DOMINANT SALT FORMS OF PYRIMIDINE DERIVATIVES, AND CRYSTAL FORMS THEREOF

Abstract

Disclosed are sodium salts of pyrimidine derivatives, and a series of crystal forms thereof. The series of crystal forms exhibit a good druggability, such as stability, fluidity, compressibility, etc., and provide a variety of options of APIs for subsequent drug product development.

Claims

1.-30. (canceled)

31. A crystal form of Compound 1, comprising a crystal form I, a crystal form II, a crystal form III, a crystal form IV, a crystal form V, a crystal form VII or a crystal form VIII, ##STR00003## wherein, (i) an XRPD pattern of the crystal form I of Compound 1 has diffraction peaks at angles 2θ of 6.4, 9.8, 12.8, 15.8, 16.2, 17.8, 18.7, 19.3, 20.3, 24.0, 24.6, 27.6, 28.1±0.2°; (ii) an XRPD pattern of the crystal form II of Compound 1 has diffraction peaks at angles 2θ of 5.8, 9.3, 10.0, 11.6, 13.7, 17.0, 18.9, 22.8, 24.2±0.2°; (iii) an XRPD pattern of the crystal form III of Compound 1 has diffraction peaks at angles 2θ of 4.6, 5.4, 7.1, 9.7, 10.8, 12.4, 15.1, 17.0, 17.8, 18.9, 19.6, 20.7, 21.8, 23.7, 25.0±0.2°; (iv) an XRPD pattern of the crystal form IV of Compound 1 has diffraction peaks at angles 2θ of 5.7, 6.9, 9.3, 12.3, 14.3, 16.7, 17.8, 18.7, 19.3, 20.6, 23.8, 28.4±0.2°; (v) an XRPD pattern of the crystal form V of Compound 1 has diffraction peaks at angles 2θ of 7.1, 9.4, 12.3, 15.5, 18.8, 19.8, 20.9, 25.5, 27.1±0.2°; (vi) an XRPD pattern of the crystal form VII of Compound 1 has diffraction peaks at angles 2θ of 4.6, 5.8, 7.3, 7.8, 11.3, 14.6, 18.4±0.2°; and (vii) an XRPD pattern of the crystal form VIII of Compound 1 has diffraction peaks at angles 2θ of 6.0, 7.0, 7.6, 11.0, 12.2, 14.1, 14.4, 15.4, 18.7, 20.0, 27.8±0.2°.

32. The crystal form of Compound 1 according to claim 31, wherein (i) the XRPD pattern of the crystal form I of Compound 1 further has diffraction peaks at angles 2θ of 9.0, 15.3, 17.4, 23.1, 28.4±0.2°; (ii) the XRPD pattern of the crystal form II of Compound 1 further has diffraction peaks at angles 2θ of 12.4, 17.7, 21.0, 22.2, 30.1±0.2°; (iii) the XRPD pattern of the crystal form III of Compound 1 further has diffraction peaks at angles 2θ of 13.6, 14.1, 20.1, 21.3, 24.3, 26.1, 26.5, 28.4, 30.0±0.2°; (iv) the XRPD pattern of the crystal form IV of Compound 1 further has diffraction peaks at angles 2θ of 18.2, 18.9, 19.5, 21.6, 27.2, 30.5±0.2°; (v) the XRPD pattern of the crystal form V of Compound 1 further has diffraction peaks at angles 2θ of 12.8, 16.0, 16.3, 16.5, 20.0, 21.4, 22.2, 22.5, 23.3, 24.7, 25.7, 26.5, 31.2±0.2°; and (vi) the XRPD pattern of the crystal form VIII of Compound 1 further has diffraction peaks at angles 2θ of 4.6, 9.3, 15.7, 21.8, 22.2, 25.0, 28.5±0.2°.

33. The crystal form of Compound 1 according to claim 31, wherein (i) the diffraction peaks of the XRPD pattern of the crystal form I of Compound 1 are as shown in the table below: TABLE-US-00011 2θ No. (±0.2°) 1 6.4 2 9.0 3 9.8 4 12.8 5 14.4 6 15.3 7 15.8 8 16.2 9 17.4 10 17.8 11 18.7 12 19.3 13 20.3 14 21.4 15 22.1 16 23.1 17 23.6 18 24.0 19 24.2 20 24.6 21 26.3 22 26.5 23 27.6 24 28.1 25 28.4 26 28.8 27 29.8 28 35.2 (ii) the diffraction peaks of the XRPD pattern of the crystal form II of Compound 1 are as shown in the table below: TABLE-US-00012 2θ No. (±0.2°) 1 5.8 2 9.3 3 10.0 4 11.6 5 12.4 6 13.7 7 15.3 8 17.0 9 17.7 10 18.9 11 21.0 12 21.2 13 22.2 14 22.8 15 24.2 16 24.9 17 25.4 18 26.5 19 30.1 (iii) the diffraction peaks of the XRPD pattern of the crystal form III of Compound 1 are as shown in the table below: TABLE-US-00013 2θ No. (±0.2°) 1 4.6 2 5.4 3 7.1 4 9.7 5 10.8 6 12.4 7 13.6 8 14.1 9 15.1 10 16.3 11 17.0 12 17.8 13 18.9 14 19.6 15 20.1 16 20.7 17 21.3 18 21.8 19 22.3 20 23.7 21 24.3 22 25.0 23 25.6 24 26.1 25 26.5 26 27.4 27 28.2 28 28.4 29 30.0 (iv) the diffraction peaks of the XRPD pattern of the crystal form IV of Compound 1 are as shown in the table below: TABLE-US-00014 2θ No. (±0.2°) 1 5.7 2 6.9 3 9.3 4 9.9 5 12.3 6 13.9 7 14.3 8 15.5 9 16.2 10 16.7 11 17.8 12 18.2 13 18.7 14 18.9 15 19.3 16 19.5 17 20.6 18 20.9 19 21.6 20 22.4 21 23.5 22 23.8 23 24.2 24 25.0 25 25.9 26 27.2 27 27.7 28 28.4 29 29.4 30 30.5 (v) the diffraction peaks of the XRPD pattern of the crystal form V of Compound 1 are as shown in the table below: TABLE-US-00015 2θ No. (±0.2°) 1 7.1 2 9.4 3 12.3 4 12.8 5 14.2 6 15.5 7 16.0 8 16.3 9 16.5 10 16.8 11 17.9 12 18.8 13 19.8 14 20.0 15 20.9 16 21.4 17 22.2 18 22.5 19 23.3 20 24.7 21 25.0 22 25.5 23 25.7 24 26.5 25 27.1 26 28.3 27 30.5 28 31.2 29 32.9 (vi) the diffraction peaks of the XRPD pattern of the crystal form VII of Compound 1 are as shown in the table below: TABLE-US-00016 2θ No. (±0.2°) 1 4.6 2 5.8 3 7.3 4 7.8 5 11.3 6 14.6 7 18.4 and (vii) the diffraction peaks of the XRPD pattern of the crystal form VIII of Compound 1 are as shown in the table below: TABLE-US-00017 2θ No. (±0.2°) 1 4.6 2 6.0 3 7.0 4 7.6 5 9.3 6 11.0 7 11.5 8 12.2 9 14.1 10 14.4 11 15.4 12 15.7 13 16.9 14 18.0 15 18.7 16 20.0 17 20.9 18 21.8 19 22.2 20 22.6 21 23.3 22 25.0 23 25.7 24 27.8 25 28.5 26 30.1

34. The crystal form of Compound 1 according to claim 31, wherein (i) the XRPD pattern of the crystal form I of Compound 1 is substantially as shown in FIG. 1; (ii) the XRPD pattern of the crystal form II of Compound 1 is substantially as shown in FIG. 5; (iii) the XRPD pattern of the crystal form III of Compound 1 is substantially as shown in FIG. 9; (iv) the XRPD pattern of the crystal form IV of Compound 1 is substantially as shown in FIG. 13; (v) the XRPD pattern of the crystal form V of Compound 1 is substantially as shown in FIG. 16; (vi) the XRPD pattern of the crystal form VII of Compound 1 is substantially as shown in FIG. 23; and (vii) the XRPD pattern of the crystal form VIII of Compound 1 is substantially as shown in FIG. 27.

35. The crystal form of Compound 1 according to claim 31, wherein (i) a DSC pattern of the crystal form I of Compound 1 has starting points of endothermic peaks at 51.6, 158.2, and 335.9±3° C., and a starting point of an exothermic peak at 230.4±3° C.; (ii) a DSC pattern of the crystal form II of Compound 1 has a starting point of an endothermic peak at 335.9±3° C.; (iii) a DSC pattern of the crystal form III of Compound 1 has starting points of endothermic peaks at 33.5, and 329.0±3° C., and a starting point of an exothermic peak at 272.1±3° C.; (iv) a DSC pattern of the crystal form IV of Compound 1 has a starting point of an endothermic peak at 326.3±3° C.; (v) a DSC pattern of the crystal form V of Compound 1 has a starting point of an endothermic peak at 339.1±3° C.; (vi) a DSC pattern of the crystal form VII of Compound 1 has starting points of endothermic peaks at 71.8±3° C., and 327.4±3° C., and a starting point of an exothermic peak at 252.0±3° C.; and (vii) a DSC pattern of the crystal form VIII of Compound 1 has starting points of endothermic peaks at 44.8±3° C., 132.8±3° C., and 323.6±3° C., and a starting point of an exothermic peak at 255.7±3° C.

36. The crystal form of Compound 1 according to claim 31, wherein (i) the DSC pattern of the crystal form I of Compound 1 is substantially as shown in FIG. 2; (ii) the DSC pattern of the crystal form II of Compound 1 is substantially as shown in FIG. 6; (iii) the DSC pattern of the crystal form III of Compound 1 is substantially as shown in FIG. 10; (iv) the DSC pattern of the crystal form IV of Compound 1 is substantially as shown in FIG. 14; (v) the DSC pattern of the crystal form V of Compound 1 is substantially as shown in FIG. 17; (vi) the DSC pattern of the crystal form VII of Compound 1 is substantially as shown in FIG. 24; and (vii) the DSC pattern of the crystal form VIII of Compound 1 is substantially as shown in FIG. 28.

37. The crystal form of Compound 1 according to claim 31, wherein (i) a TGA pattern of the crystal form I of Compound 1 exhibits a weight loss of 12.06±1% at 200° C.; (ii) a TGA pattern of the crystal form II of Compound 1 does not exhibit a remarkable weight loss before 300° C.; (iii) a TGA pattern of the crystal form III of Compound 1 exhibits a weight loss of 11.40±1% at 200° C.; (iv) a TGA pattern of the crystal form IV of Compound 1 does not exhibit a remarkable weight loss before 300° C.; (v) a TGA pattern of the crystal form V of Compound 1 exhibits a weight loss of 1.26±1% before 75° C.; (vi) a TGA pattern of the crystal form VII of Compound 1 exhibits a weight loss of 9.18±1% at 200° C.; and (vii) a TGA pattern of the crystal form VIII of Compound 1 exhibits a weight loss of 12.15±1% at 200° C.

38. The crystal form of Compound 1 according to claim 37, the crystal form I of Compound 1 exhibits a weight loss of 5.85±1% at 100° C., followed by an additional weight loss of 6.21±1% at 200° C.

39. The crystal form of Compound 1 according to claim 37, wherein (i) the TGA pattern of the crystal form I of Compound 1 is substantially as shown in FIG. 3; (ii) the TGA pattern of the crystal form II of Compound 1 is substantially as shown in FIG. 7; (iii) the TGA pattern of the crystal form III of Compound 1 is substantially as shown in FIG. 11; (iv) the TGA pattern of the crystal form IV of Compound 1 is substantially as shown in FIG. 15; (v) the TGA pattern of the crystal form V of Compound 1 is substantially as shown in FIG. 18; (vi) the TGA pattern of the crystal form VII of Compound 1 is substantially as shown in FIG. 25; and (vii) the TGA pattern of the crystal form VIII of Compound 1 is substantially as shown in FIG. 29.

40. A active pharmaceutical ingredient comprising Compound 1 and/or WX-216 and/or other salt forms of WX-216, wherein the active pharmaceutical ingredient comprises at least one crystal form of Compound 1 according to claim 31. ##STR00004##

41. A active pharmaceutical ingredient comprising Compound 1 and/or WX-216 and/or other salt forms of WX-216, wherein the active pharmaceutical ingredient comprises at least one crystal form of Compound 1 according to claim 35.

42. A active pharmaceutical ingredient comprising Compound 1 and/or WX-216 and/or other salt forms of WX-216, wherein the active pharmaceutical ingredient comprises at least one crystal form of Compound 1 according to claim 37.

43. A pharmaceutical composition consisting of the active pharmaceutical ingredient of claim 40 and a pharmaceutically acceptable excipient.

44. The pharmaceutical composition according to claim 43, wherein the pharmaceutically acceptable excipient is at least one selected from the group consisting of fillers, binders, disintegrants, and lubricants.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0100] FIG. 1: the XRPD pattern of the crystal form I of Compound 1;

[0101] FIG. 2: the DSC pattern of the crystal form I of Compound 1;

[0102] FIG. 3: the TGA pattern of the crystal form I of Compound 1;

[0103] FIG. 4: the XRPD comparison pattern of the crystal form I of Compound 1;

[0104] FIG. 5: the XRPD pattern of the crystal form II of Compound 1;

[0105] FIG. 6: the DSC pattern of the crystal form II of Compound 1;

[0106] FIG. 7: the TGA pattern of the crystal form II of Compound 1;

[0107] FIG. 8: the XRPD comparison pattern of the crystal form II of Compound 1;

[0108] FIG. 9: the XRPD pattern of the crystal form III of Compound 1;

[0109] FIG. 10: the DSC pattern of the crystal form III of Compound 1;

[0110] FIG. 11: the TGA pattern of the crystal form III of Compound 1;

[0111] FIG. 12: the XRPD comparison pattern of the crystal form III of Compound 1;

[0112] FIG. 13: the XRPD pattern of the crystal form IV of Compound 1;

[0113] FIG. 14: the DSC pattern of the crystal form IV of Compound 1;

[0114] FIG. 15: the TGA pattern of the crystal form IV of Compound 1;

[0115] FIG. 16: the XRPD pattern of the crystal form V of Compound 1;

[0116] FIG. 17: the DSC pattern of the crystal form V of Compound 1;

[0117] FIG. 18: the TGA pattern of the crystal form V of Compound 1;

[0118] FIG. 19: the XRPD comparison pattern of the crystal form V of Compound 1;

[0119] FIG. 20: the XRPD pattern of the crystal form VI of Compound 1;

[0120] FIG. 21: the DSC pattern of the crystal form VI of Compound 1;

[0121] FIG. 22: the TGA pattern of the crystal form VI of Compound 1;

[0122] FIG. 23: the XRPD pattern of the crystal form VII of Compound 1;

[0123] FIG. 24: the DSC pattern of the crystal form VII of Compound 1;

[0124] FIG. 25: the TGA pattern of the crystal form VII of Compound 1;

[0125] FIG. 26: the XRPD comparison pattern of the crystal form VII of Compound 1;

[0126] FIG. 27: the XRPD pattern of the crystal form VIII of Compound 1;

[0127] FIG. 28: the DSC pattern of the crystal form VIII of Compound 1;

[0128] FIG. 29: the TGA pattern of the crystal form VIII of Compound 1.

[0129] FIG. 30: the comparison of the XRPD patterns of the crystal form IX, the crystal form VII, and the crystal VIII of Compound 1.

DETAILED DESCRIPTION

[0130] Hereinafter the present disclosure is further described in details below by reference to the examples and the drawings, but the embodiments of the present disclosure are not limited thereto.

Detection Conditions

X-Ray Powder Diffraction

[0131] X-Ray powder diffractometer: Bruker D8 Advance; [0132] 2θ Scanning angle: from 3° to 45°; [0133] Scanning Step: 0.02°; [0134] Exposure time: 0.2 second; [0135] Voltage and current of light pipe: 40 KV, 40 mA.

Differential Scanning Calorimetric Analysis

[0136] Differential scanning calorimetric analyzer: TA Discovery 2500 (TA, US); [0137] Heating rate: 10° C./min; [0138] Test method: Sample was precisely weighed, placed into a DSC Tzero sample disk, and heated to 350° C. The purging rate of nitrogen in the furnace was 50 mL/min.

Thermogravimetric Analysis

[0139] Thermogravimetric analyzer: TA Discovery 55 (TA, US); [0140] Test method: Sample was placed in an equilibrated aluminum sample disk, and automatically weighed in a heating furnace. The sample was heated at a rate of 10° C./min to 400° C. The purging rate of nitrogen was 60 mL/min at the site of the sample, and 40 mL/min at the site of balance.

Example 1. Preparation Method of Compound 1

[0141] WX-216 was prepared in accordance with the method disclosed in Example 4 of the patent WO2018041263.

[0142] 5 g of WX-216 was added into a 250 mL eggplant-shaped flask, and THF (100 mL) and NaOH (aq., 0.477 g in 1 mL of water) were added. The mixture was stirred at 30° C. for 12 hrs. The solids were filtered, and the filter cake was dried under vacuum at 40° C. to give Compound 1.

Example 2. Preparation Method of Crystal Form I of Compound 1

[0143] 10 mg of Compound 1 prepared in accordance with the method of Example 1 was weighed and suspended in 1 mL of acetone. 150 μL of solvent was added dropwise at 60° C. until the solid was completely dissolved. Then, the mixture was cooled to room temperature, stirred for 3 hrs, and then centrifuged for solid-liquid separation. The solid was dried under vacuum at room temperature to give the crystal form I of Compound 1. The obtained crystal form I has an XRPD pattern as shown in FIG. 1, a DSC pattern as shown in FIG. 2, and a TGA pattern as shown in FIG. 3.

Example 3. Preparation Method of Crystal Form I of Compound 1

[0144] An appropriate amount of Compound 1 prepared in accordance with the method of Example 1 was weighed and formulated into a saturated solution in ethylene glycol monomethyl ether. 150 μL of the saturated solution was placed at room temperature under the atmosphere of diffusion solvent acetone, and solid was precipitated after 3 days. The mixture was centrifuged for solid-liquid separation. The solid was dried at room temperature under vacuum to give the crystal form I of Compound 1.

[0145] The XRPD comparison pattern of the obtained crystal form I is as shown in FIG. 4.

Example 4. Preparation Method of Crystal Form II of Compound 1

[0146] 10 mg of the crystal form I of Compound 1 prepared in accordance with the method of Example 2 was weighed and placed in a platinum crucible, heated at a rate of 10° C./min to 300° C. for 0.5 minute, and air-cooled to room temperature to give the crystal form II of Compound 1. The obtained crystal form II has an XRPD pattern as shown in FIG. 5, a DSC pattern as shown in FIG. 6, and a TGA pattern as shown in FIG. 7.

Example 5. Preparation Method of Crystal Form II of Compound 1

[0147] An appropriate amount of Compound 1 prepared in accordance with the method of Example 1 was weighed and formulated to a saturated solution in dimethylformamide. 150 μL of the saturated solution was placed at room temperature under an atmosphere of diffusion solvent acetone, and solid was precipitated after 3 days. The mixture was centrifuged for solid-liquid separation. The solid was dried at room temperature under vacuum to give the crystal form II of Compound 1.

[0148] The XRPD comparison pattern of the crystal form II is as shown in FIG. 8.

Example 6. Preparation Method of Crystal Form III of Compound 1

[0149] 80 mg of the crystal form I of Compound 1 prepared in accordance with the method of Example 2 was weighed and placed in 3.5 mL of pure water. The suspension was stirred at 60° C. for 19 hrs, and then filtered. The filter cake was dried at room temperature under vacuum to give the crystal form III of Compound 1. The obtained crystal form III has an XRPD pattern as shown in FIG. 9, a DSC pattern as shown in FIG. 10, and a TGA pattern as shown in FIG. 11.

Example 7. Preparation Method of Crystal Form III of Compound 1

[0150] 500 mg of the crystal form I of Compound 1 prepared by the method of Example 2 was weighed and added into a mixed solution of 1.5 mL of ethanol and 7.5 mL of water, suspended and slurried at 60° C. for 4 hrs, cooled to room temperature and filtered, and dried at room temperature under vacuum to give the crystal form III of Compound 1.

[0151] The XRPD comparison pattern of the crystal form III is as shown in FIG. 12.

Example 8. Preparation Method of Crystal Form IV of Compound 1

[0152] 10 mg of the crystal form III of Compound 1 prepared in accordance with the method of Example 6 was weighed and placed in a platinum crucible, heated at a rate of 10° C./min to 280° C. for 0.5 minute, and air-cooled to room temperature to give the crystal form IV of Compound 1. The obtained crystal form IV has an XRPD pattern as shown in FIG. 13, a DSC pattern as shown in FIG. 14, and a TGA pattern as shown in FIG. 15.

Example 9. Preparation Method of Crystal Form V of Compound 1

[0153] An appropriate amount of Compound 1 prepared in accordance with the method of Example 1 was dissolved in methanol to prepare a saturated solution. 200 μL of the prepared saturated solution was added dropwise into 1.5 mL of iso-propyl acetate at room temperature. The mixture was stirred at room temperature for 19 hrs, and then centrifuged for solid-liquid separation. The solid was dried under vacuum at room temperature to give the crystal form V of Compound 1. The obtained crystal form V has an XRPD pattern as shown in FIG. 16, a DSC pattern as shown in FIG. 17, and a TGA pattern as shown in FIG. 18.

Example 10. Preparation Method of Crystal Form V of Compound 1

[0154] An appropriate amount of Compound 1 prepared in accordance with the method of Example 1 was weighed and formulated into a saturated solution in methanol. 150 μL of the saturated solution was placed at room temperature under the atmosphere of diffusion solvent acetonitrile, and solid was precipitated after 5 days. The mixture was centrifuged for solid-liquid separation. The solid was dried at room temperature under vacuum to give the crystal form V of Compound 1.

[0155] The XRPD comparison pattern of the crystal V is as shown in FIG. 19.

Example 11. Preparation Method of Crystal Form VI of Compound 1

[0156] 50 mg of the crystal form I of Compound 1 prepared in accordance with the method of Example 2 was weighed and placed in 1 mL of methanol, suspended and slurried at room temperature for 70 hrs, and then filtered to give the crystal form VI of Compound 1. The obtained crystal form VI has an XRPD pattern as shown in FIG. 20, a DSC pattern as shown in FIG. 21, and a TGA pattern as shown in FIG. 22.

Example 12. Preparation Method of Crystal Form VII of Compound 1

[0157] An appropriate amount of Compound 1 prepared in accordance with the method of Example 1 was weighed and dissolved in water to prepare a saturated solution. 200 μL of the saturated solution was added dropwise into 1.5 mL of acetonitrile at room temperature with stirring. After stirring at room temperature for 19 hrs, the mixture was centrifuged for solid-liquid separation. The obtained solid was detected, and the XRPD results indicated that the solid was a novel crystal form IX. The obtained solid was dried under vacuum at room temperature to give the crystal form VII of Compound 1. The obtained crystal form VII has an XRPD pattern as shown in FIG. 23, a DSC pattern as shown in FIG. 24, and a TGA pattern as shown in FIG. 25.

Example 13. Preparation Method of Crystal Form VII of Compound 1

[0158] 10 mg of the crystal form I of Compound 1 prepared in accordance with the method of Example 2 was weighed and suspended in 1 mL of acetonitrile. 200 μL of water was added dropwise at 60° C. until the solid was completely dissolved. Then, the mixture was cooled to room temperature, stirred for 3 hrs, and centrifuged for solid-liquid separation. The obtained solid was detected. The XRPD of the solid indicated that it was a novel crystal form IX. The obtained solid was dried at room temperature under vacuum to give the crystal form VII of Compound 1.

[0159] The XRPD comparison pattern of the crystal form VII is as shown in FIG. 26.

Example 14. Preparation Method of Crystal Form VIII of Compound 1

[0160] An appropriate amount of Compound 1 prepared in accordance with the method of Example 1 was weighed and dissolved in water to prepare a saturated solution. 1 mL of the saturated solution was added dropwise into 1.5 mL of acetonitrile at room temperature with stirring. After stirring at room temperature for 19 hrs, the mixture was filtered at the atmosphere. The wet filter cake was detected, and the XRPD results indicated that the solid was a novel crystal form IX. The filter cake was air-dried at room temperature to give the crystal form VIII of Compound 1. The obtained crystal form VIII has an XRPD pattern as shown in FIG. 27, a DSC pattern as shown in FIG. 28, and a TGA pattern as shown in FIG. 29.

[0161] The comparison of XRPD patterns of the obtained crystal form VII, crystal form VIII, and crystal form IX are as shown in FIG. 30.

Example 15. Solubility of Compound 1

[0162] Compound 1 was detected at room temperature for its solubility in 19 types of solvents. Specially, Compound 1 obtained in Example 1 was taken as sample for detecting its solubility in methanol, ethanol, water, acetonitrile, dioxane and other solvents. The results are shown in Table 1:

TABLE-US-00009 TABLE 1 Results of Solubility Tests Amount Solubility Solvent (μL) Phenomenon (mg/mL) Methanol 500 Dissolved and clear 20 < S < 50 Ethanol 3000 Not dissolved completely at S < 3.3 50° C. N-propanol 3000 Not dissolved completely at S < 3.3 50° C. Iso-propanol 3000 Not dissolved completely at S < 3.3 50° C. Acetone 3000 Not dissolved completely at S < 3.3 50° C. Methyl isobutyl ketone 3000 Not dissolved completely at S < 3.3 50° C. Ethyl acetate 3000 Not dissolved completely at S < 3.3 50° C. Ethyl formate 3000 Not dissolved completely at S < 3.3 50° C. Tetrahydrofuran 3000 Not dissolved completely at S < 3.3 50° C. Acetonitrile 3000 Not dissolved completely at S < 3.3 50° C. Dioxane 3000 Not dissolved completely at S < 3.3 50° C. Dichloromethane 3000 Not dissolved completely at S < 3.3 50° C. N-hexane 3000 Not dissolved completely at S < 3.3 50° C. Methyl tert-butyl ether 3000 Not dissolved completely at S < 3.3 50° C. Ethylene glycol 200 Dissolved and clear S > 50 monomethyl ether Ethylene glycol 3000 Not dissolved completely at S < 3.3 dimethyl ether 50° C. Dimethylformamide 200 Dissolved and clear S > 50 Dimethylsulfoxide 200 Dissolved and clear S > 50 Water 200 Dissolved and clear S > 50

[0163] The above results show that the solubility of Compound 1 as a whole is better than that of WX-216. Specially, Compound 1 has good solubility in water, methanol, ethylene glycol monomethyl ether, dimethylformamide, dimethylsulfoxide, and relatively poor solubility in other solvents. Its advantages in solubility exceed a reasonable prediction of those skilled in the art.

Example 16. Study of Stability

[0164] An amount of sample to be tested was weighed and placed in a dish under conditions including high temperature (60° C.), high humidity (25° C., 92.5% RH), light radiation (25° C., 4500 Lux) and acceleration conditions (40° C., 75% RH), respectively, and sampled for XRPD characterization on day 14.

[0165] Form I, Form II, Form III were taken for stability study under conditions including high temperature (60° C.), high humidity (25° C., 92.5% RH), light radiation (25° C., 4500 Lux), and acceleration conditions (40° C., 75% RH), and the results are shown in Table 2:

TABLE-US-00010 TABLE 2 Results of Stability Study Crystal Results on Form Conditions Day 14 Crystal High No changes Form I temperature High No changes humidity Light No changes radiation Acceleration No changes conditions Crystal High No changes Form II temperature High No changes humidity Light No changes radiation Acceleration No changes conditions Crystal High No changes Form III temperature High No changes humidity Light No changes radiation Acceleration No changes conditions

[0166] The results show that the crystal forms I-III have high stability under all the conditions of high temperature, high humidity, light radiation and acceleration conditions.

[0167] The crystal form I and the crystal form III can also be used as intermediate crystal forms for further producing some other stable crystal forms of the present disclosure.

[0168] Moreover, during the experiment and further study, the inventor further found out the follows:

[0169] The crystal form IV is obtained by heating the crystal form III to lose some crystalline water. The XRPD results show that the crystal form of crystal form IV does not change after DVS test, and it is considered that the crystal form IV has good stability.

[0170] The crystal form V can be obtained by long-term stirring in a methanol/iso-propyl acetate system at room temperature, followed by crystallization. Those skilled in the art can appreciate that the crystal form V has good stability.

[0171] The crystal form VI is an unstable crystal form, which is transformed to a crystal form V during post-treatment (drying under vacuum at ambient temperature). It can be seen that the crystal form V is finally obtained by the transition from an intermediate metastable crystal form (crystal form VI), and has high stability.

[0172] The crystal form VII and the crystal form VIII can be obtained by similar method but by different post-treatment means. During the experiment, an intermediate metastable crystal form (that is, the crystal form IX) is captured. It can be seen that the crystal form VII and the crystal form VIII are both obtained by the transition of the intermediate metastable crystal form (i.e., the crystal form IX) and have high stability.

[0173] In sum, the crystal forms of Compound 1 of the present disclosure have at least one of the effects of stability and solubility, and provide a variety of options of intermediate products and/or APIs for large-scale production of APIs and downstream processes of pharmaceutical products (e.g., the preparation process).

[0174] The above examples are preferable embodiments of the present disclosure. However, the embodiments of the present disclosure are not limited to the above examples, and any other variations, modifications, substitutions, combinations and simplifications without departing from the spirits and principles of the present disclosure are equivalent replacement embodiments and encompassed within the protection scope of the present disclosure.