Salt forms and crystals of benzazepine fused ring compounds and uses thereof

Abstract

Disclosed are salt forms, crystals, and uses of benzazepine fused ring compounds, specifically the maleate salt of the compound of formula (I) having the structure of formula (II). JPEG2025531781000054.jpg53163

Description

[Technical Field]

[0001] The present invention relates to the field of medicinal chemistry, and more particularly, the present invention relates to salt forms, crystals of benzazepine fused ring compounds and uses thereof. [Background technology]

[0002] This invention claims priority to: The application number is CN202211080826.4 and the filing date is September 5, 2022.

[0003] Hormones play an important role in regulating homeostasis in the human body, and arginine vasopressin (AVP) is closely involved in regulating water and sodium metabolism. Disorders in arginine vasopressin (AVP) metabolism can lead to various diseases, including hyponatremia, syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, liver cirrhosis, kidney disease, hypertension, and edema. Arginine vasopressin (AVP) receptor antagonists can inhibit AVP-receptor interaction, thereby treating these diseases. Arginine vasopressin V2 receptor antagonists, such as tolvaptan, are ideal for treating these diseases because they increase free water excretion without affecting electrolyte metabolism. However, commercially available AVP V2 receptor antagonists, such as tolvaptan, are metabolized by hepatic enzymes and produce large amounts of metabolites in the body, which can cause serious drug-induced hepatotoxicity. Therefore, the FDA has placed a black box warning on the product label and restricted their use.

[0004] The patent application, having application number PCT / CN2022 / 079350 and filing date March 4, 2022, provides a new AVP V2 receptor antagonist having the following structure:

[0005] [ka] Summary of the Invention

[0006] In one aspect, the present invention provides a maleate salt of the compound of formula (I), whose structure is represented by formula (II). [ka]

[0007] In another aspect, the present invention provides type A crystals of the maleate salt of the compound represented by formula (I) (i.e., the compound represented by formula (II)), wherein the powder X-ray diffraction spectrum of type A crystals 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°.

[0008] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the A-type crystal 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 powder X-ray diffraction spectrum of the A-type crystal 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 powder X-ray diffraction spectrum of the A-type crystal 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 powder X-ray diffraction spectrum of the Form A crystal has essentially the powder X-ray diffraction spectrum shown in FIG.

[0012] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the A-type crystal is as shown in Table 1 below.

[0013] Table 1 [Table 1]

[0014] In another aspect, the present invention further provides type B crystals of the maleate salt of the compound represented by formula (I) (i.e., the compound represented by formula (II)), wherein the powder X-ray diffraction spectrum of the type B crystals 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°.

[0015] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the B-type crystals 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 powder X-ray diffraction spectrum of the B-type crystals has essentially the powder X-ray diffraction spectrum shown in FIG.

[0017] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the B-type crystals are as shown in Table 2 below.

[0018] Table 2 [Table 2]

[0019] In another aspect, the present invention further discloses a fumarate salt of the compound of formula (I), whose structure is as shown in formula (III). [ka]

[0020] In another aspect, the present invention further discloses a C-type crystal of the fumarate salt of the compound represented by formula (I) (i.e., the compound represented by formula (III)), wherein the powder X-ray diffraction spectrum of the C-type crystal 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°, and 21.87±0.2°.

[0021] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the C-type crystal 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 powder X-ray diffraction spectrum of the C-type crystals has essentially the powder X-ray diffraction spectrum shown in FIG.

[0023] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the C-type crystals are as shown in Table 3 below.

[0024] Table 3 [Table 3]

[0025] In another aspect, the present invention provides the hydrochloride salt of the compound of formula (I), whose structure is represented by formula (IV). [ka]

[0026] In another aspect, the present invention provides a D-type crystal of the hydrochloride salt of the compound represented by formula (I) (i.e., the compound represented by formula (IV)), wherein the powder X-ray diffraction spectrum of the D-type crystal 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°.

[0027] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the D-type crystal 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 powder X-ray diffraction spectrum of the D-type crystals has essentially the powder X-ray diffraction spectrum shown in FIG.

[0029] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the D-type crystal is as shown in Table 4 below.

[0030] Table 4 [Table 4-1] [Table 4-2]

[0031] In another aspect, the present invention provides E-type crystals of the hydrochloride salt of the compound represented by formula (I) (i.e., the compound represented by formula (IV)), wherein the powder X-ray diffraction spectrum of the E-type crystals 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°, and 21.24±0.2°.

[0032] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the E-form crystals 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 powder X-ray diffraction spectrum of the Form E crystals has essentially the powder X-ray diffraction spectrum shown in FIG.

[0034] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the E-form crystals are as shown in Table 5 below.

[0035] Table 5 [Table 5]

[0036] In another aspect of the present invention, the present invention further provides type F crystals of the hydrochloride salt of the compound represented by formula (I) (i.e., the compound represented by formula (IV)), wherein the powder X-ray diffraction spectrum of the type F crystals 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°.

[0037] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the F-type crystal 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 powder X-ray diffraction spectrum of the F-type crystals has an X-ray powder diffraction spectrum essentially as shown in FIG.

[0039] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the F-type crystal is as shown in Table 6 below.

[0040] Table 6 [Table 6]

[0041] In another aspect, the present invention further provides a sulfate salt of the compound of formula (I), whose structure is represented by formula (V). [ka]

[0042] In another aspect of the present invention, the present invention further provides a G-type crystal of the sulfate salt of the compound represented by formula (I) (i.e., the compound represented by formula (V)), wherein the powder X-ray diffraction spectrum of the G-type crystal 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°, and 22.26±0.2°.

[0043] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the G-type crystal 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 powder X-ray diffraction spectrum of the G-type crystals has an X-ray powder diffraction spectrum essentially as shown in FIG.

[0045] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the G-form crystals of the Sulfate Salt are as shown in Table 7 below. Table 7 [Table 7]

[0046] In another aspect, the present invention further provides a succinate salt of the compound of formula (I), whose structure is represented by formula (VI). [ka]

[0047] In another aspect of the present invention, the present invention further provides H-type crystals of the succinate salt of the compound represented by formula (I) (i.e., the compound represented by formula (VI)), wherein the powder X-ray diffraction spectrum of the H-type crystals 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°.

[0048] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the H-type crystals 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°.

[0049] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the H-form crystals has an X-ray powder diffraction spectrum essentially as shown in FIG.

[0050] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the H-type crystals are as shown in Table 8 below.

[0051] Table 8 [Table 8]

[0052] In another aspect of the present invention, the present invention further provides a J-type crystal of the succinate salt of the compound represented by formula (I) (i.e., the compound represented by formula (VI)), wherein the powder X-ray diffraction spectrum of the J-type crystal 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°.

[0053] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the J-type crystal 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°.

[0054] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the J-type crystals has an X-ray powder diffraction spectrum essentially as shown in FIG.

[0055] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the J-type crystal is as shown in Table 9 below.

[0056] Table 9 [Table 9]

[0057] In another aspect, the present invention further provides a glycolate salt of the compound of formula (I), whose structure is represented by formula (VII). [ka]

[0058] In another aspect, the present invention further provides type K crystals of the glycolate salt of the compound represented by formula (I) (i.e., the compound represented by formula (VII)), wherein the powder X-ray diffraction spectrum of the type K crystals 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°, and 21.64±0.2°.

[0059] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the K-type crystal 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°.

[0060] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the Type K crystals has an X-ray powder diffraction spectrum essentially as shown in FIG.

[0061] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the K-type crystals are as shown in Table 10 below.

[0062] Table 10 [Table 10]

[0063] In another aspect, the present invention further provides a benzoate salt of the compound of formula (I), whose structure is represented by formula (VIII). [ka]

[0064] In another aspect, the present invention further provides an L-type crystal of a benzoic acid co-crystal of the compound represented by formula (I), wherein the powder X-ray diffraction spectrum of the L-type crystal 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°.

[0065] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the L-type crystal 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°.

[0066] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the Form L crystals has essentially the powder X-ray diffraction spectrum shown in FIG.

[0067] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the Form L crystal is as shown in Table 11 below.

[0068] Table 11 [Table 11]

[0069] In another aspect of the present invention, there is further provided an M-type crystal of a benzoic acid co-crystal of the compound represented by formula (I), wherein the powder X-ray diffraction spectrum of the M-type crystal 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°.

[0070] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the M-type crystal 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°.

[0071] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the M-type crystals has an X-ray powder diffraction spectrum essentially as shown in FIG.

[0072] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the M-type crystal is as shown in Table 12 below.

[0073] Table 12 [Table 12]

[0074] In another aspect of the present invention, the present invention further provides an N-type crystal of the compound represented by formula (I), wherein the powder X-ray diffraction spectrum of the N-type crystal 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°.

[0075] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the N-type crystal 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°.

[0076] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the N-type crystal has essentially the powder X-ray diffraction spectrum shown in FIG.

[0077] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the N-type crystal is as shown in Table 13 below.

[0078] Table 13 [Table 13-1] [Table 13-2]

[0079] In another aspect of the present invention, the present invention further provides an O-type crystal of the compound represented by formula (I), wherein the powder X-ray diffraction spectrum of the O-type crystal 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°.

[0080] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the O-type crystals 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°.

[0081] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the O-type crystals has essentially the powder X-ray diffraction spectrum shown in FIG.

[0082] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the O-type crystals are as shown in Table 14 below.

[0083] Table 14 [Table 14]

[0084] In another aspect of the present invention, the present invention further provides a P-type crystal of the compound represented by formula (I), wherein the powder X-ray diffraction spectrum of the P-type crystal 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°.

[0085] In some embodiments of the present invention, the P-type crystal has an X-ray powder diffraction spectrum essentially as shown in FIG.

[0086] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the P-type crystal is as shown in Table 15 below.

[0087] Table 15 [Table 15]

[0088] In another aspect of the present invention, the present invention further provides a Q-type crystal of the compound represented by formula (I), wherein the powder X-ray diffraction spectrum of the Q-type crystal 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°.

[0089] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the Q-type crystal 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°.

[0090] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the Type Q crystals has an X-ray powder diffraction spectrum essentially as shown in FIG.

[0091] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the Q-type crystal is as shown in Table 16 below.

[0092] Table 16 [Table 16-1] [Table 16-2]

[0093] In another aspect of the present invention, the present invention further provides an R-type crystal of the compound represented by formula (I), wherein the powder X-ray diffraction spectrum of the R-type crystal 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°.

[0094] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the R-type crystals has an X-ray powder diffraction spectrum essentially as shown in FIG.

[0095] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the R-type crystal is as shown in Table 17 below.

[0096] Table 17 [Table 17]

[0097] In another aspect of the present invention, the present invention further provides an S-type crystal of the compound represented by formula (I), wherein the powder X-ray diffraction spectrum of the S-type crystal 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°.

[0098] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the S-form crystals has an X-ray powder diffraction spectrum essentially as shown in FIG.

[0099] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the S-type crystal is as shown in Table 18 below.

[0100] Table 18 [Table 18]

[0101] In another aspect of the present invention, the present invention further provides a T-type crystal of the compound represented by formula (I), wherein the powder X-ray diffraction spectrum of the T-type crystal 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°.

[0102] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the T-type crystals 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°.

[0103] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the T-type crystals has essentially the powder X-ray diffraction spectrum shown in FIG.

[0104] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the T-type crystals are as shown in Table 19 below.

[0105] Table 19 [Table 19-1] [Table 19-2]

[0106] In another aspect of the present invention, the present invention further provides a U-type crystal of the compound represented by formula (I), wherein the powder X-ray diffraction spectrum of the U-type crystal 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°.

[0107] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the U-type crystals 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°.

[0108] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the U-type crystals has essentially the powder X-ray diffraction spectrum shown in FIG.

[0109] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction spectrum of the U-type crystal is as shown in Table 20 below.

[0110] Table 20 [Table 20]

[0111] [Definitions and Explanations] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patent and publication documents included herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the present invention describes the preferred methods, devices, and materials. "API" or "free state" both refer to the free base form of the compound of formula (I). "Crystal" or "crystalline form" refers to a solid having a highly ordered chemical structure, including, but not limited to, single-component or multi-component crystals and / or polycrystals of a compound, solvates, hydrates, clathrates, eutectics, salts, solvates of salts, and hydrates of salts. Crystalline forms 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 confined spaces such as nanopores or capillaries, crystallization on surfaces or templates such as polymers, crystallization in the presence of additives such as co-crystal antimolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, addition of antisolvent, grinding, and solvent drop grinding.

[0112] "Amorphous" or "amorphous form" refers to a substance formed when its particles (molecules, atoms, ions) are arranged in three-dimensional space without periodicity, and is characterized by a diffuse X-ray powder diffraction pattern lacking sharp peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural characteristics suggest a close relationship with crystalline matter. Amorphous forms of substances can be obtained by many methods known in the art. These methods include, but are not limited to, quenching, antisolvent coagulation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques. "Solvent" refers to a substance (usually a liquid) that can completely or partially dissolve another substance (usually a solid). Solvents that may be used in the practice of the present 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, 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, and the like.

[0113] "Anti-solvent" refers to a fluid that promotes precipitation of the product (or product precursor) from the solvent. An anti-solvent can include a cold gas, a fluid that promotes precipitation by chemical reaction, or a fluid that reduces the solubility of the product in the solvent. It can be the same liquid as the solvent but at a different temperature, or it can be a different liquid than the solvent. The term "solvate" refers to a crystal having a solvent on the surface, within the lattice, or both on the surface and within the lattice, where the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. A specific example of a solvate is a hydrate, in which the solvent on the surface, within the lattice, or both on the surface and within the lattice of the material is water. The hydrate may or may not have a solvent other than water on the surface, within the lattice, or both on the surface and within the lattice of the material.

[0114] Crystalline or amorphous can be distinguished by a variety of techniques, including X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate. X-ray powder diffraction (XRPD) can detect information such as crystalline changes, crystallinity, and crystalline structure state, and is a common method for identifying crystals. Peak positions in an XRPD spectrum primarily depend on the structure of the crystal and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystals of the present invention are characterized by XRPD patterns with specific peak positions, which are substantially identical to the XRPD patterns shown in the drawings of the present invention. At the same time, the measurement of 2θ in an XRPD spectrum may involve experimental error and may vary slightly between different instruments and different samples, so the 2θ value should not be considered absolute. According to the instrument conditions used in the present testing, the tolerance for diffraction peaks is ±0.2°.

[0115] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (usually α-Al2O3) as a function of temperature by continuously heating or cooling under program control. The height of the melting peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the position of the peak is relatively insensitive to experimental details. Thus, in some embodiments, the crystals described in this invention are characterized by DSC patterns with specific peak positions, which are substantially the same as the DSC patterns shown in the drawings of this invention. At the same time, experimental errors may occur in DSC spectra, and the peak positions and values ​​of DSC spectra may vary slightly between different instruments and different samples, so the peak positions or values ​​of the DSC endothermic peaks should not be considered absolute. According to the conditions of the instrument used in the tests of this invention, the melting peak tolerance is ±3°C. Glass transition refers to the transition between a highly elastic state and a glassy state of an amorphous material. This is an intrinsic property of the material, and the corresponding transition temperature, known as the glass transition temperature (Tg), is an important physical property of amorphous materials. Because glass transition is a phenomenon related to molecular motion, the glass transition temperature (Tg) depends primarily on the structure of the material and is relatively insensitive to experimental details. In some embodiments, the glass transition temperature (Tg) of the amorphous form described in the present invention is measured by differential scanning calorimetry (DSC) and characterized as having a glass transition temperature of 107.44°C. According to the conditions of the equipment used in the present testing, the tolerance for the glass transition temperature is ±3°C.

[0116] Differential scanning calorimetry (DSC) can also be used to detect and analyze crystal transformations or mixed crystals. Solids with the same chemical composition often form isomers or variants with different crystal structures under different thermodynamic conditions; this phenomenon is called homogeneous polycrystals or homogeneous polyphases. When temperature and pressure conditions change, the variants can transform into each other, a phenomenon called crystal transformation. Crystal transformations significantly change the mechanical, electrical, magnetic, and other properties of the crystal. When the temperature of a crystal transformation is within a measurable range, this transformation process can be observed in a differential scanning calorimetry (DSC) pattern. The DSC pattern is characterized by the simultaneous presence of an exothermic peak reflecting the transformation process and two or more endothermic peaks characteristic of different crystals before and after the transformation. Crystals or amorphous forms of the compounds of the present invention can undergo crystal transformations under appropriate conditions.

[0117] Thermogravimetric analysis (TGA) is a programmable technique for measuring the mass change of a substance as a function of temperature. It is suitable for determining the loss of solvent during crystallization, as well as the sublimation and decomposition processes of samples. It can also be used to infer the presence of water of crystallization or crystallization solvents. The mass change indicated by a TGA curve depends on many factors, including sample preparation and instrumentation. The mass change detected by TGA varies slightly between different instruments and samples. Under the instrumentation conditions used in this study, the mass change tolerance is ±0.3%. In the context of the present invention, all 2θ values ​​in powder X-ray diffraction patterns are expressed in degrees (°).

[0118] When referring to a pattern or / and data appearing in a pattern, a "peak" refers to a feature that is recognizable by one of skill in the art and that is not attributable to background noise. The term "essentially as shown in the figure" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the powder X-ray diffraction pattern or DSC pattern or TGA result are shown in the figure.

[0119] "Essentially pure" means a crystal that is essentially free from one or more other crystals, i.e., the purity of the crystal 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 contains other crystals that account for less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total volume or weight of the crystal. "Essentially free" means that the proportion of one or more other crystals in the total volume or weight of the crystals is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0120] "Relative intensity" refers to the ratio of the intensity of the first intense peak to the intensity of other peaks when the intensity of the first intense peak is 100% of all diffraction peaks in an X-ray powder diffraction (XRPD) pattern. In the context of the present invention, whether the word "approximately" or "about" is used or not, it means within 10%, suitably within 5%, and particularly within 1% of a given value or range. Alternatively, to those skilled in the art, the term "approximately" or "about" means within an acceptable standard error of the mean. Whenever a numerical value having a value of N is disclosed, a numerical value having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is expressly disclosed, where "+ / -" means plus or minus.

[0121] The term "comprises" is open-ended, i.e. includes the subject matter specified in the present invention but does not exclude other aspects. [Brief explanation of the drawings]

[0122] [Figure 1] 1 shows an XRPD pattern of type A crystals of the maleate salt according to an embodiment of the present invention. [Figure 2] 1 shows DSC and TGA patterns of A-type crystals of the maleate salt according to an embodiment of the present invention. [Figure 3] 1 shows the NMR pattern of the A-type crystal of the maleate salt according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 4] 1 shows a DVS curve of type A crystals of the maleate salt according to an embodiment of the present invention. [Figure 5] 1 shows XRPD patterns of type A crystals of the maleate salt before and after a DVS test according to an embodiment of the present invention. [Figure 6] 1 shows an XRPD pattern of type B crystals of the maleate salt according to an embodiment of the present invention. [Figure 7] 1 shows DSC and TGA patterns of B-type crystals of the maleate salt according to an embodiment of the present invention. [Figure 8] 1 shows an NMR pattern of B-type crystals of the maleate salt according to an embodiment of the present invention. [Figure 9] 1 shows an XRPD pattern of crystalline form C of a fumarate salt according to an embodiment of the present invention. [Figure 10] 1 shows DSC and TGA patterns of C-type crystals of the fumarate salt according to an embodiment of the present invention. [Figure 11] 1 shows the NMR pattern of the C-type crystals of the fumarate salt according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 12] 1 shows an XRPD pattern of type D crystals of the hydrochloride salt according to an embodiment of the present invention. [Figure 13] 1 shows DSC and TGA patterns of type D crystals of the hydrochloride salt according to an embodiment of the present invention. [Figure 14] 1 shows the NMR pattern of the D-type crystals of the hydrochloride salt according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 15] 1 shows an XRPD pattern of E-form crystals of the hydrochloride salt according to an embodiment of the present invention. [Figure 16] 1 shows DSC and TGA patterns of E-form crystals of the hydrochloride salt according to an embodiment of the present invention. [Figure 17] 1 shows the NMR pattern of E-type crystals of the hydrochloride salt according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 18] 1 shows an XRPD pattern of type F crystals of the hydrochloride salt according to an embodiment of the present invention. [Figure 19] 1 shows DSC and TGA patterns of type F crystals of the hydrochloride salt according to an embodiment of the present invention. [Figure 20] 1 shows the NMR pattern of F-type crystals of the hydrochloride salt according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 21] 1 shows an XRPD pattern of G-type crystals of the sulfate salt according to an embodiment of the present invention. [Figure 22] 1 shows DSC and TGA patterns of G-type crystals of the sulfate salt according to an embodiment of the present invention. [Figure 23] 1 shows the NMR pattern of the G-type crystal of the sulfate salt according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 24]1 shows an XRPD pattern of H-form crystals of succinic acid according to an embodiment of the present invention. [Figure 25] 1 shows DSC and TGA patterns of H-form crystals of succinic acid according to an embodiment of the present invention. [Figure 26] 1 shows the NMR pattern of H-type crystals of succinic acid according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 27] 1 shows an XRPD pattern of J-type crystals of succinic acid according to an embodiment of the present invention. [Figure 28] 1 shows DSC and TGA patterns of J-type crystals of succinic acid according to an embodiment of the present invention. [Figure 29] 1 shows the NMR pattern of J-type crystals of succinic acid according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 30] 1 shows an XRPD pattern of type K crystals of glycolic acid according to an embodiment of the present invention. [Figure 31] 1 shows DSC and TGA patterns of type K crystals of glycolic acid according to an embodiment of the present invention. [Figure 32] 1 shows the NMR pattern of type K crystals of glycolic acid according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 33] 1 shows an XRPD pattern of L-type crystals of benzoic acid eutectic according to an embodiment of the present invention. [Figure 34] 1 shows DSC and TGA patterns of L-type crystals of benzoic acid eutectic according to an embodiment of the present invention. [Figure 35] 1 shows the NMR pattern of L-type crystals of benzoic acid eutectic according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 36] 1 shows an XRPD pattern of M-type crystals of benzoic acid eutectic according to an embodiment of the present invention. [Figure 37] 1 shows DSC and TGA patterns of M-type crystals of benzoic acid eutectic according to an embodiment of the present invention. [Figure 38]1 shows the NMR pattern of M-type crystals of benzoic acid eutectic according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 39] 1 shows an XRPD pattern of an N-type crystal according to an embodiment of the present invention. [Figure 40] 1 shows DSC and TGA patterns of an N-type crystal according to an embodiment of the present invention. [Figure 41] 1 shows an NMR pattern of an N-type crystal according to an embodiment of the present invention. [Figure 42] 1 shows an XRPD pattern of O-type crystals according to an embodiment of the present invention. [Figure 43] 1 shows DSC and TGA patterns of O-type crystals according to an embodiment of the present invention. [Figure 44] 1 shows the NMR pattern of O-type crystals according to an embodiment of the present invention. [Figure 45] 1 shows an XRPD pattern of a P-type crystal according to an embodiment of the present invention. [Figure 46] 1 shows DSC and TGA patterns of a P-type crystal according to an embodiment of the present invention. [Figure 47] 1 shows an NMR pattern of a P-type crystal according to an embodiment of the present invention. [Figure 48] 1 shows an XRPD pattern of a Q-type crystal according to an embodiment of the present invention. [Figure 49] 1 shows DSC and TGA patterns of Q-type crystals according to an embodiment of the present invention. [Figure 50] 1 shows an XRPD pattern of an R-type crystal according to an embodiment of the present invention. [Figure 51] 1 shows DSC and TGA patterns of an R-type crystal according to an embodiment of the present invention. [Figure 52] 1 shows the NMR pattern of an R-type crystal according to an embodiment of the present invention. [Figure 53] 1 shows an XRPD pattern of the S-type crystal according to an embodiment of the present invention. [Figure 54] 1 shows DSC and TGA patterns of an S-type crystal according to an embodiment of the present invention. [Figure 55] 1 shows the NMR pattern of an S-type crystal according to an embodiment of the present invention. [Figure 56] 1 shows an XRPD pattern of a T-type crystal according to an embodiment of the present invention. [Figure 57] 1 shows DSC and TGA patterns of T-type crystals according to an embodiment of the present invention. [Figure 58] 1 shows an NMR pattern of a T-type crystal according to an embodiment of the present invention. [Figure 59] 1 shows an XRPD pattern of a U-type crystal according to an embodiment of the present invention. [Figure 60] 1 shows DSC and TGA patterns of a U-type crystal according to an embodiment of the present invention. [Figure 61] 1 shows the NMR pattern of a U-type crystal according to an embodiment of the present invention, where (a) is a comparison with the free state, and (b) is the integration result. [Figure 62] 1 shows an XRPD pattern of a stability study of crystalline form A of the maleate salt according to an embodiment of the present invention. [Figure 63] 1 shows XRPD patterns of a stability study of crystalline form C of the fumarate salt according to an embodiment of the present invention. [Figure 64] 1 shows XRPD patterns of N-type crystals from a stability study according to an embodiment of the present invention. [Figure 65] 1 shows XRPD patterns of the S-type crystals according to an embodiment of the present invention in a stability study. [Figure 66] FIG. 2 is a comparative XRPD diagram of the solid remaining after shaking the A-type crystals of the maleate salt according to an embodiment of the present invention in a medium for 24 hours. [Figure 67] FIG. 2 is a comparative XRPD diagram of the solid remaining after shaking the C-type crystals of the fumarate salt according to an embodiment of the present invention in a medium for 24 hours. DETAILED DESCRIPTION OF THE INVENTION

[0123] The present application will be specifically described below by way of examples, but is not intended to limit the present invention in any way. The present application has been described in detail herein, and specific embodiments thereof have also been disclosed, and it will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0124] All raw materials used in the present invention are commercially available unless otherwise specified.

[0125] The present application will be specifically described below by way of examples, but is not intended to limit the present invention in any way. The present application has been described in detail herein, and specific embodiments thereof have also been disclosed, and it will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0126] Common analytical methods: 1. Nuclear magnetic analysis ( 1 H NMR) A few milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent, and NMR analysis was carried out on a Bruker AVANCE-III (Bruker, GER).

[0127] 2. X-ray powder diffraction (XRPD) Instrument model: Bruker D8 ADVANCE (Unique equipment number: IARC-031-PXRD-01). Detection criteria: Chinese Pharmacopoeia 2020 Edition, Part 4, General Principles 0451. Sample preparation: The sample was placed in the center of the groove of the sample holder so that the surface of the sample was flush with the surface of the sample holder. Experimental conditions: CuKa40kv 40mA, divergence slit: 0.6mm, Soller slit: 4.0°, continuous scan, detector: LynxEye. Step width: 0.02°. Scan speed: 4° / min.

[0128] 3. Thermogravimetric analysis (TGA) The thermogravimetric analyzer model was a TA Discovery 55 (TA, US). 2–5 mg of sample was placed in an equilibrated open aluminum sample pan and automatically weighed in the TGA oven. The sample was heated to the final temperature at a rate of 10 °C / min with a nitrogen purge rate of 60 mL / min at the sample and 40 mL / min at the balance.

[0129] 4. Differential scanning calorimetry (DSC) The model of the differential scanning calorimeter was TA Discovery 2500 (TA, US). Samples of 1–2 mg were accurately weighed and placed in a perforated DSC Tzero sample pan and heated in a furnace at a rate of 10 °C / min with a nitrogen purge rate of 50 mL / min to the final temperature.

[0130] 5. Dynamic moisture sorption / desorption analysis (DVS) Dynamic moisture sorption / desorption analysis was performed using a DVS Intrinsic (SMS, UK). Tests were performed in gradient mode with a humidity change of 10% per gradient, ranging from 50% to 95%, 0% to 50%, and 0% to 90%. The end point of the gradient was determined by dm / dt, defined as when dm / dt was maintained below 0.002% for 10 minutes. After the test was completed, the samples were analyzed by XRPD to determine whether the solid morphology had changed.

[0131] 6. Polarized Light Microscopy (PLM) The polarizing microscope model was Nikon Ci-POL (Nikon, JP). A small amount of sample was placed on a slide, and the morphology of the sample was observed by selecting an appropriate lens.

[0132] 7. High-performance liquid chromatography (HPLC) The model of high performance liquid chromatography was LC-2030C 3D Plus (Shimadzu, JP), and the test conditions were as shown in Table 21.

[0133] Table 21 [Table 21]

[0134] The HPLC conditions used in testing for maleate content are shown in Table 22 below. Table 22 [Table 22]

[0135] 8. Ion chromatography (IC) The model of ion chromatography was ICS 5000 (Thermo Fisher, US), and the instrument parameters are shown in Table 23. Table 23 [Table 23]

[0136] Common test methods: 1. Raw material solubility test Approximately 20 mg of sample was weighed and added to an EP tube. A predetermined amount of solvent was added in batches at room temperature (~25°C). The solution was stirred to observe whether the solid was completely dissolved. If the solid was not dissolved even after adding 10.0 mL of solvent, the experiment was stopped. The solubility of the compound in the solvent was estimated based on the volume of solvent in which the solid was completely dissolved.

[0137] 2. Reactive crystallization method 2.1 1 equivalent dose Approximately 26 mg (0.05 mmol) of sample and 1 equivalent of acidic compound were added to a predetermined amount of selected solvent and suspended at room temperature for 2 days. The suspension was 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, it was centrifuged, the supernatant was removed, and the solid was dried under vacuum at room temperature. If a solid phase did not precipitate after cooling, antisolvent was added dropwise to the solution until a solid precipitated.

[0138] 2.2 2-equivalent dose Approximately 26 mg (0.05 mmol) of the sample and 2 equivalents of the acidic compound were added to a predetermined amount of a selected solvent and suspended at room temperature for 2 days, the suspension was centrifuged, and the solid was dried under vacuum at room temperature.

[0139] 3. Solvent evaporation method The clear solution obtained in the solubility test of the raw material was left at room temperature until the solvent completely evaporated to obtain a solid, or approximately 20 mg of each raw material was weighed out, and an appropriate amount of the selected solvent was added to a predetermined amount of poor solvent to completely dissolve the raw material, and the solution was left at room temperature to evaporate the solvent completely.

[0140] 4. Suspension method 4.1, Suspension at room temperature Different crystals were used as starting materials, and a predetermined amount of sample was added to a selected single or binary solvent to form a suspension. The suspension was stirred at room temperature for a predetermined time, then centrifuged, and the solid was dried under vacuum at room temperature.

[0141] 4.2 Suspension at 50°C Different crystals were used as starting materials, and a predetermined amount of sample was added to a selected solvent to form a suspension. The suspension was stirred at 50°C for 1 day, then centrifuged, and the solid was dried under vacuum at room temperature.

[0142] 5.Dissolution crystallization method 5.1, Solution crystallization method Approximately 20 mg of sample was weighed out and a predetermined amount of good solvent was added dropwise at room temperature to completely dissolve the sample, or the sample was prepared as a saturated solution in the good solvent and the solution was added dropwise to a 5-10-fold volume of poor solvent. After stirring for 1 hour, the reaction system, which precipitated a solid, was centrifuged and the solid was dried under vacuum at room temperature. The clear solution was continued to stir for 24 hours, and if no solid precipitated, the reaction system was placed in a refrigerator at 4°C or -15°C. The reaction system, which precipitated a solid, was centrifuged and the solid was dried under vacuum at room temperature.

[0143] 5.2 Binary solvent sequential dropping method Approximately 20 mg of sample was weighed out, and a predetermined amount of good solvent was added dropwise at room temperature to completely dissolve the sample, or a saturated solution of the good solvent was prepared, and a poor solvent was added dropwise until a solid precipitated. The mixture was stirred at room temperature for 15 minutes, and the reaction mixture, which precipitated a solid, was centrifuged and vacuum dried at room temperature. The clear solution was stirred for 24 hours, and if no solid precipitated, the reaction mixture was placed in a refrigerator at 4°C or -15°C. The reaction mixture, which precipitated a solid, was centrifuged and vacuum dried at room temperature.

[0144] 6, cooling method 6.1. Single-solvent cooling Approximately 20 mg of sample was weighed and the selected solvent, preheated to 50°C, was added dropwise until the solid was just completely dissolved. The solution was quickly transferred to room temperature and allowed to cool. After standing at room temperature for 2 hours or more, if sufficient solid had not precipitated, the solution was placed at 4°C for further cooling. If sufficient solid still had not precipitated, the solution was placed at -15°C for further cooling. Reactions in which a sufficient amount of solid had precipitated were centrifuged, and the solid was dried under vacuum at room temperature.

[0145] 6.2. Cooling of binary solvents Approximately 20 mg of sample was weighed and mixed with a predetermined amount of poor solvent at 50°C to form a suspension. A preheated good solvent was slowly added dropwise until the solid was completely dissolved, and the solution was then transferred to room temperature and allowed to cool. After leaving the solution at room temperature for more than 2 hours, if sufficient solid had not precipitated, the solution was placed at 4°C for further cooling. If sufficient solid had not yet precipitated, the solution was placed at -15°C for further cooling. After a sufficient amount of solid had precipitated, the reaction system was centrifuged, and the solid was dried under vacuum at room temperature.

[0146] 7. Vapor phase diffusion method Approximately 20 mg of sample was weighed and dissolved in a good solvent or prepared as a saturated solution in a good solvent. The clear solution was left at room temperature in a poor solvent atmosphere until a solid precipitated. The solution in the reaction system from which the solid precipitated was removed using a syringe, and an XRPD test was performed on the wet sample.

[0147] 8. Solid-state gas-phase diffusion Approximately 20 mg of amorphous sample was weighed and left in the selected solvent atmosphere at room or low temperature for 7 days, and the properties of the solid in the glass vial were periodically observed and XRPD tests were performed on the solid.

[0148] 9. Heat conversion The thermal conversion was carried out 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, maintained for 5–10 min, and then allowed to cool to room temperature to obtain a solid.

[0149] 10. Competitive water activity suspension experiment Equal amounts of selected crystal samples were weighed and added to predetermined volumes of saturated water / isopropanol solutions with different water contents (0%, 30%, and 60% water by volume), and the suspension was stirred for a predetermined time at room temperature and 60° C. The suspension was centrifuged, and the wet samples were characterized by XRPD.

[0150] 11, Stability study Approximately 20 mg of sample was weighed into a weighing bottle and placed under high temperature (60°C), high humidity (25°C / 92.5%RH), light irradiation (25°C / 4500 Lux), and accelerated irradiation (40°C / 75%RH), respectively, and sampled on the 7th and 15th days for characterization by XRPD.

[0151] 12. Solubility test The biological medium composition process is shown in Table 24. Different crystal samples were added to the biological medium and shaken at a constant temperature of 37°C for 24 hours. Samples were taken at 0.5 hours, 2 hours, and 24 hours, respectively. The sampled solutions were filtered using a 0.22 μm hydrophilic filter membrane. Part of the high-concentration sample was 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. Furthermore, the supernatant after 24 hours was sampled to test the pH value, and the remaining solid was subjected to XRPD testing.

[0152] Table 24 [Table 24]

[0153] Example 1 Preparation of Compound of Formula (I) [ka]

[0154] At room temperature, p-toluenesulfonyl chloride (21.9 g, 115 mmol) was added to a solution of 7-chloro-1,2,3,4-tetrahydrobenzo[B]azepin-5-one (15 g, 76.7 mmol) in pyridine (150 mL). The reaction solution was allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, poured into water (200 mL), extracted with ethyl acetate (100 mL x 3), and 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 separated and purified by silica gel chromatography to obtain intermediate I-1.

[0155] LC-MS (ESI) [M+H] + 349.9. 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 8.3 Hz, 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).

[0156] Intermediate I-1 (37.00 g, 106.00 mmol) was dissolved in anhydrous tetrahydrofuran (350 mL) at 25°C. Under argon gas protection and ice-water bath cooling, sodium hydride (6.36 g, 60% wt, 159.00 mmol) was added in batches. After cooling and stirring in the 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 cold saturated aqueous ammonium chloride (500 mL), concentrated to remove most of the tetrahydrofuran, and filtered. The cake was washed with purified water, slurried with petroleum ether, filtered, and dried under suction to obtain Intermediate I-2.

[0157] LC-MS (ESI) [M+H] + 408.0. Intermediate I-2 (19.00 g, 46.68 mmol) was dissolved in anhydrous N,N-dimethylformamide (187 mL) at 25 °C, and sodium carbonate (14.84 g, 140.00 mmol) and 2-(2-bromoethyl)isoindoline-1,3-dione (23.71 g, 93.36 mmol) were added sequentially. The mixture was stirred overnight at 90 °C under argon gas protection. After cooling, the reaction mixture was diluted with ethyl acetate (500 mL), washed with water (150 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was separated and purified by silica gel chromatography to give intermediate I-3.

[0158] LC-MS (ESI) [M+H] + 581.2. 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. The reaction mixture was purged with argon gas three times and then stirred at 150°C for 10 hours under argon gas protection. After cooling, the reaction mixture was diluted with ethyl acetate (400 mL), washed with water (150 mL x 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 separated and purified by silica gel chromatography to obtain intermediate I-4.

[0159] LC-MS (ESI) [M+H] + 523.2. 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 h. The mixture was concentrated under reduced pressure to remove most of the ethanol, diluted with ethyl acetate (50 mL), washed with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude intermediate I-5. The crude product was used directly in the next reaction.

[0160] LC-MS (ESI) [M+H] + 375.2. 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 to the solution while cooling in an ice-water bath. The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure to remove most of the methanol. The mixture was diluted with ethyl acetate (50 mL), washed 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 give crude intermediate I-6. The crude product was used directly in the next reaction.

[0161] LC-MS (ESI) [M+H] + 377.2. Intermediate I-6 (150 mg, 0.40 mmol) was dissolved in anhydrous methanol (20 mL) at 25 °C, and magnesium chips (2.00 g, 83.33 mmol) were added. The mixture was purged with nitrogen gas three times and stirred overnight at 70 °C under a nitrogen atmosphere (balloon). After cooling, the mixture was filtered through diatomaceous earth. The filtrate was concentrated to dryness and dissolved in a dichloromethane / methanol mixture (10 / 1, 50 mL). The mixture was washed with saturated aqueous ammonium chloride (20 mL x 3), water (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude intermediate I-7. The crude product was used directly in the next reaction.

[0162] LC-MS (ESI) [M+H] + 223.0. 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 gas protection and ice-water bath cooling, 9-fluorenylmethyl chloroformate (12.73 g, 49.33 mmol) was slowly added and stirred at 25 °C for 16 hours. The mixture was concentrated under reduced pressure at room temperature, slurried with petroleum ether, filtered, and the cake was washed with water (20 mL) and dried under suction to give Intermediate I-47.

[0163] LC-MS (ESI) [M+H] + 444.8. Methyl 6-aminonicotinate (1.0 g, 6.57 mmol) was dissolved in pyridine (20 mL) at room temperature, and 2-trifluoromethylbenzoyl chloride (1.51 g, 7.25 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with water (50 mL × 5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give intermediate I-12.

[0164] LC-MS (ESI) [M+H] + 325.0. Intermediate I-12 (1.35 g, 4.16 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and a solution of sodium hydroxide (499 mg, 12.5 mmol) in water (2 mL) was added. The reaction mixture was stirred at 70°C for 1 hour. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5-6. The mixture was filtered, and the solid was dried to obtain intermediate I-13.

[0165] LC-MS (ESI) [M+H] + 311.0. Intermediate I-47 (4.70 g, 10.58 mmol) was dissolved in anhydrous tetrahydrofuran (35 mL) at 25 °C, and pyridine (8.37 g, 106.00 mmol), intermediate I-13 (4.92 g, 15.87 mmol), and propylphosphonic anhydride (50% wt ethyl acetate solution, 20.00 g, 31.74 mmol) were added sequentially. The mixture was stirred overnight at 65 °C under argon gas protection. After cooling, the reaction mixture was concentrated to remove most of the tetrahydrofuran and diluted with ethyl acetate (150 mL). The mixture was washed sequentially with 1 N hydrochloric acid (100 mL × 2), saturated aqueous sodium bicarbonate solution (100 mL × 3), water (100 mL), and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, affording the crude product. The crude product was separated and purified by silica gel chromatography to give intermediate I-48A (Rt=1.541 min).

[0166] LCMS analytical method: Chromatography column: Waters acquity UPLC CSH 2.1 x 50 mm, 1.7 μm. Mobile phase: A: Water (0.01% trifluoroacetic acid) B: Acetonitrile (0.01% trifluoroacetic acid). Elution gradient: 5% to 95% B, 0.7 min; 95% B 0.8 min; then 5% B, 0.5 min. Flow rate: 1.0mL / min. Chromatography column temperature: 60°C. Mass spectrum scan range: 100-1000. Intermediate I-48A (Rt=1.541min)LC-MS (ESI) [M+H] + 737.3.

[0167] Intermediate I-48A (14 mg, 0.019 mmol) was dissolved in N,N-dimethylformamide (3 mL) at 25°C, pyrrolidine (35.50 mg, 0.50 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by C18 reverse-phase chromatography (formic acid system) to give compound 8.

[0168] LC-MS (ESI) [M+H] + 515.2. 1 H NMR (400 MHz, DMSO-d6) 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, 1H), 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).

[0169] Compound 8 was subjected to chiral separation by SFC to give compound 10A (Rt=1.424 min). Chiral Resolution Methods: Equipment: MG II preparative SFC (SFC-14). Chromatography column: ChiralPak AD, 250 x 30 mm ID, 10 μm. Mobile phase: A: carbon dioxide B: ethanol (0.1% aqueous ammonia). Elution gradient: 35% B. Flow rate: 80mL / min. Back pressure: 100bar. Column temperature: 38°C. Detection wavelength: 220nm. Cycle time: ~8 minutes. Chiral analysis methods: Equipment: Waters UPC2 analytical SFC (SFC-H). Chromatography column: ChiralPak AD, 150 x 4.6 mm ID, 3 μm. Mobile phase: A: carbon dioxide B: ethanol (0.05% diethylamine). Elution gradient: 40% B. Flow rate: 2.5mL / min. Back pressure: 1500psi. Column temperature: 35°C. Detection wavelength: 220nm.

[0170] Compound 10A: Rt = 1.424 min. LC-MS (ESI) [M+H] + 515.2. 1 H NMR (400 MHz, DMSO-d6) 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).

[0171] Experimental Example 2 IC of compounds of formula (I) for inhibition of vasopressin-induced activation of receptor V2R 50 test (1) Cell A HeLa cell line (HeLa-V2R) stably expressing the human vasopressin receptor V2R was constructed by Shanghai Genechem Co., Ltd. using the lentiviral infection method, and its stable expression of human V2R was verified by qPCR.

[0172] (2) Reagents DMEM cell culture medium: Brand: Gibco, Catalog Number: 11995065; Fetal Bovine Serum: Brand: Genetimes, Catalog Number: FND500; 0.25% Trypsin: Brand: Gibco, Catalog Number: 25200072; Puromycin Hydrochloride: Brand: Gibco, Catalog Number: A1113803; cAMP-GS HIRANGE Kit: Brand: Cisbio, Catalog Number: 62AM6PEC; IBMX: Brand: Sigma, Catalog Number: i5879; Vasopressin AVP: Custom-made by GL Biochem (Shanghai) Ltd.

[0173] (3) Test method HeLa-V2R cells were cultured in DMEM medium supplemented with 10% fetal bovine serum at 37°C under 5% CO2 conditions, and 2 μg / mL puromycin was added to the medium to continue screening for V2R-expressing cells. On the day of the experiment, cells were digested with trypsin, washed twice with the stimulation buffer of the cAMP-GS HIRANGE kit, resuspended, and counted to obtain 1.6 × 10 6The cells were prepared at 1000kJ / mL and IBMX was added to a final concentration of 0.5 mM. 5 μL of the cell suspension was transferred to a 384-well plate at each well, and 2.5 μL of test compound (3-fold dilutions starting from 10 μM, 10 concentration gradients) or DMSO (minimum value, Min, maximum value control) was added to the corresponding wells. After 30 minutes of incubation at room temperature, 2.5 μL of vasopressin AVP solution was added to the test compound wells and the maximum value wells to a final concentration of 2.25 nM. 2.5 μL of stimulation buffer was added to the minimum value well, and the plate was then incubated at 25°C for 60 minutes. Simultaneously, cAMP standard samples (3-fold dilutions starting from 5.6 μM, 10 concentration points) were prepared, and 10 μL of the cAMP standard samples were transferred to the corresponding wells of the 384-well plate. The cAMP-d2 fluorescent probe and anti-cAMP antibody probe included with the kit were diluted 20-fold with the lysis buffer of the cAMP-GS HIRANGE kit. 5 μL of each solution was added sequentially to each well of a 384-well plate, mixed thoroughly, briefly centrifuged, and incubated at 25°C for 2 hours. The samples were detected using the HTRF method on an Envision microplate reader, measuring fluorescence intensity at 615 nm and 665 nm. Two replicate wells were prepared for each sample tested, and 32 replicate wells were prepared for the Min and Max values, respectively.

[0174] (4) Data processing For each sample in each well, the ratio of fluorescence intensities at 665 nm and 615 nm (FI) 665 / 615 The logarithm of the standard concentration is X, and FI is 665 / 615 The standard curve was obtained by fitting the "log(inhibitor) vs response-variable slope (four parameters)" model in Prism 8.0 software, with X1000 as the Y value. 665 / 615 Using X1000 as the Y value, the cAMP concentration corresponding to each sample was calculated using Prism 8.0 software according to the standard curve described above. The formula for calculating %Inhibition is as follows:

number

number

number

[0175] Nonlinear regression was performed using the "log(inhibitor) vs response-variable slope (four parameters)" model in Prism 8.0 software, with %Inhibition (percent inhibition) as the Y value and the logarithm of the compound concentration as the X value, to calculate the IC. 50 Calculate Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hill Slope)).

[0176] The experimental results are shown in Table 25: Table 25 Evaluation of compounds for inhibition of cAMP increase in human cervical cancer cells (Human V2R Hela-Stable cell line OE2) [Table 25]

[0177] Example 3: Salt screening Fifteen acidic compounds were selected for screening salts by reactive crystallization, and the results are shown in Tables 26 and 27 below.

[0178] Table 26. Salt preliminary screening experiment using the solution suspension method (1 equivalent) [Table 26] Note: "*" indicates that the suspension was clarified and placed at -15°C, and a solid precipitated. "**" indicates that the suspension was clarified after cooling to -15°C, and a solid precipitated when n-heptane was added.

[0179] Table 27: Salt preliminary screening experiment by solution suspension method (2 equivalents) [Table 27]

[0180] From the above table, it can be seen that the compound represented by formula (I) can be formed into six types of salts: hydrochloride, sulfate, maleate, fumarate, succinate and glycolate.

[0181] Example 4 Preparation of A-type crystals of maleate salt Method 1: 513.6 mg of the compound of formula (I) and 1 equivalent of maleic acid were weighed, 16 mL of isopropanol was added, and the mixture was stirred at room temperature for 2 days. The suspension was centrifuged, and the solid was vacuum dried at 40°C for 3 days to obtain 611.5 mg of type A crystals of the maleate salt.

[0182] Method 2: Methanol (30 mL, 10.0 v / w) was added to the jacketed reaction kettle R1 at room temperature and purged with nitrogen gas three times. Free amine (3.0 g, 1 wt., 5.82 mmol, 1.0 eq.) was added to the jacketed reaction kettle R1 at room temperature and stirring was initiated. Stirring was continued until the mixture became clear. An isopropanol solution of maleic acid was prepared in the jacketed reaction kettle R2: maleic acid (0.71 g, 0.236 wt., 6.11 mmol, 1.05 eq.) was dissolved in isopropanol (60 mL, 20.0 v / w) at 25-30°C. The maleic acid / isopropanol solution was added dropwise to the reaction kettle R1 over 20 minutes, controlling the internal temperature at 20-30°C. After the addition was complete, the reaction was continued at 20-30°C for 2-5 hours. After filtration, the cake was washed once with isopropanol (9 mL, 3.0 v / w) and dried to obtain Form A crystals of the maleate salt.

[0183] Method 3: Add 10L of methanol to a 100L reaction kettle, add 4.2kg of the free base, add 6.8L of methanol, heat to 60℃, dissolve 993g of maleic acid in 33.6L of isopropanol, add the above solution slowly, cool to 25℃, and filter to obtain 4.7kg of maleate type A crystals.

[0184] Characterization of the maleate salt form A crystals was performed, and the results are shown in Figures 1-5. XRPD (Figure 1) results indicated that the maleate salt form A crystals were solid with good crystallinity. TGA (Figure 2) results indicated that the maleate salt form A crystals lost 0.5% weight when heated to 150 °C and may decompose above 200 °C. DSC (Figure 2) results indicated that the maleate salt form A crystals had an endothermic peak at 229 °C. NMR (Figure 3) results showed peak shifts at 1.50-1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm compared to the free state, suggesting salt formation in the sample. A maleic acid signal peak was observed at 6.03 ppm. Based on the integration results, the ratio of raw material to maleic acid was calculated to be 1:1. An isopropanol solvent peak was observed at 1.04 ppm, suggesting the presence of a small amount of isopropanol solvent remaining in the sample. DVS (Figure 4) results indicated that maleate type A crystals increased in weight by 0.09% at 80% RH, 0.23% at 95% RH, and 0.24% at 0% RH, indicating minimal hygroscopicity. XRPD (Figure 5) results indicated that the sample remained unchanged after the DVS test. Maleate type A crystals were found to be anhydrous with good crystallinity and minimal hygroscopicity.

[0185] Example 5: Preparation of B-type crystals of maleate 21.7 mg of maleate type A crystals were 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 type B crystals.

[0186] XRPD (Figure 6) results indicated that type B crystals were solids with good crystallinity. TGA (Figure 7) results indicated that type B crystals lost 9.7% weight when heated from room temperature to 170°C and may decompose above 220°C. DSC (Figure 7) results indicated that type B crystals had an endothermic signal corresponding to desolvation at approximately 145°C and an endothermic peak at approximately 234°C. NMR (Figure 8) results were essentially consistent with the raw material, with DMF solvent peaks observed at 2.73, 2.89, and 7.95 ppm. Based on the integration results, the ratio of the compound to DMF was calculated to be 1:0.9, and the DMF content was essentially consistent with the TGA weight loss. Thermal crystallization experiments indicated that type B crystals crystallized to type A crystals when heated to 170°C for desolvation. In summary, type B crystals are DMF solvates.

[0187] Example 6 Preparation of C-type crystals of fumarate salt 0.8 mL of isopropanol was added to 25.6 mg of the compound represented by formula (I), and 1 equivalent of fumaric acid was added thereto. The mixture was stirred at room temperature for 2 days and centrifuged to obtain C-type crystals of the fumarate salt.

[0188] XRPD (Figure 9) results indicated that the fumarate salt C-type crystals were solid with good crystallinity. TGA (Figure 10) results indicated that the sample lost 0.7% weight when heated to 150 °C and may decompose above 190 °C. DSC (Figure 10) results indicated an endothermic signal at approximately 217 °C. NMR (Figure 11) results showed peak shifts at 1.50-1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm compared to the free state, suggesting salt formation in the sample. A fumaric acid signal peak was observed at 6.57 ppm. Based on the integration results, the API to fumaric acid ratio was calculated to be 1:1. An isopropanol solvent peak was observed at 1.04 ppm, suggesting the presence of a small amount of isopropanol solvent remaining in the sample. In summary, Form C of the fumarate salt is an anhydrous crystal.

[0189] Example 7 Preparation of D-type crystals of hydrochloride 0.8 mL of isopropanol was added to 25.3 mg of the compound represented by formula (I), and 1 equivalent of concentrated hydrochloric acid was added thereto, followed by stirring at room temperature for 2 days and centrifuging to obtain D-type crystals of the hydrochloride salt. XRPD (Figure 12) results indicated that the hydrochloride salt type D crystals were solids with good crystallinity. TGA (Figure 13) results indicated that the sample lost 1.6% weight (corresponding to a weight loss of 0.5 water molecules) when heated to 150 °C and may decompose above 230 °C. DSC (Figure 13) results indicated endothermic signals at approximately 71 °C and 262 °C. NMR (Figure 14) results showed multiple peak shifts at 1.50-1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm compared to the free state, suggesting salt formation in the sample. An isopropanol solvent peak was observed at 1.04 ppm, suggesting the presence of a small amount of isopropanol solvent in the sample. Thermal crystallization experiments indicated that the hydrochloride salt type D crystals transformed into the hydrochloride salt type F crystals when heated to 150 °C. The results of ion chromatography showed that the salt formation ratio of the hydrochloride salt of type D crystal was 1:1. In summary, the hydrochloride salt of type D crystal is a hydrate.

[0190] Example 8 Preparation of E-type crystals of hydrochloride To 25.3 mg of the compound represented by formula (I) was added 1.0 mL of cyclohexane, and 1 equivalent of concentrated hydrochloric acid was added, followed by stirring at room temperature for 2 days and centrifuging to obtain E-form crystals of the hydrochloride salt.

[0191] XRPD (Figure 15) results indicated that Form E crystals of the hydrochloride salt were poorly crystalline solids. TGA (Figure 16) results indicated that the sample continued to lose weight during the heating process. DSC (Figure 16) results indicated endothermic signals at approximately 89 °C and 201 °C. NMR (Figure 17) results showed peak shifts at 1.50-1.90 ppm, 2.98 ppm, 3.07 ppm, 6.90 ppm, and 7.08 ppm compared to the free state, suggesting salt formation in the sample. A cyclohexane solvent peak was observed at 1.39 ppm, suggesting the presence of a small amount of cyclohexane solvent remaining in the sample. In summary, Form E crystals of the hydrochloride salt may be an anhydrous form that absorbs water, or it may be a hydrate.

[0192] Example 9 Preparation of F-type crystals of hydrochloride 0.8 ml of isopropanol was added to 25.4 mg of N-type crystals, and 1 equivalent of hydrochloric acid was added. The mixture was stirred at room temperature for 2 days, the suspension was centrifuged, and the solid was dried in vacuo at room temperature to obtain F-type crystals of the hydrochloride salt. XRPD (Figure 18) results indicated that Form F crystals of the hydrochloride salt were solids with good crystallinity. TGA (Figure 19) results indicated that the sample lost 0.5% weight when heated to 150 °C and may decompose above 230 °C. DSC (Figure 19) results indicated endothermic signals at approximately 316 °C and 320 °C. NMR (Figure 20) results indicated multiple peak shifts at 1.50-1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm compared to the free state, suggesting salt formation in the sample. An isopropanol solvent peak was observed at 1.04 ppm, suggesting the presence of a small amount of isopropanol solvent in the sample. Ion chromatography results indicated that the salt formation ratio of Form F crystals of the hydrochloride salt was 1:1. In summary, Form F crystals of the hydrochloride salt are anhydrous crystals.

[0193] Example 10: Preparation of G-type crystals of sulfate salt To 26.1 mg of the compound represented by formula (I) was added 1.0 mL of cyclohexane, and 1 equivalent of concentrated sulfuric acid was added, followed by stirring at room temperature for 2 days and centrifuging to obtain G-type crystals of the sulfate salt. XRPD (Figure 21) results indicated that Form G crystals of the sulfate salt were solids with good crystallinity. TGA (Figure 22) results indicated that the sample lost 3.7% weight when heated to 150 °C and may decompose above 240 °C. DSC (Figure 22) results indicated endothermic signals at approximately 282 °C and 298 °C. NMR (Figure 23) results showed peak shifts at 1.50-1.90 ppm, 2.98 ppm, 3.07 ppm, 6.90 ppm, and 7.08 ppm compared to the free state, suggesting salt formation in the sample. A cyclohexane solvent peak was observed at 1.39 ppm, suggesting the presence of very small amounts of cyclohexane solvent in the sample. In summary, Form G crystals of the sulfate salt may be anhydrous or hydrated, absorbing water.

[0194] Example 11 Preparation of H-type crystals of succinate 0.8 ml of isopropanol was added to 24.1 mg of the compound represented by formula (I), and 1 equivalent of succinic acid was added thereto. The mixture was stirred at room temperature for 2 days and centrifuged to obtain H-form crystals of the succinate salt. XRPD (Figure 24) results indicated that the succinate salt, Form H, was a solid with good crystallinity. TGA (Figure 25) results indicated that the sample lost 0.2% weight when heated to 120°C and may decompose above 170°C. DSC (Figure 25) results indicated an endothermic signal at approximately 186°C. NMR (Figure 26) results showed peak shifts at 1.50-1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm compared to the free state, suggesting salt formation in the sample. A succinic acid signal peak was observed at 2.39 ppm. Based on the integration results, the ratio of API to succinic acid was calculated to be 1:1. An isopropanol solvent peak was observed at 1.04 ppm, suggesting the presence of a small amount of isopropanol solvent remaining in the sample. In summary, the H-form of the succinate salt is an anhydrous crystal.

[0195] Example 12: Preparation of J-type crystals of succinate To 24.7 mg of the compound represented by formula (I) was added 1.0 ml of methyl tert-butyl ether, and 1 equivalent of succinic acid was added, followed by stirring at room temperature for 2 days and centrifuging to obtain J-type crystals of the succinate salt. XRPD (Figure 27) results indicated that the succinate salt, Form J, was a solid with good crystallinity. TGA (Figure 28) results indicated that the sample lost 0.6% weight when heated to 150 °C and may decompose above 170 °C. DSC results indicated an endothermic signal at approximately 177 °C. NMR (Figure 29) results showed peak shifts at 1.50-1.90 ppm, 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm compared to the free state, suggesting salt formation in the sample. A succinic acid signal peak was observed at 2.39 ppm. Based on the integration results, the ratio of API to succinic acid was calculated to be 1:1. A methyl tert-butyl ether solvent peak was observed at 1.10 ppm, suggesting the presence of a small amount of methyl tert-butyl ether solvent remaining in the sample. In summary, the succinate salt crystalline form J is an anhydrous crystalline form.

[0196] Example 13: Preparation of K-type crystals of glycolic acid To 25.9 mg of the compound represented by formula (I) was added 1.0 ml of methyl tert-butyl ether, and 1 equivalent of glycolic acid was added, followed by stirring at room temperature for 2 days and centrifuging to obtain K-type crystals of the glycolate salt. XRPD (Figure 30) results indicated that the glycolate salt form K crystals were solid with good crystallinity. TGA (Figure 31) results indicated that the sample lost 0.7% weight when heated to 70°C, continued to lose weight during the subsequent heating process, and may decompose above 150°C. DSC results indicated an endothermic signal at approximately 98°C. NMR (Figure 32) results showed peak shifts at 2.98 ppm, 3.07 ppm, 4.11 ppm, 6.90 ppm, and 7.08 ppm compared to the free state, suggesting salt formation in the sample. A glycolic acid signal peak was observed at 3.87 ppm, and a methyl tert-butyl ether solvent peak was observed at 1.10 ppm, suggesting the presence of a very small amount of methyl tert-butyl ether solvent remaining in the sample. In summary, the glycolate salt form K crystals may be an anhydrate / hydrate.

[0197] Example 14: Preparation of L-type crystals of benzoic acid eutectic 0.8 mL of isopropanol was added to 24.7 mg of the compound represented by formula (I), and 1 equivalent of benzoic acid was added thereto. The mixture was stirred at room temperature for 2 days and centrifuged to obtain L-type crystals of eutectic benzoic acid. XRPD (Figure 33) results indicated that the L-form crystals of the benzoic acid eutectic were solids with good crystallinity. TGA (Figure 34) results indicated that the sample lost 1.6% weight when heated to 100 °C and may decompose above 135 °C. DSC (Figure 34) results indicated endothermic signals at approximately 165 °C and 177 °C. NMR (Figure 35) results showed no peak shift compared to the free state, suggesting no salt formation in the sample and possible eutectic formation. Benzoic acid signal peaks were observed between 7.0 and 8.5 ppm. Based on the integration results, the ratio of API to benzoic acid was calculated to be 1:1. An isopropanol solvent peak was observed at 1.04 ppm, suggesting the presence of a small amount of isopropanol solvent remaining in the sample. In summary, the L-form crystals of the benzoic acid eutectic are anhydrous crystals.

[0198] Example 15 Preparation of M-type crystals of benzoic acid eutectic To 25.2 mg of the compound represented by formula (I) was added 1.0 mL of cyclohexane, and 1 equivalent of benzoic acid was added. The mixture was stirred at room temperature for 2 days and centrifuged to obtain M-type crystals of a benzoic acid eutectic. XRPD (Figure 36) results indicated that the M-type crystals of the benzoic acid eutectic were poorly crystalline solids. TGA (Figure 37) results indicated that the sample lost 1.0% weight when heated to 100 °C and may decompose above 135 °C. DSC (Figure 37) results indicated an endothermic signal at approximately 175 °C. NMR (Figure 38) results showed no peak shift compared to the free state, suggesting no salt formation in the sample and possible eutectic formation. Benzoic acid signal peaks were observed between 7.0 and 8.5 ppm. Based on the integration results, calculations indicated a 1:1 ratio of the starting material to benzoic acid. A cyclohexane solvent peak was observed at 1.39 ppm, suggesting a small amount of cyclohexane solvent remained in the sample. In summary, the M-type crystals of the benzoic acid eutectic are anhydrous crystals.

[0199] Example 16: Preparation of N-type crystals To 20.4 mg of the compound represented by formula (I) was added 0.5 mL of toluene, and the mixture was suspended and stirred at 50° C. for 1 day, followed by centrifugation to obtain N-type crystals. The XRPD (Figure 39) results indicated that the N-type crystals were solids with good crystallinity. The TGA (Figure 40) results indicated that the N-type crystals lost 0.6% weight when heated to 150°C and may decompose above 300°C. The DSC (Figure 40) results indicated that the N-type crystals had a melting endothermic peak at approximately 208°C. The NMR (Figure 41) results indicated that a toluene solvent peak was observed at 2.30 ppm, suggesting that a small amount of toluene solvent remained in the sample. In summary, the N-type crystals are anhydrous crystals.

[0200] Example 17 Preparation of O-type crystals 19.5 mg of the compound represented by formula (I) was dissolved in 0.6 mL of ethanol, 9.0 mL of n-heptane was slowly added, and the mixture was stirred for 15 minutes and centrifuged to obtain O-type crystals. XRPD (Figure 42) results indicated that the O-type crystals were solids with good crystallinity. TGA (Figure 43) results indicated that the O-type crystals lost 2.6% weight when heated to 200°C and may decompose above 300°C. DSC (Figure 43) results indicated that the O-type crystals had an exothermic peak at approximately 196°C, an endothermic signal at approximately 190°C, and a melting endothermic peak at approximately 208°C. Thermal crystallization experiments indicated that the O-type crystals recrystallized to form the N-type crystals after desolvation. NMR (Figure 44) results indicated that the solvent peak for ethanol was observed at 1.06 ppm in this sample. Based on the integration results, the ratio of compound to ethanol was calculated to be 1:0.25, which is consistent with the weight loss observed in TGA (theoretical weight loss: 2.2%). In summary, type O crystals are ethanol / n-propanol solvates or anhydrous forms of the ethanol / n-propanol contained in the crystals.

[0201] Example 18: Production of P-type crystals 20.9 mg of the compound represented by formula (I) was dissolved in 1.4 mL of acetonitrile and 1.0 mL of water, and the solution was left at room temperature until the solvent was completely evaporated, followed by centrifugation to obtain P-type crystals. The XRPD (Figure 45) results showed that the P-type crystals were solids with good crystallinity and clear preferred orientation. The TGA (Figure 46) results showed that the P-type crystals lost 3.3% weight when heated to 175°C and may decompose above 300°C. The DSC (Figure 46) results showed that the P-type crystals had an exothermic peak at approximately 158°C, an endothermic signal at approximately 145°C, and a melting endothermic peak at approximately 211°C. The thermal crystallization experiment showed that the P-type crystals recrystallized to form N-type crystals after desolvation. The NMR (Figure 47) results showed that this sample had no obvious organic solvent peaks. In summary, the P-type crystals are hydrates.

[0202] Example 19: Preparation of Q-type crystals 19.9 mg of the compound represented by formula (I) was dissolved in 4.5 mL of diethyl ether, and the solution was left to stand at room temperature in an open state until the solvent was completely evaporated, to obtain Q-type crystals. The XRPD (Figure 48) results indicated that the Q-type crystals were solids with good crystallinity. The TGA (Figure 49) results indicated that the Q-type crystals lost 4.6% weight when heated to 180°C and may decompose above 300°C. The DSC (Figure 49) results indicated that the Q-type crystals had an exothermic peak at approximately 181°C, endothermic signals at approximately 171°C and 198°C, and a melting endothermic peak at approximately 207°C. The thermal crystallization experiment showed that the Q-type crystals recrystallized to form the N-type crystals after desolvation.

[0203] Example 20: Preparation of R-type crystals To 19.9 mg of the compound of formula (I), 0.8 mL of acetonitrile was added dropwise at room temperature until complete dissolution, and then 3.0 mL of water was added dropwise until a solid precipitated. After suspending at room temperature for 15 minutes, the reaction system was centrifuged and dried under vacuum at room temperature to obtain R-type crystals. The XRPD (Figure 50) results showed that the R-type crystals were solids with good crystallinity. The TGA (Figure 51) results showed that the R-type crystals lost 3.7% weight when heated to 150°C and may decompose above 300°C. The DSC (Figure 51) results showed that the R-type crystals had an exothermic peak at approximately 161°C, an endothermic signal at approximately 154°C, and a melting endothermic peak at approximately 211°C. The thermal crystallization experiment showed that the R-type crystals recrystallized to form the N-type crystals after desolvation. The NMR (Figure 52) results showed that there were no obvious organic solvent peaks. In summary, the R-type crystals are hydrates.

[0204] Example 21: Preparation of S-type crystals 400.0 mg of the compound represented by formula (I) was placed in a glass vial, and 10.5 mL of a mixed solvent of isopropanol / water (1 / 6, v / v) was added and suspended at 50° C. for 1 day. The resulting solid was centrifuged and vacuum-dried at 40° C. for 1 day to obtain S-type crystals. The XRPD (Figure 53) results showed that the S-type crystals were solids with good crystallinity. The TGA (Figure 54) results showed that the S-type crystals lost 3.6% weight when heated to 150°C and may decompose above 300°C. The DSC (Figure 54) results showed that the S-type crystals had an exothermic peak at approximately 155°C, an endothermic signal at approximately 126°C, and a melting endothermic peak at approximately 210°C. The thermal crystallization experiment showed that the S-type crystals recrystallized to become the N-type crystals after desolvation. In summary, the S-type crystals are a hydrate. The NMR is shown in Figure 55.

[0205] Example 22: Preparation of T-type crystals 20.4 mg of the compound represented by formula (I) was dissolved in 0.1 mL of dichloromethane, opened at room temperature to volatilize, and dried to obtain T-type crystals. The XRPD (Figure 56) results indicated that the T-type crystals were solids with good crystallinity. The TGA (Figure 57) results indicated that the T-type crystals lost 6.7% weight when heated to 200°C and may decompose above 300°C. The DSC (Figure 57) results indicated that the T-type crystals had an exothermic peak at approximately 191°C, an endothermic signal at approximately 186°C, and a melting endothermic peak at approximately 209°C. The NMR (Figure 58) results indicated that the structure of the compound did not change, and solvent peaks of dichloromethane and a small amount of dioxane were observed 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 summary, the T-type crystals are a solvate of methylene chloride or an anhydrous form of the methylene chloride contained in the crystals.

[0206] Example 23: Preparation of U-type crystals 1.0 mL of cyclohexane was added to 23.5 mg of the compound represented by formula (I), and 1 equivalent of propionic acid was added thereto. The mixture was stirred at room temperature for 2 days, the suspension was centrifuged, and the solid was dried in vacuo at room temperature to obtain U-type crystals. XRPD (Figure 59) results indicated that it was a solid with good crystallinity. TGA (Figure 60) results indicated that the sample lost 18.0% weight when heated to 130°C, corresponding to the weight loss of two propionic acid molecules. DSC (Figure 60) results indicated endothermic signals at approximately 109°C, 121°C, and 204°C. NMR (Figure 61) results indicated no peak shift compared to the free state, indicating no salt formation in the sample. The propionic acid signal peaks were at 0.99 ppm and 2.20 ppm. Based on the integration results, the API to propionic acid ratio was calculated to be 1:2. A cyclohexane solvent peak was observed at 1.39 ppm, suggesting the presence of a small amount of cyclohexane solvent remaining in the sample. In summary, the U-type crystals are propionic acid solvates.

[0207] Example 24 Stability Studies A stability study was conducted on the maleate type A crystals and the fumarate type C, N, and S crystals under conditions of high temperature (60°C), high humidity (25°C / 92.5%RH), light irradiation (25°C / 4500 Lux), and accelerated exposure (40°C / 75%RH). Samples were taken at 7 and 15 days, respectively, and characterized by XRPD. The results are shown in Table 28 and Figures 62-65. The XRPD results showed that the maleate type A crystals and the fumarate type C crystals were stable for 15 days under high temperature, high humidity, light irradiation, and accelerated exposure conditions, and no changes in the crystals were observed.

[0208] Table 28 [Table 28]

[0209] Example 25 Solubility Test in Biological Media Kinetic solubility measurements were performed in three biological media (FaSSIF, FeSSIF and FaSSGF) and the results are shown in Table 29 below and Figures 66 and 67.

[0210] Table 29 [Table 29] *The sample was first dissolved in FaSSGF and then shaken for 24 hours, and the precipitated solid was amorphous.

[0211] In the description herein, the use of terms such as "one embodiment," "some embodiments," "examples," "specific examples," or "some examples" means that a particular feature, structure, material, or characteristic described with reference to an embodiment or example is included in at least one embodiment or example of the present invention. In this specification, general descriptions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described can be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the various embodiments or examples described herein, and the features of the various embodiments or examples, can be combined by those skilled in the art to the extent that they are not mutually inconsistent.

[0212] Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are illustrative and are not to be construed as limiting the present invention, and that changes, modifications, substitutions and variations of the above embodiments may be made by those skilled in the art within the scope of the present invention.

Claims

1. A maleate salt of the compound of formula (I), having the structure of formula (II). 【Chemical 1】

2. A type A crystal of the maleate salt of the compound of formula (I), The powder X-ray diffraction spectrum of the A-type crystal 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°, Optionally, the powder X-ray diffraction spectrum of the Form A crystal 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°; Optionally, the powder X-ray diffraction spectrum of the Form A crystal 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°; Optionally, the powder X-ray diffraction spectrum of the Form A crystal 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°; Optionally, a Form A crystal of the maleate salt of the compound of formula (I), wherein the Form A crystal has an X-ray powder diffraction spectrum essentially as shown in FIG.

1.

3. A B-type crystal of the maleate salt of the compound of formula (I), The powder X-ray diffraction spectrum of the B-type crystals 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°, Optionally, the powder X-ray diffraction spectrum of the Type B crystals 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°; Optionally, a Form B crystal of the maleate salt of the compound of formula (I), wherein the Form B crystal has an X-ray powder diffraction spectrum essentially as shown in FIG.

6.

4. A fumarate salt of the compound of formula (I), having the structure of formula (III): 【Chemistry 2】

5. Form C crystals of the fumarate salt of the compound of formula (I), The powder X-ray diffraction spectrum of the C-type crystal 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°, and 21.87±0.2°, Optionally, the powder X-ray diffraction spectrum of the C-type crystals 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°; Optionally, a Form C crystalline form of a fumarate salt of the compound of Formula (I), wherein the Form C crystalline form has an X-ray powder diffraction spectrum essentially as shown in Figure 9.

6. The hydrochloride salt of the compound of formula (I), having the structure of formula (IV): 【Chemistry 3】

7. A D-type crystal of the hydrochloride salt of the compound of formula (I), The powder X-ray diffraction spectrum of the D-type crystal 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°, Optionally, the powder X-ray diffraction spectrum of the D-type crystals 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°; Optionally, Form D crystals of the hydrochloride salt of the compound of formula (I), wherein the powder X-ray diffraction spectrum of said Form D crystals has an X-ray powder diffraction spectrum essentially as shown in FIG.

12.

8. Form E crystals of the hydrochloride salt of the compound of formula (I), The powder X-ray diffraction spectrum of the E-type crystal 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°, and 21.24±0.2°, Optionally, the powder X-ray diffraction spectrum of the Form E crystals 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°; Optionally, Form E crystals of the hydrochloride salt of the compound of formula (I), wherein the Form E crystals have an X-ray powder diffraction spectrum essentially as shown in Figure 15.

9. Form F crystals of the hydrochloride salt of the compound of formula (I), The powder X-ray diffraction spectrum of the F-type crystal 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°, Optionally, the powder X-ray diffraction spectrum of the F-type crystals 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°; Optionally, Form F crystals of the hydrochloride salt of the compound of formula (I), wherein the Form F crystals have an X-ray powder diffraction spectrum essentially as shown in Figure 18.

10. The sulfate salt of the compound of formula (I), having the structure of formula (V): 【Chemistry 4】

11. A G-type crystal of the sulfate salt of the compound represented by formula (I), The powder X-ray diffraction spectrum of the G-type crystal 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°, and 22.26±0.2°, Optionally, the powder X-ray diffraction spectrum of the G-type crystals 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°; Optionally, a Form G crystal of the sulfate salt of the compound of Formula (I), wherein the Form G crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 21.

12. A succinate salt of the compound of formula (I), having the structure of formula (VI): 【Chemistry 5】

13. H-type crystals of the succinate salt of the compound represented by formula (I), The powder X-ray diffraction spectrum of the H-type crystal 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°, Optionally, the powder X-ray diffraction spectrum of the H-type crystals 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°; Optionally, a Form H crystal of a succinate salt of the compound of formula (I), wherein the Form H crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 24.

14. A J-type crystal of the succinate salt of the compound represented by formula (I), The powder X-ray diffraction spectrum of the J-type crystal 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°, Optionally, the powder X-ray diffraction spectrum of the J-type crystal 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°; Optionally, a Form J crystal of a succinate salt of the compound of formula (I), wherein the Form J crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 27.

15. A glycolate salt of the compound of formula (I), having the structure of formula (VII): 【Chemistry 6】

16. A K-type crystal of the glycolate salt of the compound of formula (I), The powder X-ray diffraction spectrum of the K-type crystal 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°, and 21.64±0.2°, Optionally, the powder X-ray diffraction spectrum of the Type K crystal 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°; Optionally, a Form K crystal of the glycolic acid salt of the compound of formula (I), wherein the Form K crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 30.

17. A benzoate salt of the compound of formula (I), having the structure of formula (VIII): 【Chemistry 7】

18. An M-type crystal of a benzoic acid eutectic of the compound represented by formula (I), The powder X-ray diffraction spectrum of the M-type crystal 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°, Optionally, the powder X-ray diffraction spectrum of the M-type crystals 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°; Optionally, a Type M crystal of a benzoic acid co-crystal of the compound of formula (I), wherein the Type M crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 36.

19. N-type crystals of the compound represented by formula (I), The powder X-ray diffraction spectrum of the N-type crystal 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°, Optionally, the powder X-ray diffraction spectrum of the N-type crystal 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°; Optionally, a Form N crystal of the compound of Formula (I), wherein the powder X-ray diffraction spectrum of said Form N crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 39.

20. An O-type crystal of the compound represented by formula (I), The powder X-ray diffraction spectrum of the O-type crystals 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°, Optionally, the powder X-ray diffraction spectrum of the O-type crystals 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°; Optionally, a Form O crystal of the compound of formula (I), wherein the powder X-ray diffraction spectrum of said Form O crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 42.

21. A P-type crystal of the compound represented by formula (I), The powder X-ray diffraction spectrum of the P-type crystal 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°, Optionally, a P-form crystal of the compound of Formula (I), wherein the P-form crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 45.

22. A Q-type crystal of the compound represented by formula (I), The powder X-ray diffraction spectrum of the Q-type crystal 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°, Optionally, the powder X-ray diffraction spectrum of the Q-type crystals 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°; Optionally, a Form Q crystal of the compound of Formula (I), wherein the powder X-ray diffraction spectrum of said Form Q crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 48.

23. An R-type crystal of the compound represented by formula (I), The powder X-ray diffraction spectrum of the R-type crystal 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°, Optionally, a Form R crystal of the compound of formula (I), wherein the powder X-ray diffraction spectrum of the Form R crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 50.

24. An S-type crystal of the compound represented by formula (I), The powder X-ray diffraction spectrum of the S-type crystal 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°, Optionally, a Form S crystal of the compound of formula (I), wherein the powder X-ray diffraction spectrum of said Form S crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 53.

25. A T-type crystal of the compound represented by formula (I), The powder X-ray diffraction spectrum of the T-type crystals 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°, Optionally, the powder X-ray diffraction spectrum of the T-type crystals 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°; Optionally, a T-type crystal of the compound of Formula (I), wherein the powder X-ray diffraction spectrum of said T-type crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 56.

26. A U-type crystal of the compound represented by formula (I), The powder X-ray diffraction spectrum of the U-type crystal 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°, Optionally, the powder X-ray diffraction spectrum of the U-type crystals 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°; Optionally, a Form U crystal of the compound of Formula (I), wherein the powder X-ray diffraction spectrum of said Form U crystal has an X-ray powder diffraction spectrum essentially as shown in Figure 59.

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