CN119855811A

CN119855811A - Amorphous, crystalline solid of bicyclic compounds and process for preparing same

Info

Publication number: CN119855811A
Application number: CN202380065090.XA
Authority: CN
Inventors: 张勇
Original assignee: Shanghai Jiyu Pharmaceutical Technology Co ltd
Current assignee: Shanghai Jiyu Pharmaceutical Technology Co ltd
Priority date: 2022-09-30
Filing date: 2023-09-28
Publication date: 2025-04-18
Also published as: TW202423418A; WO2024067784A1

Abstract

Amorphous and 16 crystalline forms of a compound of formula (I) are provided, the crystalline forms being designated form a to form P in sequence. Also provided are processes for preparing amorphous and polymorphic forms of the compounds of formula (I).

Description

Amorphous, crystalline solid of bicyclic compounds and process for preparing same

The present application claims priority from China patent application 2022112121001 with application date 2022/9/30. The present application incorporates the entirety of the above-mentioned chinese patent application.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and in particular relates to an amorphous form and a polymorphic form of a bicyclo compound and application thereof.

Background

It is desirable in the industry to provide solid forms that have excellent physical or chemical properties during the manufacturing process of pharmaceutical products.

The applicant provides a novel CYP51 inhibitor antifungal drug in a patent application with application number of PCT/CN2022/084203 and application date of 2022, 03 and 30, and the structure of the novel CYP51 inhibitor antifungal drug is shown in a formula (I).

Disclosure of Invention

In one aspect of the invention, the invention provides a crystal form A of a compound shown in a formula (I), wherein the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2 theta angles of 3.76+/-0.2 DEG, 5.2+/-0.2 DEG, 13.75+/-0.2 DEG, 16.97+/-0.2 DEG, 17.67+/-0.2 DEG and 19.75+/-0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of form a has an X-ray powder diffraction pattern substantially as shown in figure 1.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form a is shown in table 1 below.

TABLE 1

In another aspect of the present invention, the present invention also provides a crystalline form B of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2 theta angles of 11.92 + -0.2 DEG, 16.31 + -0.2 DEG, 17.75 + -0.2 DEG, 18.74 + -0.2 DEG, 19.56 + -0.2 DEG, and 21.72 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form B has an X-ray powder diffraction pattern substantially as shown in figure 3.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form B is shown in table 2 below.

TABLE 2

In another aspect of the invention, the invention also discloses a crystal form C of the compound shown in the formula (I), wherein the X-ray powder diffraction pattern of the crystal form C has characteristic diffraction peaks at the following 2 theta angles of 10.15+/-0.2 DEG, 11.26+/-0.2 DEG, 18.24+/-0.2 DEG, 20.34+/-0.2 DEG, 20.92+/-0.2 DEG and 22.59+/-0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form C has an X-ray powder diffraction pattern substantially as shown in figure 5.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form C is shown in table 3 below.

TABLE 3 Table 3

In another aspect of the present invention, the present invention provides form D of the compound of formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles of 4.96.+ -. 0.2 °, 6.65.+ -. 0.2 °, 8.93.+ -. 0.2 °, 13.11.+ -. 0.2 °, 13.85.+ -. 0.2 °, 17.19.+ -. 0.2 °.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form D has an X-ray powder diffraction pattern substantially as shown in figure 7.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form D is shown in table 4 below.

TABLE 4 Table 4

In another aspect of the present invention, the present invention provides a crystalline form E of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta 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 °.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form E has an X-ray powder diffraction pattern substantially as shown in figure 9.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form E is shown in table 5 below.

TABLE 5

In another aspect of the invention, the invention also provides a crystalline form F of the compound of formula (I), the crystalline form F having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta 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 °.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form F has an X-ray powder diffraction pattern substantially as shown in figure 11.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form F shown is shown in table 6 below.

TABLE 6

In another aspect of the invention, the invention also provides a crystalline form G of the compound of formula (I), the crystalline form G having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles, 5.62 + -0.2 DEG, 10.58 + -0.2 DEG, 11.65 + -0.2 DEG, 14.62 + -0.2 DEG, 17.67 + -0.2 DEG, 21.13 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form G has an X-ray powder diffraction pattern substantially as shown in figure 13.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for sulfate form G is shown in table 7 below.

TABLE 7

In another aspect of the present invention, the present invention also provides form H of the compound of formula (I), wherein the X-ray powder diffraction pattern of the form H has characteristic diffraction peaks at the following 2 theta angles of 10.46 + -0.2 DEG, 12.47 + -0.2 DEG, 16.29 + -0.2 DEG, 18.41 + -0.2 DEG, 20.26 + -0.2 DEG, and 21.02 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form H has an X-ray powder diffraction pattern substantially as shown in figure 15.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form H is shown in table 8 below.

TABLE 8

In another aspect of the invention, the invention also provides a crystalline form I of the compound of formula (I), the crystalline form I having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles of 9.84 + -0.2 DEG, 10.37 + -0.2 DEG, 11.51 + -0.2 DEG, 20.24 + -0.2 DEG, 20.71 + -0.2 DEG, 22.96 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form I has an X-ray powder diffraction pattern substantially as shown in figure 17.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form I is shown in table 9 below.

TABLE 9

In another aspect of the invention, the invention also provides a crystalline form J of the compound of formula (I), wherein the crystalline form J has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles of 11.67 + -0.2 DEG, 16.08 + -0.2 DEG, 16.68 + -0.2 DEG, 18.86 + -0.2 DEG, 19.35 + -0.2 DEG, and 23.74 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form J has an X-ray powder diffraction pattern substantially as shown in figure 19.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form J is shown in table 10 below.

Table 10

In another aspect of the invention, the invention also provides a form K of the compound of formula (I), wherein the X-ray powder diffraction pattern of the form K has characteristic diffraction peaks at the following 2 theta angles of 12.04+/-0.2 DEG, 15.85+/-0.2 DEG, 18.18+/-0.2 DEG, 19.31+/-0.2 DEG, 19.56+/-0.2 DEG and 21.48+/-0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form K has an X-ray powder diffraction pattern substantially as shown in figure 21.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form K is shown in table 11 below.

TABLE 11

In another aspect of the invention, the invention also provides a crystalline form L of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles, 10.42 + -0.2 DEG, 12.43 + -0.2 DEG, 16.27 + -0.2 DEG, 18.18 + -0.2 DEG, 20.08 + -0.2 DEG, 21 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some aspects of the invention, the X-ray powder diffraction pattern of form L has an X-ray powder diffraction pattern substantially as shown in figure 23.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form L is shown in table 12 below.

Table 12

In another aspect of the present invention, the present invention also provides a crystalline form M of the compound of formula (I), having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta 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 °.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction according to rules 91 29.11.2023] [ correction according to rules 91 29.11.2023] in some aspects of the invention, the X-ray powder diffraction pattern of form N has an X-ray powder diffraction pattern substantially as shown in figure 27.

[ Correction 29.11.2023 according to rules 91 ]

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form N is shown in table 14 below.

TABLE 14

In another aspect of the invention, the invention also provides crystalline form O of the compound of formula (I), having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles, 5.02 + -0.2 DEG, 10.29 + -0.2 DEG, 12.54 + -0.2 DEG, 16.72 + -0.2 DEG, 17.62 + -0.2 DEG, 20.45 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form O has an X-ray powder diffraction pattern substantially as shown in figure 29.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form O is shown in table 15 below.

TABLE 15

In another aspect of the invention, the invention also provides crystalline form P of the compound of formula (I), having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta 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 °.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

In some aspects of the invention, the X-ray powder diffraction pattern of 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°.

[ Correction 29.11.2023 according to rules 91 ] in some embodiments of the invention, the X-ray powder diffraction pattern of form P has an X-ray powder diffraction pattern substantially as shown in figure 31.

In some aspects of the invention, the X-ray powder diffraction pattern analysis data for form P is shown in table 16 below.

Table 16

Definition and description

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

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

"Crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of the compounds. The crystalline form of a substance may be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, crystallization on a surface or template, e.g., on a polymer, crystallization in the presence of additives such as co-crystallizing anti-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, solvent drop milling, and the like.

"Amorphous" or "amorphous form" refers to a substance that forms when particles (molecules, atoms, ions) of the substance are non-periodically arranged in three dimensions, characterized by a diffuse, non-spiking X-ray powder diffraction pattern. Amorphous is a special physical form of solid material whose locally ordered structural features suggest a myriad of interactions with crystalline material. Amorphous forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, among others.

"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, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

"Antisolvent" refers to a fluid that facilitates precipitation of a product (or product precursor) from a solvent. The antisolvent may comprise a cold gas, or a fluid that promotes precipitation by 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 than the solvent.

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

Crystalline forms or amorphous forms may be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point, differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.

The X-ray powder diffraction (XRPD) can detect the information of crystal form change, crystallinity, crystal structure state and the like, and is a common means for identifying the crystal form. The peak positions of the XRPD patterns are largely dependent on the structure of the crystalline form, relatively insensitive to experimental details, and their relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystalline forms of the invention are characterized by XRPD patterns having certain peak locations, substantially as shown in the XRPD patterns provided in the figures of the invention. Meanwhile, the measure of 2θ of the XRPD pattern may have experimental errors, and the measure of 2θ of the XRPD pattern may slightly differ from instrument to instrument and sample to sample, so the value of 2θ cannot be regarded as absolute. Depending on the instrument conditions used in the test according to the invention, diffraction peaks have a margin of error of + -0.2 deg..

Differential Scanning Calorimeter (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly used α -Al ₂O₃) as a function of temperature by continuously heating or cooling under program control. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline forms of the invention are characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profile provided in the accompanying figures of the invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ from instrument to instrument and from sample to sample, so that the peak position or the value of the DSC endothermic peak cannot be regarded as absolute. Depending on the instrument conditions used in the test according to the invention, melting peaks have an error margin of + -3 ℃.

Glass transition refers to the transition of an amorphous substance between a highly elastic state and a glassy state, which is an inherent property of the substance, and its corresponding transition temperature, glass transition temperature (Tg), is an important physical property of an amorphous substance. Glass transition is a phenomenon related to molecular movement, and thus, glass transition temperature (Tg) is largely dependent on the structure of a substance, and is relatively insensitive to experimental details and the like. In some embodiments, the amorphous glass transition temperature (Tg) of the invention is characterized by having a glass transition temperature of 66 ℃ as determined by Differential Scanning Calorimetry (DSC). According to the instrument conditions used in the test according to the invention, there is an error margin of + -3 ℃ for the glass transition temperature.

Differential Scanning Calorimetry (DSC) can also be used to detect the presence or absence of seeding or miscibility of an analytical crystalline form.

Solids of the same chemical composition often form, under different thermodynamic conditions, isoforms of different crystal structures, or variants, a phenomenon known as polymorphism or homopoly-phase. When temperature and pressure conditions change, a mutual transition occurs between variants, a phenomenon known as crystalline transformation. The mechanical, electrical, magnetic and other properties of the crystal can be changed greatly due to the crystal form transformation. When the temperature of the crystal form transition is within a measurable range, the transition process can be observed on a Differential Scanning Calorimeter (DSC) chart, which is characterized in that the DSC chart has an exothermic peak reflecting the transition process and simultaneously has two or more endothermic peaks, which are characteristic endothermic peaks of different crystal forms before and after the transition. The crystalline or amorphous form of the compounds of the invention may undergo a crystalline transformation under appropriate conditions.

Thermogravimetric analysis (TGA) is a technique for measuring the mass of a substance as a function of temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition processes of a sample, and can be used to infer the presence of water of crystallization or a crystallization solvent in the crystal. The TGA profile shows a change in mass depending on many factors such as sample preparation and instrumentation, and the change in mass of TGA detection varies slightly from instrument to instrument and from sample to sample. Depending on the instrument conditions used for the test according to the invention, there is a margin of error of + -0.3% for the mass change.

The moisture adsorption/desorption isotherm measurement (DVS) is a measurement method for measuring the adsorption/desorption behavior of moisture by measuring the weight change of a solid to be measured under each relative humidity condition.

In the context of the present invention, the 2 theta values in the X-ray powder diffraction pattern are all in degrees (°).

When referring to a spectrogram or/and data appearing in the graph, a "peak" refers to a feature that one skilled in the art can recognize that is not attributable 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 DSC pattern or TGA result are shown in its figure.

By "substantially pure" is meant that one form is substantially free of the other form or forms, i.e., the purity of the 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 form contains 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% of the total volume or total weight of the forms.

By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline forms 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 the first intensity peak to the intensity of the first intensity peak in all diffraction peaks of an X-ray powder diffraction pattern (XRPD) at 100%.

In the context of the present invention, when used or whether or not the word "about" or "about" is used, means within 10%, suitably within 5%, particularly within 1% of a given value or range. Or for one of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the average value. Whenever a number is disclosed having a value of N, any number within the values of 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-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.

Drawings

FIG. 1 is an XRPD pattern for form A according to an embodiment of the invention;

FIG. 2 is an NMR chart of form A according to an embodiment of the invention;

FIG. 3 is an XRPD pattern for form B according to an embodiment of the invention;

FIG. 4 is an NMR chart of form B according to an embodiment of the invention;

FIG. 5 is an XRPD pattern for form C according to an embodiment of the invention;

FIG. 6 is an NMR chart of form C according to an embodiment of the invention;

FIG. 7 is an XRPD pattern for form D according to an embodiment of the invention;

FIG. 8 is an NMR chart of form D according to an embodiment of the invention;

FIG. 9 is an XRPD pattern for form E according to an embodiment of the invention;

FIG. 10 is an NMR chart of form E according to an embodiment of the invention;

FIG. 11 is an XRPD pattern for form F according to an embodiment of the invention;

FIG. 12 is an NMR chart of form F according to an embodiment of the invention;

FIG. 13 is an XRPD pattern for form G according to an embodiment of the invention;

FIG. 14 is an NMR chart of form G according to an embodiment of the invention;

FIG. 15 is an XRPD pattern for form H according to an embodiment of the invention;

FIG. 16 is an NMR chart of form H according to an embodiment of the invention;

FIG. 17 is an XRPD pattern for form I according to an embodiment of the invention;

FIG. 18 is an NMR chart of form I according to an embodiment of the invention;

FIG. 19 is an XRPD pattern for form J according to an embodiment of the invention;

FIG. 20 is an NMR chart of form J according to an embodiment of the invention;

FIG. 21 is an XRPD pattern for form K according to an embodiment of the invention;

FIG. 22 is an NMR chart of form K according to an embodiment of the invention;

FIG. 23 is an XRPD pattern for form L according to an embodiment of the invention;

FIG. 24 is an NMR chart of form L according to an embodiment of the invention;

FIG. 25 is an XRPD pattern for form M according to an embodiment of the invention;

FIG. 26 is an NMR chart of form M according to an embodiment of the invention;

FIG. 27 is an XRPD pattern for form N according to an embodiment of the invention;

FIG. 28 is an NMR chart of form N according to an embodiment of the invention;

FIG. 29 is an XRPD pattern for form O according to an embodiment of the invention;

FIG. 30 is an NMR chart of form O according to an embodiment of the invention;

FIG. 31 is an XRPD pattern for form P according to an embodiment of the invention;

FIG. 32 is an NMR chart of form P according to an embodiment of the invention;

FIG. 33 is an XRPD pattern for form P (a) DVS curves, (b) before and after DVS testing, according to an embodiment of the invention;

fig. 34 is a PLM image of form P according to an embodiment of the present invention;

FIG. 35 is an amorphous XRPD pattern according to an embodiment of the invention;

FIG. 36 is an NMR chart of an amorphous form according to an embodiment of the invention;

FIG. 37 is an XRPD pattern for amorphous (a) DVS curves, (b) DVS before and after testing, according to an embodiment of the invention;

FIG. 38 is an amorphous PLM image according to an embodiment of the invention;

FIG. 39 is an XRPD pattern for an amorphous stability study according to an embodiment of the invention;

FIG. 40 is an XRPD pattern for a crystal form P stability study according to an embodiment of the invention;

FIG. 41 is a graphical representation of the XRPD contrast of the solid remaining after 24h oscillation of the amorphous form in the medium, in accordance with an embodiment of the present invention;

Fig. 42 is a graph comparing solid XRPD remaining after form P is oscillated in medium for 24h according to an embodiment of the invention.

Detailed Description

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

The raw materials used in the present invention are commercially available unless otherwise specified.

General analysis method:

1. Nuclear magnetic analysis (¹ H NMR)

Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d 6 solvent and subjected to nuclear magnetic analysis on Bruker AVANCE NEO 400,400 (Bruker, GER).

2. X-ray powder diffraction (XRPD)

The solid samples obtained from the experiments were analyzed by means of an X-ray powder diffractometer Bruker D8Advance (Bruker, GER). The 2 theta scanning angle is from 3 degrees to 45 degrees, the scanning step length is 0.02 degrees, and the exposure time is 0.08 seconds. The test method is that the Cu target is K alpha 1 rays, the voltage is 40kV, the current is 40mA, and the sample disc is a zero background sample disc.

3. Thermogravimetric analysis (TGA)

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

4. Differential scanning calorimetric analysis (DSC)

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

5. Dynamic moisture desorption analysis (DVS)

Dynamic moisture desorption analysis was performed using DVS INTRINSIC (SMS, UK). The test adopts a gradient mode, the humidity change is 50% -95% -0% -50%, the humidity change amount of each gradient is 10% in the range of 0% -90%, the gradient end point is judged in a dm/dt mode, and the dm/dt is less than 0.002% and maintained for 10 minutes to be the gradient end point. After the test is completed, XRPD analysis is performed on the sample to confirm whether the solid morphology is changed.

6. Polarized light microscopic analysis (PLM)

The polarizing microscope was Nikon Ci-POL (Nikon, JP). A small amount of sample is placed on a glass slide, and a proper lens is selected to observe the appearance of the sample.

7. High Performance Liquid Chromatography (HPLC)

The high performance liquid chromatography model was SHIMADZU LC-2030C (Shimadzu, JP) and the test conditions are shown in Table 17 and Table 18.

Table 17 HPLC solubility test conditions

TABLE 18 HPLC purity test conditions

General test method:

1. Raw material solubility test

About 20mg of sample is weighed, added into an EP tube, a certain amount of solvent is added successively at room temperature (25 ℃), the solution is stirred and whether the solid is completely dissolved or not is observed, and if the solid is still undissolved after 10.0mL of solvent is added, the experiment is stopped. The solubility of a compound in the solvent is estimated based on the volume of solvent used when the solid is completely dissolved.

2. Solvent evaporation process

Clear solution obtained by raw material solubility test (general test method 1) or about 20mg of sample is weighed to prepare clear solution (system with solid precipitated is filtered), and the clear solution is left open at room temperature until the solvent is completely volatilized to obtain solid.

3. Suspension method

3.1, Suspending at room temperature

Taking different crystal forms as raw materials, adding a certain amount of samples into a single solvent or a binary solvent until a suspension is formed, suspending and stirring for a certain time at room temperature, centrifuging the suspension, and drying the solid at room temperature in vacuum.

3.2, 50 ℃ Suspension

Using the amorphous form as a starting material, a quantity of sample is added to the selected solvent until a suspension is formed, after stirring for 24 hours at 50 ℃ the suspension is centrifuged and the solid is dried in vacuo at room temperature.

3.3 Low temperature suspension

Using different crystal forms as raw materials, adding a certain amount of sample into the selected binary solvent until a suspension is formed, suspending and stirring for 24 hours at 10 ℃, centrifuging the suspension, and drying the solid at room temperature in vacuum.

4. Solvent-out crystallization method

4.1, Binary solvent anti-dripping method

About 15mg of the sample is weighed, a certain amount of good solvent is added dropwise at room temperature to dissolve the sample completely, and the solution is added dropwise to 10 times of the volume of poor solvent. After stirring for 1h, centrifugally separating the system with solid precipitation, and vacuum drying the solid at room temperature, continuously stirring the clarified solution for 24h, placing the system without solid precipitation in a refrigerator with the temperature of 4 ℃ or-15 ℃, centrifugally separating the system with solid precipitation, and vacuum drying the solid at room temperature. If no solid is precipitated, the solution is left open at room temperature until the solvent is completely volatilized to obtain solid.

4.2, Binary solvent Positive drop method

About 15mg of sample is weighed, a certain amount of good solvent is dripped at room temperature to completely dissolve the sample, and poor solvent is dripped until solid is separated out. After stirring for 1h at room temperature, centrifugally separating the system with solid precipitation, and vacuum drying the solid at room temperature, continuously stirring the clarified solution for 24h, placing the system without solid precipitation in a refrigerator at 4 or-15 ℃, centrifugally separating the system with solid precipitation, and vacuum drying the solid at room temperature. If no solid is precipitated, the solution is left open at room temperature until the solvent is completely volatilized to obtain solid.

5. Binary solvent cooling method

About 15mg of the sample was weighed and mixed with a predetermined amount of poor solvent at 50℃to form a suspension. The preheated good solvent was gradually added dropwise until the solid was just completely dissolved, and the solution was transferred to room temperature for cooling. Standing at room temperature for more than 2h, and if no sufficient solid is precipitated, placing the solution at 4 ℃ for further cooling. If sufficient solids still did not precipitate, the solution was placed at-15 ℃ for further cooling. After centrifugation of the system with sufficient solids precipitated, the solids were dried in vacuo at room temperature. If no solid is precipitated, the solution is left open at room temperature until the solvent is completely volatilized to obtain solid.

About 15mg of the sample was weighed, dissolved in the selected binary solvent at room temperature, and the solution was cooled at 4 ℃. If no sufficient solids had precipitated, the solution was placed at-15℃for further cooling. After centrifugation of the system with sufficient solids precipitated, the solids were dried in vacuo at room temperature. If no solid is precipitated, the solution is left open at room temperature until the solvent is completely volatilized to obtain solid.

6. Solution vapor diffusion process

About 15mg of the sample is weighed and dissolved in the good solvent, and the clear solution is placed in the poor solvent atmosphere and kept stand at room temperature until solid is separated out. The XRPD test was performed on the wet sample by removing the solution from the system with solids precipitated by syringe.

7. Solid gas phase diffusion process

About 15mg of the amorphous sample was weighed and placed in a selected solvent atmosphere at room temperature for 14 days, the solid state in the glass vial was observed periodically, and XRPD testing was performed on the solid.

8. Thermal crystal transformation method

The thermal crystallization is carried out using a INSTEC HCS GXY heat table (Instec Inc., US), placing 6-8mg of the sample on a heat table, heating to a target temperature at a rate of 10 ℃ per minute, keeping the temperature for 10 minutes, and then naturally cooling to room temperature to obtain a solid.

9. Competitive suspension experiments

Saturated solutions of cyclohexane at different temperatures (10-60 ℃) were prepared, solids of different crystal forms were added equally to the saturated solutions, suspended and stirred for a certain time at the selected specific temperature, and centrifuged for XRPD characterization of the wet samples.

10. Stability study

A quantity of sample (amorphous: about 10mg; crystalline form P: about 20 mg) was weighed into a weighing flask and placed under high temperature (60 ℃) and high humidity (25 ℃ C./92.5% RH), light (25 ℃ C./4500 Lux) and acceleration (40 ℃ C./75% RH), respectively, and samples were taken for XRPD characterization and HPLC testing at 7 days and 17 days.

11. Solubility test

11.1, PH solubility test

The preparation of the pH buffer is shown in Table 19. Samples of different crystal forms are added into pH buffer solution, and are sampled after shaking for 24 hours at the constant temperature of 25 ℃, the sampled solution is filtered by a 0.22 mu m water-based filter membrane, the samples with higher partial concentration are properly diluted by a diluent, the signal peak area of the solution is measured by HPLC, and finally the concentration of the compound in the solution is calculated according to 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 and tested for pH.

TABLE 19 pH preparation of buffer

11.2 Biological Medium and Water solubility test

The preparation process of the biological medium is shown in table 20. Adding samples of different crystal forms into biological medium and water, vibrating for 24h at constant temperature of 37 ℃, sampling for 0.5h,2h and 24h respectively, filtering the sampled solution with a 0.22 mu m water-based filter membrane, properly diluting the samples with higher partial concentration with a diluent, measuring the signal peak area of the solution by HPLC, and finally calculating the concentration of the compound in the solution according to the peak area, the HPLC standard curve of the raw material and the dilution factor. In addition, 24h supernatant was taken to test its pH and the remaining solids were subjected to XRPD testing.

TABLE 20 preparation of biological Medium

EXAMPLE 1 preparation of Compounds of formula (I)

Preparation of Compounds 1-4

Compound 1-1 (28.2 g,96 mmol) was added to a three-necked flask and replaced with nitrogen three times. Anhydrous diethyl ether (100 mL) was added to the three-necked flask, and methyllithium (1.6M, 120mL,192 mmol) was added dropwise at-78℃cooling temperature. After the reaction system was stirred at-78℃for 5 minutes, the temperature was gradually raised to 0℃and the stirring reaction was continued for 3 hours in an ice bath, then, the compound 1-3 (15 g,60 mmol) was added to the reaction system and the stirring was continued 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 give a crude product, which was purified by normal phase silica gel column (EtOAc/pe=0 to 5%) to give the title compounds 1 to 4 (10 g) as pale yellow liquid, yield 33％.¹H NMR(400MHz,CDCl₃)δ4.33(q,J＝7.2Hz,2H),2.44(s,6H),1.36(t,J＝7.2Hz,3H).¹⁹F NMR(376MHz,CDCl₃)δ-109.15(s,2F).

Preparation of Compounds 1-6

The compound ferric triacetylacetonate (2.2 g,6.3 mmol) was added to a three-necked flask and replaced with nitrogen three times. In a three-necked flask, anhydrous THF (80 mL), compounds 1-4 (10 g,31.6 mmol) and TMEDA (1.5 g,12.6 mmol) were sequentially added. The reaction was stirred for 5 minutes, and a THF solution 1-5 (0.5M, 102mL,50.6 mmol) of Grignard reagent 4-methoxyphenylmagnesium bromide was slowly added dropwise to a three-necked flask, and the reaction was continued with stirring at room temperature for 16 hours. After the reaction was completed, the reaction system was extracted with EtOAc (30 ml×3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by separation on a normal phase silica gel column (EtOAc/pe=0 to 5%) to give the title compounds 1 to 6 (2.1 g) as pale yellow liquid, yield 23％.¹H NMR(400MHz,CDCl₃)δ7.19–7.04(m,2H),6.92–6.77(m,2H),4.36(q,J＝7.1Hz,2H),3.79(s,3H),2.16(s,6H),1.37(t,J＝7.1Hz,3H).¹⁹F NMR(376MHz,CDCl₃)δ-111.34(s,2F).

Preparation of Compounds 1-8

Compounds 1-7 (1.1 g,5.6 mmol) were added to a three-necked flask and replaced with nitrogen three times. Anhydrous diethyl ether (15 mL) was added in a three-necked flask and n-butyllithium (1.6M, 3.5mL,5.6 mmol) was added dropwise at-78℃cooling temperature. After the reaction was stirred at-78℃for 45 minutes, an anhydrous diethyl ether solution (10 mL) in which compounds 1 to 6 (1.5 g,5.1 mmol) were dissolved was added dropwise and the reaction was continued with stirring for 1 hour. After the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (5 mL), extracted with EtOAc (20 ml×3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by normal phase silica gel column (EtOAc/pe=0-5%) to give the title compounds 1-8 (1.6 g) as yellow solid in yield 86％.¹H NMR(400MHz,CDCl₃)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).¹⁹F NMR(376MHz,CDCl₃)δ-99.65(d,J＝13.4Hz,1F),-103.94(q,J＝13.8Hz,1F),-107.21(d,J＝14.8Hz,2F).

Preparation of Compound 2-1

Compounds 1-8 (1.8 g,4.95 mmol) were added to a microwave tube, acetic acid (5 mL) was added, and the tube was capped at 95℃for 16 hours with aqueous hydrogen bromide (48 wt.% in H ₂ O,5 mL). After cooling, the mixture was dried by spin-drying, extracted with EtOAc (30 ml×3), and the organic phases were combined, dried and concentrated to give the crude product, which was purified by separation on a normal phase silica gel column (EtOAc/pe=0-30%) to give the title compound 2-1 (1.3 g) as a tan liquid in 72% yield. LC-MS (ESI) m/z 348.8[ M-H ] ^-.

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), and 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 was adjusted to ph=6 to 7 with dilute hydrochloric acid, extracted with dcm (20 ml×3), the organic phases were combined, dried and concentrated to give the crude product, which was purified by normal phase silica gel column (EtOAc/pe=0 to 10%) to give the title compound 20-1 (1.17 g, 94% yield) as a pale 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),6.74–6.63(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 stirred for 16 hours at 80 ℃ in a sealed tube. 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% aqueous formic acid; B: acetonitrile; column chromatography: agilent 10 Prep-C18250X 21.2mm; column temperature: 25 ℃ C.; gradient: 40% -60% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 20 (500 mg, yield 36%, containing a pair of enantiomers).

Compounds of formula (I) 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＝9.2Hz,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 with stirring, and after 5 minutes the compound 1, 1-trifluoro-2, 3-epoxypropane (31 mg,0.28 mmol) was added and the reaction stirred at 50℃for 16 hours. The reaction solution was filtered and the crude filtrate was purified by preparative separation (preparation method: chromatography column: agilent 10Prep-C18 250X21.2mm; column temperature: 25 ℃ C.; mobile phase: water (0.1% TFA) -acetonitrile; mobile phase acetonitrile ratio 50% -70% in 12min; flow rate 30 mL/min) to give the title compound 51 (62 mg, yield: 62%, containing two pairs of enantiomers).

Compounds of formula (I) 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＝6.6Hz,1H),5.42(d,J＝14.5Hz,1H),5.01(d,J＝14.5Hz,1H),4.35(dt,J＝11.3,6.8Hz,1H),4.12(m,1H),4.01(m,1H),1.98(dd,J＝9.4,1.7Hz,3H),1.76(dd,J＝9.4,1.7Hz,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)

The compound 51 (62 mg) was subjected to chiral preparation resolution by SFC (preparation separation method, instrument model: MGIIPREPARATIVE SFC (SFC-14), column model: CHIRALPAK AD, 250X 30mm I.D.,5 μm, mobile phase: A: CO2B: isopropanol, elution gradient: B20%, flow rate: 70mL/min, column pressure: 100bar, column temperature: 38 ℃ and detection wavelength: 220nm, period: 4 min) to give the compound of formula (I) (11 mg).

The compounds of the formula (I) LC-MS (ESI) 547.2[ M+H ] +. Chiral analysis method (column model: CHIRALPAK AD-3, 150X 4.6mm I.D.,3 μm; mobile phase: A: CO2B: isopropanol (0.05% DEA), elution gradient: 5% B of mobile phase was raised to 40% B and kept 40% B for 2.5 minutes and then 5% B was equilibrated for 2.5 minutes in 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＝9.0,6.6Hz,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＝6.6Hz,1H),5.42(d,J＝14.6Hz,1H),5.01(d,J＝14.6Hz,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 minimum inhibitory concentration (Minimal Inhibitory Concentration, MIC) test of Compounds of formula (I) against fungal growth

(1) The main reagent comprises:

RPMI1640 medium, gibco, cat# 31800-014

Sa glucose agar (Sabouraud dextrose agar, SDA) brand of Haibo, product number of HB0253-81

Voriconazole brand Adamas, product number 22105A

Amphotericin B brand name Abcam, product number ab141199

(2) The fungal strains are shown in Table 21 below:

Table 21

(3) The testing method comprises the following steps:

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

Strain preparation the strain was streaked onto SDA plates 1 day in advance with glycerol species stored at-80 ℃. Culturing at 35 deg.C and 40-60% humidity for 18-24 hr. Aspergillus fumigatus and Cryptococcus neoformans respectively need streak inoculation 3 days and 2 days in advance.

Culture medium and compound preparation liquid culture medium RPMI was prepared with pure water, and 0.165mol/L MOPS was added and pH was adjusted to 7.0, and after filtration sterilization with a filter of 0.22um filter membrane, was stored at 4℃for not more than 3 months. 0.85% physiological saline is sterilized at high temperature for 30min at 121 ℃ and then stored at room temperature (not more than 1 week). The compound was dissolved in DMSO at 12.8mg/mL and stored at-20 degrees.

For yeast, 3-5 colonies were picked from the SDA plate on the day of the test, and fully suspended in 5mL of sterilized 0.85% physiological saline. The turbidity of the bacterial liquid is measured by a turbidity meter, and the turbidity is adjusted to about 0.2. The bacterial solutions were diluted 50-fold and 20-fold (total 1000-fold) in sequence with RPMI1640 medium as inoculum solutions. The final inoculum concentration was 500-2500CFU/mL.

For Aspergillus, 5mL of physiological saline was used to cover the mycelium, spores were gently scraped off with a spreader, and the spore suspension was transferred to a sterile tube. Appropriate amounts of spore suspension were aspirated and counted under a microscope using a hemocytometer. Spore concentrations were adjusted to about 0.4-5x 10 ⁴ spores/mL with RPMI1640 medium.

The compound was diluted with DMSO up to 800 μg/mL (or 400 μg/mL) and 10 2-fold gradient dilutions were performed for a total of 11 concentrations. Transfer 2 μl of the gradient diluted compound to the corresponding well of the 96-well plate, and transfer 198 μl of the inoculum to the test plate for 24 hours at 35% (48 and 72 hours for A.fumigatus and Cryptococcus neoformans, respectively).

(4) MIC assessment:

After the incubation, the fungal growth was visually observed, and the point of minimum compound concentration at which the inhibition of yeast growth was not less than 50% (100% inhibition of aspergillus) was defined as the minimum inhibitory concentration MIC (μg/mL). MIC determination can be aided with a magnifying glass or reading OD530 nm. The test board photographs the record file. The results are shown in Table 22 below.

TABLE 22 in vitro antifungal Activity results MIC (μg/mL) for the compounds of formula (I)

EXAMPLE 3 preparation of form A

Weighing 20.3mg of a compound shown in a formula (I), adding the compound into 1.1ml of chloroform to prepare a clear solution, filtering the solution after solid precipitation, and standing the filtered solution at room temperature in an open way until the solvent is completely volatilized to obtain a crystal form A.

EXAMPLE 4 preparation of form B

Weighing 15mg of a compound sample shown in a formula (I), dropwise adding 0.07ml of ethyl acetate at room temperature to completely dissolve the sample, dropwise adding the solution into 0.7ml of n-heptane, stirring for 1 hour, centrifugally separating precipitated solids, and then drying the solids at room temperature in vacuum to obtain a crystal form B, continuously stirring the clarified solution for 24 hours, centrifugally separating the precipitated solids, and then drying the solids at room temperature in vacuum to obtain the crystal form B.

EXAMPLE 5 preparation of form C

Weighing 14.9mg of a compound sample shown in the formula (I), dropwise adding 0.06ml of butyl formate at room temperature to completely dissolve the sample, dropwise adding 0.12ml of toluene into the solution, stirring at room temperature for 1 hour, centrifuging the precipitated solid, and drying the solid at room temperature in vacuum to obtain a crystal form C, continuously stirring the clarified solution for 24 hours, centrifuging the precipitated solid, and drying the solid at room temperature in vacuum to obtain the crystal form C.

EXAMPLE 6 preparation of form D

Weighing 15.5mg of a compound sample shown in the formula (I), dropwise adding 1.16ml of chloroform at room temperature to completely dissolve the sample, dropwise adding 1.00ml of n-heptane into the solution, stirring at room temperature for 1 hour, centrifuging the precipitated solid, and drying the solid at room temperature in vacuum to obtain a crystal form D, continuously stirring the clarified solution for 24 hours, centrifuging the precipitated solid, and drying the solid at room temperature in vacuum to obtain the crystal form D.

EXAMPLE 7 preparation of form E

Weighing 15.4mg of a compound sample shown in the formula (I), dropwise adding 0.07ml of dioxane at room temperature to completely dissolve the sample, dropwise adding the solution into 0.7ml of water, stirring for 1 hour, centrifugally separating precipitated solids, and then vacuum-drying the solids at room temperature to obtain a crystal form E, continuously stirring the clarified solution for 24 hours, centrifugally separating the precipitated solids, and vacuum-drying the solids at room temperature to obtain the crystal form E.

EXAMPLE 8 preparation of form F

Weighing 14.8mg of a compound sample shown in the formula (I), dropwise adding 0.07ml of chloroform at room temperature to completely dissolve the sample, dropwise adding the solution into 0.7ml of cyclohexane, stirring for 1 hour, centrifugally separating precipitated solids, and then drying the solids at room temperature in vacuum to obtain a crystal form F, continuously stirring the clarified solution for 24 hours, centrifugally separating the precipitated solids, and then drying the solids at room temperature in vacuum to obtain the crystal form F.

EXAMPLE 9 preparation of form G

Weighing 15.1mg of a compound sample shown in the formula (I), dropwise adding 0.06ml of diethyl ether at room temperature to completely dissolve the sample, dropwise adding 0.06ml of n-heptane into the solution, stirring at room temperature for 1 hour, centrifuging the precipitated solid, drying the solid at room temperature in vacuum to obtain a crystal form G, continuously stirring the clarified solution for 24 hours, centrifuging the precipitated solid, and drying the solid at room temperature in vacuum to obtain the crystal form G.

EXAMPLE 10 preparation of form H

Weighing 15.1mg of a compound sample shown in a formula (I), dropwise adding 0.06ml of ethyl formate at room temperature to completely dissolve the sample, dropwise adding 0.06ml of n-heptane into the solution, stirring at room temperature for 1 hour, centrifuging the precipitated solid, drying the solid at room temperature in vacuum to obtain a crystal form H, continuously stirring the clarified solution for 24 hours, centrifuging the precipitated solid, and drying the solid at room temperature in vacuum to obtain the crystal form H.

EXAMPLE 11 preparation of form I

20.3Mg of the compound shown in the formula (I) is added into 1.3ml of dichloromethane to prepare a clear solution, the solution is filtered firstly after solid precipitation, and the filtered solution is left to stand at room temperature in an open way until the solvent is completely volatilized, so that the crystal form I is obtained.

EXAMPLE 12 preparation of form J

Weighing 15.3mg of a compound sample shown in a formula (I), dropwise adding 0.07ml of isopropyl acetate at room temperature to completely dissolve the sample, dropwise adding the solution into 0.7ml of cyclohexane, stirring for 1 hour, centrifugally separating precipitated solids, vacuum-drying the solids at room temperature to obtain a crystal form J, continuously stirring the clarified solution for 24 hours, centrifugally separating the precipitated solids, and vacuum-drying the solids at room temperature to obtain the crystal form J.

EXAMPLE 13 preparation of form K

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

EXAMPLE 14 preparation of form L

15.5Mg of a sample of the compound represented by formula (I) was added to 0.05ml of ethyl formate and 0.45ml of cyclohexane solvent to form a suspension, which was stirred at room temperature for 2 days, centrifuged, and the solid was dried at room temperature in vacuo to give form L.

EXAMPLE 15 preparation of form M

45.7Mg of a sample of the compound of formula (I) was added to 0.15ml of methylene chloride and 1.35ml of cyclohexane solvent to form a suspension, and after stirring for 24 hours at 10℃the suspension was centrifuged and the solid was dried under vacuum at 40℃to give form M.

EXAMPLE 16 preparation of form N

15.0Mg of a sample of the compound of formula (I) is weighed and mixed with 1.0ml of cyclohexane at 50℃to form a suspension

Turbid liquid. 1.4ml of chloroform, which had been preheated to 50℃was gradually added dropwise, and the solution was transferred to room temperature for cooling. Standing at room temperature for more than 2 hours, centrifugally separating precipitated solid, and vacuum drying the solid at room temperature to obtain the crystal form N.

EXAMPLE 17 preparation of form O

15.6Mg of an amorphous sample of the compound of formula (I) was added to 0.05ml of methylene chloride and 0.45ml of n-heptane solvent to form a suspension, which was stirred at 10℃for 24 hours, centrifuged, and the solid was dried at room temperature under vacuum to obtain form O.

EXAMPLE 18 preparation of form P

781.4Mg of a sample of the compound of formula (I) was weighed, 26.0mL of methyl tert-butyl ether/n-heptane (v/v, 1:9) binary solvent was added, stirred at room temperature for 48 hours, the supernatant was removed by centrifugation, and the solid was dried under vacuum at 40℃for 1 day. The dried solid was added to 21.5mL of methyl tert-butyl ether/n-heptane (v/v, 1:9) binary solvent, stirred at room temperature for 24h, centrifuged to remove supernatant, and the solid was dried under vacuum at 40℃for 1 day to give 699.3mg of crystalline form P.

EXAMPLE 19 amorphous preparation

436.5Mg of a sample of the compound of formula (I) was weighed, dissolved in 4.5mL of ethanol, filtered to remove insoluble impurities, and evaporated to give a fluffy white solid which was dried in vacuo at room temperature for 4 days. The resulting sample was added to 2.0mL of methylene chloride, stirred at room temperature for 24 hours, dried directly at room temperature under vacuum overnight, and dried under vacuum at 40℃for 2 days to give 280.0mg of amorphous form.

EXAMPLE 20 Crystal form P solubility test

The solubility of form P in 6 solvents was measured and the results are shown in table 23. Form P is readily soluble in ethanol, acetone and ethyl acetate (> 100 mg/mL) and acetonitrile, dichloromethane and tetrahydrofuran (> 10 mg/mL) according to the solubility test results. In the solubility test process, the crystal form P can be basically dissolved in 0.1mL of ethanol, acetone, ethyl acetate, acetonitrile and tetrahydrofuran respectively, granular substances in the solution are adhered to the EP pipe wall, the granular substances are gradually and completely dissolved along with the continuous dropwise addition of the solvent, the crystal form P can be basically dissolved in 1.1mL of dichloromethane, the continuous dropwise addition of the dichloromethane is carried out, and no sign of reduction is observed in the flocculent substances in the solution.

Table 23 results of form P solubility test

EXAMPLE 21 stability Studies

Stability studies were performed on amorphous and crystalline form P at high temperature (60 ℃), high humidity (25 ℃) 92.5% rh), light (25 ℃) 4500Lux, accelerated (40 ℃) 75% rh, and samples were taken at 7 days and 17 days for XRPD characterization and HPLC testing, respectively, and the results are shown in table 24, fig. 39, and fig. 40. XRPD results showed that amorphous and crystalline form P were stable at high temperature, high humidity, light, accelerated conditions for 17 days without form transformation, and deliquescence was observed under accelerated conditions. HPLC results showed that amorphous and crystalline form P were left for 17 days under the above conditions without significant changes in chemical purity.

TABLE 24 stability study results

Table 25 results of HPLC purity analysis of amorphous stable samples

TABLE 26 HPLC purity analysis results of crystalline form P stability samples

Example 22 pH solubility test

The solubility of amorphous and crystalline form P in different pH buffers was determined, the experimental procedure is shown in general test method 11.1, and the corresponding results are shown in Table 27. The results show that both amorphous and crystalline form P have very low solubility in buffers of different pH and are undetectable.

Table 27 pH solubility test results

Example 23 biological Medium and Water solubility test

Dynamic solubility measurements were performed on amorphous and crystalline form P in 3 biological media (FaSSIF, feSSIF and FaSSGF) and water. The experimental method is shown in general experimental method 11.2, and the corresponding results are shown in table 28, fig. 41 and fig. 42. The results show that the solubility of both amorphous and crystalline forms P in FaSSIF and FeSSIF was decreasing with time, the 24h solubility of amorphous and crystalline form P in FeSSIF was greater than FaSSIF, undetectable in fassf and water, and the remaining solid crystalline form in biological medium and water was unchanged after the solubility test.

Table 28 dynamic solubility test in biological media

In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims

Crystal form A of the Compound of formula (I)

The X-ray powder diffraction pattern of the crystal form A is characterized by having characteristic diffraction peaks at the following 2 theta angles of 3.76+/-0.2 degrees, 5.2+/-0.2 degrees, 13.75+/-0.2 degrees, 16.97+/-0.2 degrees, 17.67+/-0.2 degrees and 19.75+/-0.2 degrees by using Cu-K alpha radiation;

Optionally, the X-ray powder diffraction pattern of 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 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 form a has an X-ray powder diffraction pattern substantially as shown in figure 1.
Form B of the compound of formula (I), characterized in that it exhibits an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 figure 3.
Form C of the compound of formula (I), characterized in that it exhibits an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 figure 5.
Form D of the compound of formula (I), characterized in that it exhibits an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 form D has an X-ray powder diffraction pattern substantially as shown in figure 7.
Form E of the compound of formula (I), characterized in that it exhibits an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 form E has an X-ray powder diffraction pattern substantially as shown in figure 9.
Form F of the compound of formula (I), characterized in that it exhibits an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 form F has an X-ray powder diffraction pattern substantially as shown in figure 11.
Form G of the compound of formula (I), characterized in that it exhibits an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 form G has an X-ray powder diffraction pattern substantially as shown in figure 13.
Form H of the compound of formula (I), characterized in that it has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 form H has an X-ray powder diffraction pattern substantially as shown in figure 15.
A crystalline form I of a compound of formula (I), characterized in that Cu-ka radiation is used, the X-ray powder diffraction pattern of said crystalline form I having 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 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 form I has an X-ray powder diffraction pattern substantially as shown in figure 17.
Form J of the compound of formula (I), characterized in that the X-ray powder diffraction pattern of the form J has characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 figure 19.
Form K of the compound of formula (I), characterized in that it has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 form K has an X-ray powder diffraction pattern substantially as shown in figure 21.
Form L of the compound of formula (I), characterized in that it exhibits an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 form L has an X-ray powder diffraction pattern substantially as shown in figure 23.
A crystalline form M of a compound of formula (I), characterized in that Cu-ka radiation is used, said crystalline form M having an X-ray powder diffraction pattern with 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 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 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 form M has an X-ray powder diffraction pattern substantially as shown in figure 25.
Form N of the compound of formula (I), characterized in that it exhibits an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 form N has an X-ray powder diffraction pattern substantially as shown in figure 27.
Form O of the compound of formula (I), characterized in that it exhibits an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 form O has an X-ray powder diffraction pattern substantially as shown in figure 29.
Form P of the compound of formula (I), characterized in that it has characteristic diffraction peaks at the following 2Θ angles, using Cu-ka radiation, of 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 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 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 form P has an X-ray powder diffraction pattern substantially as shown in figure 31.
An amorphous form of a compound of formula (I), characterized in that Cu-ka radiation is used, said amorphous X-ray powder diffraction pattern having an X-ray powder diffraction pattern substantially as shown in figure 35.