SALINE AND CRYSTALLINE FORM OF THIENOPYRIMIDINONE DERIVATIVE

Abstract

Disclosed in the present invention are a salt form and a crystal form of a thienopyrimidinone derivative and a preparation method therefor. Specifically, disclosed are a salt form and a crystal form of a compound of formula (I), and a preparation method therefor.

Description

A salt form and crystal form of a thienopyrimidinone derivative

[0001] The present invention claims the following priority:

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

[0003] The present invention relates to a salt form, a crystal form and a preparation method of a thienopyrimidinone derivative, and specifically discloses a salt form, a crystal form and a preparation method of a compound of formula (I). Background Art

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

[0005] The causes of endometriosis are very complex, and its pathogenesis is not yet fully understood. Clinical drug treatment options are either to control estrogen levels, inflammation, or both. Treatment drugs are mainly divided into non-steroidal anti-inflammatory drugs, progestins, combined oral contraceptives, gonadotropin-releasing hormone (GnRH) agonists, etc. Among them, oral contraceptives have a non-response rate of nearly one-third to one-quarter of patients, progestins have the side effect of easily causing obesity, especially patients who want to get pregnant need to be prohibited from using them, and gonadotropin-releasing hormone has perimenopausal side effects. There are many problems with polypeptide GnRH receptor agonist or antagonist compounds, such as oral absorption, dosage form, dosage volume, drug stability, sustained 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 hypothalamic-pituitary-ovarian axis, thereby inhibiting the secretion of follicle-stimulating hormone and luteinizing hormone, reducing estrogen levels, with rapid onset of action and few side effects. Currently, in addition to the first to be marketed, Elagolix, a small molecule GnRH receptor antagonist that is at the forefront of research and development, in December 2020, the FDA approved the second small molecule oral antagonist, Relugolix, for the first indication of treating advanced prostate cancer. The indication for the treatment of uterine fibroids has been approved in Japan, and endometriosis has entered Phase III clinical trials. The third antagonist, Linzagolix, is in Phase III clinical trials for the treatment of endometriosis and uterine fibroids.

[0007] The crystal structure of a pharmaceutical active ingredient often affects the compound's stability. Generally speaking, amorphous drug products lack a regular crystal structure and often exhibit defects such as poor stability, easy agglomeration, small particles, and difficulty filtering. Furthermore, the solubility of a drug molecule is closely related to its oral absorption. Salting a drug with a suitable acid or base can increase its solubility. Salting can also help stabilize easily oxidizable drug molecules, facilitating storage and transportation. Therefore, in-depth research is needed to identify suitable salt and crystal forms for drug molecules, particularly novel crystal forms with excellent stability.

[0008] Summary of the Invention

[0009] The present invention provides a crystal form B of a compound of formula (I),

[0010] The X-ray powder diffraction pattern of the B crystal form using Cu Kα radiation 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 the above-mentioned B crystal form using Cu Kα radiation 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 the above-mentioned B crystal form using Cu Kα radiation 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 the above-mentioned B crystal form with Cu Kα radiation 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 the above-mentioned B crystal form with Cu Kα radiation 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 the above-mentioned B crystal form using Cu Kα radiation 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 the above-mentioned B crystal form with Cu 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° and 28.81°.

[0017] In some embodiments of the present invention, the above-mentioned B crystal form 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 the above-mentioned Form B under Cu Kα radiation is substantially as shown in FIG1 .

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

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

[0021] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned Form B shows an exothermic peak at 224.4°C±3°C.

[0022] In one embodiment of the present invention, the DSC spectrum of the above-mentioned Form B is substantially as shown in FIG2 .

[0023] In one embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned Form B shows a weight loss of 1.12% at 150°C±3°C.

[0024] In one embodiment of the present invention, the TGA spectrum of the above-mentioned Form B is substantially as shown in FIG3 .

[0025] The present invention also provides a method for preparing the crystal form B of the compound of formula (I), comprising the following steps:

[0026] (a) adding 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.;

[0027] (b) stirring for 10 to 48 hours;

[0028] (c) filtering;

[0029] (d) The filter cake is dried at 50°C-70°C.

[0030] The present invention also provides a crystal form C of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystal form C using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.18±0.20°, 8.47±0.20° and 12.8±0.20°.

[0031] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form using 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°.

[0032] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form with Cu Kα radiation 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°.

[0033] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form with Cu Kα radiation 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°.

[0034] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°, 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°.

[0035] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form using 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°.

[0036] In some embodiments of the present invention, the XRPD pattern of the above-mentioned C crystal form under Cu Kα radiation is substantially as shown in FIG4 .

[0037] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form C under Cu Kα radiation has diffraction peak data as shown in Table 2:

[0038] Table 2 XRPD diffraction data of the crystal form C of compound of formula (I)

[0039] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned Form C shows an exothermic peak at 225.1°C±3°C.

[0040] In one embodiment of the present invention, the DSC spectrum of the above-mentioned crystal form C is substantially as shown in Figure 5.

[0041] In one embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned Form C shows a weight loss of 1.13% at 150°C±3°C.

[0042] In one embodiment of the present invention, the TGA spectrum of the above-mentioned Form C is substantially as shown in FIG6 .

[0043] The present invention also provides the A1 crystal form of the compound of formula (I), wherein the A1 crystal form has a Cu Kα radiation X-ray powder diffraction pattern having 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°.

[0044] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A1 crystal form using Cu Kα radiation 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°.

[0045] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A1 crystal form with Cu Kα radiation 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°.

[0046] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A1 crystal form using Cu Kα radiation has 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°.

[0047] In some embodiments of the present invention, the XRPD pattern of the above-mentioned A1 crystal form under Cu Kα radiation is basically as shown in Figure 7.

[0048] In some embodiments of the present invention, the XRPD pattern of the A1 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 3:

[0049] Table 3 XRPD diffraction data of the crystalline form of compound A1 of formula (I)

[0050] The present invention also provides a D crystal form of the compound of formula (I), wherein the D crystal form has a Cu Kα radiation X-ray powder diffraction pattern having 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°.

[0051] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form with Cu Kα radiation 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°.

[0052] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form with Cu Kα radiation 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°.

[0053] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form using Cu Kα radiation 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°.

[0054] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form using Cu Kα radiation 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°.

[0055] In some embodiments of the present invention, the XRPD pattern of the above-mentioned D crystal form under Cu Kα radiation is substantially as shown in FIG8 .

[0056] In some embodiments of the present invention, the XRPD pattern of the above-mentioned D crystal form under Cu Kα radiation has diffraction peak data as shown in Table 4:

[0057] Table 4 XRPD diffraction data of the crystal form D of the compound of formula (I)

[0058] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned D crystal form shows an exothermic peak at 220.0°C±3°C.

[0059] In one embodiment of the present invention, the DSC spectrum of the above-mentioned Form D is substantially as shown in FIG9 .

[0060] In one embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned Form D shows a weight loss of 2.05% at 150.0°C±3°C.

[0061] In one embodiment of the present invention, the TGA spectrum of the above-mentioned D crystal form is substantially as shown in Figure 10.

[0062] The present invention also provides a crystalline form E of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form E using Cu Kα radiation 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°.

[0063] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form with Cu Kα radiation 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°.

[0064] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form with Cu Kα radiation 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°.

[0065] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form using Cu Kα radiation 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°.

[0066] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form with Cu Kα radiation 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°.

[0067] In some embodiments of the present invention, the XRPD pattern of the above-mentioned E crystal form under Cu Kα radiation is basically as shown in Figure 11.

[0068] In some embodiments of the present invention, the XRPD pattern of the above-mentioned E crystal form under Cu Kα radiation has diffraction peak data as shown in Table 5:

[0069] Table 5 XRPD diffraction data of the crystal form E of the compound of formula (I)

[0070] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned E crystal form shows an exothermic peak at 211.8°C±3°C.

[0071] In one embodiment of the present invention, the DSC spectrum of the above-mentioned E crystal form is substantially as shown in Figure 12.

[0072] 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°C±3°C.

[0073] In one embodiment of the present invention, the TGA spectrum of the above-mentioned E crystal form is substantially as shown in Figure 13.

[0074] The present invention also provides a crystalline form F of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form F using Cu Kα radiation 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°.

[0075] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form using Cu Kα radiation 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°.

[0076] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form using Cu Kα radiation 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°.

[0077] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form using Cu Kα radiation 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°.

[0078] In some embodiments of the present invention, the XRPD pattern of the above-mentioned F crystal form under Cu Kα radiation is basically as shown in Figure 14.

[0079] In some embodiments of the present invention, the XRPD pattern of the above-mentioned F crystal form under Cu Kα radiation has diffraction peak data as shown in Table 6:

[0080] Table 6 XRPD diffraction data of the crystal form F of the compound of formula (I)

[0081] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned Form F shows an exothermic peak at 225.8°C±3°C.

[0082] In one embodiment of the present invention, the DSC spectrum of the above-mentioned Form F is substantially as shown in FIG15 .

[0083] 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°C±3°C.

[0084] 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°C±3°C and a further weight loss of 4.01% at 220.0°C±3°C.

[0085] In one embodiment of the present invention, the TGA spectrum of the above-mentioned F crystal form is substantially as shown in Figure 16.

[0086] The present invention also provides a G crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of the G crystal form using Cu Kα radiation 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°.

[0087] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form using Cu Kα radiation 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°.

[0088] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form with Cu Kα radiation 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°.

[0089] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form using Cu Kα radiation 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°, 18. 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°.

[0090] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form using Cu Kα radiation 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°.

[0091] In some embodiments of the present invention, the XRPD pattern of the Cu Kα radiation of the above-mentioned G crystal form is basically as shown in Figure 17.

[0092] In some embodiments of the present invention, the XRPD pattern of the above-mentioned G crystal form under Cu Kα radiation has diffraction peak data as shown in Table 7:

[0093] Table 7 XRPD diffraction data of the crystal form G of compound of formula (I)

[0094] The present invention also provides a H crystal form of the compound of formula (I), wherein the H crystal form has a Cu Kα radiation X-ray powder diffraction pattern having 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°.

[0095] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form using Cu Kα radiation 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°.

[0096] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form using Cu Kα radiation 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°.

[0097] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form using Cu Kα radiation 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°.

[0098] In some embodiments of the present invention, the XRPD pattern of the above-mentioned H crystal form under Cu Kα radiation is basically as shown in Figure 18.

[0099] In some embodiments of the present invention, the XRPD pattern of the above-mentioned H crystal form under Cu Kα radiation has diffraction peak data as shown in Table 8:

[0100] Table 8 XRPD diffraction data of Form H of Compound (I)

[0101] The present invention also provides pharmaceutically acceptable salts of the compound of formula (I),

[0102] The pharmaceutically acceptable salt of the compound is lysine salt, dibenzylethylenediamine salt, choline salt, meglumine salt, triethylamine salt, aluminum salt, zinc salt, lithium salt, sodium salt, potassium salt, calcium salt or magnesium salt.

[0103] 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).

[0104] 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, 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.

[0105] In some embodiments of the present invention, the above m is selected from 0.8, 0.9, 1.0, 1.1 and 1.2.

[0106] In some embodiments of the present invention, the above m is selected from 1.0.

[0107] In some embodiments of the present invention, n is selected from the group consisting of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 and 1.5.

[0108] In some embodiments of the present invention, the above n is selected from 0.8, 0.9, 1.0, 1.1 and 1.2.

[0109] In some embodiments of the present invention, the above n is selected from 1.0.

[0110] 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.

[0111] In some embodiments of the present invention, the above p is selected from 0.4, 0.5, 0.6, 0.9, 1.0 and 1.1.

[0112] In some embodiments of the present invention, the above p is selected from 0.5 and 1.0.

[0113] In some embodiments of the present invention, the compound of formula (II) is selected from the compound of formula (II-1),

[0114] The present invention also provides the S1 crystal form of the compound of formula (II-1), wherein the X-ray powder diffraction pattern of the S1 crystal form using 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°.

[0115] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned S1 crystal form with Cu Kα radiation 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°.

[0116] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned S1 crystal form with Cu Kα radiation 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°.

[0117] 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°.

[0118] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned S1 crystal form using 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°, 20.3 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°.

[0119] In some embodiments of the present invention, the XRPD pattern of the Cu Kα radiation of the above-mentioned S1 crystal form is basically as shown in Figure 19.

[0120] In some embodiments of the present invention, the XRPD pattern of the S1 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 9:

[0121] Table 9 XRPD diffraction data of the crystal form S1 of the compound of formula (II-1)

[0122] In some embodiments of the present invention, the compound of formula (III) is selected from the compound of formula (III-1),

[0123] The present invention also provides the S2 crystal form of the compound of formula (III-1), wherein the X-ray powder diffraction pattern of the S2 crystal form using Cu Kα radiation 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°.

[0124] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned S2 crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.20°, 16.00°, 20.97°, 19.53°, 7.63°, and 12.65°.

[0125] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned S2 crystal form is basically as shown in Figure 21.

[0126] In some embodiments of the present invention, the XRPD pattern of the S2 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 10:

[0127] Table 10 XRPD diffraction data of the crystal form S2 of the compound of formula (III-1)

[0128] The present invention also provides the S3 crystal form of the compound of formula (III-1), wherein the X-ray powder diffraction pattern of the S3 crystal form using CuKα radiation 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°.

[0129] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned S3 crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.36°, 8.45°, 11.94°, 21.94° and 23.41°.

[0130] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned S3 crystal form is basically as shown in Figure 22.

[0131] In some embodiments of the present invention, the XRPD pattern of the S3 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 11:

[0132] Table 11 XRPD diffraction data of the crystal form S3 of the compound of formula (III-1)

[0133] In some embodiments of the present invention, the compound of formula (IV) is selected from the compound of formula (IV-1),

[0134] The present invention also provides the S4 crystal form of the compound of formula (IV-1), wherein the X-ray powder diffraction pattern of the S4 crystal form using Cu Kα radiation 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°.

[0135] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned S4 crystal form with Cu Kα radiation 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°.

[0136] 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°.

[0137] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned S4 crystal form is basically as shown in Figure 23.

[0138] In some embodiments of the present invention, the XRPD pattern of the S4 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 12:

[0139] Table 12 XRPD diffraction data of the crystal form S4 of the compound of formula (IV-1)

[0140] In some embodiments of the present invention, the compound of formula (IV) is selected from the compound of formula (IV-2),

[0141] The present invention also provides the S5 crystal form of the compound of formula (IV-2), wherein the X-ray powder diffraction pattern of the S5 crystal form using Cu Kα radiation 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°.

[0142] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned S5 crystal form with Cu Kα radiation 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°.

[0143] 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°.

[0144] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned S5 crystal form is basically as shown in Figure 25.

[0145] In some embodiments of the present invention, the XRPD pattern of the S5 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 13:

[0146] Table 13 XRPD diffraction data of the crystal form S5 of compound (IV-2)

[0147] The present invention also provides the A2 crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of the A2 crystal form using Cu Kα radiation 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°.

[0148] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A2 crystal form using Cu Kα radiation 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°.

[0149] In some embodiments of the present invention, the XRPD pattern of the above-mentioned A2 crystal form with Cu Kα radiation is basically as shown in Figure 27.

[0150] In some embodiments of the present invention, the XRPD pattern of the above-mentioned A2 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 14:

[0151] Table 14 XRPD diffraction data of the crystal form A2 of compound of formula (I)

[0152] The present invention also provides the A3 crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of the A3 crystal form using Cu Kα radiation 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°.

[0153] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A3 crystal form using Cu Kα radiation 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°.

[0154] In some embodiments of the present invention, the XRPD pattern of the above-mentioned A3 crystal form with Cu Kα radiation is basically as shown in Figure 28.

[0155] In some embodiments of the present invention, the XRPD pattern of the above-mentioned A3 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 15:

[0156] Table 15 XRPD diffraction data of the crystalline form of compound A3 of formula (I)

[0157] The present invention also provides the A4 crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of the A4 crystal form using Cu Kα radiation 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°.

[0158] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A4 crystal form using Cu Kα radiation 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°.

[0159] In some embodiments of the present invention, the XRPD pattern of the above-mentioned A4 crystal form with Cu Kα radiation is basically as shown in Figure 29.

[0160] In some embodiments of the present invention, the XRPD pattern of the A4 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 16:

[0161] Table 16 XRPD diffraction data of the crystalline form of compound A4 of formula (I)

[0162] The present invention also provides the A5 crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of the A5 crystal form using Cu Kα radiation 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°.

[0163] The present invention also provides the A5 crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of the A5 crystal form using Cu Kα radiation 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°.

[0164] In some embodiments of the present invention, the X-ray powder diffraction pattern of the A5 crystal form using Cu Kα radiation has 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°.

[0165] In some embodiments of the present invention, the XRPD pattern of the above-mentioned A5 crystal form with Cu Kα radiation is basically as shown in Figure 30.

[0166] In some embodiments of the present invention, the XRPD pattern of the A5 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 17:

[0167] Table 17 XRPD diffraction data of the crystalline form of compound A5 of formula (I)

[0168] The present invention also provides the A6 crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of the A6 crystal form using Cu Kα radiation 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°.

[0169] In some embodiments of the present invention, the X-ray powder diffraction pattern of the A6 crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16°, 7.28°, 10.66°, 14.02°, 17.37°, 24.56° and 25.76°.

[0170] In some embodiments of the present invention, the XRPD pattern of the above-mentioned A6 crystal form with Cu Kα radiation is basically as shown in Figure 31.

[0171] In some embodiments of the present invention, the XRPD pattern of the A6 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 18:

[0172] Table 18 XRPD diffraction data of the crystalline form of compound A6 of formula (I)

[0173] The present invention also provides the A7 crystal form of the compound of formula (I), wherein the X-ray powder diffraction pattern of the A7 crystal form using Cu Kα radiation 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°.

[0174] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A7 crystal form with Cu Kα radiation 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°.

[0175] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A7 crystal form with Cu Kα radiation 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°.

[0176] In some embodiments of the present invention, the XRPD pattern of the above-mentioned A7 crystal form with Cu Kα radiation is basically as shown in Figure 32.

[0177] In some embodiments of the present invention, the XRPD pattern of the A7 crystal form under Cu Kα radiation has diffraction peak data as shown in Table 19:

[0178] Table 19 XRPD diffraction data of the crystalline form of compound A7 of formula (I)

[0179] In some embodiments of the present invention, the above-mentioned crystal form G, crystal form H, crystal form A1, crystal form A2, crystal form A3, crystal form A4, crystal form A5, crystal form A6, crystal form A7, crystal form S1, crystal form S2, crystal form S3, crystal form S4 or crystal form S5 may be in the form of a non-solvate or a solvate, such as a hydrate, an organic solvate, or a combination of an organic solvate and a hydrate.

[0180] In some embodiments of the present invention, the organic solvent of the 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.

[0181] In some embodiments of the present invention, the above-mentioned crystal form G is a hydrate with a hydration coefficient of 0 to 5.0. In some embodiments of the present invention, the above-mentioned crystal form H is a hydrate with a hydration coefficient of 0 to 5.0.

[0182] In some embodiments of the present invention, the above-mentioned A1 crystal form is an organic solvate, and the organic solvent is selected from ethyl acetate, n-heptane, or an ethyl acetate / n-heptane mixture. In some embodiments of the present invention, the above-mentioned A2 crystal form is a dimethyl sulfoxide solvate. In some embodiments of the present invention, the above-mentioned A3 crystal form is a methyl tert-butyl ether solvate. In some embodiments of the present invention, the above-mentioned A4 crystal form is an acetone solvate. In some embodiments of the present invention, the above-mentioned A5 crystal form is an N-methylpyrrolidone solvate. In some embodiments of the present invention, the above-mentioned A6 crystal form is a methyl tert-butyl ether solvate. In some embodiments of the present invention, the above-mentioned A7 crystal form is a dimethyl sulfoxide solvate.

[0183] The present invention also provides the use of the above-mentioned crystal form B, crystal form C or crystal form S1 in the preparation of drugs related to GnRH receptor antagonists.

[0184] In some embodiments of the present invention, the above-mentioned GnRH receptor antagonist-related drug is a drug used to prevent and / or treat endometriosis and / or uterine fibroid-related diseases.

[0185] Technical Effects

[0186] The compounds of the present invention have a significant inhibitory effect on the human gonadotropin-releasing hormone receptor, with high plasma exposure, low clearance, long half-life, high oral bioavailability, and excellent pharmacokinetic properties. The salt and crystal forms of the present invention have simple preparation processes, are stable, and are minimally affected by heat, humidity, and light, facilitating formulation.

[0187] Definition and Description

[0188] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0189] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0190] The chemical reactions of the present invention are carried out in suitable solvents that are compatible with the chemical transformations of the present invention and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0191] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0192] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0193] The following abbreviations are used in this disclosure: ACN stands for acetonitrile; DMSO stands for dimethyl sulfoxide; N2: nitrogen; RH: relative humidity; mL: milliliter; L: liter; min: minute; °C: degrees 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 : microwatt per square centimeter; h: hour; Kg: kilogram; nM: nanomole, rpm: rotational speed; XRPD stands for X-ray powder diffraction; DSC stands for differential scanning calorimetry; TGA stands for thermogravimetric analysis; 1 H NMR stands for proton nuclear magnetic resonance.

[0194] The compounds of the present invention are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names, and all solvents used in the present invention are commercially available.

[0195] Instruments and analytical methods

[0196] (1) X-ray powder diffractometer (XRPD) instrument of the present invention

[0197] The XRPD instrument and test parameters are shown in Table 20.

[0198] Table 20 XRPD test parameters

[0199] (2) Thermogravimetric Analyzer (TGA) and Differential Scanning Calorimeter (DSC) instruments of the present invention

[0200] TGA and DSC instruments and test parameters are shown in Table 21.

[0201] Table 21 TGA and DSC test parameters

[0202] (3) Dynamic Vapor Sorption (DVS)

[0203] Instrument model: SMS DVS intrinsic plus dynamic moisture sorption instrument. Detailed DVS parameters are as follows:

[0204] Temperature: 25℃;

[0205] Protective gas and flow rate: nitrogen, 200 mL / min;

[0206] dm / dt=0.002% / min;

[0207] RH (%) test level: 10% RH;

[0208] Minimum dm / dt balance time: 10min;

[0209] Maximum equilibration time: 180 min;

[0210] RH (%) test step range: 0%-95%.

[0211] The moisture absorption evaluation is classified as follows:

[0212] Absorbs sufficient water to form a liquid: deliquescent; ΔW% ≥ 15%: extremely hygroscopic; 15% > ΔW% ≥ 2%: somewhat hygroscopic; 2% > ΔW% ≥ 0.2%: slightly hygroscopic; ΔW% < 0.2%: no or almost no hygroscopicity. ΔW% represents the weight gain of the test article due to moisture absorption at 25 ± 1°C and 80 ± 2% relative humidity.

[0213] (4) Solution NMR

[0214] Liquid-state NMR spectra were collected on a Bruker 400M NMR spectrometer using DMSO-d6 as the solvent.

[0215] (5) High Performance Liquid Chromatography / Ion Chromatography (HPLC / IC) Instruments

[0216] The molar ratio test in the experiment was performed by Agilent 1260 high performance liquid chromatograph and ion chromatograph, and the analysis conditions are shown in Table 22 and Table 23.

[0217] Table 22 HPLC test conditions

[0218] Table 23 Ion chromatography test conditions BRIEF DESCRIPTION OF THE DRAWINGS

[0219] Figure 1: XRPD spectrum of crystalline form B of compound of formula (I).

[0220] Figure 2: DSC spectrum of crystalline form B of compound of formula (I).

[0221] Figure 3: TGA spectrum of crystalline form B of compound of formula (I).

[0222] Figure 4: XRPD spectrum of Form C of Compound of Formula (I).

[0223] Figure 5: DSC spectrum of Form C of Compound of Formula (I).

[0224] Figure 6: TGA spectrum of crystalline form C of compound of formula (I).

[0225] Figure 7: XRPD spectrum of the crystalline form A1 of compound of formula (I).

[0226] Figure 8: XRPD spectrum of crystalline form D of compound of formula (I).

[0227] Figure 9: DSC spectrum of the crystalline form D of compound of formula (I).

[0228] Figure 10: TGA spectrum of the crystalline form D of the compound of formula (I).

[0229] Figure 11: XRPD spectrum of Form E of the compound of formula (I).

[0230] Figure 12: DSC spectrum of crystalline form E of compound of formula (I).

[0231] Figure 13: TGA spectrum of crystalline form E of compound of formula (I).

[0232] Figure 14: XRPD spectrum of Form F of compound of formula (I).

[0233] Figure 15: DSC spectrum of Form F of Compound of Formula (I).

[0234] Figure 16: TGA spectrum of Form F of Compound of Formula (I).

[0235] Figure 17: XRPD spectrum of Form G of compound of formula (I).

[0236] Figure 18: XRPD spectrum of Form H of the compound of formula (I).

[0237] Figure 19: XRPD pattern of the crystalline form S1 of the compound of formula (II-1).

[0238] Figure 20: Crystalline form of compound S1 of formula (II-1) 1 H NMR spectrum.

[0239] Figure 21: XRPD pattern of Form S2 of the compound of formula (III-1).

[0240] Figure 22: XRPD pattern of Form S3 of the compound of formula (III-1).

[0241] Figure 23: XRPD pattern of Form S4 of the compound of formula (IV-1).

[0242] Figure 24: S4 crystal form of the compound of formula (IV-1) 1 H NMR spectrum.

[0243] Figure 25: XRPD pattern of Form S5 of the compound of formula (IV-2).

[0244] Figure 26: S5 crystal form of the compound of formula (IV-2) 1 H NMR spectrum.

[0245] Figure 27: XRPD pattern of Form A2 of the compound of formula (I).

[0246] Figure 28: XRPD pattern of Form A3 of the compound of formula (I).

[0247] Figure 29: XRPD pattern of Form A4 of the compound of formula (I).

[0248] Figure 30: XRPD pattern of Form A5 of the compound of formula (I).

[0249] Figure 31: XRPD pattern of Form A6 of the compound of formula (I).

[0250] Figure 32: XRPD pattern of Form A7 of the compound of formula (I).

[0251] Figure 33: DVS image of Form B of the compound of formula (I). DETAILED DESCRIPTION

[0252] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0253] Reference Example 1: Intermediate BB-1

[0254] To a solution of compound B-1 (2 g, 7.95 mmol, hydrochloride) in tetrahydrofuran (20 ml) and water (10 ml) was added potassium carbonate (1.65 g, 11.92 mmol), and phenyl chloroformate (2.49 g, 15.89 mmol) was added dropwise at 5-10°C. The reaction solution was stirred at 5-10°C for 1 hour. 50 ml of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, each time with 50 ml. The organic phases were combined, 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.

[0255] Reference Example 2: Intermediate BB-2

[0256] 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) was added dropwise a dichloromethane solution (5 ml) of acetic anhydride (4.04 g, 39.57 mmol). The mixture was warmed to 25°C and stirred at 25°C for 4 hours. The reaction solution was washed with 1 mol / L hydrochloric acid (10 ml x 2), the aqueous phase was collected and extracted with dichloromethane (30 ml x 3), the combined organic phases were washed with saturated sodium bicarbonate aqueous solution (10 ml x 2), washed with saturated brine (10 ml x 2), the collected organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the intermediate compound BB-2. 1H 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).

[0257] Example 1: Preparation of compound of formula (I)

[0258] Step 1

[0259] To a solution of compound 1-1 (3,4-difluoroanisole, 40 g, 277.5 mmol) in tetrahydrofuran (400 mL) was added lithium diisopropylamide (166.53 mL, 2 mol / L) dropwise at -70°C. The reaction system was stirred at -70°C for 0.5 hour. A solution of N,N-dimethylformamide (25.62 mL, 333.06 mmol) in tetrahydrofuran (24 mL) was added dropwise at -70°C to -60°C. The reaction system was stirred at -70°C for 1 hour. Acetic acid (25 mL) and water (100 mL) were added to the reaction system at -65°C. The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed sequentially with water (100 mL x 3) and saturated brine (100 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield compound 1-2.

[0260] Step 2

[0261] To a solution of compound 1-2 (10 g, 58.10 mmol) in dichloromethane (100 ml) at -20°C, boron tribromide (29.11 g, 116.19 mmol) was added dropwise. The mixture was slowly warmed 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 warmed to 40°C and stirred at 40°C for 2 hours. The layers were separated, the aqueous phase was extracted with dichloromethane (300 ml x 2), and the combined organic phases were extracted with aqueous sodium hydroxide solution (1 mol / L, 400 ml x 3). The extract was acidified to pH 2-3 with concentrated hydrochloric acid and extracted with ethyl acetate (300 ml x 3). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 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).

[0262] Step 3

[0263] To a solution of compound 1-3 (1.5 g, 9.49 mmol) in N,N-dimethylformamide (20 ml) were added sodium iodide (284.42 mg, 1.90 mmol) and potassium carbonate (1.97 g, 14.23 mmol). The mixture was stirred at 25°C for 0.5 hours. Compound BB-2 (2.06 g, 11.39 mmol) was then added, and the mixture was warmed to 60°C and stirred at 60°C for 12 hours. The reaction system was poured into 30 ml of water and extracted with ethyl acetate (50 ml x 5). The combined organic phases were washed with water (20 ml x 5) and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 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).

[0264] Step 4

[0265] To a solution of compound 1-4 (3.25 g, 12.59 mmol) in tetrahydrofuran (30 mL) was added an aqueous solution (3 mL) of sodium borohydride (490 mg, 12.95 mmol) at 0°C, and the reaction system was stirred at 0°C for 0.5 hours. Water (10 mL) was added to the reaction system at 0°C, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with water (10 mL x 2) and saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to provide compound 1-5.

[0266] Step 5

[0267] To a solution of compound 1-5 (2.65 g, 10.18 mmol) and 5-fluoro-2-hydroxybenzaldehyde (1.57 g, 11.2 mmol) in tetrahydrofuran (20 ml) was added tri-n-butylphosphine (3.71 g, 18.33 mmol), stirred for 0.1 hour, and then a solution of azodicarbonyldipiperidine (4.62 g, 18.33 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0°C. The mixture was warmed to 25°C and stirred at 25°C for 12 hours. The reaction system was poured into 10 ml of water and extracted with ethyl acetate (30 ml x 3). The combined organic phases were washed with water (10 ml x 3) and brine (10 ml x 3). The collected organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1 / 0 to 20 / 1) to obtain compound 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).

[0268] Step 6

[0269] To a solution of compound 1-6 (1.04 g, 2.72 mmol) in dichloromethane (10 ml) at 0°C was added meta-chloroperbenzoic acid (1.66 g, 85% purity, 8.16 mmol), and the mixture was warmed to 25°C and stirred at 25°C for 12 hours. 2 ml of saturated aqueous sodium sulfite solution was added to the reaction solution, followed by 10 ml of water, and the mixture was extracted with ethyl acetate (30 ml x 3). The combined organic phases were washed with water (10 ml x 2), washed with saturated brine (10 ml x 2), and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 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).

[0270] Step 7

[0271] To a 10 mL methanol solution of compound 1-7 (1 g, 2.51 mmol) was added an aqueous solution of potassium hydroxide (1 mL, 20% purity, 489.03 μmol), and the mixture was stirred at 25° C. for 6 hours. The reaction solution was poured into 10 mL of water and then 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 phases were 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 to 3 / 1) to obtain compound 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).

[0272] Step 8

[0273] To a solution of compound 1-8 (421 mg, 1.28 mmol) in tetrahydrofuran (400 mL) at 0°C was added sodium hydroxide (135.04 mg, 60% purity, 3.38 mmol), and the mixture was stirred at 0°C for 0.5 hours. A solution of p-toluenesulfonyl chloride (244.50 mg, 1.28 mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction system at 0°C, and the mixture was stirred at 25°C for 12 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with water (10 mL x 2), saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative chromatography (petroleum ether:ethyl acetate = 3:1) to provide compound 1-9.

[0274] Step 9

[0275] To a solution of compound 1-9 (53 mg, 170.82 μmol) in acetic acid (1 ml) was added nitric acid (1.46 ml, 60% purity, 19.51 mmol) dropwise at 80°C, and 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 saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (30 ml x 5), and the combined organic phases were washed with water (30 ml x 3), washed with saturated brine (20 ml x 1), and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 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).

[0276] Step 10

[0277] To a solution of compound 1-10 (46 mg, 129.48 μmol) in ethyl acetate (10 mL) was added wet palladium on carbon (10 mg, 10% purity), and the atmosphere was replaced with hydrogen three times. The mixture was stirred at 24°C under a hydrogen atmosphere (15 psi) for 12 hours. The reaction mixture was filtered through celite, 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).

[0278] Step 11

[0279] Compound BB-1 (26.29 mg, 78.41 μmol) and triethylamine (7.93 mg, 78.41 μmol) were added to a solution of compound 1-11 (41 mg, 78.41 μmol) in tetrahydrofuran (3 ml). The mixture was stirred at 70°C for 10 hours. The reaction solution was poured into 10 ml of water and extracted with ethyl acetate (30 ml x 5). The combined organic phases were washed with water (10 ml x 3), washed with saturated brine (10 ml x 1), and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative chromatography (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).

[0280] Step 12

[0281] To a solution of compound 1-12 (22 mg, 28.57 μmol, 73.57% purity) in tetrahydrofuran (2 mL) and methanol (1 mL) was added an aqueous solution of lithium hydroxide monohydrate (5.99 mg, 142.85 μmol) (1 mL), and the mixture was stirred at 26°C for 2 hours. The reaction solution was adjusted to a pH of approximately 6 by adding 1 mol / L dilute hydrochloric acid, then extracted with ethyl acetate (5 mL x 5). The combined organic phases were washed with water (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was purified by preparative chromatography (dichloromethane:methanol = 10 / 1) to provide the compound of formula (I). MS-ESI calculated value [M+H] + 521.0, measured value 521.1.

[0282] Example 2: Preparation of the Crystalline Form of Compound A1 of Formula (I)

[0283] The compound of formula (I) (25 g) was suspended in ethyl acetate (80 mL) at 45°C to 50°C, and n-heptane (40 mL) was added with stirring. The mixture was then cooled to 15°C to 20°C and stirred for 0.5 hours. Filter the mixture, wash the filter cake with a mixed solvent of ethyl acetate (20 mL) and n-heptane (10 mL), and then with n-heptane (20 mL). The filter cake was collected and dried under vacuum to obtain a solid. XRPD analysis confirmed that the solid was the crystalline form A1 of the compound of formula (I). The XRPD spectrum is shown in Figure 7. 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).

[0284] Example 3: Preparation of Crystalline Form B of Compound (I)

[0285] Method 1: 1 g of Compound A1 (Form A1) of Formula (I) was weighed and suspended in water (10 mL) at 90°C with stirring for 14 hours. The mixture was then filtered and the filter cake was dried under reduced pressure at 50°C to obtain a solid. XRPD analysis confirmed the solid to be Compound B (Form B). The XRPD spectrum is shown in Figure 1 , the DSC spectrum is shown in Figure 2 , and the TGA spectrum is shown in Figure 3 .

[0286] Method 2: Weigh the crystalline form A1 of compound of formula (I) (0.3 g), suspend it in a mixed solvent of acetonitrile (1 ml) and water (5 ml), and stir it at 70°C for 12 hours. Then filter it, and dry the filter cake under reduced pressure at 50°C to obtain a solid. XRPD detection shows that it is the crystalline form B of compound of formula (I).

[0287] Example 4: Preparation of Crystalline Form C of Compound (I)

[0288] Compound A1 (Form A1) of Formula (I) (24.8 mg) was weighed and suspended in acetonitrile (0.5 ml) with stirring at room temperature (25±3°C) for 3 days. The mixture was then centrifuged to obtain a wet sample, which was air-dried at room temperature to obtain a solid. XRPD analysis confirmed the solid to be Compound C (Form C). The XRPD spectrum is shown in Figure 4 , the DSC spectrum is shown in Figure 5 , and the TGA spectrum is shown in Figure 6 .

[0289] Example 5: Preparation of Crystalline Form D of Compound of Formula (I)

[0290] Compound A1 (Form A1) of Formula (I) (24.5 mg) was weighed and added to dichloromethane (0.5 ml). The mixture was suspended and stirred at room temperature (25±3°C) for 3 days, followed by centrifugation to obtain a wet sample. The solid was air-dried at room temperature, and XRPD analysis confirmed the solid to be Compound D (Form D). The XRPD spectrum is shown in Figure 8 , the DSC spectrum is shown in Figure 9 , and the TGA spectrum is shown in Figure 10 .

[0291] Example 6: Preparation of Crystalline Form E of Compound of Formula (I)

[0292] Compound A1 (Form A1) of Formula (I) (25.1 mg) was weighed and suspended in 0.5 mL of tetrahydrofuran / n-heptane (volume ratio of 1:4) with stirring at room temperature (25±3°C) for 3 days. The mixture was then centrifuged to obtain a wet sample, which was then air-dried at room temperature to obtain a solid. XRPD analysis confirmed the solid to be Compound E (Form E). The XRPD spectrum is shown in Figure 11 , the DSC spectrum is shown in Figure 12 , and the TGA spectrum is shown in Figure 13 .

[0293] Example 7: Preparation of Crystalline Form F of Compound of Formula (I)

[0294] Compound A1 (Form A1) of Formula (I) (52.3 mg) was weighed and suspended in 0.75 ml of dimethyl sulfoxide / water (volume ratio of 1:4) with stirring at room temperature (25±3°C) for 5 days. The mixture was then centrifuged to obtain a wet sample, which was air-dried at room temperature to obtain a solid. The solid was then heated to 180°C and cooled to room temperature to obtain a solid. XRPD analysis confirmed the solid to be Compound F (Form F). The XRPD spectrum is shown in Figure 14 , the DSC spectrum is shown in Figure 15 , and the TGA spectrum is shown in Figure 16 .

[0295] Example 8: Preparation of Crystalline Form G of Compound (I)

[0296] Compound A1 (Form A1) of Formula (I) (24.4 mg) was weighed and suspended in 0.5 mL of methanol / water (volume ratio 69:31) with stirring at room temperature (25±3°C) for 3 days. The mixture was then centrifuged to obtain a wet sample, which was then air-dried at room temperature to obtain a solid. XRPD analysis confirmed the solid to be Compound G (Form A1). The XRPD spectrum is shown in Figure 17.

[0297] Example 9: Preparation of Crystalline Form H of Compound of Formula (I)

[0298] The compound of formula (I) in crystal form G was heated to 180° C. and then cooled to room temperature to obtain a solid, which was identified by XRPD as the compound of formula (I) in crystal form H. The XRPD spectrum is shown in FIG18 .

[0299] Example 10: Preparation of Crystalline Form S1 of Compound (II)

[0300] The A1 crystal form of the compound of formula (I) (25.0 mg) and 11.7 mg of choline were suspended in 2-methyltetrahydrofuran (0.5 ml) and stirred 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 dried in vacuo at room temperature to obtain a solid. XRPD analysis showed that it was the S1 crystal form of the compound of formula (II). 1 H NMR showed that the molar ratio of choline to the compound of formula (I) was 1.0. The XRPD spectrum is shown in Figure 19. 1 The H NMR spectrum is shown in Figure 20.

[0301] Example 11: Preparation of Crystalline Form S2 of Compound (III)

[0302] Compound A1 (Form A1) of Formula (I) (25.0 mg) and 2.0 mg of sodium hydroxide were suspended in acetonitrile (0.5 mL) and stirred at room temperature (25±3°C) for 4 days. After centrifugation, the solid was dried under vacuum at room temperature. XRPD analysis confirmed the solid to be Compound S2 (Form S2) of Formula (III). HPLC / IC analysis indicated an alkali-acid molar ratio of 1.0. The XRPD spectrum is shown in Figure 21.

[0303] Example 12: Preparation of Crystalline Form S3 of Compound (III)

[0304] Compound A1 (Form A1) of Formula (I) (25.1 mg) and 2.0 mg of sodium hydroxide were suspended in tetrahydrofuran (0.5 mL) and stirred at room temperature (25±3°C) for 4 days. After centrifugation, the solid was dried under vacuum at room temperature. XRPD analysis confirmed the solid to be Compound S3 (Form S3) of Formula (III). HPLC / IC analysis indicated an alkali-acid molar ratio of 1.2. The XRPD spectrum is shown in Figure 22.

[0305] Example 13: Preparation of Crystalline Form S4 of Compound (IV-1)

[0306] The A1 form of the compound of formula (I) (25.1 mg) and 11.5 mg of dibenzylethylenediamine were suspended in isopropanol (0.5 ml) and stirred at room temperature (25±3° C.) for 3 days. After centrifugation, the solid was dried in vacuo at room temperature. XRPD analysis revealed that the solid was the S4 form of the compound of formula (IV-1). 1 H NMR showed that the molar ratio of dibenzylethylenediamine to the compound of formula (I) was 0.9. The XRPD spectrum is shown in Figure 23. 1 The H NMR spectrum is shown in Figure 24.

[0307] Example 14: Preparation of Crystalline Form S5 of Compound (IV-2)

[0308] The A1 form of the compound of formula (I) (25.0 mg) and 11.5 mg of dibenzylethylenediamine were suspended in acetonitrile (0.5 ml) and stirred at room temperature (25±3° C.) for 3 days. After centrifugation, the solid was dried in vacuo at room temperature. XRPD analysis showed that the solid was the S5 form of the compound of formula (IV-2). 1 H NMR showed that the molar ratio of dibenzylethylenediamine to the compound of formula (I) was 0.6. The XRPD spectrum is shown in Figure 25. 1 The H NMR spectrum is shown in Figure 26.

[0309] Example 15: Preparation of Crystalline Form A2 of Compound (I)

[0310] Compound A1 (Form A1) of Formula (I) (24.7 g) was weighed and suspended in 0.5 ml of dimethyl sulfoxide / water (volume ratio of 1:4) at room temperature (25±3°C) with stirring for 3 days. The suspension was then centrifuged to obtain a wet sample, which was then air-dried at room temperature to obtain a solid. XRPD analysis confirmed the solid to be Compound A2 (Form A2). The XRPD spectrum is shown in Figure 27.

[0311] Example 16: Preparation of Crystalline Form A3 of Compound (I)

[0312] Crystalline Compound A1 (Form A1) of Formula (I) (25.1 mg) was weighed and dissolved in 0.2 mL of tetrahydrofuran. 1.5 mL of methyl tert-butyl ether was added, followed by centrifugation to obtain a wet sample. The solid was air-dried at room temperature, which was identified by XRPD as Crystalline Compound A3 of Formula (I). The XRPD spectrum is shown in Figure 28.

[0313] Example 17: Preparation of Crystalline Form A4 of Compound (I)

[0314] Compound A1 (Form A1) of Formula (I) (24.6 mg) was weighed and dissolved in 0.2 mL of acetone. 1.5 mL of n-heptane was added and stirred at 5°C for 1 day. The mixture was then transferred to -20°C and stirred for 2 days. The mixture was then centrifuged to obtain a wet sample, which was air-dried at room temperature to obtain a solid. XRPD analysis confirmed the solid to be Compound A4 (Form A4). The XRPD spectrum is shown in Figure 29.

[0315] Example 18: Preparation of Crystalline Form A5 of Compound (I)

[0316] Compound A1 (Form A1) of Formula (I) (25.2 mg) was weighed and dissolved in 0.2 mL of N-methylpyrrolidone. 1.0 mL of water was added, and the mixture was centrifuged to obtain a wet sample. The solid was dried at room temperature, and XRPD analysis confirmed it to be Compound A5 (Form A5). The XRPD spectrum is shown in Figure 30.

[0317] Example 19: Preparation of Crystalline Form A6 of Compound (I)

[0318] Compound A1 (Form A1) of Formula (I) (25.6 mg) was weighed and suspended in 0.5 mL of methanol / methyl tert-butyl ether (volume ratio of 1:4) with stirring at room temperature (25±3°C) for 3 days. The mixture was then centrifuged to obtain a wet sample, which was then air-dried at room temperature to obtain a solid. XRPD analysis confirmed the solid to be Compound A6 (Form A6). The XRPD spectrum is shown in Figure 31.

[0319] Example 20: Preparation of Crystalline Form A7 of Compound (I)

[0320] Compound A1 (Form A1) of Formula (I) (52.3 mg) was weighed and suspended in 0.75 mL of dimethyl sulfoxide / water (volume ratio of 1:4) at room temperature (25±3°C) with stirring for 5 days. The suspension was then centrifuged to obtain a wet sample, which was then air-dried at room temperature to obtain a solid. XRPD analysis confirmed the solid to be Compound A7 (Form A7). The XRPD spectrum is shown in Figure 32.

[0321] Example 21: Solid Stability Test of Crystal Form B of Compound of Formula (I)

[0322] In accordance with the "Guidelines for Stability Testing of APIs and Preparations" (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 9001), in order to evaluate the solid stability of the crystal form B of compound of formula (I), the stability of the crystal form B was investigated under influencing factors (high temperature, high humidity and light), accelerated (40°C / 75% RH) and long-term (25°C / 60% RH) conditions. Influencing factor test: Unless otherwise specified, each sample was placed in an open weighing bottle and placed in a corresponding storage container to investigate the stability at 5 and 10 days. The photostability test complies with the requirements of ICH Q1B: the illuminated sample is exposed to visible light and ultraviolet light; storage conditions: at 5000±500lux (visible light) and 90μw / cm 2 (UV) irradiation for 5 and 10 days. The total irradiance received by the sample for 10 days is not less than 1.2×10 6 Lux·h, near-ultraviolet energy is not less than 200w·h / m 2 . The illuminated sample is placed in a clean weighing bottle, spread into a single layer, not covered by anything, and placed in a light box with the open mouth for illumination. The control sample is packaged in the same way as the illuminated sample, but the weighing bottle is covered with aluminum film. Long-term accelerated test: Each sample is placed in a double-layer LDPE bag, each layer of LDPE bag is sealed with a buckle, and then placed in an aluminum foil bag and heat-sealed. The accelerated test is placed for 1, 2 and 3 months, and the long-term conditions are placed for 3 months. XRPD testing is performed on all stability samples to detect changes in crystal form.

[0323] Approximately 25 mg of sample was accurately weighed and placed in a 10 mL volumetric flask. 6 mL of acetonitrile was added and sonicated to dissolve the sample. After cooling to room temperature, water was added to the mark and shaken to dissolve the sample, resulting in a solution with a concentration of approximately 2.5 mg / mL. Liquid chromatography was used for sample injection analysis, and the test results were compared with the initial test results on day 0. Specific test results are shown in Table 24 below. The HPLC test instrument and analysis conditions are shown in Table 25.

[0324] Table 24 Solid stability test results of compound B of formula (I)

[0325] Table 25 HPLC instrument information and analysis method

[0326] 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.

[0327] Example 22: Hygroscopicity Study of Crystalline Form B of Compound of Formula (I)

[0328] The test was performed using an SMS DVS intrinsic plus dynamic moisture sorption instrument. 10-20 mg of the compound of formula (I) Form B was placed in a DVS sample tray for testing.

[0329] Experimental results: The DVS spectrum of the crystalline form B of the compound of formula (I) is shown in Figure 33, and the ΔW% is 0.535%.

[0330] Experimental conclusion: The water adsorption of the crystalline form B of the compound of formula (I) at 25°C / 80%RH is 2%>ΔW%≥0.2%, indicating that it is slightly hygroscopic.

[0331] Biological test data

[0332] Experimental Example 1 Test of the Activity of the Compounds of the Present Invention on Human Gonadotropin-Releasing Hormone Receptor

[0333] Experimental purpose: To detect the inhibitory activity of the test compound on gonadotropin-releasing hormone receptor at the cellular level using FLIPR detection technology

[0334] Main experimental materials and sources:

[0335] Fluo-4Direct TM Kit - Invitrogen-F10471

[0336] 384-well poly-lysine-coated cell plates - Greiner-781946

[0337] 384-well compound plate - Greiner-781280

[0338] Compound Preparation ECHO (Acoustic Liquid Handling System) - Labcyte

[0339] FLIPR (Fluorescence Imaging Plate Reader) - Molecular Devices

[0340] Experimental steps:

[0341] GnRH / HEK293 (human embryonic kidney 293) cells in logarithmic growth phase were cultured and washed with DPBS (Dulbecco's phosphate-buffered saline). The cells were digested in a 37°C CO2 incubator with 0.05% EDTA (ethylenediaminetetraacetic acid)-trypsin. After 1-2 minutes, the cells were removed and digested with culture medium. The cells were dispersed by repeated pipetting and harvested by centrifugation. The cells were seeded at a density of 20,000 cells per well in a 384-well polylysine-coated plate using 20 μL of culture medium. The plates were incubated overnight at 37°C in a 5% CO2 incubator.

[0342] On the second day, 20 μL of 2×Fluo-4Direct was added to each well.TM Buffer, 5% CO2, incubate at 37°C incubator for 50 minutes, and place the cells at room temperature for 10 minutes. Use ECHO to make a 4-fold 10-point gradient dilution of 0.2mM Leuprolide acetate and transfer 900nL to the compound plate. Add 30μL FLIPR buffered saline solution to the compound plate and centrifuge at 1000rpm for 1min. Run the FLIPR instrument software, follow the set program, add 10μL of experimental buffered saline solution, and read the fluorescence signal. Then add 10μL of agonist reference compound (leuprolide acetate), read the fluorescence signal, and calculate the EC 80 , prepare 6×EC 80 concentration of agonist.

[0343] 2 mM test compound and reference compound (Cetrorelix Acetate) at appropriate concentrations were diluted 4-fold in a 10-point series using ECHO, and 900 nL was transferred to the compound plate. 30 μL of FLIPR buffered saline was added to the compound plate and centrifuged at 1000 rpm for 1 minute. The FLIPR instrument software was run, and according to the program settings, 10 μL of test and reference compounds were added to the cell plate and the fluorescence signal was read. 10 μL of 6×EC was then added. 80 concentration of agonist to the cell plate and read the fluorescence signal.

[0344] Calculation of the IC of compounds for calcium influx inhibition of gonadotropin-releasing hormone receptors 50 , that is, in cells stably expressing GnRH receptors, intracellular Ca 2+ The drug concentration at which the flow was inhibited by half was used to calculate the IC of the drug using GraphPad Prism 5.0 software. 50 .

[0345] Experimental results:

[0346] The inhibitory activity of the compounds of the present invention on human gonadotropin-releasing hormone receptor was determined by the above test method, and the measured IC 50 See Table 26:

[0347] Table 26 IC inhibition of human gonadotropin-releasing hormone receptor activity by the compounds of the present invention 50

[0348] Conclusion: The compounds of the present invention have a significant inhibitory effect on human gonadotropin-releasing hormone receptor.

[0349] Experimental Example 2 Pharmacokinetic Evaluation

[0350] Experimental purpose: To study the pharmacokinetic properties of the compound of the present invention in mice.

[0351] Test plan:

[0352] Each test compound was mixed with DMAC and vortexed for 2 minutes. The DMAC solution of the test compound was mixed and vortexed for 2 minutes to prepare a 10 mg / mL clear solution. 0.0600 mL of the 10 mg / mL solution was added to 0.300 mL of Solutol and vortexed for 2 minutes. 2.400 mL of normal saline was added and vortexed for 2 minutes to obtain a 0.2 mg / mL clear solution for PO administration. 0.500 mL of the PO dosing solution was 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 and vortexed for 2 minutes. Finally, 0.400 mL of normal saline was added and vortexed for 2 minutes to obtain a 0.1 mg / mL clear solution. The IV dosing solution was filtered through a microporous filter.

[0353] Four male CD-1 mice were divided into two groups. Group 1 received a single intravenous dose of 0.5 mg / kg in a 10% DMAC / 10% Solutol / 80% saline vehicle (5 mL / kg). Group 2 received a single oral gavage of 2 mg / kg of the test compound in a 10% DMAC / 10% Solutol / 80% saline vehicle (10 mL / kg). Whole blood was collected at 0.033 (IV only), 0.083, 0.25, 0.5, 1, 2, 4, and 12 hours post-dose. Plasma was obtained after centrifugation at 3200 g at 2-8°C for 10 minutes. Plasma concentrations of the test compound were determined by LC / MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software.

[0354] Experimental results:

[0355] The test results are shown in Table 27. The meaning of each parameter: IV: intravenous injection; PO: oral administration; C0: initial blood drug concentration; C max : maximum drug concentration in the systemic circulation; T max : Reach C max Time required; T 1 / 2 : half-life; V dss : apparent volume of distribution; Cl: clearance; AUC: 0-last : Area under the drug-time curve.

[0356] Table 27 Pharmacokinetic (PK) test results of the compound of formula (I) in plasma “--” means not tested or data not available.

[0357] Conclusion: The compound of the present invention has high exposure in plasma, low clearance rate, long half-life, high oral bioavailability, and exhibits excellent pharmacokinetic properties.

Claims

1. Crystal Form B of the compound of formula (I), It is characterized in that The X-ray powder diffraction pattern of the B crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 7.35±0.20° and 18.34±0.20°.

2. The crystal form B according to claim 1, having an X-ray powder diffraction pattern having 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 crystal form B according to claim 2, wherein the 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 crystal form B according to claim 3, whose 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 crystalline form B according to claim 4, wherein the 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 crystal form B according to any one of claims 1 to 5, characterized in that Have any of the following characteristics: (1) Its XRPD pattern is basically as shown in Figure 1; (2) its differential scanning calorimetry curve has an exothermic peak at 224.4°C ± 3°C; (3) Its DSC spectrum is basically as shown in Figure 2; (4) Its thermogravimetric analysis curve shows a weight loss of 1.12% at 150°C ± 3°C; (5) Its TGA spectrum is basically as shown in Figure 3.

7. Crystal Form C of the compound of formula (I), It is characterized in that The X-ray powder diffraction pattern of the C crystal form using Cu Kα radiation has characteristic diffraction peaks at any of the following 2θ angles: (1) 7.18 ± 0.20°, 8.47 ± 0.20°, and 12.80 ± 0.20°; (2) 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°; (3) 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°; (4) 7.18°, 8.47°, 11.55°, 12.80°, 15.80°, 16.96°, 19.23°, 20.12°, 23.30° and 26.31°.

8. The crystal form C according to claim 7, characterized in that Have any of the following characteristics: (1) Its XRPD pattern is basically as shown in Figure 4; (2) its differential scanning calorimetry curve has an exothermic peak at 225.1°C ± 3°C; (3) Its DSC spectrum is basically as shown in Figure 5; (4) Its thermogravimetric analysis curve shows a weight loss of 1.13% at 150°C ± 3°C; (5) Its TGA spectrum is basically as shown in Figure 6.

9. A pharmaceutically acceptable salt of a compound of formula (I), It is characterized in that The pharmaceutically acceptable salt is lysine salt, dibenzylethylenediamine salt, choline salt, meglumine salt, triethylamine salt, aluminum salt, zinc salt, lithium salt, sodium salt, potassium salt, calcium salt or magnesium salt.

10. A pharmaceutically acceptable salt of the compound of formula (I) according to claim 9, wherein 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). Among them, 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.

11. A pharmaceutically acceptable salt of the compound of formula (I) according to claim 10, wherein The compound of formula (II) is selected from the compounds of formula (II-1), the compound of formula (III) is selected from the compounds of formula (III-1), 12. Crystal form S1 of the compound of formula (II-1), It is characterized in that The Cu Kα radiation X-ray powder diffraction pattern of the S1 crystal form has characteristic diffraction peaks at any of the following 2θ angles: (1) 8.68 ± 0.20°, 12.70 ± 0.20°, 18.12 ± 0.20°, 19.43 ± 0.20°, and 24.41 ± 0.20°; (2) 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°; (3) 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°; (4) 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°.

13. The S1 crystalline form according to claim 12, which has an XRPD pattern substantially as shown in Figure 19.

14. Use of the crystal form B according to any one of claims 1 to 6, the crystal form C according to claim 7 or 8, the crystal form S1 according to claim 12 or 13, or the salt according to any one of claims 9 to 11 in the preparation of GnRH receptor antagonist-related drugs.