristics:

[0037] 1) a TGA pattern substantially as shown in Figure 5;

[0038] 2) a DSC pattern substantially as shown in Figure 6.

[0039] Preferably, the molar ratio of water to HIF-117 in the compound of formula I hydrate Form B is 1.

[0040] For the compound of formula I tetrahydrofuran (THF) solvate Form C, the characteristics are further described as follows.

[0041] In one embodiment, the THF solvate crystalline 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.

[0042] In a preferred embodiment, the THF solvate crystalline 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.

[0043] Table 3

[0044] In a more preferred embodiment, the crystalline Form C has an XRPD pattern substantially as shown in Figure 7.

[0045] In some preferred embodiments, the THF solvate crystalline Form C of the compound of Formula I further has one or more of the following characteristics:

[0046] 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.

[0047] 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.

[0048] In some preferred embodiments, the THF solvate crystalline Form C of the compound of Formula I further has one or more of the following characteristics:

[0049] 1) a TGA pattern substantially as shown in Figure 8;

[0050] 2) a DSC pattern substantially as shown in Figure 9.

[0051] Preferably, the molar ratio of tetrahydrofuran to HIF-117 in the THF solvate crystalline Form C of the compound of Formula I is 0.3.

[0052] For the anhydrate crystalline Form D of the compound of Formula I, further characteristic descriptions are as follows.

[0053] In one embodiment, the anhydrate crystalline Form D of the compound of Formula I has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.47±0.2°, 12.97±0.2°, 15.85±0.2° and 16.44±0.2° in terms of 2θ values.

[0054] In a preferred embodiment, the anhydrate crystalline Form D 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 4. Table 4 is shown below.

[0055] Table 4

[0056] In a preferred embodiment, the compound of Formula I anhydrate Form D has an XRPD pattern substantially as shown in Figure 10.

[0057] In some preferred embodiments, the compound of Formula I anhydrate Form D further has one or more of the following characteristics:

[0058] 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.

[0059] 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.

[0060] In some preferred embodiments, the compound of Formula I anhydrate Form D further has one or more of the following characteristics:

[0061] 1) a TGA pattern substantially as shown in Figure 11;

[0062] 2) a DSC pattern substantially as shown in Figure 12.

[0063] For the compound of Formula I dimethyl sulfoxide (DMSO) solvate Form E, further characteristic descriptions are as follows.

[0064] In one embodiment, the compound of Formula I DMSO solvate Form E has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at positions 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° in terms of 2-theta values.

[0065] In a preferred embodiment, the compound of Formula I DMSO solvate Form E has XRPD characteristic peaks substantially as shown in Table 5 in terms of 2-theta values, d-values, and relative intensities. Table 5 is shown below.

[0066] Table 5

[0067] In some preferred embodiments, the compound of Formula I DMSO solvate Form E has an XRPD pattern substantially as shown in Figure 13.

[0068] In some preferred embodiments, the compound of Formula I DMSO solvate Form E further has one or more of the following characteristics:

[0069] 1) in the TGA trace, not more than 20.0 wt% weight loss on heating to 200 ± 5°C, preferably, not more than 19.8 wt% weight loss on heating to 200 ± 5°C;

[0070] 2) in the DSC trace, 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.

[0071] 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:

[0072] 1) a TGA trace substantially as shown in Figure 14;

[0073] 2) a DSC trace substantially as shown in Figure 15.

[0074] 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.

[0075] For the N-methylpyrrolidone (NMP) solvate crystalline Form F of the compound of Formula I, further characteristic descriptions are as follows.

[0076] 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 the following positions in terms of 2Θ values: 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°.

[0077] In a preferred embodiment, the NMP solvate crystalline Form F of the compound of Formula I has XRPD characteristic peaks at 2Θ values and d values and relative intensities substantially as shown in Table 6. Table 6 is shown below.

[0078] Table 6

[0079] In a more preferred embodiment, the NMP solvate crystalline Form F of the compound of Formula I has an XRPD pattern substantially as shown in Figure 16.

[0080] In some preferred embodiments, the NMP solvate crystalline Form F of the compound of Formula I further has one or more of the following characteristics:

[0081] 1) in a TGA plot, not more than 13.0 wt% weight loss on warming 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 plot, not more than 12.75 wt% weight loss on warming to 160 ± 5°C, and not more than 7.1 wt% further weight loss between 160 ± 5°C and 250 ± 5°C;

[0082] 2) in a DSC plot, endothermic peaks at 91.2 ± 5°C and 211.2 ± 5°C

[0083] In some preferred embodiments, the Form F crystalline form of the NMP solvate of the compound of Formula I further has one or more of the following characteristics:

[0084] 1) a TGA plot substantially as shown in Figure 17;

[0085] 2) a DSC plot substantially as shown in Figure 18.

[0086] Preferably, the molar ratio of N-methyl pyrrolidone to HIF-117 in the Form F crystalline form of the NMP solvate of the compound of Formula I is 0.7.

[0087] For the anhydrate Form G of the compound of Formula I, further characteristic descriptions are as follows.

[0088] In one embodiment, for the anhydrate Form G of the compound of Formula I, the X-ray powder diffraction (XRPD) pattern 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°.

[0089] In one preferred embodiment, the anhydrate Form G of the compound of Formula I has XRPD characteristic peaks at 2Θ values and d values and relative intensities substantially as shown in Table 7. Table 7 is shown below.

[0090] Table 7

[0091] In some preferred embodiments, the anhydrate Form G of the compound of Formula I has an XRPD pattern substantially as shown in Figure 19.

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

[0093] 1) in a TGA plot, not more than 2.5 wt% weight loss on warming to 200 ± 5°C; preferably, not more than 2.2 wt% weight loss on warming to 200 ± 5°C;

[0094] 2) in a DSC pattern, an endothermic peak at 222.6 ± 5 °C and an exothermic peak at 187.9 ± 5 °C.

[0095] In some preferred embodiments, the compound of Formula I anhydrate Form G further has one or more of the following characteristics:

[0096] 1) a TGA pattern substantially as shown in Figure 20;

[0097] 2) a DSC pattern substantially as shown in Figure 21.

[0098] For the compound of Formula I anhydrate Form H, further characteristic descriptions are as follows.

[0099] In one embodiment, the compound of Formula I anhydrate Form H has an X-ray powder diffraction (XRPD) pattern with peaks at positions 7.33 ± 0.2°, 10.07 ± 0.2°, 14.35 ± 0.2°, and 14.72 ± 0.2° in terms of 2-theta.

[0100] In one preferred embodiment, the compound of Formula I anhydrate Form H has XRPD characteristic peaks and d-values and relative intensities substantially as shown in Table 8 in terms of 2-theta. Table 8 is shown below.

[0101] Table 8

[0102] In some preferred embodiments, the compound of Formula I anhydrate Form H has an XRPD pattern substantially as shown in Figure 22.

[0103] In some preferred embodiments, the compound of Formula I anhydrate Form H further has one or more of the following characteristics:

[0104] 1) in a TGA pattern, no more than 5.8% weight loss upon heating to 200 ± 5 °C.

[0105] 2) in a DSC pattern, an endothermic peak at 219.0 ± 5 °C.

[0106] In some preferred embodiments, the compound of Formula I anhydrate Form H further has one or more of the following characteristics:

[0107] 1) a TGA pattern substantially as shown in Figure 23;

[0108] 2) a DSC pattern substantially as shown in Figure 24.

[0109] For the compound of Formula I hydrate Form I, further characteristic descriptions are as follows.

[0110] In one embodiment, for the hydrate crystalline Form I of the compound of Formula 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°.

[0111] In a preferred embodiment, the hydrate crystalline Form I of Formula I has the XRPD characteristic peaks and d values and relative intensities substantially as shown in Table 9. The data of Table 9 is shown below.

[0112] Table 9

[0113] In some preferred embodiments, the hydrate crystalline Form I of Formula I has an XRPD pattern substantially as shown in Figure 25.

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

[0115] 1) In the TGA pattern, there is no more than 3.1% weight loss upon heating to 200±5°C.

[0116] 2) In the DSC pattern, there are endothermic peaks at 186.1±5°C and 220.5±5°C, and an exothermic peak at 189.6±5°C. Preferably, the pattern of the differential scanning calorimetry of Form I also has an endothermic peak at 146.9±5°C.

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

[0118] 1) a TGA pattern substantially as shown in Figure 26;

[0119] 2) a DSC pattern substantially as shown in Figure 27.

[0120] Preferably, the molar ratio of water to HIF-117 in the hydrate crystalline Form I of the compound of Formula I is 0.7.

[0121] Further characteristic description for the anhydrate crystalline Form J of the compound of Formula I is as follows.

[0122] In one embodiment, the anhydrate crystalline Form J of the compound of Formula I, the X-ray powder diffraction (XRPD) pattern has 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°.

[0123] In a preferred embodiment, the compound of Formula I anhydrate Form J has XRPD characteristic peaks and d-values and relative intensities substantially as shown in Table 10 at 2-theta values. The data of Table 10 is shown below.

[0124] Table 10

[0125] In some preferred embodiments, the compound of Formula I anhydrate Form J has an XRPD pattern substantially as shown in Figure 28.

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

[0127] 1) in a TGA pattern, not more than 3.0% weight loss on heating to 150 ± 5 °C; preferably, not more than 2.7% weight loss on heating to 150 ± 5 °C;

[0128] 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.

[0129] In some preferred embodiments, the compound of Formula I anhydrate Form J further has one or more of the following characteristics:

[0130] 1) a TGA pattern substantially as shown in Figure 29;

[0131] 2) a DSC pattern substantially as shown in Figure 30.

[0132] For the compound of Formula I, 1,4-Dioxane solvate Form K.

[0133] In one embodiment, the compound of Formula I 1,4-Dioxane solvate Form K has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 2-theta values at the following positions: 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°.

[0134] In a preferred embodiment, the compound of Formula I 1,4-Dioxane solvate Form K has XRPD characteristic peaks and d-values and relative intensities substantially as shown in Table 11 at 2-theta values. Table 11 is shown below.

[0135] Table 11

[0136] In some preferred embodiments, the compound of Formula I 1,4-dioxane solvate Form K has an XRPD pattern substantially as shown in Figure 31.

[0137] In some preferred embodiments, the compound of Formula I 1,4-dioxane solvate Form K further has one or more of the following characteristics:

[0138] 1) in the TGA pattern, there is no more than 19% weight loss up to 150±5°C, preferably, there is no more than 18.85% weight loss up to 150±5°C;

[0139] 2) in the DSC pattern, there are endothermic peaks at 91.6±5°C, 216.9±5°C and 220.9±5°C.

[0140] In some preferred embodiments, the compound of Formula I 1,4-dioxane solvate Form K further has one or more of the following characteristics:

[0141] 1) a TGA pattern substantially as shown in Figure 32;

[0142] 2) a DSC pattern substantially as shown in Figure 33.

[0143] Preferably, in the compound of Formula I 1,4-dioxane solvate Form K, the molar ratio of 1,4-dioxane to HIF-117 is 0.9.

[0144] For the compound of Formula I N,N-dimethylacetamide (DMAc) solvate Form L.

[0145] In one embodiment, the form is the compound of Formula I N,N-dimethylacetamide solvate Form L having an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following positions in terms of 2-theta values: 4.84±0.2°, 6.50±0.2°, 14.54±0.2° and 21.41±0.2°.

[0146] In one preferred embodiment, the compound of Formula I DMAc solvate Form L has characteristic peaks in the XRPD pattern at one or more of the following positions in terms of 2-theta values: 8.65±0.2°, 13.02±0.2°, 16.78±0.2°, 19.47±0.2°.

[0147] In one preferred embodiment, the compound of Formula I N,N-dimethylacetamide solvate Form L has XRPD characteristic peaks at 2-theta values and d-values and relative intensities substantially as shown in Table 12, which is shown below.

[0148] Table 12

[0149] In some preferred embodiments, the crystalline Form L has an XRPD pattern substantially as shown in Figure 34.

[0150] In some preferred embodiments, the crystalline Form L of the compound of Formula I N,N-dimethylacetamide solvate further has one or more of the following characteristics:

[0151] 1) in the TGA pattern, there is no more than 13.5% weight loss upon heating to 150±5°C;

[0152] 2) in the DSC pattern, there are endothermic peaks at 86.8±5°C, 207.0±5°C and 216.0±5°C, and an exothermic peak at 95.1±5°C. Preferably, there is also an endothermic peak at 104.1±5°C.

[0153] In some preferred embodiments, the crystalline Form L of the compound of Formula I N,N-dimethylacetamide solvate further has one or more of the following characteristics:

[0154] 1) a TGA pattern substantially as shown in Figure 35;

[0155] 2) a DSC pattern substantially as shown in Figure 36.

[0156] Preferably, the molar ratio of N,N-dimethylacetamide to HIF-117 in the crystalline Form L of the compound of Formula I N,N-dimethylacetamide solvate is 0.5.

[0157] The second aspect of the present application provides a preparation method of the crystalline 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.

[0158] In a preferred embodiment, the preparation method is selected from any one of the group consisting of suspension stirring method, anti-solvent addition method, rapid cooling method, slow cooling method, gas-liquid diffusion method, temperature cycling method, and grinding method.

[0159] In the preparation method, the suspension stirring method comprises adding the compound of Formula I into a solvent, stirring, and then collecting the solid by centrifugation.

[0160] In the preparation method, the anti-solvent addition method comprises adding the compound of Formula I into a solvent, dissolving, filtering, adding an anti-solvent, stirring, and then collecting the solid by centrifugation.

[0161] In the preparation method, the rapid cooling method comprises adding the compound of Formula I into a solvent, stirring at high temperature to obtain a saturated clear solution, rapidly cooling, and then collecting the solid by centrifugation.

[0162] In the preparation method, the slow cooling method comprises adding the compound of Formula I into a solvent, stirring at high temperature to obtain a saturated clear solution, slowly cooling, and then collecting the solid by centrifugation.

[0163] In the preparation method, the gas-liquid diffusion method, the compound of formula I is added into a solvent to obtain a saturated clear solution, which is left at room temperature, and the solid is collected by centrifugation to obtain the compound of formula I.

[0164] In the preparation method, the temperature cycling method, the compound of formula I is added into a solvent to obtain a suspension, which is left at room temperature, and the solid is collected by centrifugation to obtain the compound of formula I.

[0165] In the preparation method, the grinding method, the compound of formula I is directly ground or ground with water, and the solid is collected to obtain the compound of formula I.

[0166] In the preparation method, the temperature of the reaction or crystallization can be a conventional temperature in the art.

[0167] In the preparation method, the time for crystallization is not particularly limited, and the crystallization can be performed as long as the crystal form is precipitated.

[0168] 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, the solvent 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, N-methylpyrrolidone. The selection of the specific solvent can be adjusted by a person skilled in the art according to different preparation methods.

[0169] In a more preferred embodiment, the mass-volume ratio of the compound of formula I to the solvent is 100 mg:(1-50 mL), preferably 100 mg:(1.5-47 mL).

[0170] The third aspect of the present application provides a pharmaceutical composition comprising the crystal form according to any one of the above.

[0171] The crystalline form of the compound of formula I or a solvate thereof can be a therapeutically effective amount.

[0172] 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 a researcher or clinician.

[0173] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0174] The pharmaceutically acceptable excipients can be excipients well known in the art, including, but not limited to, diluents, binders, disintegrants, lubricants, glidants, release rate controlling agents, plasticizers, preservatives, antioxidants, and the like in the case of solid formulations.

[0175] The pharmaceutical composition can be in a dosage form suitable for human administration, 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.

[0176] The fourth aspect of the present application also provides a use of the crystalline form or the pharmaceutical composition as described above in any aspect in the preparation of a medicament for preventing and / or treating anemia in dialysis patients with chronic kidney disease and non-dialysis anemia of chronic kidney.

[0177] The present application also provides a method for preventing and / or treating anemia in dialysis patients with chronic kidney disease and non-dialysis anemia of chronic kidney, which comprises administering to a subject in need thereof a therapeutically effective amount of the crystalline form or the pharmaceutical composition as described above in any aspect.

[0178] The technical solution of the present application has the following beneficial effects:

[0179] 1. There is no report on the crystalline form A, the crystalline form B, the crystalline form C, the crystalline form D, the crystalline form E, the crystalline form F, the crystalline form G, the crystalline form H, the crystalline form I, the crystalline form J, the crystalline form K, and the crystalline form L of [(5-hydroxy-2-naphthalen-1-yl-[1,7]naphthyridine-6-carbonyl)-amino] acetic acid in the prior art. This application first discovers the new crystalline forms of the compound. Through a large number of experiments and screening, the present application first prepares the crystalline form A, the crystalline form B, the crystalline form C, the crystalline form D, the crystalline form E, the crystalline form F, the crystalline form G, the crystalline form H, the crystalline form I, the crystalline form J, the crystalline form K, and the crystalline form L. It is considered that the crystalline form A, the crystalline form D, the crystalline form G, the crystalline form H, and the crystalline form J are anhydrous substances, the hydrate crystalline form B and the hydrate crystalline form I will be converted into the anhydrous crystalline form A under heating conditions, the solvent compound crystalline form E, the solvent compound crystalline form K, and the solvent compound crystalline form L will be converted into the anhydrous crystalline form J after heating, the solvent compound crystalline form C will be converted into the anhydrous crystalline form D after heating, and the solvent compound crystalline form F will be converted into the anhydrous crystalline form A after heating, indicating that the anhydrous crystalline form has good thermal stability, and the crystalline form A, the crystalline form D, the crystalline form G, the crystalline form H, and the crystalline form J are taken as candidate objects.

[0180] 2. The present application also provides a preparation method of the crystalline form A, the crystalline form B, the crystalline form C, the crystalline form D, the crystalline form E, the crystalline form F, the crystalline form G, the crystalline form H, the crystalline form I, the crystalline form J, the crystalline form K, and the crystalline form L, which is simple in operation, high in reproducibility, free of solvent residue, friendly to the environment, and suitable for different scale production.

[0181] 3. The crystal forms A, D, G, H, and J prepared by this invention have good stability and are easy to store. They can avoid the risk of crystal transformation during drug development or production, and avoid changes in bioavailability and efficacy. They can be developed into dosage forms suitable for clinical use and have strong economic value. Attached Figure Description

[0182] Figure 1 shows the XRPD diagram of the anhydrous crystal form A of compound I.

[0183] Figure 2 is a TGA diagram of the anhydrous crystal form A of compound I.

[0184] Figure 3 shows the DSC diagram of the anhydrous crystal form A of compound I.

[0185] Figure 4 shows the XRPD diagram of the hydrate crystal form B of compound I.

[0186] Figure 5 shows the TGA diagram of crystal form B of the hydrate of compound I.

[0187] Figure 6 shows the DSC diagram of crystal form B of the hydrate of compound I.

[0188] Figure 7 shows the XRPD diagram of the THF solvate crystal form C of compound I.

[0189] Figure 8 shows the TGA diagram of crystal form C of the THF solvate of compound I.

[0190] Figure 9 shows the DSC diagram of crystal form C of the THF solvate of compound I.

[0191] Figure 10 shows the XRPD diagram of the anhydrous crystal form D of compound I.

[0192] Figure 11 is a TGA diagram of the anhydrous crystal form D of compound I.

[0193] Figure 12 shows the DSC diagram of the anhydrous crystal form D of compound I.

[0194] Figure 13 shows the XRPD diagram of crystal form E of the solvate of compound DMSO of formula I.

[0195] Figure 14 is a TGA diagram of crystal form E of the solvate of compound DMSO of formula I.

[0196] Figure 15 shows the DSC diagram of crystal form E of the solvate of compound DMSO of formula I.

[0197] Figure 16 shows the XRPD diagram of crystal form F of the NMP solvate of Formula I.

[0198] Figure 17 is a TGA diagram of the crystal form F of the NMP solvate of Formula I.

[0199] Figure 18 is a DSC pattern of Form F NMP solvate of the compound of Formula I.

[0200] Figure 19 is an XRPD pattern of Form G anhydrate of the compound of Formula I.

[0201] Figure 20 is a TGA pattern of Form G anhydrate of the compound of Formula I.

[0202] Figure 21 is a DSC pattern of Form G anhydrate of the compound of Formula I.

[0203] Figure 22 is an XRPD pattern of Form H anhydrate of the compound of Formula I.

[0204] Figure 23 is a TGA pattern of Form H anhydrate of the compound of Formula I.

[0205] Figure 24 is a DSC pattern of Form H anhydrate of the compound of Formula I.

[0206] Figure 25 is an XRPD pattern of Form I hydrate of the compound of Formula I.

[0207] Figure 26 is a TGA pattern of Form I hydrate of the compound of Formula I.

[0208] Figure 27 is a DSC pattern of Form I hydrate of the compound of Formula I.

[0209] Figure 28 is an XRPD pattern of Form J anhydrate of the compound of Formula I.

[0210] Figure 29 is a TGA pattern of Form J anhydrate of the compound of Formula I.

[0211] Figure 30 is a DSC pattern of Form J anhydrate of the compound of Formula I.

[0212] Figure 31 is an XRPD pattern of Form K 1,4-Dioxane solvate of the compound of Formula I.

[0213] Figure 32 is a TGA pattern of Form K 1,4-Dioxane solvate of the compound of Formula I.

[0214] Figure 33 is a DSC pattern of Form K 1,4-Dioxane solvate of the compound of Formula I.

[0215] Figure 34 is an XRPD pattern of Form L DMAc solvate of the compound of Formula I.

[0216] Figure 35 is a TGA pattern of Form L DMAc solvate of the compound of Formula I.

[0217] Figure 36 is a DSC pattern of Form L DMAc solvate of the compound of Formula I. DETAILED DESCRIPTION

[0218] The application will be further described in the following with specific examples, but not for limiting the protection scope of the application. The skilled in the art can make improvements to the preparation method and the use of instruments within the scope of the claims, and these improvements should also be considered as the protection scope of the application. Therefore, the protection scope of the application patent should be subject to the appended claims.

[0219] In the present application, "room temperature" generally refers to 14°C to 31°C, if not otherwise specified.

[0220] The abbreviations used in the present application are explained as follows:

[0221] XRPD: X-ray powder diffraction

[0222] DSC: differential scanning calorimetry

[0223] TGA: thermogravimetric analysis

[0224] The instruments and methods used for collecting data are as follows:

[0225] The X-ray powder diffraction pattern described in the present application is collected on a PANalytical X'Pert 3 Pro diffractometer.

[0226] PANalytical X'Pert 3 The method parameters of the X-ray powder diffraction are as follows:

[0227] X-ray type: Cu, Kα

[0228] Kα1 1.540598; Kα2 1.544426

[0229] Kα2 / Kα1 intensity ratio: 0.50

[0230] Voltage: 45 kilovolts (kV)

[0231] Current: 40 milliamps (mA)

[0232] Divergence slit: 1 / 16 degree

[0233] Scan mode: continuous

[0234] Scan range: from 3.0 to 40.0 degrees

[0235] Each step scan time: 46.665 seconds

[0236] Step size: 0.0263 degrees.

[0237] Differential scanning calorimetry (DSC) data described herein were collected on a TA Instruments Discovery DSC 2500, instrument control software is TRIOS, and analysis software is Universal Analysis. Typically, 1-5 mg 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 50 mL / min dry N2flow, while the TA software recorded the heat flow as a function of temperature. In this application, melting points are reported as onset temperatures.

[0238] Thermogravimetric analysis (TGA) data described herein were collected on a Discovery TGA 5500, 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 rate of 10 °C / min under a 50 mL / min dry N2flow, while the TA software recorded the weight change as a function of temperature.

[0239] Unless otherwise noted, the following examples were performed at room temperature.

[0240] In addition, when referring to figures such as XRPD patterns, DSC patterns, TGA patterns, and the like, 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.

[0241] 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 (2Q) 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 vary between instruments and also due to factors such as degree of crystallinity, preferred orientation, prepared sample, and other factors known to those skilled in the art.

[0242] As used herein, "substantially in agreement with the graph... " in reference to a DSC or TGA graph is also intended to encompass variations known to those skilled in the art to be associated with these analytical techniques. For a sharply bordered peak in a DSC graph, there will typically be a variation of up to ± 0.5 °C, and even greater for a broad peak (up to ± 1 °C, or up to ± 5 °C, or up to ± 8 °C). For mass loss in a TGA graph, there will typically be a variation of up to ± 1 %, or up to ± 2 %, depending on many factors such as sample preparation and the instrument, with different instruments and different samples detecting slightly different mass losses.

[0243] The impurity content data described herein were obtained using a Shimadzu LC-20A (VWD) high performance liquid chromatograph with the following method parameters:

[0244] Column: Agilent Eplicse XDB C18 (4.6 x 150 mm, 5 μm), or equivalent

[0245] Column temperature: 40 °C

[0246] Flow rate: 1.0 ml / min

[0247] Wavelength: 262 nm

[0248] Run time: 29 min

[0249] Test method: Take HIF-117, add 80 ml acetonitrile to make a solution of about 0.2 mg per 1 ml, as the test sample solution, inject into the liquid chromatograph, record the chromatogram and total impurity content.

[0250] As used herein, "anhydrous crystal form" means a crystal form that does not contain solvent and water.

[0251] Without deviating from the common knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, to obtain various preferred examples of the present application.

[0252] The reagents and raw materials used in the present application are commercially available.

[0253] Finally, the skilled person will understand that in the preparation of each of the crystal forms of the HIF-117 compound described herein, 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 crystalline form and / or amorphous form.

[0254] Examples 1-4: Preparation of Form A

[0255] A certain amount of HIF-117 solid was weighed into a 20ml glass vial at room temperature, and a corresponding volume of a solvent was added to obtain a clear solution. The sample was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 microns. Then, a certain amount of the solution was transferred into a 20ml glass vial, and a corresponding anti-solvent was added dropwise. If solid was precipitated, the sample was centrifuged to separate the solid. If no solid was precipitated after about 9ml of the anti-solvent was added, the addition of the anti-solvent was stopped, and the sample was transferred to a 5°C environment and magnetically stirred for 5 days. The sample was then transferred to room temperature and evaporated.

[0256] The solid obtained in this example was in crystalline Form A. The detailed experimental conditions involved in this example are shown in Table 13.

[0257] Table 13

[0258] Examples 5-7: Preparation of crystalline Form A

[0259] A certain amount of HIF-117 solid was weighed into a 3ml glass vial at room temperature, and a corresponding volume of a solvent was added to dissolve the solid. The sample was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 microns. The sample was sealed with a sealing film, and 4 pinholes were punched on the sealing film. The sample was then placed in a room temperature environment and slowly evaporated until solid was precipitated.

[0260] The solid obtained in this example was in crystalline Form A. The detailed experimental conditions involved in this example are shown in Table 14.

[0261] Table 14

[0262] Example 8: Preparation of crystalline Form A

[0263] HIF-117 solid 3.2kg, ethyl acetate 172kg were added into a reaction kettle, stirring was started, and heating was started until the solid was completely dissolved. After distilling out 84kg of ethyl acetate, the temperature was lowered to 5°C, and 2.24kg of HIF-117 crystalline Form A was obtained.

[0264] Examples 9-10: Preparation of crystalline Form A

[0265] A certain amount of HIF-117 solid was weighed into a 3ml glass vial at room temperature, and a corresponding volume of a solvent was added to obtain a suspension. The suspension was magnetically stirred at 50°C for 2 hours. The sample solution was filtered into a new 3ml glass vial using a polytetrafluoroethylene filter membrane with a pore size of 0.45 microns while hot. After sealing, the temperature was lowered from 50°C to 5°C, and then the sample was kept at 5°C for 5 days. If no solid was precipitated, the sample was transferred to room temperature and evaporated until solid was precipitated.

[0266] The solid obtained in this example is Form A. The detailed test conditions involved in this example are shown in Table 15.

[0267] Table 15

[0268] Example 11: Preparation of Form A

[0269] Under room temperature condition, 100.0 mg of compound HIF-117 solid was weighed into a 20 ml glass vial, 2.5 ml of 1,4-dioxane 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 water. After sealing, the vial was placed in a vapor-liquid permeation experiment at room temperature for 7 days, and then transferred to a volatile evaporation experiment at room temperature to obtain Form A of HIF-117.

[0270] Examples 1 to 11 above are different methods for preparing Form A and methods for scaling up the production thereof, and those skilled in the art can clearly understand from the above experiments that Form A can be prepared by the above-mentioned crystal preparation methods, and can also be scaled up to form a batch of Form A product.

[0271] The products of Examples 1 to 11 above were all Form A as tested by XRPD.

[0272] Form A prepared in Example 8 was tested by XRPD, and the XRPD data of the crystal form are shown in Table 1, the XRPD pattern is shown in Figure 1, the TGA pattern is shown in Figure 2, and the DSC pattern is shown in Figure 3. As can be seen from Figure 2, there is no significant weight loss when heated to about 200°C, and only 0.28% weight loss; as can be seen from Figure 3, there is an endothermic peak at about 222.0°C (peak temperature).

[0273] Example 12: Preparation of Form B

[0274] Under room temperature condition, 20.9 mg of compound HIF-117 solid was weighed into a 3 ml glass vial, 1.0 ml of tetrahydrofuran / water (volume ratio 1:1) was added to dissolve the solid, and the sample was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 μm. After sealing with a sealing film and piercing 4 holes in the film, the sample was placed in a volatile evaporation experiment at room temperature until solid was precipitated to obtain Form B of HIF-117.

[0275] Examples 13 to 20: Preparation of Form B

[0276] Under room temperature condition, an appropriate amount of Form A of compound HIF-117 solid was weighed into an HPLC glass vial or a vial, and a corresponding volume of solvent was added to obtain a suspension. The solid was collected under magnetic stirring at room temperature, 50°C or other temperatures.

[0277] The solid obtained in this example is Form B. The detailed experimental conditions involved in this example are shown in Table 16.

[0278] Table 16

[0279] The products of Examples 12-20 above were tested by XRPD, all of which were Form B. The XRPD data of Form B prepared in Example 20 are shown in Table 2, the XRPD pattern is shown in Figure 4, the TGA pattern is shown in Figure 5, and the DSC pattern is shown in Figure 6. As can be seen from Figure 5, there is a weight loss of 0.27% when heated to about 90°C, and a weight loss of 4.63% when heated from 90°C to about 200°C, suggesting that the molar ratio of water to HIF-117 is 1; as can be seen from Figure 6, there is an endothermic peak at about 130.5°C (peak temperature), an endothermic peak at 138.0°C (peak temperature), an endothermic peak at 222.5°C (peak temperature), and an exothermic peak at 135.5°C (peak temperature).

[0280] Examples 21-23: Preparation of Form C

[0281] An appropriate amount of solid compound HIF-117 was weighed into a 20-milliliter glass vial at room temperature, and an appropriate volume of a positive solvent was added to obtain a clear solution. The sample was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 micrometers. Then, an appropriate amount of the solution was transferred to a 20-milliliter glass vial, and an appropriate volume of an anti-solvent was added dropwise. If solid precipitated, the solid was separated by centrifugation. 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. The sample was then transferred to room temperature and evaporated.

[0282] The solid obtained in this example is Form C. The detailed experimental conditions involved in this example are shown in Table 17.

[0283] Table 17

[0284] Example 24: Preparation of Form C

[0285] An appropriate amount of solid compound HIF-117 was weighed into a 20-milliliter glass vial at room temperature, and an appropriate volume of a positive solvent was added to obtain a clear solution. The sample was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 micrometers. Then, an appropriate amount of the solution was transferred to a 20-milliliter glass vial, and an appropriate volume of an anti-solvent was added dropwise. If solid precipitated, the solid was separated by centrifugation. 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. The sample was then transferred to room temperature and evaporated.

[0286] 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 7, the TGA test result is shown in Figure 8, and the DSC pattern is shown in Figure 9. As shown in Figure 8, the weight loss starts at 29.4°C, and the weight loss is 3.22% when heated to 100°C, and the weight loss is 6.45% when heated from 100°C to about 200°C; as shown in Figure 9, 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, which 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, which showed that the sample was converted to Form A.

[0287] Examples 25-26: Preparation of Form D

[0288] At room temperature, an appropriate amount of compound HIF-117 raw material solid was weighed into a 20-mL glass vial, and a corresponding volume of a normal 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 μm. Then, an appropriate amount of the solution was transferred to a 20-mL glass vial, and a corresponding anti-solvent was added dropwise. If solid precipitated, the obtained solid was centrifuged and separated. If no solid precipitated after about 9 mL of the anti-solvent was added, the addition of the anti-solvent was stopped, and the sample was transferred to a 5°C environment and magnetically stirred for 5 days. If no solid precipitated, the sample was transferred to room temperature, and the solid was collected by evaporation to obtain Form D of HIF-117.

[0289] The detailed test conditions involved in this example are shown in Table 18.

[0290] Table 18

[0291] Example 27: Preparation of Form D

[0292] At room temperature, 82.3 mg of compound HIF-117 solid was weighed into 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, 0.5 mL of the solution was taken into a new 3-mL glass vial, and the vial was 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 the sample was transferred to room temperature for evaporation to collect the solid to obtain Form D of HIF-117.

[0293] The products of Examples 25-27 were all Form D by XRPD testing. The XRPD data for 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, there was only 1.92% weight loss up to about 150.0°C. As shown in Figure 12, there was an endotherm at about 189.5°C (peak temperature), an endotherm at 221.3°C (peak temperature), and an exotherm at 191.6°C (peak temperature); indicating that it was stable.

[0294] Example 28: Preparation of Form E

[0295] At room temperature, 20.8 mg of solid compound HIF-117 was placed in a 3 mL glass vial, which was placed in a 20 mL glass vial pre-filled with 4 mL of dimethyl sulfoxide, and was sealed and placed at room temperature for 7 days for vapor-solid permeation. The solid was collected to obtain Form E of HIF-117.

[0296] Examples 29-30: Preparation of Form E

[0297] At room temperature, an appropriate amount of solid compound HIF-117 was placed in a 20 mL glass vial, and an appropriate volume of a normal solvent was added to obtain a clear solution, which was filtered using a polytetrafluoroethylene filter membrane with a pore size of 0.45 μm. Then, an appropriate amount of the solution was transferred to a 20 mL glass vial, and an appropriate amount of an anti-solvent was added dropwise to the vial. The sample was transferred to room temperature to evaporate and precipitate a solid to obtain Form E of HIF-117.

[0298] The detailed test conditions in this example are shown in Table 19.

[0299] Table 19

[0300] Example 31: Preparation of Form E

[0301] At room temperature, 20.8 mg of solid compound HIF-117 was placed in a 3 mL glass vial, which was placed in a 20 mL glass vial pre-filled with 4 mL of dimethyl sulfoxide, and was sealed and placed at room temperature for 7 days for vapor-solid permeation. The solid was collected to obtain Form E of HIF-117.

[0302] The products of Examples 28-31 were all Form E by XRPD testing. The XRPD data of Form E prepared in Example 31 is 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, it has 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). The molar ratio of dimethyl sulfoxide to HIF-117 was 0.9 by HNMR. 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 showed that the sample was converted to Form J.

[0303] Example 32: Preparation of Form F

[0304] At room temperature, 19.6 mg of solid compound HIF-117 was placed in a 3 ml glass vial, and was placed in a 20 ml glass bottle pre-filled with 4 ml of N-methylpyrrolidone. After sealing, it was placed in a 7-day gas-solid penetration at room temperature, and the solid was collected to obtain Form F of HIF-117.

[0305] The XRPD data of Form F prepared in this example is 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, it has an endothermic peak at about 91.2°C (peak temperature), and an endothermic peak at 211.2°C (peak temperature). The molar ratio of N-methylpyrrolidone to HIF-117 was 0.7 by HNMR. 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 showed that the sample was converted to Form A.

[0306] Example 33: Preparation of Form G

[0307] At room temperature, 123.1 mg of solid compound HIF-117 was placed in a 20 ml glass vial, 3.0 ml of 1,4-dioxane was added to obtain a clear solution, then 0.5 ml of the solution was transferred to a 20 ml glass vial, and 9 ml of methanol was added dropwise to the vial, the sample was transferred to a 5°C environment and magnetically stirred for five days, and the sample was transferred to room temperature to evaporate and collect the solid to obtain Form G of HIF-117.

[0308] Example 34: Preparation of Form G

[0309] Under room temperature condition, 100.0 mg of compound HIF-117 solid was weighed into a 20 ml glass vial, 2.5 ml of 1,4-dioxane 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 acetonitrile. After sealing, it was placed in a gas-liquid permeation at room temperature for 7 days, and then transferred to a solid collection at room temperature by evaporation to obtain HIF-117 Form G.

[0310] Examples 35-40: Preparation of Form G

[0311] Under room temperature condition, 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 mixture was stirred magnetically at room temperature, 50°C or other temperatures, and the solid was collected to obtain HIF-117 Form G.

[0312] The detailed experimental conditions involved in this example are shown in Table 20.

[0313] Table 20

[0314] The products of Examples 33-40 above were tested by XRPD, and all were Form G. The XRPD data of 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, there was a weight loss of 2.19% when heated to about 200.0°C. As can be seen from Figure 21, there was an exothermic peak at about 187.9°C (peak temperature), and an endothermic peak at 222.6°C (peak temperature).

[0315] Examples 41-42: Preparation of Form H

[0316] Under room temperature condition, 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 mixture was stirred magnetically at room temperature, and the solid was collected to obtain HIF-117 Form H.

[0317] The detailed experimental conditions involved in this example are shown in Table 21.

[0318] Table 21

[0319] The products of the above Examples 41-42 were tested by XRPD, and all were Form H. The XRPD data of Form H prepared from 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 is a weight loss of 5.79% when heated to about 200.0°C. As can be seen from Figure 24, there is an endothermic peak at about 219.0°C (peak temperature).

[0320] Example 43: Preparation of Form I

[0321] At room temperature, 100.0 mg of solid compound HIF-117 was placed in a 20 mL glass vial, 2.5 mL of 1,4-dioxane 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 isopropanol. After sealing, it was left to volatilize at room temperature, and a solid precipitated to obtain Form I of HIF-117.

[0322] Examples 44-46: Preparation of Form I

[0323] At room temperature, an appropriate amount of solid compound HIF-117 was placed in a 3 mL glass vial, and a corresponding volume of solvent was added to obtain a suspension. After magnetic stirring at 50°C for two hours, the sample solution was filtered while hot into a new 3 mL glass vial using a polytetrafluoroethylene filter membrane with a pore size of 0.45 μm, and after sealing, it was cooled from 50°C to 5°C, and a solid precipitated to obtain Form I of HIF-117. The detailed test conditions in this example are shown in Table 22.

[0324] Table 22

[0325] The products of the above Examples 43-46 were tested by XRPD, all of which were Form I. 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, 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.

[0326] Example 47: Preparation of Form J

[0327] 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 left to evaporate at room temperature until solid precipitated to obtain Form J of HIF-117.

[0328] Example 48: Preparation of Form J

[0329] 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 in the sealing film, and then left to slowly evaporate at room temperature until solid precipitated to obtain Form J of HIF-117.

[0330] The products of the above Examples 47-48 were tested by XRPD, all of which were Form J. 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 from Figure 29, it has a weight loss of 2.68% when heated to about 150.0°C. As can be seen from Figure 30, there is an endothermic peak at about 214.5°C (peak temperature), an endothermic peak at about 220.4°C (peak temperature), and a smaller endothermic peak at about 84°C (peak temperature).

[0331] Examples 49-50: Preparation of Form K

[0332] An appropriate amount of compound HIF-117 solid was weighed out at room temperature and placed in a 3-milliliter glass vial, and a corresponding volume of solvent was added to dissolve the solid. The sample was sealed with a sealing film, four pinholes were punched in the sealing film, and the sample was then placed in a room-temperature environment for slow evaporation until the solid precipitated to obtain HIF-117 crystalline form K. The detailed test conditions involved in this example are shown in Table 23.

[0333] Table 23

[0334] The products from Examples 49-50 were tested by XRPD, and were all crystalline form K. The XRPD data for the crystalline form K prepared in Example 49 are shown in Table 11, the XRPD pattern is shown in Figure 31, the TGA pattern is shown in Figure 32, and the DSC pattern is shown in Figure 33. As can be seen from Figure 32, there was a weight loss of 18.81% when heated to about 150.0°C. As can be seen from Figure 33, there was an endothermic peak at about 91.6°C (peak temperature), an endothermic peak at about 216.9°C (peak temperature), and an endothermic peak at about 220.9°C (peak temperature). HNMR detection showed that the molar ratio of 1,4-dioxane to HIF-117 was 0.9. To study the DSC signals of crystalline form K, the crystalline form K prepared in Example 49 was heated to 150°C and cooled to room temperature, and then tested by XRPD. The results showed that the crystalline form K was converted to crystalline form J after heating.

[0335] Example 51: Preparation of crystalline form L

[0336] An appropriate amount of compound HIF-117 solid was weighed out at room temperature and placed in a 3-milliliter glass vial, and a corresponding volume of solvent was added to dissolve the solid. The sample was sealed with a sealing film, four pinholes were punched in the sealing film, and the sample was then placed in a room-temperature environment for slow evaporation until the solid precipitated to obtain HIF-117 crystalline form K. The detailed test conditions involved in this example are shown in Table 23.

[0337] The XRPD data of the product of this Example 51 in Form L is shown in Table 12, the XRPD pattern is shown in Figure 34, the TGA pattern is shown in Figure 35, and the DSC pattern is shown in Figure 36. As can be seen from Figure 35, it has a weight loss of 13.47% when heated to about 150.0°C. As can be seen from Figure 36, there is an endothermic peak at about 86.8°C (peak temperature), an endothermic peak at about 207.0°C (peak temperature), an endothermic peak at about 216.0°C (peak temperature), and an exothermic peak at about 95.1°C (peak temperature). In addition, there is an endothermic peak at about 104.1°C (peak temperature). The molar ratio of N,N-dimethylacetamide to HIF-117 is 0.5 as detected by HNMR. To study the DSC signal of Form L, the product of Example 51 in Form L was heated to 130°C and cooled to room temperature, and then the XRPD was tested, which showed that Form L was converted to Form J after heating.

[0338] Example 52: Suspension competition experiment between Form A, Form D, Form G, Form H, Form J

[0339] 7.5 mg of HIF-117 was weighed in EtOAc, and after stirring and equilibrating at room temperature and 50°C for 3 hours, it was filtered. The filtrate was transferred to a HPLC vial with free Form A and Form G, and continued to be stirred and suspended at room temperature and 50°C. After 7 days of suspension competition in the EtOAc system, Form J was added, after 11 days, Form H was added, and after 19 days, Form D and Form I were added.

[0340] Table 24

[0341] The XRPD results show that Form A is the more thermodynamically stable crystal form at room temperature and 50°C.

[0342] Example 53: Hygroscopicity study of Form A

[0343] The Form A sample was subjected to dynamic water adsorption test (DVS) under constant temperature conditions of 25°C and humidity changes of 0%RH-95%RH-0%RH. The results are shown in Table 25:

[0344] Table 25

[0345] It is shown that the Form A sample is not prone to absorbing water during storage, is easy to store, and can have a long shelf life.

[0346] Example 54: Mechanical stability of Form A

[0347] After tabletting Form A using different pressures of 2000 bar, 4000 bar, and 6000 bar, the XRPD was tested, which showed that the crystal form did not change significantly.

[0348] Example 55: Stability test of Form A

[0349] 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), 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 , and the ultraviolet lamp irradiation time was controlled to be 48 h). Samples were taken at 5, 10, and 30 days for testing (total impurities and XRPD), and the results are shown in Table 26.

[0350] Table 26

[0351] The stability results show that the Form A is stable in terms of crystal form under high temperature, high humidity, and light-avoiding conditions, and no significant changes have occurred. The impurities have increased under light conditions, and the purity has hardly changed under high temperature, high humidity, and light (light-avoiding) conditions. It exhibits good stability.

[0352] Example 56: Bioavailability of Form A

[0353] 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 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.

[0354] 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 A) has good in vivo absorption characteristics and good bioavailability in rats.

[0355] 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 crystalline form of a compound of structural formula I ###0001### or a solvate thereof, characterized in that, 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; wherein the crystal form A, the crystal form D, the crystal form G, the crystal form H, and the crystal form J are anhydrous, the crystal form B and the crystal form I are hydrates, the crystal form C is a tetrahydrofuran solvate, the crystal form E is a dimethyl sulfoxide solvate, the crystal form F is an N-methyl pyrrolidone solvate, the crystal form K is a 1,4-dioxane solvate, and the 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 the crystal form A has characteristic peaks at 2-theta 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 2-theta 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 2-theta 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 2-theta 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 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°; and / or, the X-ray powder diffraction pattern of the crystal form F has characteristic peaks at 2-theta 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 2-theta 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 2-theta 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 the crystal form I has characteristic peaks at 2-theta 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 crystalline form J has characteristic peaks at 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° in terms of 2θ value; and / or the X-ray powder diffraction pattern of the crystalline form K has characteristic peaks at 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° in terms of 2θ value; and / or the X-ray powder diffraction pattern of the crystalline form L has characteristic peaks at 4.84±0.2°, 6.50±0.2°, 14.54±0.2° and 21.41±0.2° in terms of 2θ value.

3. The morphic form of claim 2, characterized by an X-ray diffraction pattern substantially in accordance with Figure 18. the X-ray powder diffraction pattern of the crystalline form A further has characteristic peaks at at least one of 9.92±0.2°, 11.88±0.2°, 13.31±0.2°, 23.96±0.2°, 24.56±0.2°, 25.22±0.2° in terms of 2θ value; and / or the X-ray powder diffraction pattern of the crystalline form B further has characteristic peaks at at least one of 17.93±0.2°, 20.20±0.2°, 22.50±0.2°, 23.40±0.2°, 28.70±0.2° in terms of 2θ value; and / or the X-ray powder diffraction pattern of the crystalline form C is shown in Table 3; further preferably, the X-ray powder diffraction pattern of the crystalline form C is shown in Figure 7; and / or the X-ray powder diffraction pattern of the crystalline form D is shown in Table 4; further preferably, the X-ray powder diffraction pattern of the crystalline form D is shown in Figure 10; and / or the X-ray powder diffraction pattern of the crystalline form E is shown in Table 5; further preferably, the X-ray powder diffraction pattern of the crystalline form E is shown in Figure 13; and / or the X-ray powder diffraction pattern of the crystalline form F is shown in Table 6; further preferably, the X-ray powder diffraction pattern of the crystalline form F is shown in Figure 16; and / or the X-ray powder diffraction pattern of the crystalline form G is shown in Table 7; further preferably, the X-ray powder diffraction pattern of the crystalline form F is shown in Figure 19; and / or the X-ray powder diffraction pattern of the crystalline form H is shown in Table 8; further preferably, the X-ray powder diffraction pattern of the crystalline form H is shown in Figure 22; and / or the X-ray powder diffraction pattern of the crystalline form I is shown in Table 9; further preferably, the X-ray powder diffraction pattern of the crystalline form I is shown in Figure 25; and / or the X-ray powder diffraction pattern of the crystalline form J is shown in Table 10; further preferably, the X-ray powder diffraction pattern of the crystalline form J is shown in Figure 28; and / or the X-ray powder diffraction pattern of the crystalline form K is shown in Table 11; further preferably, the X-ray powder diffraction pattern of the crystalline form K is shown in Figure 31; and / or the X-ray powder diffraction pattern of the crystal form L further has characteristic peaks at at least one of the following 2Q values: 8.65±0.2°, 13.02±0.2°, 16.78±0.2°, 19.47±0.2°.

4. The morphic form of claim 3, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30. the X-ray powder diffraction pattern of the crystal form A further has characteristic peaks at at least one of the following 2Q 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°, 23.82±0.2°; preferably, the X-ray powder diffraction pattern of the crystal form A is as shown in Table 1; more preferably, the X-ray powder diffraction pattern of the crystal form A is as shown in FIG. 1; and / or the X-ray powder diffraction pattern of the crystal form B is as shown in Table 2; more preferably, the X-ray powder diffraction pattern of the crystal form B is as shown in FIG. 4; and / or the X-ray powder diffraction pattern of the crystal form L is as shown in Table 12; more preferably, the X-ray powder diffraction pattern of the crystal form L is as shown in FIG.

34.

5. The morphic form of claim 1, characterized by, the crystal form A has no obvious weight loss when heated to 200±5 °C in the thermogravimetric analysis, preferably the crystal form A has no more than 0.5% weight loss when heated to 200±5 °C in the thermogravimetric analysis; more preferably, the thermogravimetric analysis of the crystal form A is substantially the same as that shown in FIG. 2; and / or the crystal form B has no obvious weight loss when heated to 90±5 °C in the thermogravimetric analysis, preferably the crystal form B has no more than 0.5% weight loss when heated to 90±5 °C in the thermogravimetric analysis; more preferably, the crystal form B has no more than 5% weight loss when heated to 200±5 °C in the thermogravimetric analysis; more preferably, the thermogravimetric analysis of the crystal form B is substantially the same as that shown in FIG. 5; and / or the crystal form C has no more than 3.5% weight loss when heated to 100±5 °C in the thermogravimetric analysis; preferably, the crystal form C has no more than 10% weight loss when heated to 200±5 °C in the thermogravimetric analysis; more preferably, the thermogravimetric analysis of the crystal form C is substantially the same as that shown in FIG. 8; and / or the crystal form D has no more than 2.0% weight loss when heated to 150±5 °C in the thermogravimetric analysis; more preferably, the thermogravimetric analysis of the crystal form D is substantially the same as that shown in FIG. 11; and / or the crystal form E has no more than 20% weight loss when heated to 200±5 °C in the thermogravimetric analysis; preferably, the crystal form E has no more than 19.8% weight loss when heated to 200±5 °C in the thermogravimetric analysis; more preferably, the thermogravimetric analysis of the crystal form E is substantially the same as that shown in FIG. 14; and / or the crystal form F has no more than 13.0% weight loss when heated to 160±5 °C in the thermogravimetric analysis, preferably, the crystal form F has no more than 7.5% weight loss between 160±5 °C and 250±5 °C in the thermogravimetric analysis; more preferably, the thermogravimetric analysis of the crystal form F is substantially the same as that shown in FIG. 17; and / or the thermogravimetric analysis profile of the crystalline Form G has a weight loss of no more than 2.5% up to 200 ± 5 °C; preferably, the thermogravimetric analysis profile of the crystalline Form G has a weight loss of no more than 2.2% up to 200 ± 5 °C; further preferably, the thermogravimetric analysis profile of the crystalline Form G is substantially in accordance with FIG. 20; and / or the thermogravimetric analysis profile of the crystalline Form H has a weight loss of no more than 5.8% up to 200 ± 5 °C; further preferably, the thermogravimetric analysis profile of the crystalline Form H is substantially in accordance with FIG. 23; and / or the thermogravimetric analysis profile of the crystalline Form I has a weight loss of no more than 3.1% up to 200 ± 5 °C; further preferably, the thermogravimetric analysis profile of the crystalline Form I is substantially in accordance with FIG. 26; and / or the thermogravimetric analysis profile of the crystalline Form J has a weight loss of no more than 3.0% up to 150 ± 5 °C; further preferably, the thermogravimetric analysis profile of the crystalline Form J is substantially in accordance with FIG. 29; and / or the thermogravimetric analysis profile of the crystalline Form K has a weight loss of no more than 19% up to 150 ± 5 °C; further preferably, the thermogravimetric analysis profile of the crystalline Form K is substantially in accordance with FIG. 32; and / or the thermogravimetric analysis profile of the crystalline Form L has a weight loss of no more than 13.5% up to 150 ± 5 °C; further preferably, the thermogravimetric analysis profile of the crystalline Form L is substantially in accordance with FIG.

35.

6. The morphic form of claim 1, characterized by, the differential scanning calorimetry profile of the crystalline Form A has an endothermic peak at 222.0 ± 5 °C, further preferably, the differential scanning calorimetry profile of the crystalline Form A is substantially in accordance with FIG. 3; and / or the differential scanning calorimetry profile of the crystalline Form B has endothermic peaks at 130.5 ± 5 °C, 138.0 ± 5 °C and 222.5 ± 5 °C, and an exothermic peak at 135.5 ± 5 °C; further preferably, the differential scanning calorimetry profile of the crystalline Form B is substantially in accordance with FIG. 6; and / or the differential scanning calorimetry profile of the crystalline Form C has 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; further preferably, the differential scanning calorimetry profile of the crystalline Form C is substantially in accordance with FIG. 9; and / or the differential scanning calorimetry profile of the crystalline Form D has endothermic peaks at 189.5 ± 5 °C, 221.3 ± 5 °C, and an exothermic peak at 191.6 ± 5 °C; further preferably, the differential scanning calorimetry profile of the crystalline Form D is substantially in accordance with FIG. 12; and / or the differential scanning calorimetry profile of the crystalline Form E has endothermic peaks at 79.1 ± 5 °C and 100.5 ± 5 °C; preferably, further endothermic peaks at 161.5 ± 5 °C and / or 200.2 ± 5 °C; further preferably, the differential scanning calorimetry profile of the crystalline Form E is substantially in accordance with FIG. 15; and / or the differential scanning calorimetry profile of the crystalline Form F has endothermic peaks at 91.2 ± 5 °C and 211.2 ± 5 °C; further preferably, the differential scanning calorimetry profile of the crystalline Form F is substantially in accordance with FIG. 18; and / or, the differential scanning calorimetry profile of the crystalline Form G has an endothermic peak at 222.6±5 °C, and an exothermic peak at 187.9±5 °C; further preferably, the differential scanning calorimetry profile of the crystalline Form G is substantially in accordance with FIG. 21; and / or, the differential scanning calorimetry profile of the crystalline Form H has an endothermic peak at 219.0±5 °C; further preferably, the differential scanning calorimetry profile of the crystalline Form H is substantially in accordance with FIG. 24; and / or, the differential scanning calorimetry profile of the crystalline Form I has endothermic peaks at 186.1±5 °C and 220.5±5 °C, and an exothermic peak at 189.6±5 °C; preferably, the differential scanning calorimetry profile of the crystalline Form I further has an endothermic peak at the 146.9±5 °C; further preferably, the differential scanning calorimetry profile of the crystalline Form I is substantially in accordance with FIG. 27; and / or, the differential scanning calorimetry profile of the crystalline Form J has endothermic peaks at 214.5±5 °C and 220.4±5 °C, preferably, further has an endothermic peak at 84.0±5 °C; further preferably, the differential scanning calorimetry profile of the crystalline Form J is substantially in accordance with FIG. 30; and / or, the differential scanning calorimetry profile of the crystalline Form K has endothermic peaks at 91.6±5 °C, 216.9±5 °C and 220.9±5 °C; further preferably, the differential scanning calorimetry profile of the crystalline Form K is substantially in accordance with FIG. 33; and / or, the differential scanning calorimetry profile of the crystalline Form L has endothermic peaks at 86.8±5 °C, 207.0±5 °C and 216.0±5 °C, and an exothermic peak at 95.1±5 °C; preferably, the differential scanning calorimetry profile of the crystalline Form L further has an endothermic peak at 104.1±5 °C; further preferably, the differential scanning calorimetry profile of the crystalline Form L is substantially in accordance with FIG.

36.

7. A process for preparing the crystalline 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 a corresponding crystalline form is prepared.

8. The method of claim 7, wherein, The solvent is selected from one or more of water, alcohols, ketones, esters, alkanes, aromatic hydrocarbons, halogenated hydrocarbons, nitriles, ethers, aliphatic hydrocarbons; more preferably, is 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.

9. A pharmaceutical composition, characterized by, It comprises the crystalline form according to any one of claims 1-6; preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

10. Use of the crystalline form according to any one of claims 1-6 or the pharmaceutical composition of claim 9 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 of chronic kidney disease.

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