WO2024067784A1

WO2024067784A1 - Amorphous form and crystalline solid of bicyclic compound and preparation method therefor

Info

Publication number: WO2024067784A1
Application number: PCT/CN2023/122465
Authority: WO
Inventors: 张勇
Original assignee: 上海济煜医药科技有限公司
Priority date: 2022-09-30
Filing date: 2023-09-28
Publication date: 2024-04-04

Abstract

Provided are an amorphous form and 16 crystal forms of a compound represented by formula (I). The crystal forms are named in order from crystal form A to crystal form P. Also provided is a preparation method for the amorphous form and polymorphs of the compound represented by formula (I).

Description

Amorphous and crystalline solids of bicyclic compounds and preparation methods thereof

This application claims the priority of Chinese patent application No. 2022112121001 filed on September 30, 2022. This application cites the entire text of the above Chinese patent application.

Technical Field

The present invention belongs to the field of pharmaceutical chemistry, and in particular, relates to an amorphous form, a polymorphic form and applications of a bicyclic compound.

Background technique

The industry is looking forward to providing solid forms with excellent physical or chemical properties in the manufacturing process of pharmaceuticals.

The applicant in this case provided a new CYP51 inhibitor antifungal drug in a patent application with application number PCT/CN2022/084203 and application date March 30, 2022, whose structure is shown in formula (I).

Summary of the invention

In one aspect of the present invention, the present invention provides a crystalline form A of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 3.76±0.2°, 5.2±0.2°, 13.75±0.2°, 16.97±0.2°, 17.67±0.2°, and 19.75±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 3.76±0.2°, 5.2±0.2°, 5.82±0.2°, 13.75±0.2°, 14.7±0.2°, 16.97±0.2°, 17.67±0.2°, 18.41±0.2°, 19.75±0.2°, and 21.09±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 3.76±0.2°, 5.2±0.2°, 5.82±0.2°, 13.07±0.2°, 13.75±0.2°, 14.7±0.2°, 15.85±0.2°, 16.97±0.2°, 17.67±0.2°, 18.41±0.2°, 19.23±0.2°, 19.75±0.2°, 21.09±0.2°, 21.87±0.2°, and 22.92±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form A is shown in Table 1 below.

Table 1

In another aspect of the present invention, the present invention also proposes a crystalline form B of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2θ angles: 11.92±0.2°, 16.31±0.2°, 17.75±0.2°, 18.74±0.2°, 19.56±0.2°, and 21.72±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2θ angles: 9.88±0.2°, 11.92±0.2°, 16.31±0.2°, 17.19±0.2°, 17.75±0.2°, 18.74±0.2°, 19.56±0.2°, 20.59±0.2°, 21.72±0.2°, and 23.68±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2θ angles: 9.88±0.2°, 10.89±0.2°, 11.92±0.2°, 13.11±0.2°, 14.84±0.2°, 16.31±0.2°, 17.19±0.2°, 17.75±0.2°, 18.74±0.2°, 19.56±0.2°, 20.59±0.2°, 21.27±0.2°, 21.72±0.2°, 22.84±0.2°, and 23.68±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form B has an X-ray powder diffraction pattern substantially as shown in FIG. 3 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form B is shown in Table 2 below.

Table 2

In another aspect of the present invention, the present invention also discloses a crystalline form C of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2θ angles: 10.15±0.2°, 11.26±0.2°, 18.24±0.2°, 20.34±0.2°, 20.92±0.2°, and 22.59±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2θ angles: 10.15±0.2°, 11.26±0.2°, 14.27±0.2°, 16.57±0.2°, 17.75±0.2°, 18.24±0.2°, 20.34±0.2°, 20.92±0.2°, 22.59±0.2°, and 27.33±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2θ angles: 7.04±0.2°, 10.15±0.2°, 10.97±0.2°, 11.26±0.2°, 14.27±0.2°, 16.57±0.2°, 17.75±0.2°, 18.24±0.2°, 20.34±0.2°, 20.92±0.2°, 22.59±0.2°, 23.78±0.2°, 24.87±0.2°, 25.97±0.2°, and 27.33±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form C has an X-ray powder diffraction pattern substantially as shown in FIG. 5 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form C is shown in Table 3 below.

table 3

In another aspect of the present invention, the present invention provides a crystalline form D of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2θ angles: 4.96±0.2°, 6.65±0.2°, 8.93±0.2°, 13.11±0.2°, 13.85±0.2°, and 17.19±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2θ angles: 4.34±0.2°, 4.96±0.2°, 6.65±0.2°, 8.93±0.2°, 13.11±0.2°, 13.85±0.2°, 17.19±0.2°, 17.95±0.2°, 18.84±0.2°, and 20.01±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2θ angles: 4.34±0.2°, 4.96±0.2°, 6.65±0.2°, 8.93±0.2°, 13.11±0.2°, 13.85±0.2°, 14.54±0.2°, 15.89±0.2°, 17.19±0.2°, 17.95±0.2°, 18.84±0.2°, 19.4±0.2°, 20.01±0.2°, 22.16±0.2°, and 22.86±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form D has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form D is shown in Table 4 below.

Table 4

In another aspect of the present invention, the present invention provides a crystalline form E of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2θ angles: 10.42±0.2°, 12.6±0.2°, 16.59±0.2°, 18.24±0.2°, 20.22±0.2°, and 22.42±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2θ angles: 10.42±0.2°, 12.6±0.2°, 13.5±0.2°, 16.59±0.2°, 17.71±0.2°, 18.24±0.2°, 20.22±0.2°, 20.88±0.2°, 22.42±0.2°, and 24.11±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2θ angles: 3.76±0.2°, 10.42±0.2°, 12.6±0.2°, 13.5±0.2°, 14.51±0.2°, 15.23±0.2°, 16.59±0.2°, 17.71±0.2°, 18.24±0.2°, 20.22±0.2°, 20.88±0.2°, 21.44±0.2°, 22.42±0.2°, 23.5±0.2°, and 24.11±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form E has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form E is shown in Table 5 below.

table 5

In another aspect of the present invention, the present invention also proposes a crystalline form F of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2θ angles: 11.94±0.2°, 15.75±0.2°, 18.06±0.2°, 19.27±0.2°, 20.47±0.2°, and 21.39±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2θ angles: 3.35±0.2°, 4.11±0.2°, 10.09±0.2°, 11.24±0.2°, 11.94±0.2°, 15.75±0.2°, 18.06±0.2°, 19.27±0.2°, 20.47±0.2°, and 21.39±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2θ angles: 3.35±0.2°, 4.11±0.2°, 5.18±0.2°, 5.7±0.2°, 10.09±0.2°, 11.24±0.2°, 11.94±0.2°, 15.75±0.2°, 16.59±0.2°, 18.06±0.2°, 19.27±0.2°, 20.47±0.2°, 21.39±0.2°, 22.46±0.2°, and 24.24±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form F has an X-ray powder diffraction pattern substantially as shown in FIG. 11 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form F is shown in Table 6 below.

Table 6

In another aspect of the present invention, the present invention also proposes a crystalline form G of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form G has characteristic diffraction peaks at the following 2θ angles: 5.62±0.2°, 10.58±0.2°, 11.65±0.2°, 14.62±0.2°, 17.67±0.2°, and 21.13±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form G has characteristic diffraction peaks at the following 2θ angles: 5.62±0.2°, 10.58±0.2°, 11.65±0.2°, 14.62±0.2°, 15.34±0.2°, 17.67±0.2°, 19.95±0.2°, 20.51±0.2°, 21.13±0.2°, and 21.66±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form G has characteristic diffraction peaks at the following 2θ angles: 5.62±0.2°, 9.34±0.2°, 9.8±0.2°, 10.58±0.2°, 11.65±0.2°, 14.62±0.2°, 15.34±0.2°, 17.67±0.2°, 18.61±0.2°, 19.95±0.2°, 20.51±0.2°, 21.13±0.2°, 21.66±0.2°, 23.33±0.2°, and 25.02±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form G has an X-ray powder diffraction pattern substantially as shown in FIG. 13 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the sulfate crystal form G is shown in Table 7 below.

Table 7

In another aspect of the present invention, the present invention also provides a crystalline form H of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form H has characteristic diffraction peaks at the following 2θ angles: 10.46±0.2°, 12.47±0.2°, 16.29±0.2°, 18.41±0.2°, 20.26±0.2°, and 21.02±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form H has characteristic diffraction peaks at the following 2θ angles: 10.46±0.2°, 11.34±0.2°, 12.47±0.2°, 16.29±0.2°, 17.89±0.2°, 18.41±0.2°, 19.5±0.2°, 20.26±0.2°, 21.02±0.2°, and 22.42±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form H has characteristic diffraction peaks at the following 2θ angles: 10.46±0.2°, 11.34±0.2°, 12.47±0.2°, 13.53±0.2°, 16.29±0.2°, 16.97±0.2°, 17.89±0.2°, 18.41±0.2°, 19.07±0.2°, 19.5±0.2°, 20.26±0.2°, 21.02±0.2°, 22.42±0.2°, 24.01±0.2°, and 25.53±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form H has an X-ray powder diffraction pattern substantially as shown in FIG. 15 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form H is shown in Table 8 below.

Table 8

In another aspect of the present invention, the present invention also provides a crystalline form I of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form I has characteristic diffraction peaks at the following 2θ angles: 9.84±0.2°, 10.37±0.2°, 11.51±0.2°, 20.24±0.2°, 20.71±0.2°, and 22.96±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form I has characteristic diffraction peaks at the following 2θ angles: 9.84±0.2°, 10.37±0.2°, 11.51±0.2°, 14.27±0.2°, 17.95±0.2°, 18.3±0.2°, 20.24±0.2°, 20.71±0.2°, 21.25±0.2°, and 22.96±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form I has an X-ray powder diffraction pattern substantially as shown in Figure 17.

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystalline form I is shown in Table 9 below.

Table 9

In another aspect of the present invention, the present invention also proposes a crystalline form J of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form J has characteristic diffraction peaks at the following 2θ angles: 11.67±0.2°, 16.08±0.2°, 16.68±0.2°, 18.86±0.2°, 19.35±0.2°, and 23.74±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form J has characteristic diffraction peaks at the following 2θ angles: 9.67±0.2°, 10.91±0.2°, 11.67±0.2°, 16.08±0.2°, 16.68±0.2°, 17.21±0.2°, 18.86±0.2°, 19.35±0.2°, 21.27±0.2°, and 23.74±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form J has characteristic diffraction peaks at the following 2θ angles: 5.49±0.2°, 6.3±0.2°, 9.67±0.2°, 10.91±0.2°, 11.67±0.2°, 12.87±0.2°, 14.68±0.2°, 16.08±0.2°, 16.68±0.2°, 17.21±0.2°, 18.86±0.2°, 19.35±0.2°, 20.32±0.2°, 21.27±0.2°, and 23.74±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form J has an X-ray powder diffraction pattern substantially as shown in FIG. 19 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form J is shown in Table 10 below.

Table 10

In another aspect of the present invention, the present invention also proposes a crystalline form K of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form K has characteristic diffraction peaks at the following 2θ angles: 12.04±0.2°, 15.85±0.2°, 18.18±0.2°, 19.31±0.2°, 19.56±0.2°, 21.48±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form K has characteristic diffraction peaks at the following 2θ angles: 11.42±0.2°, 12.04±0.2°, 15.85±0.2°, 16.64±0.2°, 18.18±0.2°, 19.31±0.2°, 19.56±0.2°, 20.57±0.2°, 21.48±0.2°, and 24.28±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form K has characteristic diffraction peaks at the following 2θ angles: 5.76±0.2°, 10.17±0.2°, 11.42±0.2°, 12.04±0.2°, 15.85±0.2°, 16.64±0.2°, 18.18±0.2°, 18.72±0.2°, 19.31±0.2°, 19.56±0.2°, 20.57±0.2°, 21.48±0.2°, 22.51±0.2°, 24.28±0.2°, and 25.6±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form K has an X-ray powder diffraction pattern substantially as shown in Figure 21.

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form K is shown in Table 11 below.

Table 11

In another aspect of the present invention, the present invention also proposes a crystalline form L of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2θ angles: 10.42±0.2°, 12.43±0.2°, 16.27±0.2°, 18.18±0.2°, 20.08±0.2°, 21±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2θ angles: 10.42±0.2°, 11.28±0.2°, 12.43±0.2°, 13.48±0.2°, 16.27±0.2°, 18.18±0.2°, 20.08±0.2°, 21±0.2°, 22.36±0.2°, and 23.91±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2θ angles: 3.08±0.2°, 10.42±0.2°, 11.28±0.2°, 12.43±0.2°, 13.48±0.2°, 14.47±0.2°, 16.27±0.2°, 16.82±0.2°, 18.18±0.2°, 20.08±0.2°, 21±0.2°, 22.36±0.2°, 23.91±0.2°, 25.47±0.2°, and 28.15±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form L has an X-ray powder diffraction pattern substantially as shown in Figure 23.

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form L is shown in Table 12 below.

Table 12

In another aspect of the present invention, the present invention also proposes a crystalline form M of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form M has characteristic diffraction peaks at the following 2θ angles: 5.33±0.2°, 7.04±0.2°, 14.7±0.2°, 15.85±0.2°, 18.43±0.2°, and 21.11±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form M has characteristic diffraction peaks at the following 2θ angles: 4.38±0.2°, 5.33±0.2°, 7.04±0.2°, 14.06±0.2°, 14.7±0.2°, 15.85±0.2°, 17.38±0.2°, 18.43±0.2°, 19.11±0.2°, and 21.11±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form M has characteristic diffraction peaks at the following 2θ angles: 4.38±0.2°, 4.87±0.2°, 5.33±0.2°, 7.04±0.2°, 10.6±0.2°, 14.06±0.2°, 14.7±0.2°, 15.85±0.2°, 17.38±0.2°, 18.43±0.2°, 19.11±0.2°, 19.58±0.2°, 21.11±0.2°, 21.78±0.2°, and 27.78±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form N has an X-ray powder diffraction pattern substantially as shown in Figure 27.

[Corrected 29.11.2023 in accordance with Article 91]

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form N is shown in Table 14 below.

Table 14

In another aspect of the present invention, the present invention also proposes a crystalline form O of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form O has characteristic diffraction peaks at the following 2θ angles: 5.02±0.2°, 10.29±0.2°, 12.54±0.2°, 16.72±0.2°, 17.62±0.2°, and 20.45±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form O has characteristic diffraction peaks at the following 2θ angles: 5.02±0.2°, 10.29±0.2°, 12.54±0.2°, 13.59±0.2°, 15.34±0.2°, 16.72±0.2°, 17.62±0.2°, 19.75±0.2°, 20.45±0.2°, and 25.37±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form O has characteristic diffraction peaks at the following 2θ angles: 5.02±0.2°, 10.29±0.2°, 12.54±0.2°, 13.59±0.2°, 14.25±0.2°, 15.34±0.2°, 16.72±0.2°, 17.62±0.2°, 19.75±0.2°, 20.45±0.2°, 20.9±0.2°, 22.61±0.2°, 23.33±0.2°, 25.37±0.2°, and 26.79±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form O has an X-ray powder diffraction pattern substantially as shown in Figure 29.

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form O is shown in Table 15 below.

Table 15

In another aspect of the present invention, the present invention also proposes a crystalline form P of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form P has characteristic diffraction peaks at the following 2θ angles: 11.53±0.2°, 14.72±0.2°, 15.98±0.2°, 17.01±0.2°, 17.54±0.2°, and 19.5±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form P has characteristic diffraction peaks at the following 2θ angles: 9.57±0.2°, 11.05±0.2°, 11.53±0.2°, 12.82±0.2°, 14.72±0.2°, 15.98±0.2°, 17.01±0.2°, 17.54±0.2°, 19.09±0.2°, and 19.5±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form P has characteristic diffraction peaks at the following 2θ angles: 9.57±0.2°, 11.05±0.2°, 11.53±0.2°, 12.82±0.2°, 14.72±0.2°, 15.98±0.2°, 17.01±0.2°, 17.54±0.2°, 19.09±0.2°, 19.5±0.2°, 20.24±0.2°, 20.88±0.2°, 21.43±0.2°, 22.14±0.2°, and 23.89±0.2°.

[Corrected 29.11.2023 in accordance with Article 91]
In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form P has an X-ray powder diffraction pattern substantially as shown in Figure 31.

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form P is shown in Table 16 below.

Table 16

Definition and Description

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those of ordinary skill in the art to which the present invention belongs. All patents and publications to which the present invention relates are incorporated herein by reference in their entirety. Although any methods and materials similar or identical to those described herein may be used in the practice or testing of the present invention, preferred methods, apparatus and materials are described herein.

"API" or "free state" refers to the free base form of the compound represented by formula (I).

"Crystal form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, inclusion compounds, co-crystals, salts, solvates of salts, hydrates of salts of compounds. The crystalline form of a substance can be obtained by many methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, for example, in a nanopore or capillary, crystallization on a surface or template, for example, on a polymer, crystallization in the presence of an additive such as a co-crystallization countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, grinding and solvent drop grinding, etc.

"Amorphous" or "amorphous form" refers to a substance formed when the particles (molecules, atoms, ions) of a substance are arranged in a three-dimensional space without periodicity, and is characterized by a diffuse X-ray powder diffraction pattern without peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural characteristics suggest that it is inextricably linked to crystalline substances. The amorphous form of a substance can be obtained by many methods known in the art. This method includes, but is not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion technology, etc.

"Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

"Anti-solvent" refers to a fluid that promotes precipitation of a product (or a product precursor) from a solvent. The anti-solvent may include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid from the solvent.

"Solvate" means that the crystal has a solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice, wherein the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof, etc. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice is water. On the surface of the substance, in the crystal lattice, or on the surface and in the crystal lattice, the hydrate may or may not have other solvents except water.

Crystalline or amorphous forms can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

X-ray powder diffraction (XRPD) can detect information such as changes in crystal forms, crystallinity, and crystal structure states, and is a common means of identifying crystal forms. The peak position of the XRPD spectrum depends mainly on the structure of the crystal form, is relatively insensitive to experimental details, and its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention. At the same time, the measurement of 2θ of the XRPD spectrum may have experimental errors, and the measurement of 2θ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of 2θ cannot be regarded as absolute. According to the instrument conditions used in the test of the present invention, there is an error tolerance of ±0.2° for the diffraction peak.

Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (usually α-Al ₂ O ₃ ) as a function of temperature by continuous heating or cooling under program control. The height of the melting peak of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form of the present invention is characterized by a DSC graph with a characteristic peak position, which is substantially as shown in the DSC graph provided in the accompanying drawings of the present invention. At the same time, DSC spectra may have experimental errors, and the peak positions and peak values of DSC spectra may vary slightly between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the instrument conditions used in the test of the present invention, the melting peak has an error tolerance of ±3°C.

Glass transition refers to the transition of amorphous materials between a highly elastic state and a glassy state, which is an inherent property of the material; its corresponding transition temperature is the glass transition temperature (Tg), which is an important physical property of amorphous materials. Glass transition is a phenomenon related to molecular motion, and therefore, the glass transition temperature (Tg) mainly depends on the structure of the material, and is relatively insensitive to experimental details. In some embodiments, the glass transition temperature (Tg) of the amorphous material of the present invention is measured by differential scanning calorimetry (DSC), characterized in that it has a glass transition temperature of 66°C. According to the instrument conditions used in the test of the present invention, the glass transition temperature has an error tolerance of ±3°C.

Differential scanning calorimetry (DSC) can also be used to detect and analyze whether there is crystal transformation or mixed crystal phenomenon.

Solids with the same chemical composition often form isomers with different crystal structures, or variants, under different thermodynamic conditions. This phenomenon is called polymorphism or polyphase phenomenon. When the temperature and pressure conditions change, the variants will transform into each other, which is called crystal transformation. Due to the crystal transformation, the mechanical, electrical, magnetic and other properties of the crystal will change greatly. When the temperature of the crystal transformation is within the measurable range, this transformation process can be observed on the differential scanning calorimetry (DSC) graph, characterized in that the DSC graph has an exothermic peak reflecting this transformation process, and at the same time has two or more endothermic peaks, which are the characteristic endothermic peaks of different crystal forms before and after the transformation. The crystal form or amorphous form of the compound of the present invention can undergo crystal transformation under appropriate conditions.

Thermogravimetric analysis (TGA) is a technique for measuring the mass change of a substance with temperature under program control. It is suitable for checking the loss of solvent in crystals or the process of sample sublimation and decomposition, and can infer the presence of crystal water or crystallization solvent in the crystals. The mass change shown by the TGA curve depends on many factors such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. According to the instrument conditions used in the test of the present invention, the mass change has an error tolerance of ±0.3%.

The moisture adsorption/desorption isotherm measurement (DVS) is a measurement method that measures the adsorption and desorption behavior of moisture by measuring the weight change of a solid object under various relative humidity conditions.

In the context of the present invention, 2θ values in X-ray powder diffraction patterns are given in degrees (°).

When referring to a spectrum and/or data appearing in a graph, a "peak" refers to a feature that can be identified by one skilled in the art and which cannot be attributed to background noise.

The term "substantially as shown" means that 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 in the X-ray powder diffraction pattern or the DSC pattern or the TGA results are shown in its pattern.

"Substantially pure" means that one crystalline form is substantially free of one or more other crystalline forms, that is, the purity of the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystalline form contains other crystalline forms, and the percentage of the other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

"Substantially free" means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

“Relative intensity” refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD) when the intensity of the first strongest peak is 100%.

In the context of the present invention, when or whether the words "about" or "approximately" are used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error range of the mean. Whenever a number having a value of N is disclosed, any number having a value within N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+/-10% will be explicitly disclosed, where "+/-" means plus or minus.

The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is an XRPD diagram of Form A according to an embodiment of the present invention;

FIG2 is an NMR diagram of Form A according to an embodiment of the present invention;

FIG3 is an XRPD diagram of Form B according to an embodiment of the present invention;

FIG4 is an NMR diagram of Form B according to an embodiment of the present invention;

FIG5 is an XRPD diagram of Form C according to an embodiment of the present invention;

FIG6 is an NMR diagram of Form C according to an embodiment of the present invention;

FIG7 is an XRPD diagram of Form D according to an embodiment of the present invention;

FIG8 is an NMR diagram of Form D according to an embodiment of the present invention;

FIG9 is an XRPD diagram of Form E according to an embodiment of the present invention;

FIG10 is an NMR diagram of Form E according to an embodiment of the present invention;

FIG11 is an XRPD diagram of Form F according to an embodiment of the present invention;

FIG12 is an NMR diagram of Form F according to an embodiment of the present invention;

FIG13 is an XRPD diagram of Form G according to an embodiment of the present invention;

FIG14 is an NMR diagram of Form G according to an embodiment of the present invention;

FIG15 is an XRPD diagram of Form H according to an embodiment of the present invention;

FIG16 is an NMR diagram of Form H according to an embodiment of the present invention;

FIG17 is an XRPD diagram of Form I according to an embodiment of the present invention;

FIG18 is an NMR diagram of Form I according to an embodiment of the present invention;

FIG19 is an XRPD diagram of Form J according to an embodiment of the present invention;

FIG20 is an NMR diagram of Form J according to an embodiment of the present invention;

FIG21 is an XRPD diagram of Form K according to an embodiment of the present invention;

FIG22 is an NMR diagram of Form K according to an embodiment of the present invention;

FIG23 is an XRPD diagram of Form L according to an embodiment of the present invention;

FIG24 is an NMR diagram of Form L according to an embodiment of the present invention;

FIG25 is an XRPD diagram of Form M according to an embodiment of the present invention;

FIG26 is an NMR diagram of Form M according to an embodiment of the present invention;

FIG27 is an XRPD diagram of Form N according to an embodiment of the present invention;

FIG28 is an NMR diagram of Form N according to an embodiment of the present invention;

FIG29 is an XRPD diagram of Form O according to an embodiment of the present invention;

FIG30 is an NMR diagram of Form O according to an embodiment of the present invention;

FIG31 is an XRPD diagram of Form P according to an embodiment of the present invention;

FIG32 is an NMR diagram of Form P according to an embodiment of the present invention;

FIG33 is (a) a DVS curve of Form P according to an embodiment of the present invention; (b) an XRPD diagram before and after the DVS test;

FIG34 is a PLM image of a crystal form P according to an embodiment of the present invention;

FIG35 is an XRPD pattern of an amorphous form according to an embodiment of the present invention;

FIG36 is an NMR graph of an amorphous form according to an embodiment of the present invention;

Figure 37 is an amorphous (a) DVS curve according to an embodiment of the present invention; (b) XRPD diagram before and after DVS test;

FIG38 is an amorphous PLM image according to an embodiment of the present invention;

FIG39 is an XRPD diagram of amorphous stability study according to an embodiment of the present invention;

FIG40 is an XRPD diagram of a stability study of Form P according to an embodiment of the present invention;

FIG41 is a comparison diagram of XRPD of the remaining solid after the amorphous phase was shaken in a medium for 24 hours according to an embodiment of the present invention;

Figure 42 is a comparison chart of XRPD of the solid remaining after the crystal form P according to an embodiment of the present invention was oscillated in a medium for 24 hours.

Detailed ways

The present application is described in detail below by way of examples, but it is not intended that there is any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

Unless otherwise specified, the raw materials used in the present invention are commercially available.

General analysis methods:

1. Nuclear magnetic resonance analysis ( ¹ H NMR)

Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and analyzed by NMR on Bruker AVANCE NEO 400 (Bruker, GER).

2. X-ray powder diffraction (XRPD)

The solid samples obtained in the experiment were analyzed by X-ray powder diffractometer Bruker D8Advance (Bruker, GER). The 2θ scanning angle was from 3° to 45°, the scanning step was 0.02°, and the exposure time was 0.08 seconds. The test method was Cu target Kα1 radiation, voltage 40kV, current 40mA, and the sample pan was a zero background sample pan.

3. Thermogravimetric analysis (TGA)

The model of the thermogravimetric analyzer is TA Discovery 550 (TA, US). 2-5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C/min, and the nitrogen purge rate at the sample was 60 mL/min and the nitrogen purge rate at the balance was 40 mL/min.

4. Differential Scanning Calorimetry (DSC)

The model of the differential scanning calorimeter was TA Discovery 250 (TA, US). 1-2 mg of sample was accurately weighed and placed in a DSC Tzero sample pan with holes and heated to the final temperature at a rate of 10 °C/min, with nitrogen purge rate of 50 mL/min in the furnace.

5. Dynamic moisture adsorption and desorption analysis (DVS)

Dynamic moisture adsorption and desorption analysis was performed using DVS Intrinsic (SMS, UK). The test used a gradient mode, with humidity changes of 50%-95%-0%-50%. The humidity change for each gradient in the range of 0% to 90% was 10%. The gradient endpoint was determined using the dm/dt method, with dm/dt less than 0.002% and maintained for 10 minutes as the gradient endpoint. After the test was completed, the sample was subjected to XRPD analysis to confirm whether the solid morphology had changed.

6. Polarized light microscopy (PLM)

The model of polarizing microscope is Nikon Ci-POL (Nikon, JP). Place a small amount of sample on a glass slide and select a suitable lens to observe the sample morphology.

7. High Performance Liquid Chromatography (HPLC)

The HPLC model was SHIMADZU LC-2030C (Shimadzu, JP). The test conditions were shown in Tables 17 and 18.

Table 17 HPLC solubility test conditions

Table 18 HPLC purity test conditions

General test methods:

1. Raw material solubility test

Weigh about 20 mg of sample and add it to an EP tube. At room temperature (~25°C), add a certain amount of solvent gradually. Stir the solution and observe whether the solid is completely dissolved. If it is still not dissolved after adding 10.0 mL of solvent, stop the experiment. Estimate the solubility of the compound in the solvent based on the volume of solvent used when the solid is completely dissolved.

2. Solvent evaporation method

The clear solution obtained from the raw material solubility test (general test method 1) or about 20 mg of the sample is weighed to prepare a clear solution (filter the system with solid precipitation), and it is left to stand at room temperature in an open air until the solvent is completely evaporated to obtain a solid.

3. Suspension method

3.1. Room temperature suspension

Different crystal forms are used as raw materials, a certain amount of sample is added to a selected single solvent or binary solvent until a suspension is formed, and after being suspended and stirred at room temperature for a certain period of time, the suspension is centrifuged and the solid is vacuum dried at room temperature.

3.2, 50℃ suspension

Using amorphous as raw material, a certain amount of sample is added to the selected solvent until a suspension is formed. After suspension and stirring at 50° C. for 24 hours, the suspension is centrifuged and the solid is vacuum dried at room temperature.

3.3 Low temperature suspension

Using different crystal forms as raw materials, a certain amount of sample was added to the selected binary solvent until a suspension was formed. After suspension and stirring at 10° C. for 24 hours, the suspension was centrifuged and the solid was vacuum dried at room temperature.

4. Dissolution crystallization method

4.1. Binary solvent back-titration method

Weigh about 15 mg of sample, add a certain amount of good solvent at room temperature to completely dissolve the sample, and add the solution to 10 times the volume of poor solvent. After stirring for 1 hour, centrifuge the system with solid precipitation, and vacuum dry the solid at room temperature; continue to stir the clear solution for 24 hours, and place the system without solid precipitation in a 4 or -15℃ refrigerator, centrifuge the system with solid precipitation, and vacuum dry the solid at room temperature. If there is still no solid precipitation, leave the solution open at room temperature until the solvent completely evaporates to obtain a solid.

4.2. Binary solvent positive drop method

Weigh about 15 mg of sample, add a certain amount of good solvent at room temperature to completely dissolve the sample, and add poor solvent until solid precipitates. After stirring at room temperature for 1 hour, centrifuge the system with solid precipitation, and vacuum dry the solid at room temperature; continue to stir the clear solution for 24 hours, and place the system without solid precipitation in a 4 or -15℃ refrigerator, centrifuge the system with solid precipitation, and vacuum dry the solid at room temperature. If there is still no solid precipitation, leave the solution open at room temperature until the solvent completely evaporates to obtain a solid.

5. Binary solvent cooling method

Weigh about 15 mg of sample and mix it with a certain amount of poor solvent at 50°C to form a suspension. Gradually add the preheated good solvent until the solid is just completely dissolved, and transfer the solution to room temperature for cooling. Let it stand at room temperature for more than 2 hours. If there is not enough solid precipitation, place the solution at 4°C for further cooling. If there is still not enough solid precipitation, place the solution at -15°C for further cooling. For the system with sufficient solid precipitation, centrifuge and vacuum dry the solid at room temperature. If there is still no solid precipitation, let the solution stand at room temperature in the open until the solvent is completely evaporated to obtain a solid.

Weigh about 15 mg of sample, dissolve it in the selected binary solvent at room temperature, and cool the solution at 4°C. If no sufficient solid precipitates, cool the solution at -15°C. Centrifuge the system with sufficient solid precipitation and vacuum dry the solid at room temperature. If no solid precipitates, leave the solution open at room temperature until the solvent evaporates completely to obtain a solid.

6. Solution gas diffusion method

Weigh about 15 mg of sample and dissolve it in a good solvent. Place the clear solution in a poor solvent atmosphere and let it stand at room temperature until solid precipitates. Use a syringe to remove the solution in the system with solid precipitation, and perform XRPD test on the wet sample.

7. Solid gas diffusion method

About 15 mg of an amorphous sample was weighed and placed in a selected solvent atmosphere at room temperature for 14 days. The properties of the solid in the glass vial were regularly observed and the solid was subjected to XRPD testing.

8. Thermal transfer method

Thermal crystallization was performed using an Instec HCS424GXY hot stage (Instec Inc., US). 6-8 mg of sample was placed on a glass slide on the hot stage and heated to the target temperature at a rate of 10°C/min. The temperature was kept constant for 10 min, and then the sample was naturally cooled to room temperature to obtain a solid.

9. Competitive suspension experiment

Saturated solutions of cyclohexane at different temperatures (10-60° C.) were prepared, and solids of different crystal forms were added to the saturated solutions in equal amounts. After suspension and stirring for a certain period of time under the selected specific temperature conditions, the solutions were centrifuged and the wet samples were characterized by XRPD.

10. Stability study

A certain amount of sample (amorphous: about 10 mg; crystalline form P: about 20 mg) was weighed and placed in a weighing bottle, and placed under high temperature (60°C), high humidity (25°C/92.5% RH), light (25°C/4500Lux), and acceleration (40°C/75% RH), respectively. Samples were taken on 7 days and 17 days for XRPD characterization and HPLC testing.

11. Solubility test

11.1. pH Solubility Test

The preparation process of pH buffer solution is shown in Table 19. Samples of different crystal forms were added to pH buffer solution and shaken at a constant temperature of 25°C for 24 hours before sampling. The sampled solution was filtered with a 0.22 μm water filter membrane, and some samples with higher concentrations were appropriately diluted with diluents. The signal peak area of the solution was measured by HPLC, and finally the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution multiple. In addition, the remaining liquid was centrifuged and the remaining supernatant was taken to test its pH value.

Table 19 Preparation process of pH buffer

11.2. Biological media and water solubility test

The preparation process of the biological medium is shown in Table 20. Samples of different crystal forms were added to the biological medium and water and shaken at a constant temperature of 37°C for 24 hours. Samples were taken at 0.5h, 2h and 24h, respectively. The sampled solutions were filtered with a 0.22μm water filter membrane. Some samples with higher concentrations were appropriately diluted with diluents. The signal peak area of the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material and the dilution multiple. In addition, the pH value of the supernatant after 24h was tested, and the remaining solid was tested by XRPD.

Table 20 Preparation process of biological medium

Example 1 Preparation of the compound represented by formula (I)

Preparation of Compound 1-4

Compound 1-1 (28.2 g, 96 mmol) was added to a three-necked flask and replaced with nitrogen three times. Anhydrous ether (100 mL) was added to the three-necked flask, and methyl lithium (1.6 M, 120 mL, 192 mmol) was added dropwise at a cooling temperature of -78 °C. After the reaction system was stirred at -78 °C for 5 minutes, the temperature was gradually raised to 0 °C and the reaction was continued to stir for 3 hours in an ice bath. Subsequently, compound 1-3 (15 g, 60 mmol) was added to the reaction system and the reaction was continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction system was extracted with EtOAc (100 mL × 3), the organic phases were combined, dried and concentrated to obtain a crude product, and the title compound 1-4 (10 g) was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-5%) to obtain a light yellow liquid with a yield of 33%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.33 (q, J=7.2 Hz, 2H), 2.44 (s, 6H), 1.36 (t, J=7.2 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -109.15 (s, 2F).

Preparation of Compound 1-6

Add the compound triacetylacetonate iron (2.2g, 6.3mmol) into a three-necked flask and replace the atmosphere with nitrogen three times. Add anhydrous THF (80mL), compound 1-4 (10g, 31.6mmol) and TMEDA (1.5g, 12.6mmol) into the three-necked flask in sequence. Stir the reaction system for 5 minutes, slowly drop the Grignard reagent 4-methoxyphenylmagnesium bromide THF solution 1-5 (0.5M, 102mL, 50.6mmol) into the three-necked flask, and continue stirring the reaction at room temperature for 16 hours. After the reaction is completed, extract the reaction system with EtOAc (30mL×3), combine the organic phases, dry and concentrate to obtain a crude product, and separate and purify it by a normal phase silica gel column (EtOAc/PE＝0-5%) to obtain the title compound 1-6 (2.1g) as a light yellow liquid with a yield of 23%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.19-7.04 (m, 2H), 6.92-6.77 (m, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 2.16 (s, 6H), 1.37 (t, J=7.1 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -111.34 (s, 2F).

Preparation of Compound 1-8

Compound 1-7 (1.1 g, 5.6 mmol) was added to a three-necked flask and replaced with nitrogen three times. Anhydrous ether (15 mL) was added to the three-necked flask, and n-butyl lithium (1.6 M, 3.5 mL, 5.6 mmol) was added dropwise at a cooling temperature of -78 ° C. After the reaction system was stirred at -78 ° C for 45 minutes, anhydrous ether solution (10 mL) containing compound 1-6 (1.5 g, 5.1 mmol) was added dropwise and the reaction was continued to stir for 1 hour. After the reaction was completed, saturated ammonium chloride solution (5 mL) was added to the reaction system to quench, and extracted with EtOAc (20 mL × 3), the organic phases were combined, dried and concentrated to obtain a crude product, and the title compound 1-8 (1.6 g) was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-5%) as a yellow solid with a yield of 86%. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.92–7.77 (m, 1H), 7.18–7.06 (m, 2H), 7.03–6.88 (m, 2H), 6.88–6.80 (m, 2H), 3.79 (s, 3H), 2.21 (s, 6H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ-99.65 (d, J=13.4 Hz, 1F), -103.94 (q, J=13.8 Hz, 1F), -107.21 (d, J=14.8 Hz, 2F).

Preparation of compound 2-1

Compound 1-8 (1.8 g, 4.95 mmol) was added to a microwave tube, acetic acid (5 mL), aqueous hydrogen bromide solution (48 wt.% in H ₂ O, 5 mL), and the tube was sealed at 95°C for 16 hours. After cooling, the mixture was spin-dried and extracted with EtOAc (30 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-30%) to obtain the title compound 2-1 (1.3 g) as a brown-yellow liquid with a yield of 72%. LC-MS (ESI): m/z 348.8 [MH] ^- .

Preparation of Compound 20-1

Compound 2-1 (1.2 g, 3.43 mmol) was dissolved in a mixed solvent of dichloromethane (15 mL) and water (15 mL), trimethylsulfoxide iodide (3.02 g, 13.7 mmol) and sodium hydroxide (549 mg, 13.7 mmol) were added, and the reaction system was refluxed for 16 hours. After cooling to room temperature, the reaction system was adjusted to pH 6-7 with dilute hydrochloric acid, extracted with DCM (20 mL × 3), and the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-10%) to obtain the title compound 20-1 (1.17 g, yield 94%) as a light yellow oil. LC-MS (ESI): m/z 363.0[M-H]-.1H NMR (400MHz, DMSO-d6) δ9.34(s,1H),7.67(td,J＝8.5,6.5Hz,1H),7.35(ddd,J＝10.5,9.3,2.6Hz,1H),7.16(tdd,J＝8.5,2.6,0.9Hz,1H),7.02–6.93(m,2H),6.74–6.6 3(m,2H),3.40–3.36(m,1H),3.11–3.05(m,1H),2.03–1.94(m,6H).19F NMR(376MHz,DMSO-d6)δ-107.77–-107.88(m,1F),-108.07–-108.22(m,1F),-108.71–-108.81(m,1F),-108.93–-109.06(m,1F).

Preparation of compound 20

Compound 20-1 (1.17 g, 3.21 mmol) was dissolved in DMF solution (10 mL), and compound 1-H tetrazole (225 mg, 12.9 mmol) and potassium carbonate (444 mg, 12.9 mmol) were added respectively. The reaction system was sealed and stirred at 80 °C for 16 hours. After the reaction system was cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 40%-60% acetonitrile in 12 min; flow rate: 30 mL/min) to obtain the title compound 20 (500 mg, yield 36%, containing a pair of enantiomers).

Compound 20: LC-MS (ESI): m/z 435.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ9.31 (br.s, 1H), 9.14 (s, 1H), 7.53 (m, 1H), 7.28 (m, 1H), 7.16 (s, 1H), 7.00 ( m,1H),6.96–6.84(m,2H),6.67–6.58(m,2H),5.42(d,J＝12Hz,1H),5.01(d, J＝12Hz,1H),1.94(dd,J＝9.5,1.7Hz,3H),1.72(dd,J＝9.5,1.7Hz,3H).19F NMR(376MHz,DMSO-d6)δ-102.85–-103.32 (m, 1F), -109.01–-109.42 (m, 2F), -109.67 (d, J = 9.2 Hz, 1F).

Preparation of compound 51

Compound 20 (80 mg, 0.18 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (51 mg, 0.37 mmol) was added under stirring, and the reaction was continued for 5 minutes before adding compound 1,1,1-trifluoro-2,3-epoxypropane (31 mg, 0.28 mmol), and the reaction was continued at 50°C for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10Prep-C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% in 12 min; flow rate 30 mL/min) to obtain the title compound 51 (62 mg, yield: 62%, containing two pairs of enantiomers).

Compound 51: LC-MS (ESI): m/z 547.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 7.54 (td, J＝9.0, 6.7Hz, 1H), 7.28 (ddd, J＝12.0, 9.0, 2.6Hz, 1H), 7.15 ( s, 1H), 7.09–6.96 (m, 3H), 6.92–6.82 (m, 2H), 6.63 (d, J = 6.6 Hz, 1H), 5.42 (d, J = 14.5 Hz, 1H), 5.01 (d ,J＝14.5Hz,1H),4.35 (dt, J = 11.3, 6.8 Hz, 1H), 4.12 (m, 1H), 4.01 (m, 1H), 1.98 (dd, J = 9.4, 1.7 Hz, 3H), 1.76 (dd, J = 9.4, 1.7 Hz,3H).19F NMR(376MHz,DMSO-d6)δ-76.06(s,3F),-102.96–-103.17(m,1F),-109.22–-109.32(m,2F),-109.63(d, J＝9.2Hz,1F).

Preparation of compounds of formula (I)

Compound 51 (62 mg) was subjected to SFC chiral preparative separation (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); chromatographic column model: ChiralPak AD, 250×30 mm I.D., 5 μm; mobile phase: A: CO2 B: isopropanol; elution gradient: B 20%; flow rate: 70 mL/min; column pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle: ~4 min) to obtain compound of formula (I) (11 mg).

Compound of formula (I): LC-MS (ESI): 547.2 [M+H] +. Chiral analysis method (chromatographic column model: ChiralPak AD-3, 150×4.6mm I.D., 3μm; mobile phase: A: CO2B: isopropanol (0.05% DEA); elution gradient: mobile phase 5% B increased to 40% B within 5 minutes and maintained at 40% B for 2.5 minutes, then 5% B balanced for 2.5 minutes; flow rate: 2.5mL/min; column temperature: 35℃; column pressure: 100bar; detection wavelength: 220nm; RT=4.257min). 1H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 7.54 (td, J＝9.0, 6.6 Hz, 1H), 7.36–7.19 (m, 1H), 7.15 (s, 1H), 7.06–7.03 (m, 2H), 7.03–6.98 (m, 1H), 6.93–6.79 (m, 2H), 6.63 (d, J＝6.6 Hz, 1H), 5.42 (d, J＝14.6 Hz, 1H), 5.01 (d, J＝14.6 Hz, 1H), 4.44–4.25 (m, 1H), 4.11(dd, J＝10.6,4.2Hz,1H), 4.01(dd, J＝10.6,6.4Hz,1H), 1.98(dd, J＝9.4,1.6Hz,3H), 1.76(dd, J＝9.4,1.6Hz,3H).19F NMR(376MHz,DMSO-d6)δ-76.06(s,3F),-102.96–-103.17(m,1F),-109.22–-109.32(m,2F),-109.64(d,J＝9.6Hz,1F).

Example 2 Minimal Inhibitory Concentration (MIC) Test of the Compound of Formula (I) on Fungal Growth

(1) Main reagents:

RPMI1640 culture medium: Brand: Gibco, Product No.: 31800-014

Sabouraud dextrose agar (SDA): Brand: Haibo, Product No.: HB0253-81

Voriconazole: Brand: Adamas, Item No.: 22105A

Amphotericin B: Brand: Abcam, Catalog Number: ab141199

(2) Fungal strains are shown in Table 21 below:

Table 21

(3) Test method:

MIC testing was performed according to the guidelines and requirements of CLSI M27 (for yeast) and M38 (for Aspergillus).

Preparation of strains: One day in advance, streak the strains on the SDA plate using glycerol stock stored at -80℃. Incubate for 18-24 hours at 35℃ and 40-60% humidity. Aspergillus fumigatus and Cryptococcus neoformans need to be streaked 3 and 2 days in advance, respectively.

Preparation of culture medium and compounds: Liquid culture medium RPMI is prepared with pure water, and 0.165 mol/L MOPS is added and the pH is adjusted to 7.0. After sterilization by filtering with a 0.22 um filter membrane, it is stored at 4°C (no more than 3 months). After high temperature sterilization at 121°C for 30 minutes with 0.85% saline, it is stored at room temperature (no more than 1 week). The compound is dissolved in DMSO to 12.8 mg/mL and stored at -20°C.

For yeast, pick 3-5 colonies from the SDA plate on the day of the test and fully suspend them in 5 mL of sterilized 0.85% saline. Measure the turbidity of the bacterial solution with a turbidity meter and adjust the turbidity to about 0.2. Dilute the bacterial solution 50 times and 20 times (a total of 1000 times) with RPMI1640 medium as the inoculum. The final inoculum concentration is 500-2500 CFU/mL.

For Aspergillus, take 5 mL of saline to cover the hyphae, gently scrape off the spores with a spreader, and then transfer the spore suspension to a sterile test tube. Take an appropriate amount of spore suspension and count it under a microscope using a hemocytometer. Use RPMI1640 medium to adjust the spore concentration to about 0.4-5x 10 ⁴ spores/mL.

The compound was diluted with DMSO to a maximum of 800 μg/mL (or 400 μg/mL) and 10 two-fold serial dilutions were performed, for a total of 11 concentrations. 2 μL of serially diluted compounds were transferred to the corresponding wells of a 96-well plate, and 198 μL of inoculum was transferred to the test plate and incubated at 35 degrees for 24 hours (48 and 72 hours for Aspergillus fumigatus and Cryptococcus neoformans, respectively).

(4) MIC assessment:

After the incubation, the fungal growth was visually observed. The lowest compound concentration point at which yeast growth was inhibited by ≥50% (Aspergillus inhibition was 100%) was defined as the minimum inhibitory concentration MIC (μg/mL). A magnifying glass or reading OD530nm can be used to assist in MIC determination. The test plate was photographed and recorded for archiving. The results are shown in Table 22 below.

Table 22: In vitro antifungal activity results of compounds of formula (I) MIC (μg/mL)

Example 3 Preparation of Form A

20.3 mg of the compound represented by formula (I) was weighed and added to 1.1 ml of chloroform to prepare a clear solution. After the solid precipitated, it was filtered first, and the filtered solution was left to stand in an open air at room temperature until the solvent was completely evaporated to obtain Form A.

Example 4 Preparation of Form B

Weigh 15 mg of the compound represented by formula (I) sample, add 0.07 ml of ethyl acetate at room temperature to completely dissolve the sample, add the solution dropwise into 0.7 ml of n-heptane, stir for 1 hour, centrifuge the precipitated solid, and vacuum dry the solid at room temperature to obtain Form B; continue to stir the clear solution for 24 hours, centrifuge the precipitated solid, and vacuum dry the solid at room temperature to obtain Form B.

Example 5 Preparation of Form C

14.9 mg of the compound sample represented by formula (I) was weighed, 0.06 ml of butyl formate was added dropwise at room temperature to completely dissolve the sample, 0.12 ml of toluene was added dropwise to the solution, and after stirring at room temperature for 1 hour, the precipitated solid was centrifuged and then dried under vacuum at room temperature to obtain Form C; the clarified solution was stirred for 24 hours, the precipitated solid was centrifuged and then dried under vacuum at room temperature to obtain Form C.

Example 6 Preparation of Form D

15.5 mg of the compound represented by formula (I) was weighed, 1.16 ml of chloroform was added dropwise at room temperature to completely dissolve the sample, 1.00 ml of n-heptane was added dropwise to the solution, and after stirring at room temperature for 1 hour, the precipitated solid was centrifuged and then dried under vacuum at room temperature to obtain Form D; the clarified solution was stirred for 24 hours, the precipitated solid was centrifuged and then dried under vacuum at room temperature to obtain Form D.

Example 7 Preparation of Form E

Weigh 15.4 mg of the compound represented by formula (I) sample, add 0.07 ml of dioxane at room temperature to completely dissolve the sample, add the solution dropwise into 0.7 ml of water, stir for 1 hour, centrifuge the precipitated solid, and then vacuum dry the solid at room temperature to obtain Form E; continue to stir the clear solution for 24 hours, centrifuge the precipitated solid, and then vacuum dry the solid at room temperature to obtain Form E.

Example 8 Preparation of Form F

Weigh 14.8 mg of the compound represented by formula (I) sample, add 0.07 ml of chloroform at room temperature to completely dissolve the sample, add the solution dropwise into 0.7 ml of cyclohexane, stir for 1 hour, centrifuge the precipitated solid, and vacuum dry the solid at room temperature to obtain Form F; continue to stir the clear solution for 24 hours, centrifuge the precipitated solid, and vacuum dry the solid at room temperature to obtain Form F.

Example 9 Preparation of Form G

Weigh 15.1 mg of the compound represented by formula (I) sample, add 0.06 ml of ether at room temperature to completely dissolve the sample, add 0.06 ml of n-heptane to the solution, stir at room temperature for 1 hour, centrifuge the precipitated solid, and vacuum dry the solid at room temperature to obtain Form G; continue to stir the clear solution for 24 hours, centrifuge the precipitated solid, and vacuum dry the solid at room temperature to obtain Form G.

Example 10 Preparation of Form H

15.1 mg of the compound represented by formula (I) was weighed, 0.06 ml of ethyl formate was added dropwise at room temperature to completely dissolve the sample, 0.06 ml of n-heptane was added dropwise to the solution, and after stirring at room temperature for 1 hour, the precipitated solid was centrifuged and then dried under vacuum at room temperature to obtain Form H; the clarified solution was stirred for 24 hours, the precipitated solid was centrifuged and then dried under vacuum at room temperature to obtain Form H.

Example 11 Preparation of Form I

20.3 mg of the compound represented by formula (I) was added to 1.3 ml of dichloromethane to prepare a clear solution. After the solid precipitated, it was filtered first, and the filtered solution was left to stand in an open air at room temperature until the solvent was completely evaporated to obtain Form I.

Example 12 Preparation of Form J

Weigh 15.3 mg of the compound represented by formula (I) sample, add 0.07 ml of isopropyl acetate dropwise at room temperature to completely dissolve the sample, add the solution dropwise into 0.7 ml of cyclohexane, stir for 1 hour, centrifuge the precipitated solid, and then vacuum dry the solid at room temperature to obtain Form J; continue to stir the clear solution for 24 hours, centrifuge the precipitated solid, and then vacuum dry the solid at room temperature to obtain Form J.

Example 13 Preparation of Form K

15.1 mg of the compound sample represented by formula (I) was added to 0.05 ml of chloroform and 0.45 ml of n-heptane solvent to form a suspension. After suspending and stirring at room temperature for 2 days, the suspension was centrifuged and the solid was vacuum dried at room temperature to obtain Form K.

Example 14 Preparation of Form L

15.5 mg of the compound sample represented by formula (I) was added to 0.05 ml of ethyl formate and 0.45 ml of cyclohexane solvent to form a suspension, which was suspended and stirred at room temperature for 2 days. The suspension was centrifuged and the solid was vacuum dried at room temperature to obtain Form L.

Example 15 Preparation of Form M

45.7 mg of the compound sample represented by formula (I) was added to 0.15 ml of dichloromethane and 1.35 ml of cyclohexane solvent to form a suspension. After suspension and stirring at 10° C. for 24 hours, the suspension was centrifuged and the solid was vacuum dried at 40° C. to obtain Form M.

Example 16 Preparation of Form N

Weigh 15.0 mg of the compound represented by formula (I) and mix it with 1.0 ml of cyclohexane at 50°C to form a suspension.

turbid liquid. 1.4 ml of chloroform preheated to 50°C was gradually added dropwise, and the solution was transferred to room temperature for cooling. The solution was allowed to stand at room temperature for more than 2 hours, and the precipitated solid was centrifuged and then vacuum dried at room temperature to obtain Form N.

Example 17 Preparation of Form O

15.6 mg of an amorphous sample of the compound represented by formula (I) was added to 0.05 ml of dichloromethane and 0.45 ml of n-heptane solvent to form a suspension. After suspension and stirring at 10° C. for 24 hours, the suspension was centrifuged and the solid was vacuum dried at room temperature to obtain Form O.

Example 18 Preparation of Form P

Weigh 781.4 mg of the compound sample represented by formula (I), add 26.0 mL of methyl tert-butyl ether/n-heptane (v/v, 1:9) binary solvent, suspend and stir at room temperature for 48 hours, centrifuge to remove the supernatant, and vacuum dry the solid at 40°C for 1 day. Add the dried solid to 21.5 mL of methyl tert-butyl ether/n-heptane (v/v, 1:9) binary solvent, suspend and stir at room temperature for 24 hours, centrifuge to remove the supernatant, and vacuum dry the solid at 40°C for 1 day to obtain 699.3 mg of Form P.

Example 19 Preparation of amorphous

Weigh 436.5 mg of the compound represented by formula (I), dissolve the sample in 4.5 mL of ethanol, filter to remove insoluble impurities, and rotary evaporate to obtain a fluffy white solid, which is vacuum dried at room temperature for 4 days. Add the obtained sample to 2.0 mL of dichloromethane, suspend and stir at room temperature for 24 hours, directly vacuum dry at room temperature overnight, and then vacuum dry at 40°C for 2 days to obtain 280.0 mg of amorphous.

Example 20 Solubility Test of Form P

The solubility of Form P in 6 solvents was determined, and the results are shown in Table 23. According to the solubility test results, Form P is easily soluble in ethanol, acetone and ethyl acetate (>100 mg/mL); soluble in acetonitrile, dichloromethane and tetrahydrofuran (>10 mg/mL). During the solubility test, it was observed that Form P was basically soluble in 0.1 mL of ethanol, acetone, ethyl acetate, acetonitrile and tetrahydrofuran, respectively, and there were granular substances attached to the EP tube wall in the solution. As the solvent continued to be added, the granular substances gradually dissolved completely; Form P was basically soluble in 1.1 mL of dichloromethane, and dichloromethane was continued to be added, and no signs of reduction of flocculent substances in the solution were observed.

Table 23 Crystalline Form P solubility test results

Example 21 Stability Study

The stability of amorphous and crystalline P was studied under high temperature (60°C), high humidity (25°C/92.5%RH), light (25°C/4500Lux), and accelerated (40°C/75%RH) conditions. Samples were taken for XRPD characterization and HPLC testing at 7 days and 17 days, respectively. The results are shown in Table 24, Figure 39, and Figure 40. The XRPD results showed that the amorphous and crystalline P were stable under high temperature, high humidity, light, and accelerated conditions for 17 days, and no crystal transformation occurred. Deliquescence was observed under accelerated conditions. The HPLC results showed that the chemical purity of the amorphous and crystalline P did not change significantly after being placed under the above conditions for 17 days.

Table 24 Stability study results

Table 25 HPLC purity analysis results of amorphous stability samples

Table 26 HPLC purity analysis results of Form P stability samples

Example 22 pH Solubility Test

The solubility of amorphous and crystalline P was measured in different pH buffers. The experimental method is shown in General Test Method 11.1, and the corresponding results are shown in Table 27. The results show that the solubility of amorphous and crystalline P in different pH buffers is very low and is not detected.

Table 27 pH solubility test results

Example 23 Biological Media and Water Solubility Test

The dynamic solubility of amorphous and crystalline P in three biological media (FaSSIF, FeSSIF and FaSSGF) and water was determined. The experimental method is shown in General Test Method 11.2, and the corresponding results are shown in Table 28 and Figures 41 and 42. The results show that the solubility of amorphous in FaSSIF and FeSSIF and crystalline P in FeSSIF has a downward trend over time. The 24h solubility of amorphous and crystalline P in FeSSIF is greater than that in FaSSIF, and it is not detected in FaSSGF and water. After the solubility test, the remaining solid crystalline in the biological medium and water has no change.

Table 28 Dynamic solubility test in biological media

In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

Crystalline Form A of the Compound Represented by Formula (I)

Characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 3.76±0.2°, 5.2±0.2°, 13.75±0.2°, 16.97±0.2°, 17.67±0.2°, 19.75±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 3.76±0.2°, 5.2±0.2°, 5.82±0.2°, 13.75±0.2°, 14.7±0.2°, 16.97±0.2°, 17.67±0.2°, 18.41±0.2°, 19.75±0.2°, 21.09±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 3.76±0.2°, 5.2±0.2°, 5.82±0.2°, 13.07±0.2°, 13.75±0.2°, 14.7±0.2°, 15.85±0.2°, 16.97±0.2°, 17.67±0.2°, 18.41±0.2°, 19.23±0.2°, 19.75±0.2°, 21.09±0.2°, 21.87±0.2°, 22.92±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG1 .
The crystalline form B of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2θ angles: 11.92±0.2°, 16.31±0.2°, 17.75±0.2°, 18.74±0.2°, 19.56±0.2°, 21.72±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2θ angles: 9.88±0.2°, 11.92±0.2°, 16.31±0.2°, 17.19±0.2°, 17.75±0.2°, 18.74±0.2°, 19.56±0.2°, 20.59±0.2°, 21.72±0.2°, 23.68±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2θ angles: 9.88±0.2°, 10.89±0.2°, 11.92±0.2°, 13.11±0.2°, 14.84±0.2°, 16.31±0.2°, 17.19±0.2°, 17.75±0.2°, 18.74±0.2°, 19.56±0.2°, 20.59±0.2°, 21.27±0.2°, 21.72±0.2°, 22.84±0.2°, 23.68±0.2°;

Optionally, the X-ray powder diffraction pattern of Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 3 .
The crystalline form C of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2θ angles: 10.15±0.2°, 11.26±0.2°, 18.24±0.2°, 20.34±0.2°, 20.92±0.2°, 22.59±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2θ angles: 10.15±0.2°, 11.26±0.2°, 14.27±0.2°, 16.57±0.2°, 17.75±0.2°, 18.24±0.2°, 20.34±0.2°, 20.92±0.2°, 22.59±0.2°, 27.33±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2θ angles: 7.04±0.2°, 10.15±0.2°, 10.97±0.2°, 11.26±0.2°, 14.27±0.2°, 16.57±0.2°, 17.75±0.2°, 18.24±0.2°, 20.34±0.2°, 20.92±0.2°, 22.59±0.2°, 23.78±0.2°, 24.87±0.2°, 25.97±0.2°, 27.33±0.2°;

Optionally, the X-ray powder diffraction pattern of Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 5 .
The crystalline form D of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2θ angles: 4.96±0.2°, 6.65±0.2°, 8.93±0.2°, 13.11±0.2°, 13.85±0.2°, 17.19±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2θ angles: 4.34±0.2°, 4.96±0.2°, 6.65±0.2°, 8.93±0.2°, 13.11±0.2°, 13.85±0.2°, 17.19±0.2°, 17.95±0.2°, 18.84±0.2°, 20.01±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2θ angles: 4.34±0.2°, 4.96±0.2°, 6.65±0.2°, 8.93±0.2°, 13.11±0.2°, 13.85±0.2°, 14.54±0.2°, 15.89±0.2°, 17.19±0.2°, 17.95±0.2°, 18.84±0.2°, 19.4±0.2°, 20.01±0.2°, 22.16±0.2°, 22.86±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form D has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
The crystalline form E of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2θ angles: 10.42±0.2°, 12.6±0.2°, 16.59±0.2°, 18.24±0.2°, 20.22±0.2°, 22.42±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2θ angles: 10.42±0.2°, 12.6±0.2°, 13.5±0.2°, 16.59±0.2°, 17.71±0.2°, 18.24±0.2°, 20.22±0.2°, 20.88±0.2°, 22.42±0.2°, 24.11±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2θ angles: 3.76±0.2°, 10.42±0.2°, 12.6±0.2°, 13.5±0.2°, 14.51±0.2°, 15.23±0.2°, 16.59±0.2°, 17.71±0.2°, 18.24±0.2°, 20.22±0.2°, 20.88±0.2°, 21.44±0.2°, 22.42±0.2°, 23.5±0.2°, 24.11±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form E has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .
The crystalline form F of the compound represented by formula (I), characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2θ angles: 11.94±0.2°, 15.75±0.2°, 18.06±0.2°, 19.27±0.2°, 20.47±0.2°, 21.39±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2θ angles: 3.35±0.2°, 4.11±0.2°, 10.09±0.2°, 11.24±0.2°, 11.94±0.2°, 15.75±0.2°, 18.06±0.2°, 19.27±0.2°, 20.47±0.2°, 21.39±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2θ angles: 3.35±0.2°, 4.11±0.2°, 5.18±0.2°, 5.7±0.2°, 10.09±0.2°, 11.24±0.2°, 11.94±0.2°, 15.75±0.2°, 16.59±0.2°, 18.06±0.2°, 19.27±0.2°, 20.47±0.2°, 21.39±0.2°, 22.46±0.2°, 24.24±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form F has an X-ray powder diffraction pattern substantially as shown in FIG. 11 .
The crystalline form G of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form G has characteristic diffraction peaks at the following 2θ angles: 5.62±0.2°, 10.58±0.2°, 11.65±0.2°, 14.62±0.2°, 17.67±0.2°, 21.13±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form G has characteristic diffraction peaks at the following 2θ angles: 5.62±0.2°, 10.58±0.2°, 11.65±0.2°, 14.62±0.2°, 15.34±0.2°, 17.67±0.2°, 19.95±0.2°, 20.51±0.2°, 21.13±0.2°, 21.66±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form G has characteristic diffraction peaks at the following 2θ angles: 5.62±0.2°, 9.34±0.2°, 9.8±0.2°, 10.58±0.2°, 11.65±0.2°, 14.62±0.2°, 15.34±0.2°, 17.67±0.2°, 18.61±0.2°, 19.95±0.2°, 20.51±0.2°, 21.13±0.2°, 21.66±0.2°, 23.33±0.2°, 25.02±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form G has an X-ray powder diffraction pattern substantially as shown in FIG. 13 .
The crystalline form H of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form H has characteristic diffraction peaks at the following 2θ angles: 10.46±0.2°, 12.47±0.2°, 16.29±0.2°, 18.41±0.2°, 20.26±0.2°, 21.02±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form H has characteristic diffraction peaks at the following 2θ angles: 10.46±0.2°, 11.34±0.2°, 12.47±0.2°, 16.29±0.2°, 17.89±0.2°, 18.41±0.2°, 19.5±0.2°, 20.26±0.2°, 21.02±0.2°, 22.42±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form H has characteristic diffraction peaks at the following 2θ angles: 10.46±0.2°, 11.34±0.2°, 12.47±0.2°, 13.53±0.2°, 16.29±0.2°, 16.97±0.2°, 17.89±0.2°, 18.41±0.2°, 19.07±0.2°, 19.5±0.2°, 20.26±0.2°, 21.02±0.2°, 22.42±0.2°, 24.01±0.2°, 25.53±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form H has an X-ray powder diffraction pattern substantially as shown in FIG. 15 .
The crystalline form I of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I has characteristic diffraction peaks at the following 2θ angles: 9.84±0.2°, 10.37±0.2°, 11.51±0.2°, 20.24±0.2°, 20.71±0.2°, 22.96±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form I has characteristic diffraction peaks at the following 2θ angles: 9.84±0.2°, 10.37±0.2°, 11.51±0.2°, 14.27±0.2°, 17.95±0.2°, 18.3±0.2°, 20.24±0.2°, 20.71±0.2°, 21.25±0.2°, 22.96±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline Form I has an X-ray powder diffraction pattern substantially as shown in Figure 17.
The crystalline form J of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form J has characteristic diffraction peaks at the following 2θ angles: 11.67±0.2°, 16.08±0.2°, 16.68±0.2°, 18.86±0.2°, 19.35 ±0.2°, 23.74±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form J has characteristic diffraction peaks at the following 2θ angles: 9.67±0.2°, 10.91±0.2°, 11.67±0.2°, 16.08±0.2°, 16.68±0.2°, 17.21±0.2°, 18.86±0.2°, 19.35±0.2°, 21.27±0.2°, 23.74±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form J has characteristic diffraction peaks at the following 2θ angles: 5.49±0.2°, 6.3±0.2°, 9.67±0.2°, 10.91±0.2°, 11.67±0.2°, 12.87±0.2°, 14.68±0.2°, 16.08±0.2°, 16.68±0.2°, 17.21±0.2°, 18.86±0.2°, 19.35±0.2°, 20.32±0.2°, 21.27±0.2°, 23.74±0.2°;

Optionally, the X-ray powder diffraction pattern of Form J has an X-ray powder diffraction pattern substantially as shown in FIG. 19 .
The crystalline form K of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form K has characteristic diffraction peaks at the following 2θ angles: 12.04±0.2°, 15.85±0.2°, 18.18±0.2°, 19.31±0.2°, 19.56±0.2°, 21.48±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form K has characteristic diffraction peaks at the following 2θ angles: 11.42±0.2°, 12.04±0.2°, 15.85±0.2°, 16.64±0.2°, 18.18±0.2°, 19.31±0.2°, 19.56±0.2°, 20.57±0.2°, 21.48±0.2°, 24.28±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form K has characteristic diffraction peaks at the following 2θ angles: 5.76±0.2°, 10.17±0.2°, 11.42±0.2°, 12.04±0.2°, 15.85±0.2°, 16.64±0.2°, 18.18±0.2°, 18.72±0.2°, 19.31±0.2°, 19.56±0.2°, 20.57±0.2°, 21.48±0.2°, 22.51±0.2°, 24.28±0.2°, 25.6±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form K has an X-ray powder diffraction pattern substantially as shown in Figure 21.
The crystalline form L of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2θ angles: 10.42±0.2°, 12.43±0.2°, 16.27±0.2°, 18.18±0.2°, 20.08±0.2°, 21±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2θ angles: 10.42±0.2°, 11.28±0.2°, 12.43±0.2°, 13.48±0.2°, 16.27±0.2°, 18.18±0.2°, 20.08±0.2°, 21±0.2°, 22.36±0.2°, 23.91±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2θ angles: 3.08±0.2°, 10.42±0.2°, 11.28±0.2°, 12.43±0.2°, 13.48±0.2°, 14.47±0.2°, 16.27±0.2°, 16.82±0.2°, 18.18±0.2°, 20.08±0.2°, 21±0.2°, 22.36±0.2°, 23.91±0.2°, 25.47±0.2°, 28.15±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form L has an X-ray powder diffraction pattern substantially as shown in Figure 23.
The crystalline form M of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form M has characteristic diffraction peaks at the following 2θ angles: 5.33±0.2°, 7.04±0.2°, 14.7±0.2°, 15.85±0.2°, 18.43±0.2°, 21.11±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form M has characteristic diffraction peaks at the following 2θ angles: 4.38±0.2°, 5.33±0.2°, 7.04±0.2°, 14.06±0.2°, 14.7±0.2°, 15.85±0.2°, 17.38±0.2°, 18.43±0.2°, 19.11±0.2°, 21.11±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form M has characteristic diffraction peaks at the following 2θ angles: 4.38±0.2°, 4.87±0.2°, 5.33±0.2°, 7.04±0.2°, 10.6±0.2°, 14.06±0.2°, 14.7±0.2°, 15.85±0.2°, 17.38±0.2°, 18.43±0.2°, 19.11±0.2°, 19.58±0.2°, 21.11±0.2°, 21.78±0.2°, 27.78±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form M has an X-ray powder diffraction pattern substantially as shown in Figure 25.
The crystalline form N of the compound represented by formula (I), characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form N has characteristic diffraction peaks at the following 2θ angles: 4.9±0.2°, 12.7±0.2°, 13.5±0.2°, 16.62±0.2°, 17.38±0.2°, 18.3±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form N has characteristic diffraction peaks at the following 2θ angles: 3.17±0.2°, 4.48±0.2°, 4.9±0.2°, 5.12±0.2°, 12.7±0.2°, 13.5±0.2°, 16.62±0.2°, 17.38±0.2°, 18.3±0.2°, 20.92±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form N has characteristic diffraction peaks at the following 2θ angles: 3.17±0.2°, 4.48±0.2°, 4.9±0.2°, 5.12±0.2°, 6.62±0.2°, 8.33±0.2°, 14.58±0.2°, 12.7±0.2°, 13.5±0.2°, 16.62±0.2°, 17.38±0.2°, 18.3±0.2°, 19.56±0.2°, 20.92±0.2°, 22.2±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form N has an X-ray powder diffraction pattern substantially as shown in Figure 27.
The crystalline form O of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form O has characteristic diffraction peaks at the following 2θ angles: 5.02±0.2°, 10.29±0.2°, 12.54±0.2°, 16.72±0.2°, 17.62±0.2°, 20.45±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form O has characteristic diffraction peaks at the following 2θ angles: 5.02±0.2°, 10.29±0.2°, 12.54±0.2°, 13.59±0.2°, 15.34±0.2°, 16.72±0.2°, 17.62±0.2°, 19.75±0.2°, 20.45±0.2°, 25.37±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form O has characteristic diffraction peaks at the following 2θ angles: 5.02±0.2°, 10.29±0.2°, 12.54±0.2°, 13.59±0.2°, 14.25±0.2°, 15.34±0.2°, 16.72±0.2°, 17.62±0.2°, 19.75±0.2°, 20.45±0.2°, 20.9±0.2°, 22.61±0.2°, 23.33±0.2°, 25.37±0.2°, 26.79±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form O has an X-ray powder diffraction pattern substantially as shown in Figure 29.
The crystalline form P of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form P has characteristic diffraction peaks at the following 2θ angles: 11.53±0.2°, 14.72±0.2°, 15.98±0.2°, 17.01±0.2°, 17.54±0.2°, 19.5±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form P has characteristic diffraction peaks at the following 2θ angles: 9.57±0.2°, 11.05±0.2°, 11.53±0.2°, 12.82±0.2°, 14.72±0.2°, 15.98±0.2°, 17.01±0.2°, 17.54±0.2°, 19.09±0.2°, 19.5±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form P has characteristic diffraction peaks at the following 2θ angles: 9.57±0.2°, 11.05±0.2°, 11.53±0.2°, 12.82±0.2°, 14.72±0.2°, 15.98±0.2°, 17.01±0.2°, 17.54±0.2°, 19.09±0.2°, 19.5±0.2°, 20.24±0.2°, 20.88±0.2°, 21.43±0.2°, 22.14±0.2°, 23.89±0.2°;

Optionally, the X-ray powder diffraction pattern of the crystalline form P has an X-ray powder diffraction pattern substantially as shown in Figure 31.
The amorphous form of the compound represented by formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the amorphous form has an X-ray powder diffraction pattern substantially as shown in Figure 35.