Benzazepine ring compounds, salt forms, crystal forms, and uses thereof

Abstract

A benzazepine ring compound salt type, crystal form and application thereof, in particular to a maleate salt of a compound shown in formula (I), the structure of the maleate salt is shown in formula (II).

Description

[0001] This invention claims the following priority:

[0002] Application number CN 202211080826.4, application date September 5, 2022. Technical Field

[0003] This invention belongs to the field of medicinal chemistry, specifically, it relates to the salt form, crystal form and application of benzozazepine cyclic compounds. Background Technology

[0004] Hormones play a crucial role in regulating homeostasis within the human body, with arginine vasopressin (AVP) being closely related to the regulation of water and sodium metabolism. Disorders of arginine vasopressin (AVP) metabolism can cause various diseases, including hyponatremia, syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, cirrhosis, kidney disease, hypertension, and edema. Arginine vasopressin (AVP) receptor antagonists inhibit the binding of AVP to its receptors, thereby treating these diseases. Arginine vasopressin V2 receptor antagonists, such as tolvaptan, can increase free water excretion without affecting electrolyte metabolism, making them ideal drugs for treating these conditions. However, marketed AVP V2 receptor antagonists, such as tolvaptan, are metabolized by hepatic enzymes, producing large amounts of metabolites in the body and leading to severe drug-induced hepatotoxicity. The FDA has issued a black box warning on the drug's label, restricting its use.

[0005] Patent application number PCT / CN2022 / 079350, filed on March 4, 2022, discloses a novel AVP V2 receptor antagonist with the structure shown below. . Summary of the Invention

[0006] In one aspect of the invention, the present invention provides a maleate salt of the compound shown in formula (I), the structure of which is shown in formula (II). , .

[0007] In another aspect of the invention, the present invention proposes a maleate salt of the compound shown in formula (I) (i.e., the compound shown in formula (II)) crystal form A, the X-ray powder diffraction pattern of crystal form A having characteristic diffraction peaks at the following 2θ angles: 9.14±0.2°, 12.88±0.2°, 18.31±0.2°, 18.90±0.2°, 20.60±0.2°, 27.61±0.2°.

[0008] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ angles: 9.14±0.2°, 12.88±0.2°, 17.19±0.2°, 18.31±0.2°, 18.90±0.2°, 20.60±0.2°, 21.45±0.2°, and 27.61±0.2°.

[0009] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ angles: 9.14±0.2°, 12.88±0.2°, 17.19±0.2°, 18.31±0.2°, 18.90±0.2°, 19.70±0.2°, 20.20±0.2°, 20.60±0.2°, 21.45±0.2°, 21.91±0.2°, and 27.61±0.2°.

[0010] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ angles: 9.14±0.2°, 12.88±0.2°, 17.19±0.2°, 18.31±0.2°, 18.90±0.2°, 19.70±0.2°, 20.20±0.2°, 20.60±0.2°, 21.45±0.2°, 21.91±0.2°, 25.96±0.2°, 26.53±0.2°, 27.61±0.2°, 29.22±0.2°, and 30.20±0.2°.

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form A has essentially the following characteristics: Figure 1 The X-ray powder diffraction pattern shown is shown.

[0012] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of crystal form A are shown in Table 1 below.

[0013] Table 1

[0014] In another aspect of the invention, the invention also provides a maleate salt of the compound shown in formula (I) (i.e., the compound shown in formula (II)) crystal form B, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 8.97±0.2°, 15.73±0.2°, 18.31±0.2°, 20.15±0.2°, 21.12±0.2°, 24.70±0.2°.

[0015] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form B has characteristic diffraction peaks at the following 2θ angles: 7.40±0.2°, 8.97±0.2°, 10.11±0.2°, 13.94±0.2°, 15.73±0.2°, 18.31±0.2°, 19.02±0.2°, 20.15±0.2°, 21.12±0.2°, and 24.70±0.2°.

[0016] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form B has essentially the following characteristics: Figure 6 The X-ray powder diffraction pattern shown is shown.

[0017] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of crystal form B are shown in Table 2 below.

[0018] Table 2

[0019] In another aspect of the invention, the invention also discloses a fumarate of the compound shown in formula (I), the structure of which is shown in formula (III). .

[0020] In another aspect of the invention, the present invention also discloses a fumarate of the compound shown in formula (I) (i.e., the compound shown in formula (III)) crystal form C, the X-ray powder diffraction pattern of crystal form C having characteristic diffraction peaks at the following 2θ angles: 12.77±0.2°, 14.44±0.2°, 20.00±0.2°, 20.64±0.2°, 21.33±0.2°, 21.87±0.2°.

[0021] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form C has characteristic diffraction peaks at the following 2θ angles: 12.77±0.2°, 13.17±0.2°, 14.44±0.2°, 17.18±0.2°, 20.00±0.2°, 20.64±0.2°, 21.33±0.2°, 21.87±0.2°, 23.43±0.2°, and 25.86±0.2°.

[0022] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form C has essentially the following characteristics: Figure 9 The X-ray powder diffraction pattern shown is shown.

[0023] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of crystal form C are shown in Table 3 below.

[0024] Table 3

[0025] In another aspect of the invention, the invention provides a hydrochloride salt of the compound shown in formula (I), the structure of which is shown in formula (IV). .

[0026] In another aspect of the invention, the present invention proposes a crystal form D of the hydrochloride salt of the compound shown in formula (I) (i.e., the compound shown in formula (IV)), the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 8.13±0.2°, 9.27±0.2°, 9.91±0.2°, 13.53±0.2°, 16.37±0.2°, 17.09±0.2°.

[0027] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form D has characteristic diffraction peaks at the following 2θ angles: 8.13±0.2°, 9.27±0.2°, 9.91±0.2°, 12.86±0.2°, 13.53±0.2°, 16.37±0.2°, 17.09±0.2°, 18.67±0.2°, 21.77±0.2°, and 23.81±0.2°.

[0028] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form D has essentially the following characteristics: Figure 12 The X-ray powder diffraction pattern shown is shown.

[0029] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of crystal form D are shown in Table 4 below.

[0030] Table 4

[0031] In another aspect of the invention, the present invention proposes a hydrochloride salt of the compound shown in formula (I) (i.e., the compound shown in formula (IV)) crystal form E, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 3.86±0.2°, 13.60±0.2°, 14.19±0.2°, 18.06±0.2°, 20.50±0.2°, 21.24±0.2°.

[0032] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form E has characteristic diffraction peaks at the following 2θ angles: 3.86±0.2°, 6.74±0.2°, 11.73±0.2°, 13.60±0.2°, 14.19±0.2°, 18.06±0.2°, 20.50±0.2°, 21.24±0.2°, 23.72±0.2°, and 24.06±0.2°.

[0033] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form E has substantially the following characteristics: Figure 15 The X-ray powder diffraction pattern shown is shown.

[0034] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form E are shown in Table 5 below.

[0035] Table 5

[0036] In another aspect of the invention, the invention also proposes a hydrochloride salt of the compound shown in formula (I) (i.e., the compound shown in formula (IV)) crystal form F, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 5.84±0.2°, 11.77±0.2°, 13.29±0.2°, 17.82±0.2°, 20.49±0.2°, 20.94±0.2°.

[0037] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form F has characteristic diffraction peaks at the following 2θ angles: 5.84±0.2°, 11.77±0.2°, 13.29±0.2°, 14.34±0.2°, 17.82±0.2°, 18.67±0.2°, 20.49±0.2°, 20.94±0.2°, 23.02±0.2°, and 23.68±0.2°.

[0038] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form F has substantially the following characteristics: Figure 18 The X-ray powder diffraction pattern shown is shown.

[0039] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form F shown are shown in Table 6 below.

[0040] Table 6

[0041] In another aspect of the invention, a sulfate of the compound shown in formula (I) is also provided, the structure of which is shown in formula (V). .

[0042] In another aspect of the invention, the invention also proposes a sulfate form G of the compound shown in formula (I) (i.e., the compound shown in formula (V)), the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 10.30±0.2°, 13.02±0.2°, 16.60±0.2°, 18.53±0.2°, 20.67±0.2°, 22.26±0.2°.

[0043] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form G has characteristic diffraction peaks at the following 2θ angles: 6.46±0.2°, 10.30±0.2°, 13.02±0.2°, 16.60±0.2°, 17.66±0.2°, 18.53±0.2°, 19.98±0.2°, 20.67±0.2°, 22.26±0.2°, and 23.62±0.2°.

[0044] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form G has substantially the following characteristics: Figure 21 The X-ray powder diffraction pattern shown is shown.

[0045] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the sulfate crystal form G are shown in Table 7 below.

[0046] Table 7

[0047] In another aspect of the invention, the invention also provides a succinate of the compound shown in formula (I), the structure of which is shown in formula (VI). .

[0048] In another aspect of the invention, the invention also proposes a succinate of the compound shown in formula (I) (i.e., the compound shown in formula (VI)) crystal form H, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 10.30±0.2°, 14.63±0.2°, 18.59±0.2°, 20.13±0.2°, 21.83±0.2°, 22.30±0.2°.

[0049] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form H has characteristic diffraction peaks at the following 2θ angles: 10.30±0.2°, 12.91±0.2°, 14.63±0.2°, 18.59±0.2°, 19.41±0.2°, 20.13±0.2°, 20.69±0.2°, 21.83±0.2°, 22.30±0.2°, and 23.65±0.2°.

[0050] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form H has substantially the following characteristics: Figure 24 The X-ray powder diffraction pattern shown is shown.

[0051] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form H are shown in Table 8 below.

[0052] Table 8

[0053] In another aspect of the invention, the invention also provides a succinate crystal form J of the compound shown in formula (I) (i.e., the compound shown in formula (VI)), wherein the X-ray powder diffraction pattern of crystal form J has characteristic diffraction peaks at the following 2θ angles: 9.61±0.2°, 11.56±0.2°, 12.93±0.2°, 17.12±0.2°, 17.71±0.2°, and 19.95±0.2°.

[0054] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form J has characteristic diffraction peaks at the following 2θ angles: 9.61±0.2°, 11.56±0.2°, 12.93±0.2°, 13.76±0.2°, 17.12±0.2°, 17.71±0.2°, 19.51±0.2°, 19.95±0.2°, 21.83±0.2°, and 22.42±0.2°.

[0055] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form J has substantially the following characteristics: Figure 27 The X-ray powder diffraction pattern shown is shown.

[0056] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form J are shown in Table 9 below.

[0057] Table 9

[0058] In another aspect of the invention, the invention also provides an glycolate of the compound shown in formula (I), the structure of which is shown in formula (VII). .

[0059] In another aspect of the invention, the invention also proposes a crystal form K of the glycolate of the compound shown in formula (I) (i.e., the compound shown in formula (VII)), wherein the X-ray powder diffraction pattern of the crystal form K has characteristic diffraction peaks at the following 2θ angles: 12.51±0.2°, 15.99±0.2°, 18.71±0.2°, 20.18±0.2°, 20.59±0.2°, 21.64±0.2°.

[0060] 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: 12.51±0.2°, 13.62±0.2°, 15.99±0.2°, 16.65±0.2°, 18.71±0.2°, 20.18±0.2°, 20.59±0.2°, 21.64±0.2°, 22.62±0.2°, and 24.53±0.2°.

[0061] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form K has substantially the following characteristics: Figure 30 The X-ray powder diffraction pattern shown is shown.

[0062] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form K are shown in Table 10 below.

[0063] Table 10

[0064] In another aspect of the invention, the invention also provides a benzoate of the compound shown in formula (I), the structure of which is shown in formula (VIII). .

[0065] In another aspect of the invention, the invention also proposes a benzoic acid eutectic form L of the compound shown in formula (I), wherein the X-ray powder diffraction pattern of the form L has characteristic diffraction peaks at the following 2θ angles: 8.14±0.2°, 8.76±0.2°, 9.55±0.2°, 12.62±0.2°, 16.43±0.2°, and 18.05±0.2°.

[0066] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form L has characteristic diffraction peaks at the following 2θ angles: 8.14±0.2°, 8.76±0.2°, 9.55±0.2°, 12.62±0.2°, 16.43±0.2°, 17.68±0.2°, 18.05±0.2°, 18.95±0.2°, 19.32±0.2°, and 19.73±0.2°.

[0067] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form L has substantially the following characteristics: Figure 33 The X-ray powder diffraction pattern shown is shown.

[0068] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form L are shown in Table 11 below.

[0069] Table 11

[0070] In another aspect of the invention, the invention also proposes a benzoic acid eutectic crystal form M of the compound shown in formula (I), wherein the X-ray powder diffraction pattern of crystal form M has characteristic diffraction peaks at the following 2θ angles: 9.31±0.2°, 13.77±0.2°, 14.54±0.2°, 19.84±0.2°, 20.34±0.2°, and 21.70±0.2°.

[0071] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form M has characteristic diffraction peaks at the following 2θ angles: 9.31±0.2°, 13.77±0.2°, 14.54±0.2°, 16.55±0.2°, 17.66±0.2°, 18.68±0.2°, 19.84±0.2°, 20.34±0.2°, 21.70±0.2°, and 23.32±0.2°.

[0072] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form M has substantially the following characteristics: Figure 36 The X-ray powder diffraction pattern shown is shown.

[0073] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form M are shown in Table 12 below.

[0074] Table 12

[0075] In another aspect of the invention, the invention also proposes a crystal form N of the compound shown in formula (I), wherein the X-ray powder diffraction pattern of the crystal form N has characteristic diffraction peaks at the following 2θ angles: 10.38±0.2°, 13.54±0.2°, 14.41±0.2°, 16.32±0.2°, 18.10±0.2°, and 19.05±0.2°.

[0076] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form N has characteristic diffraction peaks at the following 2θ angles: 10.38±0.2°, 13.54±0.2°, 14.41±0.2°, 15.90±0.2°, 16.32±0.2°, 18.10±0.2°, 19.05±0.2°, 22.14±0.2°, 22.91±0.2°, and 23.66±0.2°.

[0077] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form N has substantially the following characteristics: Figure 39 The X-ray powder diffraction pattern shown is shown.

[0078] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form N are shown in Table 13 below.

[0079] Table 13

[0080] In another aspect of the invention, the invention also provides a crystal form O of the compound shown in formula (I), wherein the X-ray powder diffraction pattern of crystal form O has characteristic diffraction peaks at the following 2θ angles: 4.75±0.2°, 9.65±0.2°, 15.70±0.2°, 16.88±0.2°, 18.00±0.2°, and 18.97±0.2°.

[0081] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form O has characteristic diffraction peaks at the following 2θ angles: 4.75±0.2°, 9.65±0.2°, 15.70±0.2°, 16.88±0.2°, 18.00±0.2°, 18.97±0.2°, 19.89±0.2°, 21.86±0.2°, 22.67±0.2°, and 24.30±0.2°.

[0082] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form O has substantially the following characteristics: Figure 42 The X-ray powder diffraction pattern shown is shown.

[0083] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form O are shown in Table 14 below.

[0084] Table 14

[0085] In another aspect of the invention, the invention also proposes a crystal form P of the compound shown in formula (I), wherein the X-ray powder diffraction pattern of the crystal form P has characteristic diffraction peaks at the following 2θ angles: 13.07±0.2°, 17.98±0.2°, 21.64±0.2°, 23.78±0.2°, 26.36±0.2°, and 33.13±0.2°.

[0086] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form P has substantially the following characteristics: Figure 45 The X-ray powder diffraction pattern shown is shown.

[0087] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form P are shown in Table 15 below.

[0088] Table 15

[0089] In another aspect of the invention, the invention also proposes a crystal form Q of the compound shown in formula (I), wherein the X-ray powder diffraction pattern of crystal form Q has characteristic diffraction peaks at the following 2θ angles: 3.48±0.2°, 10.60±0.2°, 12.32±0.2°, 15.41±0.2°, 16.60±0.2°, and 17.09±0.2°.

[0090] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form Q has characteristic diffraction peaks at the following 2θ angles: 3.48±0.2°, 10.60±0.2°, 12.32±0.2°, 15.41±0.2°, 16.60±0.2°, 17.09±0.2°, 17.75±0.2°, 18.79±0.2°, 20.49±0.2°, and 21.40±0.2°.

[0091] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form Q has substantially the following characteristics: Figure 48 The X-ray powder diffraction pattern shown is shown.

[0092] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form Q are shown in Table 16 below.

[0093] Table 16

[0094] In another aspect of the invention, the invention also proposes a crystal form R of the compound shown in formula (I), wherein the X-ray powder diffraction pattern of the crystal form R has characteristic diffraction peaks at the following 2θ angles: 6.70±0.2°, 13.30±0.2°, 18.15±0.2°, 21.39±0.2°, 22.97±0.2°, and 26.71±0.2°.

[0095] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form R has substantially the following characteristics: Figure 50 The X-ray powder diffraction pattern shown is shown.

[0096] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form R are shown in Table 17 below.

[0097] Table 17

[0098] In another aspect of the invention, the invention also proposes a crystal form S of the compound shown in formula (I), wherein the X-ray powder diffraction pattern of the crystal form S has characteristic diffraction peaks at the following 2θ angles: 14.97±0.2°, 15.34±0.2°, 17.97±0.2°, 22.81±0.2°, 23.54±0.2°, and 24.69±0.2°.

[0099] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form S has substantially the following characteristics: Figure 53 The X-ray powder diffraction pattern shown is shown.

[0100] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form S are shown in Table 18 below.

[0101] Table 18

[0102] In another aspect of the invention, the invention also proposes a crystal form T of the compound shown in formula (I), wherein the X-ray powder diffraction pattern of the crystal form T has characteristic diffraction peaks at the following 2θ angles: 15.84±0.2°, 17.03±0.2°, 17.60±0.2°, 20.01±0.2°, 22.22±0.2°, and 22.82±0.2°.

[0103] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form T has characteristic diffraction peaks at the following 2θ angles: 13.64±0.2°, 14.70±0.2°, 15.84±0.2°, 17.03±0.2°, 17.60±0.2°, 19.01±0.2°, 20.01±0.2°, 22.22±0.2°, 22.82±0.2°, and 24.45±0.2°.

[0104] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form T has substantially the following characteristics: Figure 56 The X-ray powder diffraction pattern shown is shown.

[0105] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form T are shown in Table 19 below.

[0106] Table 19

[0107] In another aspect of the invention, the invention also proposes a crystal form U of the compound shown in formula (I), wherein the X-ray powder diffraction pattern of the crystal form U has characteristic diffraction peaks at the following 2θ angles: 8.01±0.2°, 9.27±0.2°, 12.68±0.2°, 16.15±0.2°, 17.94±0.2°, and 19.31±0.2°.

[0108] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form U has characteristic diffraction peaks at the following 2θ angles: 8.01±0.2°, 9.27±0.2°, 12.68±0.2°, 16.15±0.2°, 17.94±0.2°, 19.31±0.2°, 22.16±0.2°, 22.82±0.2°, 23.80±0.2°, and 24.08±0.2°.

[0109] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form U has substantially the following characteristics: Figure 59 The X-ray powder diffraction pattern shown is shown.

[0110] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the crystal form U are shown in Table 20 below.

[0111] Table 20

[0112] Definitions and Explanations

[0113] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0114] "API" or "free state" both refer to the free base form of the compound shown in formula (I).

[0115] "Crystal form" or "crystalline shape" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts. The crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0116] "Amorphous" or "amorphous form" refers to matter formed when its particles (molecules, atoms, ions) are arranged non-periodically in three-dimensional space. It is characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous matter is a special physical form of solid matter, and its locally ordered structural features suggest a close connection with crystalline substances. The amorphous form of matter can be obtained through many methods known in the art. These methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, etc.

[0117] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, etc. 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-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, etc.

[0118] An antisolvent is a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Antisolvents can include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of a product in a solvent; they can be the same liquid as the solvent but at a different temperature, or they can be a different liquid from the solvent.

[0119] "Solvate" refers to a solvent present on the surface of a crystal, in the crystal lattice, or both on the surface and in the crystal lattice. 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, etc. N , N -Dimethylacetamide, N , 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, and mixtures thereof, etc. A specific example of a solvate is a hydrate, wherein the solvent is water on the surface, in the lattice, or both on the surface and in the lattice. A hydrate may or may not have other solvents besides water on the surface, in the lattice, or both on the surface and in the lattice of a substance.

[0120] Crystalline or amorphous forms can be identified using a variety of techniques, 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, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0121] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra mainly depend on the crystal structure and are relatively insensitive to experimental details, while their relative peak heights depend 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 essentially as shown in the XRPD patterns provided in the accompanying drawings. Meanwhile, the measurement of 2θ in the XRPD spectrum can have experimental errors; the measurement of 2θ in the XRPD spectrum may differ slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. According to the instrument conditions used in the experiments of the present invention, the diffraction peaks have a range of ±0.2. o Error tolerance.

[0122] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature under programmed control by continuously heating or cooling. The melting peak height of the 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 described in this invention is characterized by a DSC plot with characteristic peak positions, which is essentially as shown in the DSC plots provided in the accompanying drawings. However, DSC spectra can be subject to experimental error; the peak positions and peak values ​​of DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak positions or peak values ​​of the DSC endothermic peaks cannot be considered absolute. Under the conditions of the instrument used in the experiments according to this invention, the melting peak has ±3... o The error tolerance of C.

[0123] The glass transition refers to the transition of an amorphous substance between a rubbery state and a glassy state, and is an inherent property of the substance; the corresponding transition temperature is called the glass transition temperature (Tg), which is an important physical property of amorphous substances. The glass transition is a phenomenon related to molecular motion; therefore, the glass transition temperature (Tg) mainly depends on the structure of the substance and is relatively insensitive to experimental details. In some embodiments, the glass transition temperature (Tg) of the amorphous substance described in this invention is determined by differential scanning calorimetry (DSC), characterized by a value of 107.44. o The glass transition temperature of C. Based on the apparatus used in the experiment according to the present invention, the glass transition temperature exists within ±3... o The error tolerance of C.

[0124] Differential scanning calorimetry (DSC) can also be used to detect and analyze whether there is crystal transformation or mixed crystal phenomenon in the crystal form.

[0125] Solids with the same chemical composition often form isomers, or polymorphs, with different crystal structures under different thermodynamic conditions. This phenomenon is called polymorphism or polyphase polymorphism. When temperature and pressure conditions change, these polymorphs can transform into each other; this phenomenon is called crystal form transformation. Due to crystal form transformation, the mechanical, electrical, and magnetic properties of the crystal undergo significant changes. When the temperature of the crystal form transformation is within a measurable range, this transformation process can be observed on a differential scanning calorimeter (DSC) chart. The DSC chart is characterized by having an exothermic peak reflecting this transformation process, and simultaneously possessing two or more endothermic peaks, which are characteristic endothermic peaks of the different crystal forms before and after the transformation. The crystal form or amorphous form of the compounds of this invention can undergo crystal form transformation under appropriate conditions.

[0126] Thermogravimetric analysis (TGA) is a technique used under programmed control to determine the change in mass of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. Based on the instrumentation used in this invention, there is an error tolerance of ±0.3% for the mass change.

[0127] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0128] When referring to a spectrum or / and the data appearing in the graph, a "peak" refers to a feature that a person skilled in the art can identify and that is not attributable to background noise.

[0129] The term "basically 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 an X-ray powder diffraction pattern, DSC pattern, or TGA result are shown in its pattern.

[0130] "Substantially pure" means that a crystal form substantially contains no other crystal forms, i.e., the purity of the crystal 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 crystal form contains other crystal forms whose percentage in the total volume or total weight of the crystal 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%.

[0131] "Substantially free of" means that one or more other crystal forms account for 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% of the total volume or weight of the crystal form.

[0132] "Relative intensity" refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak in an X-ray powder diffraction pattern (XRPD) is 100%.

[0133] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error of the average value. Whenever a number with 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% is explicitly disclosed, where "+ / -" refers to addition or subtraction.

[0134] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects. Attached Figure Description

[0135] Figure 1 This is an XRPD diagram of maleate crystal form A according to an embodiment of the present invention; Figure 2 These are DSC and TGA diagrams of maleate crystal form A according to an embodiment of the present invention; Figure 3 Here are the NMR spectra of maleate crystal form A according to an embodiment of the present invention: (a) Comparison with the free state; (b) Integration results; Figure 4 The figure shows the DVS curve of maleate crystal form A according to an embodiment of the present invention; Figure 5 These are XRPD images of maleate crystal form A before and after DVS testing according to an embodiment of the present invention; Figure 6 This is an XRPD diagram of maleate crystal form B according to an embodiment of the present invention; Figure 7 These are DSC and TGA images of maleate crystal form B according to an embodiment of the present invention; Figure 8 This is the NMR spectrum of maleate crystal form B according to an embodiment of the present invention; Figure 9 This is an XRPD diagram of fumarate crystal form C according to an embodiment of the present invention; Figure 10 These are DSC and TGA images of fumarate crystal form C according to an embodiment of the present invention; Figure 11 NMR spectra of fumarate crystal form C according to an embodiment of the present invention: (a) comparison with the free state; (b) integration results; Figure 12 This is an XRPD diagram of hydrochloride crystal form D according to an embodiment of the present invention; Figure 13 These are DSC and TGA diagrams of hydrochloride crystal form D according to an embodiment of the present invention; Figure 14 NMR spectra of hydrochloride crystal form D according to an embodiment of the present invention: (a) comparison with the free state; (b) integration results; Figure 15 This is an XRPD diagram of the hydrochloride crystal form E according to an embodiment of the present invention; Figure 16 These are DSC and TGA diagrams of hydrochloride crystal form E according to an embodiment of the present invention; Figure 17 The following are NMR spectra of hydrochloride crystal form E according to an embodiment of the present invention: (a) comparison with the free state; (b) integration results; Figure 18 This is an XRPD diagram of the hydrochloride crystal form F according to an embodiment of the present invention; Figure 19 These are DSC and TGA images of hydrochloride crystal form F according to an embodiment of the present invention; Figure 20 The following are NMR spectra of hydrochloride crystal form F according to an embodiment of the present invention: (a) comparison with the free state; (b) integration results; Figure 21 This is an XRPD diagram of sulfate crystal form G according to an embodiment of the present invention; Figure 22 These are DSC and TGA diagrams of sulfate crystal form G according to an embodiment of the present invention; Figure 23 Here are the NMR spectra of sulfate crystal form G according to an embodiment of the present invention: (a) comparison with the free state; (b) integration results; Figure 24 This is an XRPD diagram of succinate crystal form H according to an embodiment of the present invention; Figure 25 These are DSC and TGA diagrams of succinate crystal form H according to an embodiment of the present invention; Figure 26 NMR spectra of succinate crystal form H according to an embodiment of the present invention: (a) comparison with the free state; (b) integration results; Figure 27 This is an XRPD diagram of succinate crystal form J according to an embodiment of the present invention; Figure 28 These are DSC and TGA diagrams of succinate crystal form J according to an embodiment of the present invention; Figure 29 The following are NMR spectra of succinate crystal form J according to an embodiment of the present invention: (a) comparison with the free state; (b) integration results; Figure 30 This is an XRPD diagram of the glycolate crystal form K according to an embodiment of the present invention; Figure 31 These are DSC and TGA diagrams of glycolate crystal form K according to an embodiment of the present invention; Figure 32 Here are the NMR spectra of the glycolate crystal form K according to an embodiment of the present invention: (a) comparison with the free state; (b) integration results; Figure 33 This is an XRPD diagram of the eutectic form L of benzoic acid according to an embodiment of the present invention; Figure 34 These are DSC and TGA images of benzoic acid eutectic form L according to an embodiment of the present invention; Figure 35 NMR spectra of benzoic acid eutectic form L according to embodiments of the present invention: (a) comparison with the free state; (b) integration results; Figure 36 This is an XRPD diagram of the eutectic form M of benzoic acid according to an embodiment of the present invention; Figure 37 These are DSC and TGA diagrams of benzoic acid eutectic form M according to an embodiment of the present invention; Figure 38 The following are NMR spectra of benzoic acid eutectic form M according to an embodiment of the present invention: (a) comparison with the free state; (b) integration results; Figure 39 This is an XRPD diagram of crystal form N according to an embodiment of the present invention; Figure 40 These are DSC and TGA diagrams of crystal form N according to an embodiment of the present invention; Figure 41 This is an NMR spectrum of crystal form N according to an embodiment of the present invention; Figure 42 This is an XRPD diagram of crystal form O according to an embodiment of the present invention; Figure 43 These are DSC and TGA diagrams of crystal form O according to an embodiment of the present invention; Figure 44 This is an NMR spectrum of crystal form O according to an embodiment of the present invention; Figure 45 This is an XRPD diagram of crystal form P according to an embodiment of the present invention; Figure 46 These are DSC and TGA diagrams of crystal form P according to an embodiment of the present invention; Figure 47 This is the NMR spectrum of crystal form P according to an embodiment of the present invention; Figure 48This is an XRPD diagram of crystal form Q according to an embodiment of the present invention; Figure 49 These are DSC and TGA diagrams of crystal form Q according to an embodiment of the present invention; Figure 50 This is an XRPD diagram of crystal form R according to an embodiment of the present invention; Figure 51 These are DSC and TGA diagrams of crystal form R according to an embodiment of the present invention; Figure 52 This is the NMR spectrum of crystal form R according to an embodiment of the present invention; Figure 53 This is an XRPD diagram of crystal form S according to an embodiment of the present invention; Figure 54 These are DSC and TGA diagrams of crystal form S according to an embodiment of the present invention; Figure 55 This is the NMR spectrum of crystal form S according to an embodiment of the present invention; Figure 56 This is an XRPD diagram of crystal form T according to an embodiment of the present invention; Figure 57 These are DSC and TGA diagrams of crystal form T according to an embodiment of the present invention; Figure 58 This is the NMR spectrum of crystal form T according to an embodiment of the present invention; Figure 59 This is an XRPD diagram of crystal form U according to an embodiment of the present invention; Figure 60 These are DSC and TGA diagrams of crystal form U according to an embodiment of the present invention; Figure 61 NMR spectra of crystal form U according to an embodiment of the present invention: (a) comparison with the free state; (b) integration results; Figure 62 This is an XRPD diagram of the stability study of maleate crystal form A according to an embodiment of the present invention; Figure 63 This is an XRPD diagram of the stability study of fumarate crystal form C according to an embodiment of the present invention; Figure 64 This is an XRPD diagram of the stability study of N crystal form according to an embodiment of the present invention; Figure 65 This is an XRPD diagram of the stability study of crystal form S according to an embodiment of the present invention; Figure 66 This is a comparison diagram of the residual solid XRPD after maleate crystal form A was oscillated in a medium for 24 h according to an embodiment of the present invention; Figure 67This is a comparison diagram of the remaining solid XRPD after fumarate crystal form C was oscillated in a medium for 24 hours according to an embodiment of the present invention. Detailed Implementation

[0136] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific implementations of the present application without departing from the spirit and scope thereof.

[0137] Unless otherwise specified, all raw materials used in this invention are commercially available.

[0138] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific implementations of the present application without departing from the spirit and scope thereof.

[0139] General analysis methods: 1. Nuclear magnetic resonance analysis (NMR) 1 H NMR) Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and analyzed by nuclear magnetic resonance on a Bruker AVANCE-III (Bruker, GER).

[0140] 2. X-ray powder diffraction (XRPD)

[0141] Instrument model: Bruker D8 ADVANCE (Instrument unique number: IARC-031-PXRD-01).

[0142] Testing basis: General Chapter 0451, Part IV, Chinese Pharmacopoeia 2020 Edition.

[0143] Sample preparation: Place the sample in the center of the sample holder groove, and make the sample surface flush with the sample holder surface.

[0144] Experimental conditions: Cu Ka 40kV 40mA, divergence slit 0.6mm, cable slit 4.0°, continuous scanning, detector: LynxEye.

[0145] Step size: 0.02°.

[0146] Scanning speed: 4° / min.

[0147] 3. Thermogravimetric analysis (TGA)

[0148] The thermogravimetric analyzer was a TA Discovery 55 (TA, US). 2–5 mg of sample was placed in a pre-equilibrated open aluminum sample pan and automatically weighed within the TGA furnace. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at 60 mL / min at the sample location and 40 mL / min at the balance location.

[0149] 4. Differential Scanning Calorimetry (DSC)

[0150] The differential scanning calorimeter was a TA Discovery 2500 (TA, US). 1–2 mg samples were accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at a rate of 50 mL / min.

[0151] 5. Dynamic moisture adsorption-desorption analysis (DVS)

[0152] Dynamic moisture adsorption-desorption analysis was performed using DVS Intrinsic (SMS, UK). The test employed a gradient mode with humidity variations of 50%-95%-0%-50%. Within the 0% to 90% range, each gradient represented a 10% change in humidity. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the endpoint. After the test, XRPD analysis was performed on the samples to confirm whether the solid morphology had changed.

[0153] 6. Polarizing Microscopy (PLM) Analysis

[0154] The polarizing microscope used was a Nikon Ci-POL (Nikon, JP). A small amount of sample was placed on a glass slide, and a suitable lens was selected to observe the sample morphology.

[0155] 7. High Performance Liquid Chromatography (HPLC)

[0156] The high-performance liquid chromatograph was LC-2030C 3D Plus (Shimadzu, JP), and the test conditions are shown in Table 21.

[0157] Table 21

[0158] The HPLC conditions used for maleate content testing are shown in Table 22 below.

[0159] Table 22

[0160] 8. Ion chromatography (IC)

[0161] The ion chromatograph was an ICS 5000 (Thermo Fisher, US), and the instrument parameters are shown in Table 23.

[0162] Table 23

[0163] General test methods: 1. Raw material solubility test Weigh approximately 20 mg of the sample and add it to an EP tube. At room temperature (~25 °C), gradually add a certain amount of solvent while stirring the solution and observing whether the solid completely dissolves. If the solid remains undissolved 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 to completely dissolve the solid.

[0164] 2. Reaction crystallization method

[0165] 2.1 Equivalent Feeding

[0166] Approximately 26 mg (0.05 mmol) of the sample and 1 equivalent of the acidic compound were added to a selected solvent and suspended at room temperature for 2 days. The suspension was then centrifuged, and the solid was dried under vacuum at room temperature. If the solution was clear, it was placed in a refrigerator (-15 °C). If a solid phase precipitated, the supernatant was removed by centrifugation, and the solution was dried under vacuum at room temperature. If no solid phase precipitated after cooling, the antisolvent was added dropwise to the solution until a solid precipitated.

[0167] 2.2 Equivalent Feeding

[0168] Approximately 26 mg (0.05 mmol) of sample and 2 equivalents of acidic compound were added to a certain amount of selected solvent and suspended at room temperature for 2 days. The suspension was then centrifuged and the solid was dried under vacuum at room temperature.

[0169] 3. Solvent evaporation method

[0170] The clear solution obtained from the raw material solubility test is left to stand at room temperature in an open container until the solvent has completely evaporated to obtain a solid. Alternatively, approximately 20 mg of raw material is weighed and an appropriate amount of the selected solvent is added dropwise to a certain amount of unsuitable solvent until it is completely dissolved. The solution is then left to stand at room temperature to evaporate until the solvent has completely evaporated.

[0171] 4. Suspension method

[0172] 4.1 Room temperature suspension

[0173] Different crystal forms were used as starting materials. A certain amount of sample was added to the selected single or binary solvent until a suspension was formed. After being suspended and stirred at room temperature for a certain period of time, the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0174] 4.2, Suspension at 50℃

[0175] Different crystal forms were used as starting materials. A certain amount of sample was added to the selected solvent until a suspension was formed. After suspending and stirring at 50 °C for 1 day, the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0176] 5. Dissolution crystallization method

[0177] 5.1 Dissolution-crystallization method

[0178] Weigh approximately 20 mg of sample and add a certain amount of good solvent at room temperature to completely dissolve the sample or prepare a saturated solution of good solvent. Add the solution dropwise to 5-10 times its volume of poor solvent. After stirring for 1 h, centrifuge the system with precipitated solids and dry the solids under vacuum at room temperature. Continue stirring the clear solution for 24 h. Place the system without precipitated solids in a refrigerator at 4 or -15°C. Centrifuge the system with precipitated solids and dry the solids under vacuum at room temperature.

[0179] 5.2 Binary Solvent Direct Titration Method

[0180] Weigh approximately 20 mg of sample, add a certain amount of good solvent at room temperature to completely dissolve the sample or prepare a saturated solution of good solvent, then add a poor solvent until solid precipitates. After stirring at room temperature for 15 min, centrifuge the system with solid precipitate and dry the solid under vacuum at room temperature; continue stirring the clear solution for 24 h. If no solid precipitates, place the system at 4 or -15℃. Centrifuge the system with solid precipitate and dry the solid under vacuum at room temperature.

[0181] 6. Cooling method

[0182] 6.1 Cooling with a single solvent

[0183] Weigh approximately 20 mg of the sample and add preheated solvent at 50°C until the solid is just completely dissolved. Quickly transfer the solution to room temperature to cool. Let it stand at room temperature for at least 2 hours. If no sufficient solid precipitates, further cool the solution at 4°C. If no sufficient solid still precipitates, further cool the solution at -15°C. For systems with sufficient solid precipitate, centrifuge and then vacuum dry the solid at room temperature.

[0184] 6.2 Cooling of binary solvents

[0185] Weigh approximately 20 mg of the sample and mix it with a certain amount of poor solvent at 50°C to form a suspension. Gradually add preheated good solvent until the solid is just completely dissolved. Transfer the solution to room temperature and cool. Let it stand at room temperature for at least 2 hours. If no sufficient solid precipitates, cool the solution further at 4°C. If no sufficient solid still precipitates, cool the solution further at -15°C. For systems with sufficient solid precipitate, centrifuge and then vacuum dry the solid at room temperature.

[0186] 7. Gas-phase diffusion method

[0187] Weigh approximately 20 mg of sample and dissolve it in a good solvent or prepare a saturated solution in a good solvent. Place the clear solution in a poor solvent atmosphere and let it stand at room temperature until solid precipitates. Remove the solution from the system where solid has precipitated using a syringe, and perform XRPD testing on the wet sample.

[0188] 8. Solid-gas diffusion

[0189] Weigh approximately 20 mg of the amorphous sample and place it in a selected solvent atmosphere at room temperature or low temperature for 7 days. Observe the solid properties in the glass vial periodically and perform XRPD testing on the solid.

[0190] 9. Thermal transfer crystal

[0191] Thermal crystallization was performed using an Instec HCS424GXY hot stage (Instec Inc., USA). 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 20 °C / min. The temperature was held for 5-10 min and then allowed to cool naturally to room temperature to obtain a solid.

[0192] 10. Competitive water activity suspension experiment

[0193] Equal amounts of the selected crystal form sample were weighed and added to water / isopropanol saturated solutions with different water contents (0%, 30%, 60%, water volume percentage). The solutions were then suspended and stirred at room temperature and 60°C for a certain period of time. The suspensions were centrifuged, and the wet samples were characterized by XRPD.

[0194] 11. Stability Study

[0195] Weigh approximately 20 mg of sample into a weighing bottle and place it under high temperature (60 °C), high humidity (25 °C / 92.5% RH), light (25 °C / 4500 Lux), and accelerated conditions (40 °C / 75% RH), respectively. Samples were taken at 7 and 15 days for XRPD characterization.

[0196] 12. Solubility Test

[0197] The preparation process of the biological medium is shown in Table 24. Samples of different crystal forms were added to the biological medium and incubated at 37 °C with shaking for 24 h. Samples were taken at 0.5 h, 2 h, and 24 h. The sampled solutions were filtered through a 0.22 μm aqueous filter membrane. Some samples with higher concentrations were appropriately diluted with diluent. 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 factor. In addition, the pH value of the supernatant after 24 h was tested, and the remaining solids were subjected to XRPD analysis.

[0198] Table 24

[0199] Example 1 Preparation of the compound shown in formula (I)

[0200]

[0201] At room temperature, p-toluenesulfonyl chloride (21.9 g, 115 mmol) was added to a pyridine (150 mL) solution of 7-chloro-1,2,3,4-tetrahydrobenzo[B]azapyro-5-one (15 g, 76.7 mmol). The reaction mixture was reacted at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined. The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the residue was purified by silica gel chromatography to obtain intermediate I-1.

[0202] LC-MS (ESI) [M+H] + 349.9.

[0203] 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 8.3Hz, 2H), 7.47 (dd, J = 8.6, 2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 3.83 (t, J= 6.5 Hz, 2H), 2.43 (s, 3H), 2.40 – 2.35 (m, 2H), 2.00 – 1.91 (m, 2H).

[0204] At 25 °C, intermediate I-1 (37.00 g, 106.00 mmol) was dissolved in anhydrous tetrahydrofuran (350 mL). Under argon protection and ice-water bath cooling, sodium hydride (6.36 g, 60% wt, 159.00 mmol) was added in portions. After stirring in an ice-water bath for 1 hour, dimethyl carbonate (19.08 g, 212.00 mmol) was added, and the mixture was heated to 50 °C and stirred for 24 hours. After cooling, the reaction mixture was slowly poured into a cold saturated ammonium chloride aqueous solution (500 mL), concentrated to remove most of the tetrahydrofuran, and filtered. The filter cake was washed with water, then slurried with petroleum ether, filtered, and the filter cake was dried to obtain intermediate I-2.

[0205] LC-MS (ESI) [M+H] + 408.0.

[0206] Intermediate I-2 (19.00 g, 46.68 mmol) was dissolved in anhydrous N,N-dimethylformamide (187 mL) at 25 °C, followed by the addition of sodium carbonate (14.84 g, 140.00 mmol) and 2-(2-bromoethyl)isoindoline-1,3-dione (23.71 g, 93.36 mmol). The mixture was stirred overnight at 90 °C under argon protection. After cooling, the reaction solution was diluted with ethyl acetate (500 mL), washed with water (150 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-3.

[0207] LC-MS (ESI) [M+H] + 581.2.

[0208] Intermediate I-3 (20.00 g, 34.48 mmol) was dissolved in dimethyl sulfoxide / water (130 mL / 13 mL) at 25 °C, and sodium chloride (16.70 g, 28.60 mmol) was added. After purging the system three times with argon, the mixture was stirred at 150 °C for 10 hours under argon protection. After cooling, the reaction solution was diluted with ethyl acetate (400 mL), washed with water (150 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-4.

[0209] LC-MS (ESI) [M+H] + 523.2.

[0210] Intermediate I-4 (200 mg, 0.38 mmol) was dissolved in ethanol (7 mL) at 25 °C, and 85% hydrazine hydrate (0.35 mL) was added. The reaction mixture was stirred at 35 °C for 4 hours. Most of the ethanol was removed by vacuum concentration, and the mixture was diluted with ethyl acetate (50 mL). The solution was washed successively with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain crude intermediate I-5. The crude product was used directly in the next reaction step.

[0211] LC-MS (ESI) [M+H] + 375.2.

[0212] Intermediate I-5 (170 mg, 0.45 mmol) was dissolved in methanol (10 mL) at 25 °C, and sodium borohydride (190 mg, 5.00 mmol) was slowly added under ice-water bath cooling. After stirring the reaction solution at room temperature for 1 hour, most of the methanol was removed by concentration under reduced pressure. The solution was diluted with ethyl acetate (50 mL), washed successively with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate I-6. The crude product was used directly in the next reaction step.

[0213] LC-MS (ESI) [M+H] + 377.2.

[0214] Intermediate I-6 (150 mg, 0.40 mmol) was dissolved in anhydrous methanol (20 mL) at 25 °C, and magnesium filings (2.00 g, 83.33 mmol) were added. The mixture was purged with nitrogen three times and stirred overnight at 70 °C under a nitrogen atmosphere (balloon). After cooling, the mixture was filtered through a diatomaceous earth filter, and the filtrate was concentrated to dryness. It was dissolved in a dichloromethane / methanol mixture (10 / 1, 50 mL), washed with saturated ammonium chloride aqueous solution (20 mL × 3), washed with water (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate I-7. The crude product was used directly in the next reaction step.

[0215] LC-MS (ESI) [M+H] + 223.0.

[0216] Intermediate I-7 (7.30 g, 32.89 mmol) and triethylamine (10.10 g, 100.00 mmol) were dissolved in anhydrous dichloromethane (100 mL) at 25 °C. Under argon protection and ice-water bath cooling, fluorenyl chloroformate (12.73 g, 49.33 mmol) was slowly added, and the mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under reduced pressure at room temperature, slurried with petroleum ether, filtered, and the filter cake was washed with water (20 mL) and dried to obtain intermediate I-47.

[0217] LC-MS (ESI) [M+H] + 444.8.

[0218] At room temperature, methyl 6-aminonicotinic acid (1.0 g, 6.57 mmol) was dissolved in pyridine (20 mL), and 2-trifluoromethylbenzoyl chloride (1.51 g, 7.25 mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with water (50 mL × 5). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain intermediate I-12.

[0219] LC-MS (ESI) [M+H] + 325.0.

[0220] At room temperature, intermediate I-12 (1.35 g, 4.16 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of sodium hydroxide (499 mg, 12.5 mmol) in water (2 mL) was added. After the addition was complete, the reaction mixture was stirred at 70 °C for 1 hour. After the reaction was complete, the pH of the reaction solution was adjusted to 5-6 with 1 N hydrochloric acid. The mixture was filtered, and the solid was dried to obtain intermediate I-13.

[0221] LC-MS (ESI) [M+H] + 311.0.

[0222] At 25 °C, intermediate I-47 (4.70 g, 10.58 mmol) was dissolved in anhydrous tetrahydrofuran (35 mL), followed by the addition of pyridine (8.37 g, 106.00 mmol), intermediate I-13 (4.92 g, 15.87 mmol), and 1-propylphosphonic anhydride (50% wt ethyl acetate solution, 20.00 g, 31.74 mmol). The mixture was stirred overnight at 65 °C under argon protection. After cooling, the reaction solution was concentrated to remove most of the tetrahydrofuran and diluted with ethyl acetate (150 mL). The solution was washed successively with 1 N hydrochloric acid (100 mL × 2), saturated sodium bicarbonate aqueous solution (100 mL × 3), water (100 mL), and saturated sodium chloride aqueous solution (100 mL). The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-48A (Rt = 1.541 min).

[0223] LCMS analysis method: Column: Waters acquity UPLC CSH 2.1×50mm, 1.7µm.

[0224] Mobile phase: A: Water (0.01% trifluoroacetic acid) B: Acetonitrile (0.01% trifluoroacetic acid).

[0225] Elution gradient: 5%-95% B, 0.7 min; 95% B, 0.8 min; then 5% B, 0.5 min.

[0226] Flow rate: 1.0 mL / min.

[0227] Column temperature: 60 ℃.

[0228] Mass spectrometry scan range: 100 – 1000.

[0229] Intermediate I-48A (Rt = 1.541 min) LC-MS (ESI) [M+H] + 737.3.

[0230] Intermediate I-48A (14 mg, 0.019 mmol) was dissolved in N,N-dimethylformamide (3 mL) at 25 °C, and pyrrolidine (35.50 mg, 0.50 mmol) was added. The mixture was stirred at 25 °C for 1 hour. The solution was diluted with ethyl acetate (20 mL), washed with water (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by C18 reversed-phase chromatography (formic acid system) to obtain compound 8.

[0231] LC-MS (ESI) [M+H]+ 515.2.

[0232] 1 H NMR (400 MHz, DMSO- d 6) δ 11.18 (s, 1H), 8.13 – 7.90 (m, 2H), 7.88 –7.52 (m, 6H), 7.09 (dd, J = 8.3, 2.7 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.90(dt, J = 13.7, 3.3 Hz, 1H), 4.14 (d, J = 9.2 Hz, 1H), 3.80 – 3.35 (m, 1 H), 3.15 – 3.03 (m, 1H), 3.03 – 2.92 (m, 1H), 2.66 (t, J = 12.7 Hz, 1H), 2.09(dd, J = 12.1, 4.1 Hz, 2H), 1.86 – 1.64 (m, 2H), 1.64 – 1.51 (m, 1H).

[0233] Compound 8 was chirally resolved by SFC to obtain compound 10A (Rt = 1.424 min).

[0234] Chiral decomposition method: Instrument: MG II preparative SFC (SFC-14).

[0235] Column: ChiralPak AD, 250×30mm ID, 10µm.

[0236] Mobile phase: A: Carbon dioxide B: Ethanol (0.1% ammonia).

[0237] Elution gradient: 35% B.

[0238] Flow rate: 80 mL / min.

[0239] Back pressure: 100 bar.

[0240] Column temperature: 38 ℃.

[0241] Detection wavelength: 220 nm.

[0242] Cycle time: ~8 min.

[0243] Chiral analysis methods: Instrument: Waters UPC2 analytical SFC (SFC-H).

[0244] Column: ChiralPak AD, 150×4.6mm ID, 3µm.

[0245] Mobile phase: A: Carbon dioxide B: Ethanol (0.05% diethylamine).

[0246] Elution gradient: 40% B.

[0247] Flow rate: 2.5 mL / min.

[0248] Back pressure: 1500 psi.

[0249] Column temperature: 35 ℃.

[0250] Detection wavelength: 220 nm.

[0251] Compound 10A: Rt = 1.424 min.

[0252] LC-MS (ESI) [M+H] + 515.2.

[0253] 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.18 (s, 1H), 8.30 – 7.88 (m, 2H), 7.88 –7.55 (m, 6H), 7.10 (dd, J = 8.4, 2.7 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.90(dt, J = 13.5, 3.2 Hz, 1H), 4.14 (d, J = 9.2 Hz, 1H), 3.40 – 3.39 (m, 1 H), 3.13 – 2.90 (m, 2H), 2.66 (t, J = 12.3 Hz, 1H), 2.16 – 2.05 (m, 2H), 1.87 –1.49 (m, 3H).

[0254] Example 2. Inhibition IC50 of compound (I) on vasopressin-induced V2R activation of angiotensin receptor. 50test

[0255] (1) Cell

[0256] The HeLa cell line stably expressing human vasopressin receptor V2R (HeLa-V2R) was constructed by Shanghai Jikai Gene Chemical Technology Co., Ltd. using lentiviral infection and its stable expression of human V2R was verified by qPCR.

[0257] (2) Reagents

[0258] DMEM cell culture medium: Brand: Gibco, Catalog No.: 11995065; Fetal bovine serum: Brand: Gibco, Catalog No.: FND500; 0.25% trypsin: Brand: Gibco, Catalog No.: 25200072; Puromycin Dihydrochloride: Brand: Gibco, Catalog No.: A1113803; cAMP-GS HIRANGE KIT: Brand: Cisbio, Catalog No.: 62AM6PEC; IBMX: Brand: Sigma, Catalog No.: i5879; Vasopressin AVP: Customized by Jier Biochemical (Shanghai) Co., Ltd.

[0259] (3) Testing methods

[0260] HeLa-V2R cells were cultured in DMEM medium supplemented with 10% fetal bovine serum at 37°C and 5% CO2. Cells expressing V2R were continuously screened by adding 2 μg / mL puromycin to the medium. On the day of the experiment, cells were digested with trypsin, washed twice with stimulation buffer from the cAMP-GS HIRANGE kit, resuspended, counted, and prepared into 1.6 x 10⁻⁶ cells. 6Cells / ml, add IBMX to a final concentration of 0.5 mM. Transfer 5 μL of cell suspension / well to a 384-well plate, and add 2.5 μL of different concentrations of the test compound (3-fold dilution starting from 10 μM, 10 concentration gradients) or DMSO (Min, Max control) to the corresponding wells. After incubating at room temperature for 30 minutes, add 2.5 μL of vasopressin AVP solution to the test compound wells and the maximum value well to a final concentration of 2.25 nM, and add 2.5 μL of stimulation buffer to the minimum value well. Incubate at 25°C for 60 minutes. Simultaneously prepare cAMP standard samples (3-fold dilution starting from 5.6 μM, 10 concentration points), and transfer 10 μL of cAMP standard to the corresponding wells of the 384-well plate. Dilute the cAMP-d2 fluorescent and anti-cAMP antibody probes provided in the cAMP-GS HIRANGE kit 20-fold with the lysis buffer provided in the kit, and add 5 μL of each to each well of a 384-well plate. After mixing, centrifuge briefly and incubate at 25°C for 2 hours before detection. Sample detection was performed using the HTRF method on an Envision microplate reader, measuring fluorescence intensity at 615 nm and 665 nm. Each sample was prepared in duplicate, with 32 replicates for both the minimum and maximum values.

[0261] (4) Data processing

[0262] Calculate the fluorescence intensity ratio FI of each well sample at 665 nm and 615 nm wavelengths. 665 / 615 With X as the logarithm of the standard concentration, FI 665 / 615 X1000 represents the Y value. A standard curve was obtained by fitting the curve using the "log(inhibitor) vs response – variable slope (four parameters)" model in Prism 8.0 software. The test well FI... 665 / 615 X1000 is the Y value. The cAMP concentration of each sample is calculated in Prism 8.0 software based on the standard curve mentioned above.

[0263] The formula for calculating %Inhibition (inhibition percentage) is as follows:

[0264] in The average calculated value of cAMP concentration in all maximum wells; Ccmpd is the average calculated cAMP concentration in all minimum wells; Ccmpd is the calculated cAMP concentration of the analyte.

[0265] Using %Inhibition (inhibition percentage) as Y and the logarithm of compound concentration as X, a nonlinear regression was performed in Prism 8.0 software using the "log(inhibitor) vs response – variable slope (four parameters)" model to calculate IC. 50 Where Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC) 50 -X) Hill Slope).

[0266] The experimental results are shown in Table 25: Table 25: Evaluation of the inhibitory effect of compounds on the increase of cAMP in human cervical cancer cells (Human V2R Hela-Stable cell line OE2).

[0267] Example 3 Salt type screening

[0268] Fifteen acidic compounds were selected for salt type screening using the reaction crystallization method. The results are shown in Tables 26 and 27 below.

[0269] Table 26 Solution suspension method (1 equivalent) Salt type screening experiment

[0270] Note:" "This indicates that the substance clarifies after suspension and precipitates solids when placed at -15°C." "This indicates that the substance clarifies after suspension and cooling to -15°C, and solid precipitates out upon the addition of n-heptane."

[0271] Table 27 Solution suspension method (2 equivalents) Salt type screening experiment

[0272] As shown in the table above, the compound represented by formula (I) can be converted into six salts, namely hydrochloride, sulfate, maleate, fumarate, succinate and glycolate.

[0273] Example 4 Preparation of maleate crystal form A

[0274] Method 1: Weigh 513.6 mg of the compound shown in formula (I) and 1 equivalent of maleic acid, add 16 mL of isopropanol, stir at room temperature for 2 days, centrifuge the suspension, and vacuum dry the solid at 40 °C for 3 days. 611.5 mg of maleate crystal form A was obtained.

[0275] Method 2: At room temperature, add methanol (30 mL, 10.0 v / w) to jacketed reactor R1; purge with nitrogen three times; at room temperature, add free amine (3.0 g, 1 w, 5.82 mmol, 1.0 eq.) to jacketed reactor R1 and start stirring; stir until dissolved; in jacketed reactor R2, prepare an isopropanol solution of maleic acid: at 25-30℃, dissolve maleic acid (0.71 g, 0.236 w, 6.11 mmol, 1.05 eq) in isopropanol (60 mL, 20.0 v / w); add the prepared maleic acid / isopropanol solution dropwise to reactor R1, controlling the internal temperature at 20-30℃, and the dropwise addition time is 20 minutes; after the dropwise addition is complete, react at 20-30℃ for 2-5 hours; filter, wash the filter cake once with isopropanol (9 mL, 3.0 v / w), and dry to obtain maleate crystal form A.

[0276] Method 3: Add 10L of methanol to a 100L reactor, add 4.2kg of free alkali, add 6.8L of methanol, heat to 60℃, dissolve 993g of maleic acid in 33.6L of isopropanol, slowly add the above solution dropwise, cool to 25℃, filter to obtain 4.7kg of maleate crystal form A.

[0277] The maleate crystal form A was characterized, and the characterization results are shown in Figures 1 to 12. Figure 5 As shown. XRPD ( Figure 1 The results showed that maleate crystal form A was a well-crystallized solid. TGA ( Figure 2 The results showed that maleate crystal form A experienced a 0.5% weight loss during heating to 150 °C, and decomposition may occur above 200 °C. (DSC) Figure 2 The results showed that maleate crystal form A had an endothermic peak at 229°C. NMR ( Figure 3 The results showed that, compared with the free state, the peaks at 1.50–1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm shifted, suggesting that the sample had formed a salt. A maleic acid signal peak was visible at 6.03 ppm; based on the integration results, the ratio of the raw material to maleic acid was calculated to be 1:1. A solvent peak for isopropanol was visible at 1.04 ppm, suggesting that a small amount of isopropanol solvent remained in the sample. DVS ( Figure 4 The results showed that maleate crystal form A increased in weight by 0.09% at 80% RH, increased in weight by 0.23% at 95% RH, and lost weight by 0.24% at 0% RH, indicating that maleate crystal form A has almost no hygroscopicity; XRPD ( Figure 5 The results showed that the sample did not undergo a change in crystal form after the DVS test. This indicates that maleate crystal form A is a highly crystalline, amorphous form with almost no hygroscopicity.

[0278] Example 5 Preparation of maleate crystal form B

[0279] 21.7 mg of maleate crystal form A was dissolved in 0.5 mL of DMF, 1.5 mL of isopropanol was added, the mixture was heated to 60 °C, slowly cooled to 15 °C, and filtered to obtain maleate crystal form B.

[0280] XRPD ( Figure 6 The results showed that crystal form B was a well-crystallized solid. TGA ( Figure 7 The results showed that crystal form B experienced a 9.7% weight loss during heating from room temperature to 170°C, and decomposition may occur above 220°C. (DSC) Figure 7 The results showed that crystal form B exhibited an endothermic signal corresponding to solvent removal at around 145℃ and an endothermic peak at around 234℃. NMR ( Figure 8 The results were largely consistent with those of the raw materials. Solvent peaks for DMF were observed at 2.73, 2.89, and 7.95 ppm. Based on the integration results, the ratio of the compound to DMF was 1:0.9, and the DMF content was largely consistent with the TGA weight loss. Thermal crystallization experiments showed that crystal form B transformed into crystal form A after solvent removal at 170℃. In conclusion, crystal form B is a DMF solvate.

[0281] Example 6 Preparation of fumarate crystal form C

[0282] 25.6 mg of the compound shown in formula (I) was added to 0.8 mL of isopropanol, 1 equivalent of fumaric acid was added, stirred at room temperature for 2 days, and centrifuged to obtain fumarate crystal form C.

[0283] XRPD ( Figure 9 The results showed that fumarate crystal form C is a well-crystallized solid. TGA ( Figure 10 The results showed that the sample experienced a 0.7% weight loss during heating to 150℃, and decomposition may occur after 190℃. (DSC) Figure 10 The results showed an endothermic signal at around 217℃. NMR ( Figure 11 The results showed that, compared with the free state, the peaks at 1.50–1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm shifted, indicating that the sample had formed a salt. A fumaric acid signal peak was visible at 6.57 ppm, and based on the integration results, the ratio of API to fumaric acid was calculated to be 1:1. An isopropanol solvent peak was visible at 1.04 ppm, indicating that a small amount of isopropanol solvent remained in the sample. In conclusion, fumarate crystal form C is the amorphous form.

[0284] Example 7 Preparation of hydrochloride crystal form D

[0285] 25.3 mg of the compound shown in formula (I) was added to 0.8 mL of isopropanol and 1 equivalent of concentrated hydrochloric acid. The mixture was stirred at room temperature for 2 days and centrifuged to obtain hydrochloride crystal form D.

[0286] XRPD ( Figure 12 The results showed that hydrochloride crystal form D is a well-crystallized solid. TGA ( Figure 13 The results showed that the sample experienced a 1.6% weight loss (corresponding to a loss of 0.5 water molecules) during heating to 150 °C; decomposition may occur after 230 °C. (DSC) Figure 13 The results showed endothermic signals at approximately 71℃ and 262℃. NMR ( Figure 14 The results showed that compared with the free state, several peaks at 1.50–1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm shifted, suggesting that the sample had formed a salt. A solvent peak for isopropanol was visible at 1.04 ppm, indicating a small amount of isopropanol solvent residue in the sample. Thermal crystallization experiments showed that hydrochloride crystal form D transformed into hydrochloride crystal form F after heating to 150 °C. Ion chromatography results showed that the salt formation ratio of hydrochloride crystal form D was 1:1. In conclusion, hydrochloride crystal form D is a hydrate.

[0287] Example 8 Preparation of hydrochloride crystal form E

[0288] 25.3 mg of the compound shown in formula (I) was added to 1.0 mL of cyclohexane, 1 equivalent of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 2 days. After centrifugation, hydrochloride crystal form E was obtained.

[0289] XRPD ( Figure 15 The results showed that hydrochloride crystal form E is a poorly crystallized solid. TGA ( Figure 16 The results showed that the sample continued to lose weight during heating. (DSC) Figure 16 The results showed endothermic signals at approximately 89℃ and 201℃. NMR ( Figure 17 The results showed that, compared with the free state, the peaks at 1.50–1.90 ppm, 2.98 ppm, 3.07 ppm, 6.90 ppm, and 7.08 ppm shifted, suggesting that the sample had formed a salt. A solvent peak for cyclohexane was visible at 1.39 ppm, indicating that a small amount of cyclohexane solvent remained in the sample. In conclusion, the hydrochloride crystal form E is likely an anhydrous form or hydrate with adsorbed water.

[0290] Example 9 Preparation of hydrochloride crystal form F

[0291] 25.4 mg of crystalline form N was added to 0.8 ml of isopropanol and 1 equivalent of hydrochloric acid. The mixture was stirred at room temperature for 2 days. The suspension was then centrifuged and the solid was dried under vacuum at room temperature to obtain crystalline form F of hydrochloride.

[0292] XRPD ( Figure 18 The results showed that hydrochloride crystal form F is a well-crystallized solid. TGA ( Figure 19 The results showed that the sample experienced a 0.5% weight loss during heating to 150 °C and may decompose after 230 °C. (DSC) Figure 19 The results showed endothermic signals around 316 ℃ and 320 ℃. NMR ( Figure 20 The results showed that, compared with the free state, the peaks at 1.50–1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm shifted, suggesting that the sample had formed a salt. A solvent peak of isopropanol was visible at 1.04 ppm, indicating that a small amount of isopropanol solvent remained in the sample. Ion chromatography results showed that the salt formation ratio of hydrochloride crystal form F was 1:1. In conclusion, hydrochloride crystal form F is an amorphous form.

[0293] Example 10 Preparation of sulfate crystal form G

[0294] 26.1 mg of the compound shown in formula (I) was added to 1.0 mL of cyclohexane, 1 equivalent of concentrated sulfuric acid was added, and the mixture was stirred at room temperature for 2 days. After centrifugation, the sulfate crystal form G was obtained.

[0295] XRPD ( Figure 21 The results showed that sulfate crystal form G was a well-crystallized solid. TGA ( Figure 22 The results showed that the sample experienced a 3.7% weight loss during heating to 150℃, and decomposition may occur after 240℃. (DSC) Figure 22 The results showed endothermic signals at approximately 282℃ and 298℃. NMR ( Figure 23 The results showed that, compared with the free state, the peaks at 1.50–1.90 ppm, 2.98 ppm, 3.07 ppm, 6.90 ppm, and 7.08 ppm shifted, suggesting that the sample had formed a salt. A solvent peak for cyclohexane was visible at 1.39 ppm, indicating that a very small amount of cyclohexane solvent remained in the sample. In conclusion, sulfate crystal form G is likely an anhydrous form or hydrate with adsorbed water.

[0296] Example 11 Preparation of succinate crystal form H

[0297] 24.1 mg of the compound shown in formula (I) was added to 0.8 ml of isopropanol, 1 equivalent of succinic acid was added, and the mixture was stirred at room temperature for 2 days. After centrifugation, succinate crystal form H was obtained.

[0298] XRPD ( Figure 24 The results showed that succinate crystal form H is a well-crystallized solid. TGA ( Figure 25 The results showed that the sample experienced a 0.2% weight loss during heating to 120℃, and decomposition may occur after 170℃. (DSC) Figure 25 The results showed an endothermic signal at around 186℃. NMR ( Figure 26 The results showed that, compared with the free state, the peaks at 1.50–1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm shifted, suggesting that the sample had formed a salt. A succinic acid signal peak was visible at 2.39 ppm, and based on the integration results, the ratio of API to succinic acid was calculated to be 1:1. An isopropanol solvent peak was visible at 1.04 ppm, suggesting that a small amount of isopropanol solvent remained in the sample. In conclusion, succinate crystal form H is the amorphous form.

[0299] Example 12 Preparation of Succinate Crystal Form J

[0300] 24.7 mg of the compound shown in formula (I) was added to 1.0 mL of methyl tert-butyl ether, 1 equivalent of succinic acid was added, the mixture was stirred at room temperature for 2 days, and centrifuged to obtain succinate crystal form J.

[0301] XRPD ( Figure 27 The results showed that succinate crystal form J is a well-crystallized solid. TGA ( Figure 28 The results showed that the sample experienced a 0.6% weight loss during heating to 150℃, and decomposition may occur after 170℃. DSC results showed an endothermic signal around 177℃. NMR ( Figure 29 The results showed that, compared with the free state, the peaks at 1.50–1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm shifted, suggesting that the sample had formed a salt. A succinic acid signal peak was visible at 2.39 ppm, and based on the integration results, the ratio of API to succinic acid was calculated to be 1:1. A solvent peak for methyl tert-butyl ether was visible at 1.10 ppm, suggesting that a small amount of methyl tert-butyl ether solvent remained in the sample. In conclusion, succinate crystal form J is an amorphous form.

[0302] Example 13 Preparation of glycolate crystal form K

[0303] 25.9 mg of the compound shown in formula (I) was added to 1.0 mL of methyl tert-butyl ether, 1 equivalent of glycolic acid was added, the mixture was stirred at room temperature for 2 days, and centrifuged to obtain glycolate crystal form K.

[0304] XRPD ( Figure 30 The results showed that glycolate crystal form K was a well-crystallized solid. TGA ( Figure 31 The results showed that the sample lost 0.7% weight during heating to 70℃, and continued to lose weight during subsequent heating, possibly decomposing after 150℃. DSC results showed an endothermic signal around 98℃. NMR ( Figure 32 The results showed that, compared with the free state, the peaks at 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm shifted, suggesting that the sample had formed a salt. A glycolic acid signal peak was visible at 3.87 ppm, and a solvent peak for methyl tert-butyl ether was visible at 1.10 ppm, suggesting that a very small amount of methyl tert-butyl ether solvent remained in the sample. In conclusion, the glycolate crystal form K is likely an anhydrous / hydrated form.

[0305] Example 14 Preparation of Benzoic Acid Eutectic Form L

[0306] 24.7 mg of the compound shown in formula (I) was added to 0.8 mL of isopropanol, 1 equivalent of benzoic acid was added, stirred at room temperature for 2 days, and centrifuged to obtain benzoic acid eutectic crystal form L.

[0307] XRPD ( Figure 33 The results showed that the eutectic form L of benzoic acid was a well-crystallized solid. TGA ( Figure 34 The results showed that the sample experienced a 1.6% weight loss during heating to 100 °C and may decompose after 135 °C. (DSC) Figure 34 The results showed endothermic signals at approximately 165℃ and 177℃. NMR ( Figure 35 The results showed no peak shift compared to the free state, suggesting that the sample did not form a salt and may have formed a eutectic. A benzoic acid signal peak was visible in the 7.0–8.5 ppm range, and based on the integration results, the ratio of API to benzoic acid was calculated to be 1:1. An isopropanol solvent peak was visible at 1.04 ppm, indicating a small amount of isopropanol solvent residue in the sample. In conclusion, the benzoic acid eutectic form L is an amorphous form.

[0308] Example 15 Preparation of benzoic acid eutectic form M

[0309] 25.2 mg of the compound shown in formula (I) was added to 1.0 mL of cyclohexane, 1 equivalent of benzoic acid was added, stirred at room temperature for 2 days, and centrifuged to obtain benzoic acid eutectic crystal form M.

[0310] XRPD ( Figure 36 The results showed that the eutectic form M of benzoic acid was a poorly crystallized solid. (TGA) Figure 37The results showed that the sample experienced a 1.0% weight loss during heating to 100℃ and may decompose after 135℃. (DSC) Figure 37 The results showed an endothermic signal at around 175℃. NMR ( Figure 38 The results showed no peak shift compared to the free state, suggesting that the sample did not form a salt and may have formed a eutectic. A benzoic acid signal peak was visible in the 7.0–8.5 ppm range, and based on the integration results, the ratio of raw material to benzoic acid was calculated to be 1:1. A cyclohexane solvent peak was visible at 1.39 ppm, indicating a small amount of cyclohexane solvent residue in the sample. In conclusion, the benzoic acid eutectic crystal form M is the amorphous form.

[0311] Example 16 Preparation of Crystal Form N

[0312] 20.4 mg of the compound shown in formula (I) was added to 0.5 mL of toluene, suspended and stirred at 50 °C for one day, and centrifuged to obtain crystal form N.

[0313] XRPD ( Figure 39 The results showed that crystal form N was a well-crystallized solid. TGA ( Figure 40 The results showed that crystalline nitrogen (N) experienced a 0.6% weight loss upon heating to 150°C, and decomposition may occur above 300°C. (DSC) Figure 40 The results showed that crystalline N exhibits a melting endothermic peak at around 208℃. NMR ( Figure 41 The results showed a visible toluene solvent peak at 2.30 ppm, indicating that the sample contained a small amount of residual toluene solvent. In conclusion, crystal form N is an amorphous form.

[0314] Example 17 Preparation of Crystal Form O

[0315] 19.5 mg of the compound shown in formula (I) was dissolved in 0.6 mL of ethanol, and 9.0 mL of n-heptane was slowly added. The mixture was suspended and stirred for 15 minutes, and then centrifuged to obtain crystal form O.

[0316] XRPD ( Figure 42 The results showed that crystal form O was a well-crystallized solid. TGA ( Figure 43 The results showed that crystalline O experienced a 2.6% weight loss during heating to 200 °C, and decomposition may occur above 300 °C. (DSC) Figure 43 The results showed that crystalline O exhibited an exothermic peak around 196 °C, an endothermic signal around 190 °C, and a melting endothermic peak around 208 °C. The thermal crystallization experiment indicated that crystalline O recrystallized into crystalline N after solvent removal. NMR ( Figure 44The results showed that the sample exhibited a solvent peak of ethanol at 1.06 ppm. Based on the integration results, the ratio of the compound to ethanol was calculated to be 1:0.25, which is consistent with the weight loss observed by TGA (theoretical weight loss of 2.2%). In conclusion, crystal form O is either an ethanol / n-propanol solvate, or an anhydrous form of ethanol / n-propanol encapsulated within the crystal.

[0317] Example 18 Preparation of crystal form P

[0318] 20.9 mg of the compound shown in formula (I) was dissolved in 1.4 mL of acetonitrile and 1.0 mL of water. The solution was allowed to stand at room temperature to evaporate until the solvent was completely evaporated. The solution was then centrifuged to obtain crystal form P.

[0319] XRPD ( Figure 45 The results showed that crystal form P is a solid with good crystallinity and a distinct preferred orientation. (TGA) Figure 46 The results showed that crystalline form P experienced a 3.3% weight loss during heating to 175 °C, and decomposition may occur above 300 °C. (DSC) Figure 46 The results showed that crystalline P exhibited an exothermic peak around 158 °C, an endothermic signal around 145 °C, and a melting endothermic peak around 211 °C. The thermal crystallization experiment indicated that crystalline P recrystallized into crystalline N after solvent removal. NMR ( Figure 47 The results showed that the sample had no obvious organic solvent peaks. In conclusion, crystal form P is a hydrate.

[0320] Example 19 Preparation of crystal form Q

[0321] 19.9 mg of the compound shown in formula (I) was dissolved in 4.5 mL of diethyl ether and left to stand at room temperature with the container open until the solvent was completely evaporated to obtain crystal form Q.

[0322] XRPD ( Figure 48 The results showed that crystal form Q was a well-crystallized solid. TGA ( Figure 49 The results showed that crystal form Q experienced a 4.6% weight loss during heating to 180 °C, and decomposition may occur above 300 °C. (DSC) Figure 49 The results showed that crystal form Q exhibited an exothermic peak at around 181 °C; endothermic signals at around 171 °C and 198 °C; and a melting endothermic peak at around 207 °C. The thermal crystallization experiment indicated that crystal form Q recrystallized into crystal form N after solvent removal.

[0323] Example 20 Preparation of crystal form R

[0324] 19.9 mg of the compound shown in formula (I) was dissolved completely by adding 0.8 mL of acetonitrile at room temperature, followed by adding 3.0 mL of water until a solid precipitated. After suspending at room temperature for 15 min, the system was centrifuged and dried under vacuum at room temperature to obtain crystal form R.

[0325] XRPD ( Figure 50 The results showed that crystal form R was a well-crystallized solid. TGA ( Figure 51 The results showed that crystal form R experienced a 3.7% weight loss during heating to 150 °C, and decomposition may occur above 300 °C. (DSC) Figure 51 The results showed that crystalline form R exhibited an exothermic peak around 161 °C, an endothermic signal around 154 °C, and a melting endothermic peak around 211 °C. The thermal crystallization experiment indicated that crystalline form R recrystallized into crystalline form N after solvent removal. NMR ( Figure 52 The results showed no obvious organic solvent peaks. In conclusion, crystal form R is a hydrate.

[0326] Example 21 Preparation of crystal form S

[0327] Take 400.0 mg of the compound shown in formula (I) in a glass vial, add 10.5 mL of a mixed solvent of isopropanol / water (1 / 6, v / v), and suspend at 50 °C for 1 day. Centrifuge the resulting solid and dry it under vacuum at 40 °C for 1 day to obtain crystal form S.

[0328] XRPD ( Figure 53 The results showed that crystal form S was a well-crystallized solid. (TGA) Figure 54 The results showed that crystal form S experienced a 3.6% weight loss during heating to 150 °C, and decomposition may occur above 300 °C. (DSC) Figure 54 The results showed that crystalline form S exhibited an exothermic peak around 155 °C, an endothermic signal around 126 °C, and a melting endothermic peak around 210 °C. Thermal crystallization experiments indicated that crystalline form S recrystallized into crystalline form N after solvent removal. In conclusion, crystalline form S is a hydrate. NMR data can be found in [reference needed]. Figure 55 .

[0329] Example 22 Preparation of crystal form T

[0330] 20.4 mg of the compound shown in formula (I) was dissolved in 0.1 mL of dichloromethane and evaporated to dryness at room temperature to give crystal form T.

[0331] XRPD ( Figure 56 The results showed that crystal form T was a solid with good crystallinity. TGA ( Figure 57The results showed that crystal form T experienced a 6.7% weight loss during heating to 200 °C, and decomposition may occur above 300 °C. (DSC) Figure 57 The results showed that crystal form T exhibited an exothermic peak around 191 °C, an endothermic signal around 186 °C, and a melting endothermic peak around 209 °C. NMR ( Figure 58 The results showed that the compound structure remained unchanged, with solvent peaks of dichloromethane and a small amount of dioxane visible at 5.76 ppm and 3.57 ppm. Based on the integration results, the ratio of the compound to dichloromethane was calculated to be 1:0.25. In conclusion, crystal form T is a solvate of dichloromethane or an anhydrous form of dichloromethane encapsulated within crystals.

[0332] Example 23 Preparation of crystal form U

[0333] 23.5 mg of the compound shown in formula (I) was added to 1.0 mL of cyclohexane and 1 equivalent of propionic acid. The mixture was stirred at room temperature for 2 days. The suspension was then centrifuged and the solid was dried under vacuum at room temperature to obtain crystal form U.

[0334] XRPD ( Figure 59 The results showed that it was a well-crystallized solid. TGA ( Figure 60 The results showed that the sample experienced an 18.0% weight loss during heating to 130 °C, corresponding to a weight loss of approximately 2 propionic acid molecules. (DSC) Figure 60 The results showed endothermic signals at approximately 109℃, 121℃, and 204℃. NMR ( Figure 61 The results showed no peak shift compared to the free state, indicating that the sample had not formed a salt. Propionic acid signal peaks were visible at 0.99 ppm and 2.20 ppm, and the API to propionic acid ratio was calculated to be 1:2 based on the integration results. A cyclohexane solvent peak was visible at 1.39 ppm, suggesting a small amount of cyclohexane solvent residue in the sample. In conclusion, crystal form U is a propionic acid solvate.

[0335] Example 24 Stability Study

[0336] Stability studies were conducted on maleate crystal form A, fumarate crystal form C, crystal form N, and crystal form S under high temperature (60 °C), high humidity (25 °C / 92.5% RH), light exposure (25 °C / 4500 Lux), and accelerated conditions (40 °C / 75% RH). Samples were taken at 7 and 15 days for XRPD characterization. The results are shown in Table 28. Figures 62-65 As shown in the figure. XRPD results show that maleate crystal form A and fumarate crystal form C are stable for 15 days under high temperature, high humidity, light, and accelerated conditions, and no crystal form transformation occurs.

[0337] Table 28

[0338] Example 25 Solubility Test of Biological Media

[0339] Dynamic solubility was determined in three biological media (FaSSIF, FeSSIF, and FaSSGF), and the results are shown in Table 29 below. Figure 66 , 67 As shown.

[0340] Table 29

[0341] The sample was first dissolved in FaSSGF and then shaken for 24 h. The precipitated solid was amorphous.

[0342] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0343] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A maleate salt of the compound shown in formula (I), having the structure shown in formula (II), 、 。 2. The maleate crystal form A of the compound shown in formula (II), wherein, The X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ angles: 9.14±0.2°, 12.88±0.2°, 18.31±0.2°, 18.90±0.2°, 20.60±0.2°, and 27.61±0.2°. 。 3. The maleate crystal form B of the compound shown in formula (II), wherein, The X-ray powder diffraction pattern of crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.97±0.2°, 15.73±0.2°, 18.31±0.2°, 20.15±0.2°, 21.12±0.2°, and 24.70±0.2°. 。 4. A fumarate salt of the compound shown in formula (I), having the structure shown in formula (III), 。 5. The fumarate crystal form C of the compound shown in formula (III), wherein, The X-ray powder diffraction pattern of crystal form C has characteristic diffraction peaks at the following 2θ angles: 12.77±0.2°, 14.44±0.2°, 20.00±0.2°, 20.64±0.2°, 21.33±0.2°, 21.87±0.2°; 。 6. A hydrochloride salt of the compound shown in formula (I), having the structure shown in formula (IV), 。 7. The hydrochloride crystal form D of the compound shown in formula (IV), wherein, The X-ray powder diffraction pattern of the crystal form D has characteristic diffraction peaks at the following 2θ angles: 8.13±0.2°, 9.27±0.2°, 9.91±0.2°, 13.53±0.2°, 16.37±0.2°, and 17.09±0.2°. 。 8. The hydrochloride crystal form E of the compound shown in formula (IV), wherein, The X-ray powder diffraction pattern of crystal form E has characteristic diffraction peaks at the following 2θ angles: 3.86±0.2°, 13.60±0.2°, 14.19±0.2°, 18.06±0.2°, 20.50±0.2°, 21.24±0.2°; 。 9. The hydrochloride crystal form F of the compound shown in formula (IV), wherein, The X-ray powder diffraction pattern of the crystal form F has characteristic diffraction peaks at the following 2θ angles: 5.84±0.2°, 11.77±0.2°, 13.29±0.2°, 17.82±0.2°, 20.49±0.2°, and 20.94±0.2°. 。 10. A sulfate of the compound shown in formula (I), having the structure shown in formula (V), 。 11. The sulfate crystal form G of the compound shown in formula (V), wherein, The X-ray powder diffraction pattern of the crystal form G has characteristic diffraction peaks at the following 2θ angles: 10.30±0.2°, 13.02±0.2°, 16.60±0.2°, 18.53±0.2°, 20.67±0.2°, 22.26±0.2°; 。 12. A succinate of the compound shown in formula (I), having the structure shown in formula (VI), 。 13. The succinate crystal form H of the compound shown in formula (VI), wherein, The X-ray powder diffraction pattern of the crystal form H has characteristic diffraction peaks at the following 2θ angles: 10.30±0.2°, 14.63±0.2°, 18.59±0.2°, 20.13±0.2°, 21.83±0.2°, and 22.30±0.2°. 。 14. The succinate crystal form J of the compound shown in formula (VI), wherein, The X-ray powder diffraction pattern of crystal form J has characteristic diffraction peaks at the following 2θ angles: 9.61±0.2°, 11.56±0.2°, 12.93±0.2°, 17.12±0.2°, 17.71±0.2°, and 19.95±0.2°. 。 15. An glycolate of the compound shown in formula (I), having the structure shown in formula (VII), 。 16. The glycolate crystal form K of the compound shown in formula (VII), wherein, The X-ray powder diffraction pattern of the crystal form K has characteristic diffraction peaks at the following 2θ angles: 12.51±0.2°, 15.99±0.2°, 18.71±0.2°, 20.18±0.2°, 20.59±0.2°, 21.64±0.2°; 。 17. A benzoate of the compound shown in formula (I), having the structure shown in formula (VIII), 。 18. The benzoic acid eutectic form M of the compound shown in formula (VIII), wherein, The X-ray powder diffraction pattern of the crystal form M has characteristic diffraction peaks at the following 2θ angles: 9.31±0.2°, 13.77±0.2°, 14.54±0.2°, 19.84±0.2°, 20.34±0.2°, and 21.70±0.2°. 。 19. The crystal form N of the compound shown in formula (I), wherein, The X-ray powder diffraction pattern of the N crystal form has characteristic diffraction peaks at the following 2θ angles: 10.38±0.2°, 13.54±0.2°, 14.41±0.2°, 16.32±0.2°, 18.10±0.2°, and 19.05±0.2°. 。 20. The crystal form O of the compound shown in formula (I), wherein, The X-ray powder diffraction pattern of the crystal form O has characteristic diffraction peaks at the following 2θ angles: 4.75±0.2°, 9.65±0.2°, 15.70±0.2°, 16.88±0.2°, 18.00±0.2°, and 18.97±0.2°. 。 21. The crystal form P of the compound shown in formula (I), wherein, The X-ray powder diffraction pattern of the crystal form P has characteristic diffraction peaks at the following 2θ angles: 13.07±0.2°, 17.98±0.2°, 21.64±0.2°, 23.78±0.2°, 26.36±0.2°, and 33.13±0.2°. 。 22. The crystal form Q of the compound shown in formula (I), wherein, The X-ray powder diffraction pattern of the crystal form Q has characteristic diffraction peaks at the following 2θ angles: 3.48±0.2°, 10.60±0.2°, 12.32±0.2°, 15.41±0.2°, 16.60±0.2°, and 17.09±0.2°. 。 23. The crystal form R of the compound shown in formula (I), wherein, The X-ray powder diffraction pattern of the crystal form R has characteristic diffraction peaks at the following 2θ angles: 6.70±0.2°, 13.30±0.2°, 18.15±0.2°, 21.39±0.2°, 22.97±0.2°, and 26.71±0.2°. 。 24. The crystal form S of the compound shown in formula (I), wherein, The X-ray powder diffraction pattern of the crystal form S has characteristic diffraction peaks at the following 2θ angles: 14.97±0.2°, 15.34±0.2°, 17.97±0.2°, 22.81±0.2°, 23.54±0.2°, 24.69±0.2°; 。 25. The crystal form T of the compound shown in formula (I), wherein, The X-ray powder diffraction pattern of the crystal form T has characteristic diffraction peaks at the following 2θ angles: 15.84±0.2°, 17.03±0.2°, 17.60±0.2°, 20.01±0.2°, 22.22±0.2°, 22.82±0.2°; 。 26. The crystal form U of the compound shown in formula (I), wherein, The X-ray powder diffraction pattern of the crystal form U has characteristic diffraction peaks at the following 2θ angles: 8.01±0.2°, 9.27±0.2°, 12.68±0.2°, 16.15±0.2°, 17.94±0.2°, and 19.31±0.2°. 。

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