Salt form and crystal form of a thienone derivative

Abstract

This invention discloses a salt form, crystal form and preparation method of a thienone derivative, specifically the salt form, crystal form and preparation method of the compound of formula (I).

Description

[0001] This invention claims the following priority:

[0002] CN202210984344.5, application date August 16, 2022. Technical Field

[0003] This invention relates to a salt form, crystal form and preparation method of a thienopyrimidine ketone derivative, specifically disclosing the salt form, crystal form and preparation method of the compound of formula (I). Background Technology

[0004] Endometriosis is the growth of endometrial glands or stroma outside the uterus. Symptoms include chronic pelvic pain, dysmenorrhea, and infertility. It is extremely difficult to cure and prone to recurrence, making it considered one of the most challenging gynecological diseases. Clinical medications for this disease have drawbacks such as long treatment duration, numerous side effects, and inconvenient administration. It is estimated that approximately 176 million women worldwide suffered from endometriosis in 2021.

[0005] The causes of endometriosis are very complex, and its pathogenesis is not fully understood. Clinical drug treatment plans either control estrogen levels, control inflammation, or both. Treatment drugs mainly include nonsteroidal anti-inflammatory drugs (NSAIDs), progestins, combined oral contraceptives, and gonadotropin-releasing hormone (GnRH) agonists. Among these, oral contraceptives have a non-response rate of approximately one-third to one-quarter of patients; progestins have the side effect of easily causing obesity, and should be contraindicated, especially for patients wanting to conceive; and gonadotropin-releasing hormone has perimenopausal side effects. Peptide GnRH receptor agonists or antagonists have many problems, such as oral absorption, dosage form, dose-volume relationship, drug stability, duration of action, and metabolic stability.

[0006] GnRH receptor antagonists competitively bind to GnRH receptors, blocking the binding of GnRH to the receptors and directly inhibiting the hypothalamus-pituitary-ovarian axis. This, in turn, suppresses the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), lowering estrogen levels. They are characterized by rapid onset of action and minimal side effects. Currently, besides Elagolix, the first small-molecule GnRH receptor antagonist to be marketed, Relugolix, the second small-molecule oral antagonist approved by the FDA in December 2020, has its first indication approved for the treatment of advanced prostate cancer. Its indication for treating uterine fibroids has been approved in Japan, and its indication for endometriosis has entered phase III clinical trials. The third antagonist, Linzagolix, is also in phase III clinical trials for the treatment of both endometriosis and uterine fibroids.

[0007] The crystal structure of a pharmaceutical active ingredient often affects its stability. Generally, amorphous drug products lack regular crystal structures and often have defects, such as poor stability, tendency to clump, small particle size, and difficulty in filtration. Furthermore, the solubility of a drug molecule is closely related to its oral absorption. Drugs can increase their solubility by forming salts with suitable acids or bases. Simultaneously, salt formation can help increase the stability of easily oxidized drug molecules, facilitating storage and transportation. Therefore, we need to conduct in-depth research and find suitable salt forms and crystal forms for drug molecules, especially new crystal forms with good stability. Summary of the Invention

[0008] This invention provides the B crystal form of the compound of formula (I).

[0009]

[0010] The X-ray powder diffraction pattern of Cu Kα radiation of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 7.35±0.20° and 18.34±0.20°.

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 7.35±0.20°, 11.45±0.20°, 12.33±0.20° and 18.34±0.20°.

[0012] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 7.35±0.20°, 11.45±0.20°, 12.33±0.20°, 18.34±0.20°, 22.41±0.20°, 26.54±0.20° and 27.08±0.20°.

[0013] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 7.35±0.20°, 11.45±0.20°, 12.33±0.20°, 13.75±0.20°, 17.89±0.20°, 18.34±0.20°, 20.92±0.20°, 22.41±0.20°, 25.43±0.20°, 26.54±0.20°, and 27.08±0.20°.

[0014] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 7.35±0.20°, 9.17±0.20°, 11.45±0.20°, 12.33±0.20°, 13.75±0.20°, 17.89±0.20°, 18.34±0.20°, 20.92±0.20°, 22.41±0.20°, 23.57±0.20°, 24.46±0.20°, 25.43±0.20°, 26.54±0.20°, 27.08±0.20°, and 28.81±0.20°.

[0015] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 7.35±0.20°, 18.34±0.20°, and / or 9.17±0.20°, and / or 11.45±0.20°, and / or 12.33±0.20°, and / or 13.17±0.20°, and / or 13.75±0.20°, and / or 14.34±0.20°, and / or 14.67±0.20°, and / or 16.50±0.20°, and / or 17. 43±0.20°, and / or 17.89±0.20°, and / or 19.45±0.20°, and / or 20.92±0.20°, and / or 22.41±0.20°, and / or 23.57±0.20°, and / or 24.46±0.20°, and / or 25.43±0.20°, and / or 25.89±0.20°, and / or 26.54±0.20°, and / or 27.08±0.20°, and / or 28.81±0.20°, and / or 31.69±0.20°.

[0016] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.62°, 7.35°, 9.17°, 11.45°, 12.33°, 13.17°, 13.75°, 14.34°, 14.67°, 16.50°, 17.43°, 17.89°, 18.34°, 19.45°, 20.92°, 21.68°, 22.41°, 23.57°, 24.46°, 25.43°, 25.89°, 26.54°, 27.08°, and 28.81°.

[0017] In some embodiments of the present invention, the above-mentioned B-type Cu The X-ray powder diffraction pattern of Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.62°, 7.35°, 9.17°, 11.45°, 12.33°, 13.17°, 13.75°, 14.34°, 14.67°, 16.50°, 17.43°, 17.89°, 18.34°, 19.45°, 20.92°, 21.68°, 22.41°, 23.57°, 24.46°, 25.43°, 25.89°, 26.54°, 27.08°, 28.81°, 30.27°, 31.69°, 33.32°, 33.71°, 33.99°, 35.25°, 36.92°, and 37.69°.

[0018] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned B-type crystal is essentially as follows: Figure 1 As shown.

[0019] In some embodiments of the present invention, the diffraction peak data of the XRPD pattern of Cu Kα radiation of the above-mentioned B crystal form are shown in Table 1:

[0020] Table 1 shows the XRPD diffraction data of compound B (I) crystal form.

[0021]

[0022]

[0023] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned B crystal form shows a peak value with an exothermic peak at 224.4℃±3℃.

[0024] In one embodiment of the present invention, the DSC spectrum of the B crystal form is substantially as follows: Figure 2 As shown.

[0025] In one embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned B crystal form shows a weight loss of 1.12% at 150℃±3℃.

[0026] In one embodiment of the present invention, the TGA pattern of the B crystal form is substantially as follows: Figure 3 As shown.

[0027] The present invention also provides a method for preparing the B crystal form of the compound of formula (I), comprising the following steps:

[0028] (a) Add the compound of formula (I) to water or a mixed solvent of acetonitrile / water (volume ratio 1:5 to 1:50) at 70°C to 95°C;

[0029] (b) Stir for 10–48 hours;

[0030] (c) Filtering;

[0031] (d) The filter cake is dried at 50℃-70℃.

[0032] The present invention also provides the C crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of Cu Kα radiation of the C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.18±0.20°, 8.47±0.20° and 12.8±0.20°.

[0033] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.18±0.20°, 8.47±0.20°, 12.80±0.20°, 15.80±0.20° and 23.30±0.20°.

[0034] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.18±0.20°, 8.47±0.20°, 11.55±0.20°, 12.80±0.20°, 15.80±0.20°, 16.96±0.20°, 19.23±0.20° and 20.12±0.20°.

[0035] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.18±0.20°, 8.47±0.20°, 11.55±0.20°, 12.80±0.20°, 15.80±0.20°, 16.96±0.20°, 19.23±0.20°, 20.12±0.20°, 23.30±0.20° and 26.31±0.20°.

[0036] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C-type has characteristic diffraction peaks at the following 2θ angles: 7.18±0.20°, 8.47±0.20°, 12.80±0.20°, and / or 11.55±0.20°, and / or 15.80±0.20°, and / or 16.96±0.20°, and / or 19.23±0.20°, and / or 20.12±0.20°, and / or 23.30±0.20° and / or 26.31±0.20°.

[0037] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.18°, 8.47°, 11.55°, 12.80°, 15.80°, 16.96°, 19.23°, 20.12°, 23.30° and 26.31°.

[0038] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned C-type crystal is essentially as follows: Figure 4 As shown.

[0039] In some embodiments of the present invention, the diffraction peak data of the XRPD pattern of Cu Kα radiation of the above-mentioned C crystal form are shown in Table 2:

[0040] Table 2 shows the XRPD diffraction data of compound C (I)

[0041]

[0042] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned C crystal form shows a peak value with an exothermic peak at 225.1℃±3℃.

[0043] In one embodiment of the present invention, the DSC pattern of the C-type crystal is substantially as follows: Figure 5 As shown.

[0044] In one embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned C crystal form shows a weight loss of 1.13% at 150℃±3℃.

[0045] In one embodiment of the present invention, the TGA pattern of the C-type crystal is substantially as follows: Figure 6 As shown.

[0046] The present invention also provides the Al crystal form of the compound of formula (I), wherein the Cu Kα radiation X-ray powder diffraction pattern of the Al crystal form has characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.13±0.20°, 11.01±0.20°, 21.60±0.20° and 22.10±0.20°.

[0047] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned Al crystal form has characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.13±0.20°, 11.01±0.20°, 16.15±0.20°, 21.60±0.20°, 22.10±0.20°, 23.66±0.20°, and 24.60±0.20°.

[0048] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned Al crystal form has characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.13±0.20°, 9.71±0.20°, 11.01±0.20°, 11.81±0.20°, 15.17±0.20°, 16.15±0.20°, 21.60±0.20°, 22.10±0.20°, 23.01±0.20°, 23.66±0.20°, and 24.60±0.20°.

[0049] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the Al crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 7.15°, 7.85°, 9.13°, 9.71°, 11.01°, 11.81°, 12.63°, 13.12°, 15.17°, 15.72°, 16.15°, 16.90°, 17.43°, 18.30°, 18.81°, 19.32°. °, 19.67°, 20.39°, 21.60°, 22.10°, 23.01°, 23.66°, 24.60°, 25.40°, 26.17°, 26.94°, 27.42°, 28.16°, 29.94°, 30.54°, 32.96°, 33.50°, 35.54°, 37.22° and 38.58°.

[0050] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the Al crystal form described above is essentially as follows: Figure 7 As shown.

[0051] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the Al crystal form described above are shown in Table 3:

[0052] Table 3 shows the XRPD diffraction data of compound A1 (Formula I).

[0053]

[0054]

[0055] The present invention also provides a D-type of the compound of formula (I), wherein the Cu Kα radiation X-ray powder diffraction pattern of the D-type has characteristic diffraction peaks at the following 2θ angles: 7.35±0.20°, 13.02±0.20°, 16.18±0.20°, 20.10±0.20° and 21.91±0.20°.

[0056] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 7.35±0.20°, 13.02±0.20°, 16.18±0.20°, 20.10±0.20°, 21.91±0.20°, 24.41±0.20°, 25.03±0.20° and 27.49±0.20°.

[0057] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 7.35±0.20°, 9.36±0.20°, 10.90±0.20°, 13.02±0.20°, 16.18±0.20°, 18.80±0.20°, 20.10±0.20°, 21.91±0.20°, 22.40±0.20°, 24.41±0.20°, 25.03±0.20°, and 27.49±0.20°.

[0058] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 7.35°, 8.41°, 9.36°, 10.49°, 10.90°, 11.55°, 12.11°, 13.02°, 13.79°, 14.68°, 15.07°, 16.18°, 16.53°, 16.77°, 17.83°, 18.80°, 20.10°, 20.75°, 21.75°, 21.91°, 22.40°, 23.45°, 24.41°, 25.03°, 26.48°, 26.86°, 27.49°, 28.45°, and 29.04°.

[0059] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.35°, 8.41°, 9.36°, 10.49°, 10.90°, 11.55°, 12.11°, 13.02°, 13.79°, 14.68°, 15.07°, 16.18°, 16.53°, 16.77°, 17.8°. 3°, 18.80°, 20.10°, 20.75°, 21.75°, 21.91°, 22.40°, 23.45°, 24.41°, 25.03°, 26.48°, 26.86°, 27.49°, 28.45°, 29.04°, 30.16°, 30.67°, 31.56° and 34.26°.

[0060] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned D-type crystal is essentially as follows: Figure 8 As shown.

[0061] In some embodiments of the present invention, the diffraction peak data of the XRPD pattern of Cu Kα radiation of the above-mentioned D crystal form are shown in Table 4:

[0062] Table 4 shows the XRPD diffraction data of compound D (I).

[0063]

[0064]

[0065] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned D crystal form shows a peak value with an exothermic peak at 220.0℃±3℃.

[0066] In one embodiment of the present invention, the DSC pattern of the above-mentioned D crystal form is substantially as follows: Figure 9 As shown.

[0067] In one embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned D crystal form shows a weight loss of 2.05% at 150.0℃±3℃.

[0068] In one embodiment of the present invention, the TGA pattern of the above-mentioned D crystal form is substantially as follows: Figure 10 As shown.

[0069] The present invention also provides the E crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of Cu Kα radiation of the E crystal form has characteristic diffraction peaks at the following 2θ angles: 4.49±0.20°, 6.15±0.20°, 13.40±0.20°, 17.26±0.20° and 26.04±0.20°.

[0070] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned E-type has characteristic diffraction peaks at the following 2θ angles: 4.49±0.20°, 6.15±0.20°, 8.92±0.20°, 11.47±0.20°, 12.30±0.20°, 13.40±0.20°, 17.26±0.20° and 26.04±0.20°.

[0071] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned E-type has characteristic diffraction peaks at the following 2θ angles: 4.49±0.20°, 6.15±0.20°, 8.92±0.20°, 11.47±0.20°, 12.30±0.20°, 13.40±0.20°, 16.56±0.20°, 17.26±0.20°, 19.03±0.20°, 21.01±0.20°, 26.04±0.20°, and 26.60±0.20°.

[0072] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned E-type has characteristic diffraction peaks at the following 2θ angles: 4.49°, 6.15°, 8.92°, 11.47°, 12.30°, 13.40°, 14.59°, 16.56°, 17.26°, 19.03°, 21.01°, 22.16°, 23.88°, 24.54°, 26.04°, 26.60°, 27.47°, and 27.96°.

[0073] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned E-type has characteristic diffraction peaks at the following 2θ angles: 4.49°, 6.15°, 8.92°, 11.47°, 12.30°, 13.40°, 14.59°, 16.56°, 17.26°, 19.03°, 21.01°, 22.16°, 23.88°, 24.54°, 26.04°, 26.60°, 27.47°, 27.96°, 30.60°, 31.71°, 33.61°, and 37.65°.

[0074] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned E-crystal form is essentially as follows: Figure 11 As shown.

[0075] In some embodiments of the present invention, the diffraction peak data of the XRPD pattern of Cu Kα radiation of the above-mentioned E crystal form are shown in Table 5:

[0076] Table 5 shows the XRPD diffraction data of compound E crystal form (I).

[0077]

[0078]

[0079] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned E crystal form shows a peak value with an exothermic peak at 211.8℃±3℃.

[0080] In one embodiment of the present invention, the DSC spectrum of the above-mentioned E-type crystal is substantially as follows: Figure 12 As shown.

[0081] In one embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned E crystal form shows a weight loss of 2.61% at 150.0℃±3℃.

[0082] In one embodiment of the present invention, the TGA pattern of the above-mentioned E-type crystal is substantially as follows: Figure 13 As shown.

[0083] The present invention also provides the F crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of Cu Kα radiation of the F crystal form has characteristic diffraction peaks at the following 2θ angles: 8.20±0.20°, 16.73±0.20°, 21.84±0.20°, 23.99±0.20° and 24.56±0.20°.

[0084] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 8.20±0.20°, 16.73±0.20°, 17.90±0.20°, 19.03±0.20°, 20.38±0.20°, 21.84±0.20°, 23.99±0.20° and 24.56±0.20°.

[0085] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 8.20±0.20°, 13.49±0.20°, 16.73±0.20°, 17.90±0.20°, 19.03±0.20°, 20.38±0.20°, 21.84±0.20°, 22.38±0.20°, 23.99±0.20°, 24.56±0.20°, 25.45±0.20°, and 29.34±0.20°.

[0086] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 8.20°, 10.86°, 11.79°, 12.41°, 13.49°, 14.79°, 16.73°, 17.90°, 19.03°, 20.38°, 21.84°, 22.38°, 22.91°, 23.99°, 24.56°, 25.45°, 26.43°, 27.33°, 28.76°, and 29.34°.

[0087] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned F-type crystal is essentially as follows: Figure 14As shown.

[0088] In some embodiments of the present invention, the diffraction peak data of the XRPD pattern of Cu Kα radiation of the above-mentioned F crystal form are shown in Table 6:

[0089] Table 6 shows the XRPD diffraction data of compound F (I)

[0090]

[0091]

[0092] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned F crystal form shows a peak value with an exothermic peak at 225.8℃±3℃.

[0093] In one embodiment of the present invention, the DSC spectrum of the above-mentioned F crystal form is substantially as follows: Figure 15 As shown.

[0094] In one embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned F crystal form shows a weight loss of 2.20% at 150.0℃±3℃.

[0095] In one embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned F crystal form shows a weight loss of 2.20% at 150.0℃±3℃ and a further weight loss of 4.01% at 220.0℃±3℃.

[0096] In one embodiment of the present invention, the TGA pattern of the above-mentioned F crystal form is substantially as follows: Figure 16 As shown.

[0097] The present invention also provides the G crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of Cu Kα radiation of the G crystal form has characteristic diffraction peaks at the following 2θ angles: 8.55±0.20°, 12.62±0.20°, 24.96±0.20° and 25.39±0.20°.

[0098] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned G crystal form has characteristic diffraction peaks at the following 2θ angles: 8.55±0.20°, 12.62±0.20°, 14.95±0.20°, 15.64±0.20°, 19.90±0.20°, 24.96±0.20°, 25.39±0.20° and 26.90±0.20°.

[0099] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned G crystal form has characteristic diffraction peaks at the following 2θ angles: 8.55±0.20°, 12.62±0.20°, 14.95±0.20°, 15.64±0.20°, 18.87±0.20°, 19.90±0.20°, 22.54±0.20°, 24.96±0.20°, 25.39±0.20°, 25.85±0.20°, 26.90±0.20°, and 28.15±0.20°.

[0100] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned G crystal form has characteristic diffraction peaks at the following 2θ angles: 6.34°, 8.31°, 8.55°, 9.05°, 10.71°, 11.67°, 12.22°, 12.62°, 12.86°, 14.18°, 14.95°, 15.64°, 16.02°, 16.49°, 17.15°, 1 7.66°, 18.16°, 18.87°, 19.34°, 19.90°, 21.16°, 21.49°, 22.54°, 22.77°, 23.34°, 24.20°, 24.61°, 24.96°, 25.39°, 25.85°, 26.90°, 28.15°, 29.12° and 29.80°.

[0101] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned G crystal form has characteristic diffraction peaks at the following 2θ angles: 6.34°, 8.31°, 8.55°, 9.05°, 10.71°, 11.67°, 12.22°, 12.62°, 12.86°, 14.18°, 14.95°, 15.64°, 16.02°, 16.49°, 17.15°, 17.66°, 18.16°, 18.87°, 1 9.34°, 19.90°, 21.16°, 21.49°, 22.54°, 22.77°, 23.34°, 24.20°, 24.61°, 24.96°, 25.39°, 25.85°, 26.90°, 28.15°, 29.12°, 29.80°, 30.59°, 31.76°, 32.57°, 33.72°, 35.90°, and 37.86°.

[0102] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned G crystal form is essentially as follows: Figure 17 As shown.

[0103] In some embodiments of the present invention, the diffraction peak data of the XRPD pattern of Cu Kα radiation of the above-mentioned G crystal form are shown in Table 7:

[0104] Table 7 shows the XRPD diffraction data of compound G (I) crystal form.

[0105]

[0106]

[0107]

[0108] The present invention also provides the H crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of Cu Kα radiation of the H crystal form has characteristic diffraction peaks at the following 2θ angles: 9.57±0.20°, 12.16±0.20°, 12.58±0.20°, 16.74±0.20° and 25.02±0.20°.

[0109] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned H-type has characteristic diffraction peaks at the following 2θ angles: 9.57±0.20°, 12.16±0.20°, 12.58±0.20°, 16.14±0.20°, 16.74±0.20°, 19.10±0.20°, 25.02±0.20° and 25.79±0.20°.

[0110] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned H-type has characteristic diffraction peaks at the following 2θ angles: 9.57±0.20°, 11.52±0.20°, 12.16±0.20°, 12.58±0.20°, 16.14±0.20°, 16.74±0.20°, 19.10±0.20°, 21.39±0.20°, 23.69±0.20°, 25.02±0.20°, 25.79±0.20°, and 26.86±0.20°.

[0111] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned H-type has characteristic diffraction peaks at the following 2θ angles: 6.42°, 8.37°, 9.57°, 11.52°, 12.16°, 12.58°, 12.97°, 13.99°, 16.14°, 16.74°, 17.94°, 19.10°, 19.46°, 21.07°, 21.39°, 21.96°, 23.69°, 25.02°, 25.79°, and 26.86°.

[0112] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the H-type crystal is essentially as follows: Figure 18 As shown.

[0113] In some embodiments of the present invention, the diffraction peak data of the XRPD pattern of Cu Kα radiation of the above-mentioned H-type crystal are shown in Table 8:

[0114] Table 8 shows the XRPD diffraction data of compound H (I) crystal form.

[0115]

[0116]

[0117] The present invention also provides pharmaceutically acceptable salts of compounds of formula (I),

[0118]

[0119] The pharmaceutically acceptable salts of the compound are lysine salts, dibenzylethylenediamine salts, choline salts, meglumine salts, triethylamine salts, aluminum salts, zinc salts, lithium salts, sodium salts, potassium salts, calcium salts, or magnesium salts.

[0120] In some embodiments of the present invention, the structure of the choline salt of the compound of formula (I) is shown in formula (II), the structure of the sodium salt of the compound of formula (I) is shown in formula (III), and the structure of the dibenzylethylenediamine salt of the compound of formula (I) is shown in formula (IV).

[0121]

[0122] Wherein, m is selected from 0.5 to 1.5; n is selected from 0.5 to 1.5; and p is selected from 0.4 to 1.5. In some embodiments of the present invention, the above m is selected from 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, and 1.5.

[0123] In some embodiments of the present invention, m is selected from 0.8, 0.9, 1.0, 1.1 and 1.2.

[0124] In some embodiments of the present invention, m is selected from 1.0.

[0125] In some embodiments of the present invention, the above n is selected from 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 and 1.5.

[0126] In some embodiments of the present invention, n is selected from 0.8, 0.9, 1.0, 1.1 and 1.2.

[0127] In some embodiments of the present invention, n is selected from 1.0.

[0128] In some embodiments of the present invention, the above p is selected from 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 and 1.5.

[0129] In some embodiments of the present invention, p is selected from 0.4, 0.5, 0.6, 0.9, 1.0 and 1.1.

[0130] In some embodiments of the present invention, p is selected from 0.5 and 1.0.

[0131] In some embodiments of the present invention, the compound of formula (II) is selected from the compound of formula (II-1).

[0132]

[0133] The present invention also provides the S1 crystal form of the compound of formula (II-1), wherein the X-ray powder diffraction pattern of Cu Kα radiation of the S1 crystal form has characteristic diffraction peaks at the following 2θ angles: 8.68±0.20°, 12.70±0.20°, 18.12±0.20°, 19.43±0.20° and 24.41±0.20°.

[0134] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned S1 crystal form has characteristic diffraction peaks at the following 2θ angles: 8.68±0.20°, 12.27±0.20°, 12.70±0.20°, 15.20±0.20°, 18.12±0.20°, 18.95±0.20°, 19.43±0.20° and 24.41±0.20°.

[0135] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned S1 crystal form has characteristic diffraction peaks at the following 2θ angles: 8.68±0.20°, 12.27±0.20°, 12.70±0.20°, 15.20±0.20°, 16.94±0.20°, 17.37±0.20°, 18.12±0.20°, 18.95±0.20°, 19.43±0.20°, 24.41±0.20°, 25.51±0.20°, and 27.62±0.20°.

[0136] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned S1 crystal form has characteristic diffraction peaks at the following 2θ angles: 5.98°, 8.68°, 9.67°, 11.39°, 12.27°, 12.70°, 13.61°, 15.20°, 16.09°, 16.94°, 17.37°, 18.12°, 18.95°, 19.43°, 19.93°, 20.35°, 20.91°, 21.44°, 21.69°, 22.05°, 23.32°, 23.85°, 24.41°, 25.51°, 27.11°, 27.62°, 29.05°, and 29.85°.

[0137] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned S1 crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 5.98°, 8.68°, 9.67°, 11.39°, 12.27°, 12.70°, 13.61°, 15.20°, 16.09°, 16.94°, 17.37°, 18.12°, 18.95°, 19.43°, 19.93°, 20.3°. 5°, 20.91°, 21.44°, 21.69°, 22.05°, 23.32°, 23.85°, 24.41°, 25.51°, 27.11°, 27.62°, 29.05°, 29.85°, 30.91°, 32.34°, 32.68°, 34.67°, 36.58°, 37.86° and 39.38°.

[0138] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the S1 crystal form described above is essentially as follows: Figure 19 As shown.

[0139] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the above-mentioned S1 crystal form are shown in Table 9:

[0140] Table 9 shows the XRPD diffraction data of compound S1 (II-1).

[0141]

[0142]

[0143] In some embodiments of the present invention, the compound of formula (III) is selected from the compound of formula (III-1).

[0144]

[0145] The present invention also provides the S2 crystal form of the compound of formula (III-1), wherein the X-ray powder diffraction pattern of Cu Kα radiation of the S2 crystal form has characteristic diffraction peaks at the following 2θ angles: 5.20±0.20°, 7.63±0.20°, 16.00±0.20°, 19.53±0.20° and 20.97±0.20°.

[0146] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned S2 crystal form has characteristic diffraction peaks at the following 2θ angles: 5.20°, 16.00°, 20.97°, 19.53°, 7.63°, and 12.65°.

[0147] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the S2 crystal form described above is essentially as follows: Figure 21 As shown.

[0148] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the S2 crystal form are shown in Table 10:

[0149] Table 10 XRPD diffraction data of the S2 crystal form of compound (III-1)

[0150]

[0151] The present invention also provides the S3 crystal form of the compound of formula (III-1), wherein the CuKα radiation X-ray powder diffraction pattern of the S3 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.36±0.20°, 8.45±0.20°, 11.94±0.20°, 21.94±0.20° and 23.41±0.20°.

[0152] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned S3 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.36°, 8.45°, 11.94°, 21.94° and 23.41°.

[0153] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the S3 crystal form described above is essentially as follows: Figure 22 As shown.

[0154] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the S3 crystal form are shown in Table 11:

[0155] Table 11 XRPD diffraction data of compound S3 (III-1)

[0156]

[0157] In some embodiments of the present invention, the compound of formula (IV) is selected from the compound of formula (IV-1).

[0158]

[0159] The present invention also provides the S4 crystal form of the compound of formula (IV-1), wherein the Cu Kα radiation X-ray powder diffraction pattern of the S4 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.48±0.20°, 7.81±0.20°, 11.07±0.20°, 12.32±0.20°, 17.23±0.20°, 18.30±0.20°, 19.02±0.20° and 21.46±0.20°.

[0160] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned S4 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.48±0.20°, 7.81±0.20°, 9.30±0.20°, 11.07±0.20°, 12.32±0.20°, 16.62±0.20°, 17.23±0.20°, 18.30±0.20°, 19.02±0.20°, 21.46±0.20°, 24.10±0.20°, and 25.19±0.20°.

[0161] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned S4 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.48°, 7.81°, 9.30°, 11.07°, 11.44°, 12.32°, 13.40°, 14.63°, 15.92°, 16.62°, 17.23°, 18.30°, 19.02°, 20.10°, 21.46°, 24.10°, 25.19°, 26.24°, and 29.80°.

[0162] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the S4 crystal form described above is essentially as follows: Figure 23 As shown.

[0163] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the S4 crystal form are shown in Table 12:

[0164] Table 12 shows the XRPD diffraction data of compound S4 (IV-1).

[0165]

[0166]

[0167] In some embodiments of the present invention, the compound of formula (IV) is selected from the compound of formula (IV-2).

[0168]

[0169] The present invention also provides the S5 crystal form of the compound of formula (IV-2), wherein the Cu Kα radiation X-ray powder diffraction pattern of the S5 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.76±0.20°, 8.21±0.20°, 9.60±0.20°, 15.81±0.20°, 16.90±0.20°, 22.18±0.20°, 22.98±0.20° and 25.74±0.20°.

[0170] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned S5 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.76±0.20°, 8.21±0.20°, 9.60±0.20°, 15.81±0.20°, 16.90±0.20°, 20.28±0.20°, 21.15±0.20°, 22.18±0.20°, 22.98±0.20°, 23.92±0.20°, 24.93±0.20°, and 25.74±0.20°.

[0171] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned S5 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.76°, 8.21°, 9.60°, 11.60°, 13.44°, 14.38°, 15.81°, 16.90°, 19.79°, 20.28°, 21.15°, 22.18°, 22.98°, 23.92°, 24.93°, 25.74°, 28.46°, and 30.72°.

[0172] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the S5 crystal form described above is essentially as follows: Figure 25 As shown.

[0173] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the S5 crystal form are shown in Table 13:

[0174] Table 13 XRPD diffraction data of compound S5 (IV-2)

[0175]

[0176]

[0177] The present invention also provides the A2 crystal form of the compound of formula (I), wherein the Cu Kα radiation X-ray powder diffraction pattern of the A2 crystal form has characteristic diffraction peaks at the following 2θ angles: 6.94±0.20°, 13.39±0.20°, 13.93±0.20°, 17.88±0.20°, 20.41±0.20°, 22.09±0.20°, 24.08±0.20° and 25.04±0.20°.

[0178] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A2 crystal form has characteristic diffraction peaks at the following 2θ angles: 6.94°, 13.39°, 13.93°, 17.88°, 20.41°, 22.09°, 24.08° and 25.04°.

[0179] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the A2 crystal form described above is essentially as follows: Figure 27 As shown.

[0180] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the A2 crystal form are shown in Table 14:

[0181] Table 14 XRPD diffraction data of compound A2 crystal form (I)

[0182]

[0183] The present invention also provides the A3 crystal form of the compound of formula (I), wherein the Cu Kα radiation X-ray powder diffraction pattern of the A3 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.47±0.20°, 5.75±0.20°, 8.16±0.20°, 10.04±0.20°, 14.71±0.20°, 15.81±0.20°, 21.67±0.20° and 23.30±0.20°.

[0184] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A3 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.47°, 5.75°, 8.16°, 10.04°, 14.71°, 15.81°, 21.67° and 23.30°.

[0185] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the A3 crystal form described above is essentially as follows: Figure 28 As shown.

[0186] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the A3 crystal form are shown in Table 15:

[0187] Table 15 XRPD diffraction data of compound A3 (I)

[0188]

[0189] The present invention also provides the A4 crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of Cu Kα radiation of the A4 crystal form has characteristic diffraction peaks at the following 2θ angles: 8.07±0.20°, 16.82±0.20°, 13.30±0.20°, 19.08±0.20°, 17.66±0.20°, 20.54±0.20°, 21.99±0.20° and 25.61±0.20°.

[0190] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A4 crystal form has characteristic diffraction peaks at the following 2θ angles: 8.07°, 10.87°, 12.40°, 13.30°, 16.82°, 17.66°, 19.08°, 20.54°, 21.99° and 25.61°.

[0191] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the A4 crystal form described above is essentially as follows: Figure 29 As shown.

[0192] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the A4 crystal form are shown in Table 16:

[0193] Table 16 shows the XRPD diffraction data of compound A4 (I).

[0194]

[0195] The present invention also provides the A5 crystal form of the compound of formula (I), wherein the Cu Kα radiation X-ray powder diffraction pattern of the A5 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.71±0.20°, 9.86±0.20°, 13.43±0.20°, 14.61±0.20°, 17.32±0.20°, 18.66±0.20°, 24.52±0.20°, and 26.82±0.20°.

[0196] The present invention also provides the A5 crystal form of the compound of formula (I), wherein the Cu Kα radiation X-ray powder diffraction pattern of the A5 crystal form has characteristic diffraction peaks at the following 2θ angles: 4.71±0.20°, 9.34±0.20°, 9.86±0.20°, 10.45±0.20°, 11.34±0.20°, 13.43±0.20°, 14.61±0.20°, 17.32±0.20°, 26.82±0.20°, 18.66±0.20°, 24.52±0.20°, and 25.85±0.20°.

[0197] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A5 crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 4.71°, 9.34°, 9.86°, 10.45°, 11.34°, 11.48°, 12.50°, 13.43°, 13.99°, 14.61°, 16.36°, 16.98°, 17.32°, 18.66°, 19.06°, 19.50°, 20.0°. 1°, 20.45°, 20.76°, 21.34°, 22.04°, 23.32°, 23.68°, 24.52°, 25.09°, 25.85°, 26.28°, 26.82°, 28.10°, 28.43°, 29.47°, 30.21°, 30.75°, 31.96°, 32.44°, 32.86° and 33.49°.

[0198] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the A5 crystal form described above is essentially as follows: Figure 30 As shown.

[0199] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the A5 crystal form are shown in Table 17:

[0200] Table 17 XRPD diffraction data of compound A5 (Formula I)

[0201]

[0202]

[0203] The present invention also provides the A6 crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of Cu Kα radiation of the A6 crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 7.28±0.20°, 10.66±0.20°, 14.02±0.20°, 17.37±0.20°, 24.56±0.20° and 25.76±0.20°.

[0204] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A6 crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16°, 7.28°, 10.66°, 14.02°, 17.37°, 24.56° and 25.76°.

[0205] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the A6 crystal form described above is essentially as follows: Figure 31 As shown.

[0206] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the A6 crystal form are shown in Table 18:

[0207] Table 18 shows the XRPD diffraction data of compound A6 (I) crystal form.

[0208]

[0209] The present invention also provides the A7 crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of Cu Kα radiation of the A7 crystal form has characteristic diffraction peaks at the following 2θ angles: 8.03±0.20°, 12.00±0.20°, 16.10±0.20°, 17.58±0.20°, 18.35±0.20°, 20.76±0.20°, 23.98±0.20° and 25.42±0.20°.

[0210] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A7 crystal form has characteristic diffraction peaks at the following 2θ angles: 8.03±0.20°, 10.41±0.20°, 12.00±0.20°, 16.10±0.20°, 17.58±0.20°, 18.35±0.20°, 20.76±0.20°, 21.23±0.20°, 22.87±0.20°, 23.98±0.20°, 24.98±0.20°, and 25.42±0.20°.

[0211] In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A7 crystal form has characteristic diffraction peaks at the following 2θ angles: 8.03°, 10.41°, 12.00°, 13.44°, 14.74°, 16.10°, 16.60°, 17.23°, 17.58°, 18.35°, 20.76°, 21.23°, 22.25°, 22.87°, 23.98°, 24.98°, 25.42°, 27.16°, 29.39°, 29.81°, 31.93°, and 33.38°.

[0212] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the A7 crystal form described above is essentially as follows: Figure 32 As shown.

[0213] In some embodiments of the present invention, the diffraction peak data of the Cu Kα radiation XRPD pattern of the A7 crystal form are shown in Table 19:

[0214] Table 19 shows the XRPD diffraction data of compound A7 (I) crystal form.

[0215]

[0216] In some embodiments of the present invention, the aforementioned crystal forms G, H, A1, A2, A3, A4, A5, A6, A7, S1, S2, S3, S4, or S5 can be in the form of non-solvents or in the form of solvates, such as hydrates, organic solvates, or a combination of organic solvates and hydrates.

[0217] In some embodiments of the present invention, the organic solvent of the above-mentioned organic solvate is selected from ethyl acetate, n-hexane, cyclohexane, n-heptane, dimethyl sulfoxide, methyl tert-butyl ether, tetrahydrofuran, methanol, ethanol, isopropanol, acetonitrile, acetone or N-methylpyrrolidone.

[0218] In some embodiments of the present invention, the G crystal form is a hydrate with a hydration coefficient of 0 to 5.0. In some embodiments of the present invention, the H crystal form is a hydrate with a hydration coefficient of 0 to 5.0.

[0219] In some embodiments of the present invention, the A1 crystal form is an organic solvate, wherein the organic solvent is selected from ethyl acetate, n-heptane, or a mixture of ethyl acetate and n-heptane. In some embodiments of the present invention, the A2 crystal form is a dimethyl sulfoxide solvate. In some embodiments of the present invention, the A3 crystal form is a methyl tert-butyl ether solvate. In some embodiments of the present invention, the A4 crystal form is an acetone solvate. In some embodiments of the present invention, the A5 crystal form is an N-methylpyrrolidone solvate. In some embodiments of the present invention, the A6 crystal form is a methyl tert-butyl ether solvate. In some embodiments of the present invention, the A7 crystal form is a dimethyl sulfoxide solvate.

[0220] The present invention also provides the application of the above-mentioned B crystal form, C crystal form or S1 crystal form in the preparation of drugs related to GnRH receptor antagonists.

[0221] In some embodiments of the present invention, the aforementioned GnRH receptor antagonist-related drugs are drugs for the prevention and / or treatment of endometriosis and / or uterine fibroid-related diseases.

[0222] Technical effect

[0223] The compounds of this invention exhibit significant inhibitory effects on human gonadotropin-releasing hormone receptors, with high plasma exposure, low clearance, long half-life, and high oral bioavailability, demonstrating excellent pharmacokinetic properties. The preparation processes for the salt and crystal forms of this invention are simple, and the salt and crystal forms are stable, minimally affected by heat, humidity, and light, facilitating formulation.

[0224] Definitions and Explanations

[0225] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0226] The intermediate compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0227] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0228] The present invention will be described in detail below through embodiments, which are not intended to limit the present invention in any way.

[0229] The structures of the compounds of this invention can be confirmed using conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystals are used to collect diffraction intensity data using a Bruker D8venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0230] This invention uses the following abbreviations: ACN represents acetonitrile; DMSO represents dimethyl sulfoxide. N2: nitrogen; RH: relative humidity; mL: milliliter; L: liter; min: minute; ℃: degree Celsius; μm: micrometer; mm: millimeter; μL: microliter; mol / L: mole per liter; mg: milligram; s: second; nm: nanometer; MPa: megapascal; lux: lux; μw / cm 2 Microwatts per square centimeter; h: hour; Kg: kilogram; nM: nanomolar; rpm: rotational speed; XRPD represents X-ray powder diffraction; DSC represents differential scanning calorimetry; TGA represents thermogravimetric analysis. 1 H NMR represents the hydrogen nuclear magnetic resonance spectrum.

[0231] The compounds of this invention are named according to conventional naming principles in the art or using The software names are used, and commercially available compounds are named according to the supplier's catalog. All solvents used in this invention are commercially available.

[0232] Instruments and Analytical Methods

[0233] (1) The X-ray powder diffractometer (XRPD) instrument of this invention

[0234] The XRPD instrument and test parameters are shown in Table 20.

[0235] Table 20 XRPD Test Parameters

[0236]

[0237] (2) The thermogravimetric analyzer (TGA) and differential scanning calorimeter (DSC) instruments of this invention

[0238] The TGA and DSC instruments and test parameters are shown in Table 21.

[0239] Table 21 TGA and DSC Test Parameters

[0240]

[0241] (3) Dynamic Vapor Sorption (DVS)

[0242] Instrument model: SMS DVS intrinsic plus dynamic moisture adsorption meter. Detailed DVS parameters are as follows:

[0243] Temperature: 25℃;

[0244] Protective gas and flow rate: Nitrogen, 200 mL / min;

[0245] dm / dt = 0.002% / min;

[0246] RH (%) test step: 10% RH;

[0247] Minimum dm / dt equilibration time: 10 min;

[0248] Maximum equilibration time: 180 min;

[0249] RH (%) test range: 0%-95%.

[0250] Hygroscopicity evaluation is classified as follows:

[0251] Absorbs sufficient moisture to form a liquid: deliquescent; ΔW% ≥ 15%: highly hygroscopic; 15% > ΔW% ≥ 2%: hygroscopic; 2% > ΔW% ≥ 0.2%: slightly hygroscopic; ΔW% < 0.2%: no or almost no hygroscopicity. ΔW% represents the weight gain of the test sample at 25±1℃ and 80±2%RH due to moisture absorption.

[0252] (4) Liquid NMR

[0253] Liquid NMR spectra were acquired using a Bruker 400M NMR spectrometer with DMSO-d6 as the solvent.

[0254] (5) High-performance liquid chromatography / ion chromatography (HPLC / IC) instrument

[0255] The molar ratio was tested using an Agilent 1260 high-performance liquid chromatograph and an ion chromatograph, and the analytical conditions are shown in Tables 22 and 23.

[0256] Table 22 High Performance Liquid Chromatography Test Conditions

[0257]

[0258] Table 23 Ion Chromatography Test Conditions

[0259] Attached Figure Description

[0260] Figure 1 XRPD spectrum of compound B in formula (I).

[0261] Figure 2 DSC spectrum of compound B (I)

[0262] Figure 3 TGA spectrum of compound B in formula (I).

[0263] Figure 4 XRPD spectrum of compound C crystal form (I).

[0264] Figure 5 DSC spectrum of the C crystal form of compound (I).

[0265] Figure 6 TGA spectrum of compound C crystal form (I).

[0266] Figure 7 XRPD spectrum of compound A1 (Formula I).

[0267] Figure 8 XRPD spectrum of compound D (I)

[0268] Figure 9 DSC spectrum of compound D of formula (I).

[0269] Figure 10 TGA spectrum of compound D of formula (I).

[0270] Figure 11 XRPD spectrum of compound E crystal form (I).

[0271] Figure 12 DSC spectrum of compound E crystal form (I).

[0272] Figure 13 TGA spectrum of compound E crystal form (I).

[0273] Figure 14 XRPD spectrum of compound F (I)

[0274] Figure 15 DSC spectrum of compound F of formula (I).

[0275] Figure 16 TGA spectrum of compound F of formula (I).

[0276] Figure 17 XRPD spectrum of compound G (I) crystal form.

[0277] Figure 18 XRPD spectrum of compound H (I)

[0278] Figure 19 XRPD diagram of the crystal form of compound S1 of formula (II-1).

[0279] Figure 20 : The crystal form of compound S1 of formula (II-1) 1 H NMR spectrum.

[0280] Figure 21 XRPD diagram of the S2 crystal form of compound (III-1).

[0281] Figure 22 XRPD diagram of the S3 crystal form of compound (III-1).

[0282] Figure 23 XRPD diagram of the S4 crystal form of compound (IV-1).

[0283] Figure 24 The S4 crystal form of compound (IV-1) 1 H NMR spectrum.

[0284] Figure 25 XRPD diagram of the S5 crystal form of compound (IV-2).

[0285] Figure 26 The S5 crystal form of compound (IV-2) 1 H NMR spectrum.

[0286] Figure 27 XRPD diagram of the A2 crystal form of compound (I).

[0287] Figure 28 XRPD diagram of the A3 crystal form of compound (I).

[0288] Figure 29 XRPD diagram of the A4 crystal form of compound (I).

[0289] Figure 30 XRPD diagram of the A5 crystal form of compound (I).

[0290] Figure 31 XRPD diagram of the A6 crystal form of compound (I).

[0291] Figure 32 XRPD diagram of the A7 crystal form of compound (I).

[0292] Figure 33 DVS diagram of the B crystal form of compound (I). Detailed Implementation

[0293] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0294] Reference Example 1: Intermediate BB-1

[0295]

[0296] To a mixture of 2 g (7.95 mmol) tetrahydrofuran (20 mL) and water (10 mL) containing compound B-1, potassium carbonate (1.65 g, 11.92 mmol) was added, followed by dropwise addition of phenyl chloroformate (2.49 g, 15.89 mmol) at 5–10 °C. The reaction mixture was stirred at 5–10 °C for 1 hour. 50 mL of water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL each time). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Ethyl acetate (5 mL) and petroleum ether (50 mL) were added, and the mixture was stirred at 30 °C for 30 minutes. The mixture was filtered, and the filter cake was dried under reduced pressure to obtain compound BB-1. MS-ESI calculated value [M+H] + 336.1, measured value 336.1.

[0297] Reference Example 2: Intermediate BB-2

[0298]

[0299] To a solution of compound B-2 (3-bromopropanol, 5 g, 35.97 mmol) and 4-dimethylaminopyridine (439.49 mg, 3.6 mmol) in dichloromethane (25 mL), a solution of acetic anhydride (4.04 g, 39.57 mmol) in dichloromethane (5 mL) was added dropwise. The mixture was heated to 25 °C and stirred at 25 °C for 4 hours. The reaction solution was washed with 1 mol / L hydrochloric acid (10 mL × 2), the aqueous phase was collected and extracted with dichloromethane (30 mL × 3), the combined organic phases were washed with saturated sodium bicarbonate aqueous solution (10 mL × 2), washed with saturated brine (10 mL × 2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give intermediate compound BB-2. 1 H NMR (400MHz, CDCl3) δ = 4.18-4.25 (m, 2H), 3.44-3.51 (m, 2H), 2.15-2.23 (m, 2H), 2.07 (s, 3H).

[0300] Example 1: Preparation of compound (I)

[0301]

[0302]

[0303] Step 1

[0304] At -70°C, lithium diisopropylaminolithium (166.53 mL, concentration: 2 mol / L) was added dropwise to a tetrahydrofuran (400 mL) solution of compound 1-1 (3,4-difluoroanisole, 40 g, 277.5 mmol), and the reaction mixture was stirred at -70°C for 0.5 h. From -70°C to -60°C, a tetrahydrofuran (24 mL) solution of N,N-dimethylformamide (25.62 mL, 333.06 mmol) was added dropwise to the reaction mixture, and the reaction mixture was stirred at -70°C for 1 h. At -65°C, acetic acid (25 mL) and water (100 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed successively with water (100 mL × 3) and saturated brine (100 mL × 3). The collected organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-2.

[0305] Step 2

[0306] At -20°C, boron tribromide (29.11 g, 116.19 mmol) was added dropwise to a solution of compounds 1-2 (10 g, 58.10 mmol) in dichloromethane (100 mL). The mixture was slowly heated to 25°C and stirred at 25°C for 12 hours. Methanol (200 mL) and water (100 mL) were added dropwise to the reaction system, and the mixture was heated to 40°C and stirred at 40°C for 2 hours. The mixture was separated, and the aqueous phase was extracted with dichloromethane (300 mL × 2). The combined organic phases were extracted with an aqueous sodium hydroxide solution (1 mol / L, 400 mL × 3). The extract was acidified to pH 2–3 with concentrated hydrochloric acid, extracted with ethyl acetate (300 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compounds 1-3. 1 H NMR (400MHz, CDCl3) δ = 11.13 (s, 1H), 10.29 (s, 1H), 7.37 (q, J = 9.3Hz, 1H), 6.77-6.68 (m, 1H).

[0307] Step 3

[0308] Sodium iodide (284.42 mg, 1.90 mmol) and potassium carbonate (1.97 g, 14.23 mmol) were added to a solution of compounds 1-3 (1.5 g, 9.49 mmol) in N,N-dimethylformamide (20 mL). The mixture was stirred at 25 °C for 0.5 h. Then, compound BB-2 (2.06 g, 11.39 mmol) was added, and the mixture was heated to 60 °C and stirred at 60 °C for 12 h. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (50 mL × 5). The combined organic phases were washed with water (20 mL × 5) and once with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compounds 1-4. 1 H NMR(400MHz, CDCl3)δ=10.45-10.38(m,1H),7.37-7.28(m,1H),6.74-6.65(m, 1H), 4.28 (t, J = 6.2Hz, 2H), 4.16-4.13 (m, 2H), 2.22-2.16 (m, 2H), 2.06 (s, 3H).

[0309] Step 4

[0310] At 0°C, 3 mL of an aqueous solution of sodium borohydride (490 mg, 12.95 mmol) was added to a tetrahydrofuran (30 mL) solvent of compounds 1-4 (3.25 g, 12.59 mmol). The reaction mixture was stirred at 0°C for 0.5 h. At 0°C, 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with water (10 mL × 2) and saturated brine (10 mL × 10 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compounds 1-5.

[0311] Step 5

[0312] To a solution of compounds 1-5 (2.65 g, 10.18 mmol) and 5-fluoro-2-hydroxybenzaldehyde (1.57 g, 11.2 mmol) in tetrahydrofuran (20 mL), tri-n-butylphosphine (3.71 g, 18.33 mmol) was added, and the mixture was stirred for 0.1 h. Then, a solution of azodicarbonyl dipiperidine (4.62 g, 18.33 mmol) in tetrahydrofuran (5 mL) was added dropwise at 0 °C. The mixture was heated to 25 °C and stirred at 25 °C for 12 h. The reaction mixture was poured into 10 mL of water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with water (10 mL × 3) and brine (10 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1 / 0 to 20 / 1) to give compounds 1-6. 1H NMR (400MHz, CDCl3) δ = 10.31 (d, J = 3.2Hz, 1H), 7.49 (dd, J = 3.2, 8.4Hz, 1H), 7.33-7.27 (m, 1H), 7.23-7.18 (m, 1H), 7.18-7.11 ( m,1H),6.72-6.57(m,1H),5.25(d,J=2.8Hz,2H),4.19(t,J=6.2Hz,2H),4.06(t,J=6.2Hz,2H),2.09-2.06(m,2H),2.04(s,3H).

[0313] Step 6

[0314] At 0 °C, m-chloroperoxybenzoic acid (1.66 g, 85% purity, 8.16 mmol) was added to a solution of compounds 1-6 (1.04 g, 2.72 mmol) in dichloromethane (10 mL). The mixture was heated to 25 °C and stirred at 25 °C for 12 hours. 2 mL of saturated sodium sulfite aqueous solution was added to the reaction mixture, followed by 10 mL of water. The mixture was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with water (10 mL × 2), then with saturated brine (10 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The crude product was purified by chromatographic chromatography (petroleum ether: ethyl acetate = 3:1) to give compounds 1-7. 1 H NMR (400MHz, CDCl3) δ = 8.19 (s, 1H), 7.18-7.08 (m, 2H), 7.00-6.93 (m, 1H), 6.89 (dd, J = 3.2, 8.4Hz, 1H), 6.63- 6.57(m,1H),5.14-5.09(m,2H),4.23(t,J=6.2Hz,2H),4.04(t,J=6.2Hz,2H),2.14-2.09(m,2H),2.06(s,3H).

[0315] Step 7

[0316] An aqueous solution of potassium hydroxide (1 mL, 20% purity, 489.03 μmol) was added to 10 mL of a methanol solution of compounds 1-7 (1 g, 2.51 mmol). The mixture was stirred at 25 °C for 6 hours. The reaction solution was poured into 10 mL of water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with water (10 mL × 2) and saturated brine (10 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 5 / 1-3 / 1) to give compounds 1-8. 1H NMR (400MHz, CDCl3) δ = 7.15 (q, J = 9.2Hz, 1H), 7.00 (dd, J = 5.2, 8.8Hz, 1H), 6.91 (s, 1H), 6.69-6.62 (m, 2H) ,6.53(dt,J=3.0,8.6Hz,1H),5.17(d,J=2.0Hz,2H),4.22(t,J=5.8Hz,2H),3.88(q,J=5.0Hz,2H),2.49(br s,1H),2.15-2.05(m,2H).

[0317] Step 8

[0318] At 0 °C, sodium hydrogen (135.04 mg, 60% purity, 3.38 mmol) was added to a tetrahydrofuran (400 mL) solvent of compounds 1-8 (421 mg, 1.28 mmol), and the mixture was stirred at 0 °C for 0.5 h. At 0 °C, a tetrahydrofuran solution (5 mL) of p-toluenesulfonyl chloride (244.50 mg, 1.28 mmol) was added dropwise to the reaction system, and the mixture was stirred at 25 °C for 12 h. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with water (10 mL × 2), then with saturated brine (10 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The crude product was purified by preparative chromatography (petroleum ether: ethyl acetate = 3:1) to give compounds 1-9.

[0319] Step 9

[0320] Nitric acid (1.46 mL, 60% purity, 19.51 mmol) was added dropwise to a 1 mL acetic acid solution of compounds 1-9 (53 mg, 170.82 μmol) at 80 °C. The mixture was stirred at 80 °C for 2 hours. The reaction solution was poured into 40 mL of ice water, and the pH was adjusted to 7 with a saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (30 mL × 5). The combined organic phases were washed with water (30 mL × 3), washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compounds 1-10. 1 H NMR (400MHz, CDCl3) δ = 7.92 (d, J = 7.6Hz, 1H), 7.14-7.10 (m, 1H), 6.76-6.73 (d, J = 12.0Hz, 1H), 6. 57-6.12(m,1H),5.20(d,J=1.2Hz,2H),4.48-4.42(m,2H),4.37-4.31(m,2H),2.17-2.14(m,2H).

[0321] Step 10

[0322] To a 10 mL solution of compound 1-10 (46 mg, 129.48 μmol) in ethyl acetate, wet palladium on carbon (10 mg, 10% purity) was added, followed by purging with hydrogen three times. The mixture was stirred at 24 °C for 12 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered with diatomaceous earth as an aid, filtered, and the filtrate was concentrated to give compound 1-11. ESI calculated value [M+H] + 326.1, measured value 326.1; 1 H NMR (400MHz, CDCl3) δ = 7.17-7.07 (m, 2H), 6.82-6.78 (m, 1H), 6.76 (d, J = 11.6Hz, 1H), 6.68 (d, J = 9.0Hz, 1H), 6.63-6.56 (m, 1H), 5.07 (d, J = 2.0Hz, 2H), 4.35-4.31 (m, 2H), 4.16-4.11 (m, 2H), 2.13-2.09 (m, 2H).

[0323] Step 11

[0324] Compound BB-1 (26.29 mg, 78.41 μmol) and triethylamine (7.93 mg, 78.41 μmol) were added to a tetrahydrofuran (3 mL) solution of compound 1-11 (41 mg, 78.41 μmol). The mixture was stirred at 70 °C for 10 hours. The reaction mixture was then poured into 10 mL of water and extracted with ethyl acetate (30 mL × 5). The combined organic phases were washed with water (10 mL × 3), then with saturated brine (10 mL × 1), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated and purified by chromatographic purification (petroleum ether:ethyl acetate = 2 / 1) to give compound 1-12. MS-ESI calculated value [M+H] + 567.1, measured value 567.1; 1 H NMR (400MHz, CDCl3) δ = 8.86 (s, 1H), 7.97 (s, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.16-7.06 (m, 1H), 6.84 (d, J = 11.6Hz, 1H), 6.78 (m, 1H), 6.57 (br s,1H),5.16(d,J=1.6Hz,2H),4.36(t,J=5.2Hz,2H),4.22(t,J=5.2Hz,2H),3.91(s,3H),3.90(s,3H),2.11(m,2H).

[0325] Step 12

[0326] A solution of compounds 1-12 (22 mg, 28.57 μmol, 73.57% purity) in tetrahydrofuran (2 mL) and methanol (1 mL) was added to an aqueous solution of lithium hydroxide monohydrate (5.99 mg, 142.85 μmol) (1 mL). The mixture was stirred at 26 °C for 2 hours. The pH of the reaction mixture was adjusted to approximately 6 by adding 1 mol / L dilute hydrochloric acid, followed by extraction with ethyl acetate (5 mL × 5). The combined organic phases were washed with water (5 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative chromatography (dichloromethane:methanol = 10 / 1) to obtain compound (I). MS-ESI calculated value [M+H] + 521.0, measured value 521.1.

[0327] Example 2: Preparation of the crystal form of compound A1 of formula (I)

[0328]

[0329] 25 g of compound (I) was suspended in 80 mL of ethyl acetate at 45-50 °C. While stirring, 40 mL of n-heptane was added, and the mixture was then allowed to cool naturally to 15-20 °C and stirred for 0.5 hours. The mixture was filtered, and the filter cake was washed with a mixture of 20 mL of ethyl acetate and 10 mL of n-heptane, followed by washing with 20 mL of n-heptane. The filter cake was collected and vacuum dried to obtain a solid. XRPD analysis confirmed it to be the A1 crystal form of compound (I). The XRPD spectrum is shown below. Figure 7 As shown. MS-ESI calculated value [M+H] + 521.0, measured value 521.1; 1 H NMR (400MHz, DMSO-d6) δ = 14.54 (br s, 1H), 12.02 (s, 1H), 7.46-7.34 (m, 2H), 7.26 (d, J = 7.8Hz, 1H), 7.18 (d, J = 11.6Hz, 1H), 7.05 (br dd,J=2.0,9.4Hz,1H),5.17-5.01(m,2H),4.48(br t,J=4.8Hz,2H),4.30(br t,J=4.6Hz,2H),1.97(br s,2H).

[0330] Example 3: Preparation of crystal form B of compound (I)

[0331]

[0332] Method 1: Weigh 1 gram of compound A1 (crystal form) of formula (I), suspend and stir in water (10 mL) at 90 °C for 14 hours, then filter. Dry the filter cake under reduced pressure at 50 °C to obtain a solid, which is identified by XRPD as compound B (crystal form) of formula (I). The XRPD spectrum is shown below. Figure 1 As shown, the DSC spectrum is as follows Figure 2 As shown, the TGA spectrum is as follows Figure 3 As shown.

[0333] Method 2: Weigh 0.3 g of compound A1 crystal form of formula (I), suspend and stir in a mixed solvent of acetonitrile (1 mL) and water (5 mL) at 70 °C for 12 hours, then filter, and dry the filter cake under reduced pressure at 50 °C to obtain a solid, which is identified by XRPD as compound B crystal form of formula (I).

[0334] Example 4: Preparation of the C crystal form of compound (I)

[0335]

[0336] Weigh 24.8 mg of compound A1 (formula (I)) and suspend it in acetonitrile (0.5 mL) at room temperature (25 ± 3 °C) with stirring for 3 days. Then centrifuge to obtain a wet sample, and air dry at room temperature to obtain a solid. XRPD analysis confirmed it to be compound C (formula (I)). The XRPD spectrum is shown below. Figure 4 As shown, the DSC spectrum is as follows Figure 5 As shown, the TGA spectrum is as follows Figure 6 As shown.

[0337] Example 5: Preparation of crystal form D of compound (I)

[0338]

[0339] Weigh 24.5 mg of compound A1 (crystal form) of formula (I), add 0.5 mL of dichloromethane, and suspend and stir at room temperature (25 ± 3 °C) for 3 days. Then centrifuge to obtain a wet sample, and air-dry at room temperature to obtain a solid. XRPD analysis confirmed it to be compound D (crystal form) of formula (I). The XRPD spectrum is shown below. Figure 8 As shown, the DSC spectrum is as follows Figure 9 As shown, the TGA spectrum is as follows Figure 10 As shown.

[0340] Example 6: Preparation of crystal form E of compound (I)

[0341]

[0342] 25.1 mg of compound A1 (formula (I)) was weighed and suspended in 0.5 mL of tetrahydrofuran / n-heptane (volume ratio 1:4) at room temperature (25±3℃) for 3 days with stirring. The mixture was then centrifuged to obtain a wet sample, which was dried at room temperature to obtain a solid. XRPD analysis confirmed it to be compound E (formula (I)). The XRPD spectrum is shown below. Figure 11 As shown, the DSC spectrum is as follows Figure 12 As shown, the TGA spectrum is as follows Figure 13 As shown.

[0343] Example 7: Preparation of crystal form F of compound (I)

[0344]

[0345] 52.3 mg of compound A1 (formula (I)) was weighed and suspended in 0.75 mL of dimethyl sulfoxide / water (volume ratio 1:4) at room temperature (25±3℃) for 5 days with stirring. The mixture was then centrifuged to obtain a wet sample, which was dried at room temperature to obtain a solid. The solid was then heated to 180℃ and cooled to room temperature to obtain another solid. XRPD analysis confirmed that the solid was compound F (formula (I)). The XRPD spectrum is shown below. Figure 14 As shown, the DSC spectrum is as follows Figure 15 As shown, the TGA spectrum is as follows Figure 16 As shown.

[0346] Example 8: Preparation of the G crystal form of compound (I)

[0347]

[0348] 24.4 mg of compound A1 (formula (I)) was weighed and suspended in 0.5 mL of methanol / water (volume ratio 69:31) at room temperature (25±3℃) for 3 days with stirring. The mixture was then centrifuged to obtain a wet sample, which was dried at room temperature to obtain a solid. XRPD analysis confirmed it to be compound G (formula (I)). The XRPD spectrum is shown below. Figure 17 As shown.

[0349] Example 9: Preparation of the H crystal form of compound (I)

[0350]

[0351] Compound G of formula (I) was heated to 180°C and then cooled to room temperature to obtain a solid, which, according to XRPD analysis, was identified as compound H of formula (I). The XRPD spectrum is shown below. Figure 18 As shown.

[0352] Example 10: Preparation of the crystal form of compound S1 of formula (II)

[0353]

[0354] The A1 crystal form of compound (I) (25.0 mg) was suspended and stirred with 11.7 mg of choline in 0.5 mL of 2-methyltetrahydrofuran at room temperature (25 ± 3 °C) for 3 days, then transferred to 5 °C and stirred for 1 day, and then transferred to -20 °C and stirred for 2 days. After centrifugation, the solid was obtained by vacuum drying at room temperature and XRPD analysis showed that it was the S1 crystal form of compound (II). 1 ¹H NMR showed that the molar ratio of choline to compound (I) was 1.0. The XRPD spectrum is shown below. Figure 19 As shown, 1 H NMR spectrum as shown Figure 20 As shown.

[0355] Example 11: Preparation of the S2 crystal form of compound (III)

[0356]

[0357] Compound A1 (25.0 mg) of formula (I) and 2.0 mg of sodium hydroxide were suspended and stirred in acetonitrile (0.5 mL) at room temperature (25 ± 3 °C) for 4 days. After centrifugation, the solid was dried under vacuum at room temperature. XRPD analysis confirmed it to be compound S2 of formula (III). HPLC / IC showed a base-to-acid molar ratio of 1.0. The XRPD spectrum is shown below. Figure 21 As shown.

[0358] Example 12: Preparation of the S3 crystal form of compound (III)

[0359]

[0360] Compound A1 (25.1 mg) of formula (I) was suspended and stirred in tetrahydrofuran (0.5 mL) at room temperature (25 ± 3 °C) for 4 days. After centrifugation, the solid was dried under vacuum at room temperature. XRPD analysis confirmed it to be compound S3 of formula (III). HPLC / IC showed a base-to-acid molar ratio of 1.2. The XRPD spectrum is shown below. Figure 22 As shown.

[0361] Example 13: Preparation of the S4 crystal form of compound (IV-1)

[0362]

[0363] The A1 crystal form of compound (I) (25.1 mg) was suspended and stirred with 11.5 mg of dibenzylethylenediamine in isopropanol (0.5 mL) at room temperature (25 ± 3 °C) for 3 days. After centrifugation, the solid was dried under vacuum at room temperature and identified by XRPD as the S4 crystal form of compound (IV-1). 1 ¹H NMR showed that the molar ratio of dibenzylethylenediamine to compound (I) was 0.9. The XRPD spectrum is shown below. Figure 23As shown, 1 H NMR spectrum as shown Figure 24 As shown.

[0364] Example 14: Preparation of the S5 crystal form of compound (IV-2)

[0365]

[0366] The A1 crystal form (25.0 mg) of compound (I) was suspended and stirred in acetonitrile (0.5 mL) at room temperature (25 ± 3 °C) for 3 days. After centrifugation, the solid was dried under vacuum at room temperature and identified by XRPD as the S5 crystal form of compound (IV-2). 1 ¹H NMR showed that the molar ratio of dibenzylethylenediamine to compound (I) was 0.6. The XRPD spectrum is shown below. Figure 25 As shown, 1 H NMR spectrum as shown Figure 26 As shown.

[0367] Example 15: Preparation of the crystal form of compound A2 of formula (I)

[0368]

[0369] 24.7 g of compound A1 (formula I) was weighed and suspended in 0.5 mL of dimethyl sulfoxide / water (volume ratio 1:4) at room temperature (25±3℃) for 3 days with stirring. The mixture was then centrifuged to obtain a wet sample, which was dried at room temperature to obtain a solid. XRPD analysis confirmed it to be compound A2 (formula I). ​​The XRPD spectrum is shown below. Figure 27 As shown.

[0370] Example 16: Preparation of the crystal form of compound A3 of formula (I)

[0371]

[0372] Weigh 25.1 mg of compound A1 (formula (I)), dissolve it in 0.2 mL of tetrahydrofuran, add 1.5 mL of methyl tert-butyl ether, then centrifuge to obtain a wet sample. Dry the sample at room temperature to obtain a solid, which was identified by XRPD as compound A3 (formula (I)). The XRPD spectrum is shown below. Figure 28 As shown.

[0373] Example 17: Preparation of the crystal form of compound A4 of formula (I)

[0374]

[0375] Weigh out 24.6 mg of compound A1 (formula I), dissolve it in 0.2 mL of acetone, add 1.5 mL of n-heptane, stir at 5 °C for 1 day, transfer to -20 °C and stir for 2 days, then centrifuge to obtain a wet sample. Dry the sample at room temperature to obtain a solid, which was identified by XRPD as compound A4 (formula I). ​​The XRPD spectrum is shown below. Figure 29 As shown.

[0376] Example 18: Preparation of the crystal form of compound A5 of formula (I)

[0377]

[0378] Weigh 25.2 mg of compound A1 (formula I), dissolve it in 0.2 mL of N-methylpyrrolidone, add 1.0 mL of water, then centrifuge to obtain a wet sample. Dry the sample at room temperature to obtain a solid, which was identified by XRPD as compound A5 (formula I). ​​The XRPD spectrum is shown below. Figure 30 As shown.

[0379] Example 19: Preparation of the crystal form of compound A6 of formula (I)

[0380]

[0381] Weigh 25.6 mg of compound A1 (formula (I) crystal form) and suspend it in 0.5 mL of methanol / methyl tert-butyl ether (volume ratio 1:4) at room temperature (25±3℃) for 3 days with stirring. Then centrifuge to obtain a wet sample, and air dry at room temperature to obtain a solid. XRPD analysis confirmed it to be compound A6 (formula (I) crystal form). The XRPD spectrum is shown below. Figure 31 As shown.

[0382] Example 20: Preparation of the crystal form of compound A7 of formula (I)

[0383]

[0384] 52.3 mg of compound A1 (formula (I)) was weighed and suspended in 0.75 mL of dimethyl sulfoxide / water (volume ratio 1:4) at room temperature (25±3℃) for 5 days with stirring. The mixture was then centrifuged to obtain a wet sample, which was dried at room temperature to obtain a solid. XRPD analysis confirmed that the solid was compound A7 (formula (I)). The XRPD spectrum is shown below. Figure 32 As shown.

[0385] Example 21: Solid stability test of compound B of formula (I)

[0386] In accordance with the "Guidelines for Stability Testing of Active Pharmaceutical Ingredients and Preparations" (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 9001), to evaluate the solid stability of crystal form B of compound (I), stability was investigated under influencing factors (high temperature, high humidity, and light), accelerated (40℃ / 75% RH), and long-term (25℃ / 60% RH) conditions. Influencing factor tests: Unless otherwise specified, each sample was placed in an open weighing bottle and placed in the corresponding storage container to investigate stability at 5 and 10 days. Light stability testing complied with ICH Q1B requirements: Samples were exposed to visible and ultraviolet light; storage conditions: 5000±500 lux (visible light) and 90 μw / cm². 2 Irradiation under (UV) conditions for 5 and 10 days. The total irradiance received by the 10-day sample was not less than 1.2 × 10⁻⁶. 6 Lux·h, near-ultraviolet energy not less than 200 W·h / m 2 The samples to be exposed to light were placed in a clean weighing bottle, laid out in a single layer, uncovered, and placed open in a light chamber for exposure. The control samples were packaged in the same way as the exposed samples, but the weighing bottles were covered with aluminum foil. Long-term accelerated testing: Each sample was placed in a double-layered LDPE bag, each layer sealed with a buckle, then placed in an aluminum foil bag and heat-sealed. Accelerated testing was conducted for 1, 2, and 3 months, and long-term testing for 3 months. XRPD testing was performed on all stability samples to detect changes in crystal form.

[0387] Accurately weigh approximately 25 mg of sample and place it in a 10 mL volumetric flask. Add 6 mL of acetonitrile and sonicate to dissolve. After cooling to room temperature, add water to the mark and shake well to dissolve the sample, obtaining a solution with a concentration of approximately 2.5 mg / mL. Perform HPLC analysis on the sample. Compare the detection results with the initial detection results on day 0. Specific experimental results are shown in Table 24 below. The HPLC testing instruments and analytical conditions are shown in Table 25.

[0388] Table 24 shows the solid stability test results of compound B crystal form (I).

[0389]

[0390]

[0391] Table 25 HPLC Instrument Information and Analytical Methods

[0392]

[0393] Conclusion: The purity and crystal form of compound B of formula (I) did not change significantly under all stability conditions (high temperature, high humidity, light, long-term and accelerated), and it has good chemical stability.

[0394] Example 22: Study on the hygroscopicity of crystal form B of formula (I)

[0395] The test was performed using an SMS DVS intrinsic plus dynamic moisture adsorption instrument. 10-20 mg of compound (I) crystal form B was placed in the DVS sample tray for testing.

[0396] Experimental results: The DVS spectrum of compound B of formula (I) is as follows Figure 33 As shown, ΔW% is 0.535%.

[0397] Experimental conclusion: The B crystal form of compound (I) has a water adsorption of 2% > ΔW% ≥ 0.2% at 25℃ / 80%RH, and is slightly hygroscopic.

[0398] Biological test data

[0399] Experimental Example 1: Test of the activity of the compound of the present invention on human gonadotropin-releasing hormone receptor.

[0400] Experimental Objective: To detect the inhibitory activity of test compounds on gonadotropin-releasing hormone receptors at the cellular level using FLIPR detection technology.

[0401] Main experimental materials and their sources:

[0402] Fluo-4Direct TM Reagent kit – Invitrogen-F10471

[0403] 384-well poly-L-lysine-coated cell plate – Greiner-781946

[0404] 384-well compound plate – Greiner-781280

[0405] Compound preparation ECHO (acoustic pipetting system) – Labcyte

[0406] FLIPR (Fluorescence Imaging Plate Reader) – Molecular Devices

[0407] Experimental steps:

[0408] GnRH / HEK293 (human embryonic kidney cells 293) cells in logarithmic growth phase were cultured, washed with DPBS (Dupuyet phosphate-buffered saline), and then digested with 0.05% EDTA (ethylenediaminetetraacetic acid)-trypsin in a 37°C CO2 incubator for 1-2 minutes. Cells were then removed and culture medium was added to terminate the digestion. After repeated pipetting to disperse the cells, they were centrifuged and collected. Cells were seeded at a density of 20,000 cells per well (20 μL) into 384-well poly-L-lysine-coated cell plates and incubated overnight at 37°C with 5% CO2.

[0409] On the second day, add 20 μL of 2×Fluo-4Direct to each well. TM Incubate the cells in buffer solution, 5% CO2, at 37°C for 50 minutes, then place them at room temperature for 10 minutes. Perform a 4-fold serial dilution (10 spots) of 0.2 mM leuprolide acetate with ECHO, and transfer 900 nL to the compound plate. Add 30 μL of FLIPR buffer solution to the compound plate and centrifuge at 1000 rpm for 1 minute. Run the FLIPR instrument software, add 10 μL of experimental buffer solution according to the pre-set program, and read the fluorescence signal. Then add 10 μL of the agonist reference compound (leuprolide acetate), read the fluorescence signal, and calculate ECHO. 80 Prepare 6×EC 80 A stimulant concentration.

[0410] 2 mM of the test compound and an appropriate concentration of the reference compound (Cetrorelix Acetate) were serially diluted 4-fold in 10 spots using ECHO, and 900 nL of each was transferred to a cell culture plate. 30 μL of FLIPR buffer solution was added to the cell culture plate, and the plate was centrifuged at 1000 rpm for 1 min. The FLIPR instrument software was run, and following the pre-programmed steps, 10 μL of the test and reference compounds were added to the cell culture plate, and the fluorescence signal was read. Then, 10 μL of 6× ECHO was added. 80 A concentration of agonist was introduced into the cell plate, and the fluorescence signal was read.

[0411] Calculate the IC50 of the compound's inhibition of calcium flow to the gonadotropin-releasing hormone receptor. 50 That is, in cells that stably express the GnRH receptor, Ca 2+ The drug concentration at which flow is inhibited by half was calculated using GraphPad Prism 5.0 software, yielding the drug's IC50. 50 .

[0412] Experimental results:

[0413] The inhibitory activity of the compound against human gonadotropin-releasing hormone receptor in this invention was determined using the above experimental methods, and the measured IC50 value was... 50See Table 26:

[0414] Table 26 shows the IC50 inhibitory activity of the compounds in this invention against human gonadotropin-releasing hormone receptor. 50

[0415]

[0416] Conclusion: The compounds of this invention have a significant inhibitory effect on human gonadotropin-releasing hormone receptors.

[0417] Pharmacokinetic Evaluation in Experiment Example 2

[0418] Experimental objective: To study the pharmacokinetic properties of the compound of this invention in mice.

[0419] Test protocol:

[0420] Each test compound was separately mixed with DMAC, vortexed for 2 minutes, and then the DMAC solutions of the test compounds were mixed and vortexed for 2 minutes to prepare a clear solution of 10 mg / mL. 0.0600 mL of the 10 mg / mL solution was added to 0.300 mL of Solutol, vortexed for 2 minutes, and then 2.400 mL of physiological saline was added, vortexed for 2 minutes to obtain a clear solution of 0.2 mg / mL, which was used for PO group administration. 0.500 mL of the PO group administration solution was taken, vortexed for 2 minutes, 0.0500 mL of DMAC was added, mixed, and vortexed for 2 minutes, then 0.0500 mL of Solutol was added, vortexed for 2 minutes, and finally 0.400 mL of physiological saline was added, vortexed for 2 minutes to obtain a clear solution of 0.1 mg / mL, which was then filtered through a microporous membrane to obtain the injection (IV) group administration solution.

[0421] Four male CD-1 mice were randomly divided into two groups. Group 1 mice received a single intravenous administration of 0.5 mg / kg of the test compound in 10% DMAC / 10% Solutol / 80% saline solution at a volume of 5 mL / kg. Group 2 mice received a single oral gavage of 2 mg / kg of the test compound in 10% DMAC / 10% Solutol / 80% saline solution at a volume of 10 mL / kg. Whole blood was collected at 0.033 (intravenous only), 0.083, 0.25, 0.5, 1, 2, 4, and 12 hours post-administration. Plasma was obtained after centrifugation at 3200 g and 2-8 °C for 10 min. The concentration of the test compound in the plasma was determined by LC / MS / MS, and pharmacokinetic parameters were calculated using PhoenixWinNonlin software.

[0422] Experimental results:

[0423] The test results are shown in Table 27. The meanings of each parameter are: IV: intravenous injection; PO: oral administration; C0: initial blood drug concentration; Cmax Maximum drug concentration in systemic circulation; T max Reaching C max Time required; T 1 / 2 Half-life; V dss Apparent volume of distribution; Cl: Scavenging rate; AUC 0-last Area under the curve during drug administration.

[0424] Table 27 shows the pharmacokinetic (PK) test results of compound (I) in plasma.

[0425]

[0426] "--" indicates that no test was conducted or no data was obtained.

[0427] Conclusion: The compounds of this invention exhibit high plasma exposure, low clearance, long half-life, and high oral bioavailability, demonstrating excellent pharmacokinetic properties.

Claims

1. The B-crystal form of the compound of formula (I), ， Its features are, The X-ray powder diffraction pattern of the B crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 7.35±0.20°, 12.33±0.20°, 18.34±0.20° and 27.08±0.20°.

2. The B-type crystal according to claim 1, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 7.35±0.20°, 11.45±0.20°, 12.33±0.20°, 18.34±0.20°, 22.41±0.20°, 26.54±0.20° and 27.08±0.20°.

3. The B-type crystal according to claim 2, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 7.35±0.20°, 11.45±0.20°, 12.33±0.20°, 13.75±0.20°, 17.89±0.20°, 18.34±0.20°, 20.92±0.20°, 22.41±0.20°, 25.43±0.20°, 26.54±0.20° and 27.08±0.20°.

4. The B-type crystal according to claim 3, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 7.35±0.20°, 9.17±0.20°, 11.45±0.20°, 12.33±0.20°, 13.75±0.20°, 17.89±0.20°, 18.34±0.20°, 20.92±0.20°, 22.41±0.20°, 23.57±0.20°, 24.46±0.20°, 25.43±0.20°, 26.54±0.20°, 27.08±0.20°, and 28.81±0.20°.

5. The B-type crystal according to claim 4, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.62°, 7.35°, 9.17°, 11.45°, 12.33°, 13.17°, 13.75°, 14.34°, 14.67°, 16.50°, 17.43°, 17.89°, 18.34°, 19.45°, 20.92°, 21.68°, 22.41°, 23.57°, 24.46°, 25.43°, 25.89°, 26.54°, 27.08°, and 28.81°.

6. The B-type crystal according to any one of claims 1 to 5, characterized in that, Its XRPD map is basically as shown in Figure 1.

7. The B-type crystal according to any one of claims 1 to 5, characterized in that, Its differential scanning calorimetry curve has an exothermic peak at 224.4℃±3℃.

8. The B-type crystal according to any one of claims 1 to 5, characterized in that, Its DSC spectrum is basically as shown in Figure 2.

9. The B-type crystal according to any one of claims 1 to 5, characterized in that, Its thermogravimetric analysis curve shows a weight loss of 1.12% at 150℃±3℃.

10. The B-type crystal according to any one of claims 1 to 5, characterized in that, Its TGA spectrum is basically as shown in Figure 3.

11. The C-crystal form of the compound of formula (I), ， Its features are, The X-ray powder diffraction pattern of the C crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.18±0.20°, 8.47±0.20°, 12.80±0.20°, 15.80±0.20° and 23.30±0.20°.

12. The C-type according to claim 11, wherein the Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.18±0.20°, 8.47±0.20°, 12.80±0.20°, 15.80±0.20°, 16.96±0.20°, 19.23±0.20°, 20.12±0.20° and 23.30±0.20°.

13. The C-type according to claim 12, wherein the Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.18±0.20°, 8.47±0.20°, 11.55±0.20°, 12.80±0.20°, 15.80±0.20°, 16.96±0.20°, 19.23±0.20°, 20.12±0.20°, 23.30±0.20° and 26.31±0.20°.

14. The C crystal form according to claim 13, wherein the X-ray powder diffraction pattern of Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.18°, 8.47°, 11.55°, 12.80°, 15.80°, 16.96°, 19.23°, 20.12°, 23.30° and 26.31°.

15. The C-type according to claim 11, characterized in that, Its XRPD map is basically as shown in Figure 4.

16. The C-type according to claim 11, characterized in that, Its differential scanning calorimetry curve has an exothermic peak at 225.1℃±3℃.

17. The C-type according to claim 11, characterized in that, Its DSC spectrum is basically as shown in Figure 5.

18. The C-type according to claim 11, characterized in that, Its thermogravimetric analysis curve shows a weight loss of 1.13% at 150℃±3℃.

19. The C-type according to claim 11, characterized in that, Its TGA spectrum is basically as shown in Figure 6.

20. A pharmaceutically acceptable salt of a compound of formula (I). ， Its features are, The pharmaceutically acceptable salts are lysine salts, dibenzylethylenediamine salts, choline salts, meglumine salts, triethylamine salts, aluminum salts, zinc salts, or lithium salts.

21. A pharmaceutically acceptable salt of the compound of formula (I) according to claim 20, wherein, The choline salt structure of compound (I) is shown in formula (II), and the dibenzylethylenediamine salt structure of compound (I) is shown in formula (IV). ， Where m is selected from 0.5 to 1.5; p is selected from 0.4 to 1.

5.

22. A pharmaceutically acceptable salt of the compound of formula (I) according to claim 21, wherein, Compound (II) is the same as compound (II-1). 。 23. The S1 crystal form of compound (II-1), ， Its features are, The X-ray powder diffraction pattern of the S1 crystal form under Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.68±0.20°, 12.70±0.20°, 18.12±0.20°, 19.43±0.20° and 24.41±0.20°.

24. The S1 crystal form according to claim 23, wherein the Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.68±0.20°, 12.27±0.20°, 12.70±0.20°, 15.20±0.20°, 18.12±0.20°, 18.95±0.20°, 19.43±0.20° and 24.41±0.20°.

25. The S1 crystal form according to claim 24, wherein the Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.68±0.20°, 12.27±0.20°, 12.70±0.20°, 15.20±0.20°, 16.94±0.20°, 17.37±0.20°, 18.12±0.20°, 18.95±0.20°, 19.43±0.20°, 24.41±0.20°, 25.51±0.20° and 27.62±0.20°.

26. The S1 crystal form according to claim 25, wherein the X-ray powder diffraction pattern of Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.98°, 8.68°, 9.67°, 11.39°, 12.27°, 12.70°, 13.61°, 15.20°, 16.09°, 16.94°, 17.37°, 18.12°, 18.95°, 19.43°, 19.93°, 20.35°, 20.91°, 21.44°, 21.69°, 22.05°, 23.32°, 23.85°, 24.41°, 25.51°, 27.11°, 27.62°, 29.05°, and 29.85°.

27. The S1 crystal form according to claim 26, the XRPD pattern of which is basically as shown in Figure 19.

28. The use of the B crystal form according to any one of claims 1 to 6, the C crystal form according to any one of claims 7 to 19, the S1 crystal form according to any one of claims 23 to 27, or the salt according to any one of claims 20 to 22 in the preparation of GnRH receptor antagonist-related drugs.

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