Salt and crystalline forms of thienopyrimidinone derivatives

Abstract

The present invention discloses salts and crystalline forms of thienopyrimidinone derivatives and methods for preparing the same, and specifically discloses salts and crystalline forms of the compound of formula (I) and methods for preparing the same. JPEG2025526941000064.jpg43170

Description

[Technical Field]

[0001] This invention claims priority to CN202210984344.5, filed August 16, 2022.

[0002] The present invention relates to salts and crystalline forms of thienopyrimidinone derivatives and methods for preparing the same, and specifically discloses salts and crystalline forms of the compound of formula (I) and methods for preparing the same. [Background technology]

[0003] Endometriosis is a disease in which endometrial glands or stroma proliferate outside the uterus. Symptoms of endometriosis include chronic pelvic pain, menstrual pain, and infertility. It is extremely difficult to cure and prone to recurrence, making it considered one of the most intractable gynecological diseases. Clinical medication for this disease has drawbacks, including long administration times, numerous side effects, and inconvenient administration. It is known that approximately 176 million women worldwide suffered from endometriosis in 2021.

[0004] The etiology of endometriosis is highly complex, and its mechanism of pathogenesis is not fully understood. Clinical drug treatment plans focus on controlling estrogen levels, inflammation, or both. Treatments are primarily classified into nonsteroidal anti-inflammatory drugs, progesterone-based drugs, combined oral contraceptives, and gonadotropin-releasing hormone (GnRH) agonists. Oral contraceptives have a non-response rate in approximately one-third to one-quarter of patients. Progesterone has the side effect of increasing obesity, necessitating its use as a preventative measure, particularly for patients seeking pregnancy. GnRH has perimenopausal side effects. Polypeptide GnRH receptor agonist or antagonist compounds have many problems, including oral absorption, dosage form, dosage volume, drug stability, duration of action, and metabolic stability.

[0005] GnRH receptor antagonists competitively bind to GnRH receptors, blocking the binding of GnRH to the receptor and directly inhibiting the hypothalamus-pituitary-ovarian axis, thereby inhibiting the secretion of follicle-stimulating hormone and luteinizing hormone, reducing estrogen levels, with rapid efficacy and minimal side effects. Among the currently leading small molecule GnRH receptor antagonists in research and development, in addition to Elagolix, the first commercially available, the FDA approved a second small molecule oral antagonist, Relugolix, in December 2020. This small molecule oral antagonist is first indicated for the treatment of late-stage prostate cancer, has already been approved in Japan for the treatment of uterine fibroids, and has already entered phase 3 clinical trials for endometriosis. The third antagonist, Linzagolix, is in phase 3 clinical trials for both endometriosis and uterine fibroids.

[0006] The crystalline structure of active ingredients of drugs often affects the stability of the compound. Generally, amorphous drug products do not have regular crystalline structure, and often have defects such as low stability, easy to agglomerate, small particle size, and difficult to filter.In addition, the solubility of drug molecules is closely related to oral absorption, and drugs can increase solubility by forming salts with suitable acids or bases, and drug molecules that are easily oxidized can form salts to increase the stability of drug molecules, which is advantageous for storage and transportation.Therefore, the present inventors need to conduct in-depth research to find suitable salt forms and crystalline forms of drug molecules, especially novel crystalline forms with good stability. Summary of the Invention

[0007] The present invention relates to crystalline form B of the compound of formula (I), [ka] The present invention provides crystalline form B, which has characteristic diffraction peaks at 2θ angles of 4.62±0.20°, 7.35±0.20° and 18.34±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0008] In some embodiments of the present invention, the crystalline form B has characteristic diffraction peaks at 2θ angles of 4.62±0.20°, 7.35±0.20°, 11.45±0.20°, 12.33±0.20°, and 18.34±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0009] In some embodiments of the present invention, the crystalline form B has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0010] In some embodiments of the present invention, the crystalline form B has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0011] In some embodiments of the present invention, the crystalline form B has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0012] In some embodiments of the present invention, the crystalline form B has a powder X-ray diffraction pattern using Cu Kα radiation with 2θ angles of 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 1 It has characteristic diffraction peaks at the positions of 7.89±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°.

[0013] In some embodiments of the present invention, the crystalline form B has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0014] In some embodiments of the present invention, the crystalline form B is Cu In the powder X-ray diffraction pattern of Kα radiation, it has characteristic diffraction peaks at 2θ angles of 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°.

[0015] In some embodiments of the present invention, the crystalline form B has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0016] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of crystalline form B has diffraction peak data as shown in Table 1.

[0017] [Table 1]

[0018] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the crystalline form B has an exothermic peak at 224.4°C ± 3°C.

[0019] In one embodiment of the present invention, the crystalline form B has a DSC pattern essentially as shown in FIG.

[0020] In one embodiment of the present invention, the crystalline form B exhibits a weight loss of 1.12% at 150°C ± 3°C in a thermogravimetric analysis (TGA) curve.

[0021] In one embodiment of the present invention, the crystalline form B has a TGA pattern essentially as shown in FIG.

[0022] The present invention further provides a method for preparing crystalline form B of compound of formula (I), comprising the steps of: Step (a) of 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; (b) stirring for 10 to 48 hours; a filtering step (c); and (d) drying the filter cake at 50°C to 70°C.

[0023] The present invention further provides crystalline form C of the compound of formula (I), which has characteristic diffraction peaks at 2θ angles of 7.18±0.20°, 8.47±0.20° and 12.8±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0024] In some embodiments of the present invention, the crystalline form C has characteristic diffraction peaks at 2θ angles of 7.18±0.20°, 8.47±0.20°, 12.80±0.20°, 15.80±0.20°, and 23.30±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0025] In some embodiments of the present invention, the crystalline form C has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0026] In some embodiments of the present invention, the crystalline form C has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0027] In some embodiments of the present invention, the crystalline form C has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0028] In some embodiments of the present invention, the crystalline form C has characteristic diffraction peaks at 2θ angles of 7.18°, 8.47°, 11.55°, 12.80°, 15.80°, 16.96°, 19.23°, 20.12°, 23.30°, and 26.31° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0029] In some embodiments of the present invention, the crystalline form C has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0030] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form C has diffraction peak data as shown in Table 2.

[0031] [Table 2]

[0032] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the crystalline form C has an exothermic peak at 225.1°C ± 3°C.

[0033] In one embodiment of the present invention, the crystalline form C has a DSC pattern essentially as shown in FIG.

[0034] In one embodiment of the present invention, the crystalline form C exhibits a weight loss of 1.13% at 150°C ± 3°C in a thermogravimetric analysis (TGA) curve.

[0035] In one embodiment of the present invention, the crystalline form C has a TGA pattern essentially as shown in FIG.

[0036] The present invention further provides crystalline form A1 of compound of formula (I), which has characteristic diffraction peaks at 2θ angles of 7.15±0.20°, 9.13±0.20°, 11.01±0.20°, 21.60±0.20° and 22.10±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0037] In some embodiments of the present invention, the crystalline form A1 has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0038] In some embodiments of the present invention, the crystalline form A1 has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0039] In some embodiments of the present invention, the crystalline form A1 has a powder X-ray diffraction pattern using Cu Kα radiation with 2θ angles of 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°, and 20. It has characteristic diffraction peaks at the positions of 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°.

[0040] In some embodiments of the present invention, the crystalline form A1 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0041] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form A1 has diffraction peak data as shown in Table 3.

[0042] [Table 3]

[0043] The present invention further provides crystalline form D of compound of formula (I), which has characteristic diffraction peaks at 2θ angles of 7.35±0.20°, 13.02±0.20°, 16.18±0.20°, 20.10±0.20° and 21.91±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0044] In some embodiments of the present invention, the crystalline form D has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0045] In some embodiments of the present invention, the crystalline form D has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0046] In some embodiments of the present invention, the crystalline form D has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0047] In some embodiments of the present invention, the crystalline form D has a powder X-ray diffraction pattern using Cu Kα radiation with 2θ angles of 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°, 20.00°, 21.00°, 22.00°, 23.00°, 24.00°, 25.00°, 26.00°, 27.00°, 28.00°, 29.00°, 30.00°, 31.00°, 32.00°, 33.00°, 34.00°, 35.00°, 36.00°, 37.00°, 38.00°, 39.00°, 40.00°, 41.00°, 42.00°, 43.00°, 44.00°, 45.00°, 46.00°, 47.00°, 48.00°, 49.00°, 50.00°, 51.00°, 52.00°, 53.00°, 54.00°, 55.00°, 56.00°, 57.00°, 58.00°, 59.00°, 60.00°, 61.00°, 62.00°, 63.00°, 6 It has characteristic diffraction peaks at the positions of 0.10°, 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°.

[0048] In some embodiments of the present invention, the crystalline form D has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0049] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form D has diffraction peak data as shown in Table 4.

[0050] [Table 4]

[0051] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the crystalline form D has an exothermic peak at 220.0°C ± 3°C.

[0052] In one embodiment of the present invention, the crystalline form D has a DSC pattern essentially as shown in FIG.

[0053] In one embodiment of the present invention, the crystalline form D exhibits a weight loss of 2.05% at 150.0°C ± 3°C in a thermogravimetric analysis (TGA) curve.

[0054] In one embodiment of the present invention, the crystalline form D has a TGA pattern essentially as shown in FIG.

[0055] The present invention further provides crystalline form E of compound of formula (I), which has characteristic diffraction peaks at 2θ angles of 4.49±0.20°, 6.15±0.20°, 13.40±0.20°, 17.26±0.20° and 26.04±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0056] In some embodiments of the present invention, the crystalline form E has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0057] In some embodiments of the present invention, the crystalline form E has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0058] In some embodiments of the present invention, the crystalline form E has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0059] In some embodiments of the present invention, the crystalline form E has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0060] In some embodiments of the present invention, the crystalline form E has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0061] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form E has diffraction peak data as shown in Table 5.

[0062] [Table 5]

[0063] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the crystalline form E shows an exothermic peak at 211.8°C ± 3°C.

[0064] In one embodiment of the present invention, the crystalline form E has a DSC pattern essentially as shown in FIG.

[0065] In one embodiment of the present invention, the crystalline form E exhibits a weight loss of 2.61% at 150.0°C ± 3°C in a thermogravimetric analysis (TGA) curve.

[0066] In one embodiment of the present invention, the crystalline form E has a TGA pattern essentially as shown in FIG.

[0067] The present invention further provides crystalline form F of compound of formula (I), which has characteristic diffraction peaks at 2θ angles of 8.20±0.20°, 16.73±0.20°, 21.84±0.20°, 23.99±0.20° and 24.56±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0068] In some embodiments of the present invention, the crystalline form F has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0069] In some embodiments of the present invention, the crystalline form F has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0070] In some embodiments of the present invention, the crystalline form F has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0071] In some embodiments of the present invention, the crystalline form F has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0072] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form F has diffraction peak data as shown in Table 6.

[0073] [Table 6]

[0074] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the crystalline form F shows an exothermic peak at 225.8°C ± 3°C.

[0075] In one embodiment of the present invention, the crystalline form F has a DSC pattern essentially as shown in FIG.

[0076] In one embodiment of the present invention, the crystalline form F exhibits a weight loss of 2.20% at 150.0°C ± 3°C in a thermogravimetric analysis (TGA) curve.

[0077] In one embodiment of the present invention, the crystalline form F exhibits a thermogravimetric analysis (TGA) curve in which the weight loss is 2.20% at 150.0°C ± 3°C, followed by a weight loss of 4.01% at 220.0°C ± 3°C.

[0078] In one embodiment of the present invention, the crystalline form F has a TGA pattern essentially as shown in FIG.

[0079] The present invention further provides crystalline form G of compound of formula (I), which has characteristic diffraction peaks at 2θ angles of 8.55±0.20°, 12.62±0.20°, 24.96±0.20° and 25.39±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0080] In some embodiments of the present invention, the crystalline form G has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0081] In some embodiments of the present invention, the crystalline form G has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0082] In some embodiments of the present invention, the crystalline form G has a powder X-ray diffraction pattern using Cu Kα radiation with 2θ angles of 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°, 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°.

[0083] In some embodiments of the present invention, the crystalline form G has a powder X-ray diffraction pattern using Cu Kα radiation with 2θ angles of 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°, 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°, 29.80°, 30.59°, 31.76°, 32.57°, 33.72°, 35.90°, and 37.86°.

[0084] In some embodiments of the present invention, the crystalline form G has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0085] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form G has diffraction peak data as shown in Table 7.

[0086] [Table 7]

[0087] The present invention further provides crystalline form H of compound of formula (I), which has characteristic diffraction peaks at 2θ angles of 9.57±0.20°, 12.16±0.20°, 12.58±0.20°, 16.74±0.20° and 25.02±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0088] In some embodiments of the present invention, the crystalline form H has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0089] In some embodiments of the present invention, the crystalline form H has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0090] In some embodiments of the present invention, the crystalline form H has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0091] In some embodiments of the present invention, the crystalline form H has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0092] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form H has diffraction peak data as shown in Table 8.

[0093] [Table 8]

[0094] Furthermore, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I), [ka] Provided is a pharmaceutically acceptable salt of a compound of formula (I), which is a 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.

[0095] 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). [ka] 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.

[0096] In some embodiments of the present invention, m is selected from 0.8, 0.9, 1.0, 1.1, and 1.2.

[0097] In some embodiments of the present invention, m is selected from 1.0.

[0098] In some embodiments of the invention, n is selected from 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, and 1.5.

[0099] In some embodiments of the present invention, n is selected from 0.8, 0.9, 1.0, 1.1, and 1.2.

[0100] In some embodiments of the present invention, n is selected from 1.0.

[0101] In some embodiments of the invention, 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.

[0102] In some embodiments of the present invention, p is selected from 0.4, 0.5, 0.6, 0.9, 1.0, and 1.1.

[0103] In some embodiments of the present invention, p is selected from 0.5 and 1.0.

[0104] In some embodiments of the present invention, the compound of formula (II) is selected from compounds of formula (II-1). [ka]

[0105] The present invention further provides crystalline form S1 of compound of formula (II-1), which has characteristic diffraction peaks at 2θ angles of 8.68±0.20°, 12.70±0.20°, 18.12±0.20°, 19.43±0.20°, and 24.41±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0106] In some embodiments of the present invention, the crystalline form S1 has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0107] In some embodiments of the present invention, the crystalline form S1 has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0108] In some embodiments of the present invention, the crystalline form S1 has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0109] In some embodiments of the present invention, the crystalline form S1 has a powder X-ray diffraction pattern using Cu Kα radiation with 2θ angles of 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°, 21.02°, 22.01°, 23.02°, 24.01°, 25.02°, 26.02°, 27.02°, 28.02°, 29.02°, 30.02°, 31.02°, 32.02°, 33.02°, 34.02°, 35.02°, 36.02°, 37.02°, 38.02°, 39.02°, 40.02°, 41.02°, 42.02°, 43.02°, 44.02°, 45.02°, 46.02°, 47.02°, 48.02°, 49.02°, 50.02°, 51.02°, 52.02°, 53.02°, 54.02°, 55.02°, 56.02°, 57.02°, 58.02°, 59.02°, 60.02°, 61.02°, 62.02°, 63.02°, It has characteristic diffraction peaks at the positions: 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°.

[0110] In some embodiments of the present invention, the crystalline form S1 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0111] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form S1 has the diffraction peak data set forth in Table 9.

[0112] [Table 9]

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

[0114] The present invention further provides crystalline form S2 of compound of formula (III-1), which has characteristic diffraction peaks at 2θ angles of 5.20±0.20°, 7.63±0.20°, 16.00±0.20°, 19.53±0.20°, and 20.97±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0115] In some embodiments of the present invention, the crystalline form S2 has characteristic diffraction peaks at 2θ angles of 5.20°, 16.00°, 20.97°, 19.53°, 7.63°, and 12.65° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0116] In some embodiments of the present invention, the crystalline form S2 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0117] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form S2 has diffraction peak data as shown in Table 10.

[0118] [Table 10]

[0119] The present invention further provides crystalline form S3 of compound of formula (III-1), which has characteristic diffraction peaks at 2θ angles of 4.36±0.20°, 8.45±0.20°, 11.94±0.20°, 21.94±0.20°, and 23.41±0.20° in a powder X-ray diffraction pattern using CuKα radiation.

[0120] In some embodiments of the present invention, the crystalline form S3 has characteristic diffraction peaks at 2θ angles of 4.36°, 8.45°, 11.94°, 21.94°, and 23.41° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0121] In some embodiments of the present invention, the crystalline form S3 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0122] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form S3 has diffraction peak data as shown in Table 11.

[0123] [Table 11]

[0124] In some embodiments of the present invention, the compound of formula (IV) above is selected from compounds of formula (IV-1). [ka]

[0125] The present invention further provides crystalline form S4 of compound of formula (IV-1), which has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0126] In some embodiments of the present invention, the crystalline form S4 has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0127] In some embodiments of the present invention, the crystalline form S4 has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0128] In some embodiments of the present invention, the crystalline form S4 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0129] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form S4 has diffraction peak data as shown in Table 12.

[0130] [Table 12]

[0131] In some embodiments of the present invention, the compound of formula (IV) above is selected from compounds of formula (IV-2). [ka]

[0132] The present invention further provides crystalline form S5 of compound of formula (IV-2), which has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0133] In some embodiments of the present invention, the crystalline form S5 has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0134] In some embodiments of the present invention, the crystalline form S5 has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0135] In some embodiments of the present invention, the crystalline form S5 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0136] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form S5 has the diffraction peak data set forth in Table 13.

[0137] [Table 13]

[0138] The present invention further provides crystalline form A2 of compound of formula (I), which has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0139] In some embodiments of the present invention, the crystalline form A2 has characteristic diffraction peaks at 2θ angles of 6.94°, 13.39°, 13.93°, 17.88°, 20.41°, 22.09°, 24.08°, and 25.04° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0140] In some embodiments of the present invention, the crystalline form A2 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0141] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form A2 has diffraction peak data as shown in Table 14.

[0142] [Table 14]

[0143] The present invention further provides crystalline form A3 of compound of formula (I), which has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0144] In some embodiments of the present invention, the crystalline form A3 has characteristic diffraction peaks at 2θ angles of 4.47°, 5.75°, 8.16°, 10.04°, 14.71°, 15.81°, 21.67°, and 23.30° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0145] In some embodiments of the present invention, the crystalline form A3 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0146] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form A3 has diffraction peak data as shown in Table 15.

[0147] [Table 15]

[0148] The present invention further provides crystalline form A4 of compound of formula (I), which has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0149] In some embodiments of the present invention, the crystalline form A4 has characteristic diffraction peaks at 2θ angles of 8.07°, 10.87°, 12.40°, 13.30°, 16.82°, 17.66°, 19.08°, 20.54°, 21.99°, and 25.61° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0150] In some embodiments of the present invention, the crystalline form A4 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0151] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form A4 has diffraction peak data as shown in Table 16.

[0152] [Table 16]

[0153] The present invention further provides crystalline form A5 of compound of formula (I), which has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0154] The present invention further provides crystalline form A5 of compound of formula (I), which has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0155] In some embodiments of the present invention, the crystalline form A5 has a powder X-ray diffraction pattern using Cu Kα radiation with 2θ angles of 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°, 20.01°, 20.45°, 20.85°, 20.95°, 20.99°, 21.95°, 21.95°, 22.95°, 23.95°, 24.95°, 25.95°, 26.95°, 27.95°, 28.95°, 29.95°, 30.95°, 31.95°, 32.95°, 33.95°, 34.95°, 35.95°, 36.95°, 37.95°, 38.95°, 39.95°, 40.95°, 41.95°, 42.95°, 43.95°, 44.95°, 45.95°, 46.95°, 47.95°, 48.95°, 49.95°, 50.95°, 51.95°, 52.95°, 53.95°, 54.95°, 55.95°, 56.95°, 57.95°, 58.95°, It has characteristic diffraction peaks at the positions: 21.76°, 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°.

[0156] In some embodiments of the present invention, the crystalline form A5 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0157] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form A5 has diffraction peak data as shown in Table 17.

[0158] [Table 17]

[0159] The present invention further provides crystalline form A6 of compound of formula (I), which has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0160] In some embodiments of the present invention, the crystalline form A6 has characteristic diffraction peaks at 2θ angles of 6.16°, 7.28°, 10.66°, 14.02°, 17.37°, 24.56°, and 25.76° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0161] In some embodiments of the present invention, the crystalline form A6 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0162] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form A6 has diffraction peak data as shown in Table 18.

[0163] [Table 18]

[0164] The present invention further provides crystalline form A7 of compound of formula (I), which has characteristic diffraction peaks in a powder X-ray diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0165] In some embodiments of the present invention, the crystalline form A7 has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0166] In some embodiments of the present invention, the crystalline form A7 has characteristic diffraction peaks at 2θ angles of 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° in a powder X-ray diffraction pattern using Cu Kα radiation.

[0167] In some embodiments of the present invention, the crystalline form A7 has an XRPD pattern for Cu Kα radiation essentially as shown in FIG.

[0168] In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation for crystalline form A7 has diffraction peak data as shown in Table 19.

[0169] [Table 19]

[0170] In some embodiments of the present invention, crystalline form G, crystalline form H, crystalline form A1, crystalline form A2, crystalline form A3, crystalline form A4, crystalline form A5, crystalline form A6, crystalline form A7, crystalline form S1, crystalline form S2, crystalline form S3, crystalline form S4, or crystalline form S5 may be in a non-solvated form or in a solvated form, such as a hydrate, an organic solvate, or a combination of an organic solvate and a hydrate.

[0171] In some embodiments of the 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.

[0172] In some embodiments of the present invention, the crystalline form G is a hydrate having a hydration coefficient of 0 to 5.0. In some embodiments of the present invention, the crystalline form H is a hydrate having a hydration coefficient of 0 to 5.0.

[0173] In some embodiments of the invention, crystalline form A1 is an organic solvate selected from ethyl acetate, n-heptane, or an ethyl acetate / n-heptane mixture. In some embodiments of the invention, crystalline form A2 is a dimethyl sulfoxide solvate. In some embodiments of the invention, crystalline form A3 is a methyl tert-butyl ether solvate. In some embodiments of the invention, crystalline form A4 is an acetone solvate. In some embodiments of the invention, crystalline form A5 is an N-methylpyrrolidone solvate. In some embodiments of the invention, crystalline form A6 is a methyl tert-butyl ether solvate. In some embodiments of the invention, crystalline form A7 is a dimethyl sulfoxide solvate.

[0174] Furthermore, the present invention provides use of the above crystalline form B, crystalline form C or crystalline form S1 in the manufacture of a drug related to a GnRH receptor antagonist.

[0175] In some aspects of the present invention, the drug related to the GnRH receptor antagonist is a drug for preventing and / or treating diseases related to endometriosis and / or uterine fibroids. Technical effects

[0176] The compound of the present invention has a significant inhibitory effect on human gonadotropin-releasing hormone receptors, and exhibits high plasma exposure, low clearance rate, long half-life, high oral bioavailability, and excellent pharmacokinetic properties. The salt and crystalline forms of the present invention can be prepared by a simple process, and the salt and crystalline forms are stable and resistant to the effects of heat, humidity, and light, making them convenient for formulation. Definitions and Explanations

[0177] Unless otherwise stated, the following terms and phrases used herein are intended to include the following meanings: A particular phrase or term should not be considered as being indefinite or unclear unless specifically defined, and should be understood according to its ordinary meaning. When trade names appear herein, it is intended to refer to the corresponding product of the trade name or its active ingredient.

[0178] The intermediate compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed in combination with other chemical synthetic methods, and equivalent substitution forms well known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0179] The chemical reactions in specific embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical transformations of the present invention and the reagents and materials required therefor. To obtain the compounds of the present invention, those skilled in the art may need to modify or select synthetic steps or reaction flows based on existing embodiments.

[0180] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0181] The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art, and when the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in this field. For example, by using single crystal X-ray diffraction (SXRD), the grown single crystal is collected by a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is φ / ω, and the relevant data is collected. Then, the crystal structure is analyzed by a direct method (Shelxs97), and the absolute configuration can be confirmed.

[0182] In the present invention, the following abbreviations are used: ACN stands for acetonitrile and DMSO stands for dimethyl sulfoxide. N2: nitrogen gas, 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 : microwatts 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 analysis, TGA stands for thermogravimetric analysis, 1 1 H NMR stands for nuclear magnetic resonance hydrogen spectrum.

[0183] The compounds of the present invention are named according to conventional naming principles in the art or using ChemDraw® software; commercially available compounds use the vendor's catalog name; all solvents used in the present invention are commercially available. Equipment and analytical methods

[0184] (1) X-ray powder diffractometer (XRPD) instrument of the present invention The XRPD instrument and test parameters are shown in Table 20.

[0185] [Table 20]

[0186] (2) The Thermogravimetric Analyzer (TGA) and Differential Scanning Calorimeter (DSC) Instruments of the Present Invention The TGA and DSC instruments and test parameters are shown in Table 21.

[0187] [Table 21]

[0188] (3) Dynamic Vapor Sorption (DVS) The model number of the equipment is SMS DVS intrinsic plus dynamic moisture sorption equipment. The detailed DVS parameters are as follows: Temperature: 25℃ Shielding gas and flow rate: Nitrogen gas, 200mL / min dm / dt=0.002% / min RH (%) Test stage: 10% RH Minimum dm / dt equilibrium time: 10min Maximum equilibration time: 180min RH(%) test range: 0%~95%

[0189] Moisture absorption rating classification: Absorbs sufficient water to form a liquid: deliquescence, ΔW% ≥ 15%: highly hygroscopic, 15% > ΔW% ≥ 2%: hygroscopic, 2% > ΔW% ≥ 0.2%: slightly hygroscopic, ΔW% < 0.2%: no or almost no hygroscopicity. ΔW% indicates the weight gain of the test substance due to moisture absorption at 25 ± 1°C and 80 ± 2% RH.

[0190] (4) Liquid nuclear magnetic resonance (Solution NMR) Liquid nuclear magnetic resonance spectra were collected on a Bruker 400M nuclear magnetic resonance instrument using DMSO-d6 as the solvent.

[0191] (5) High-performance liquid chromatography / ion chromatography (HPLC / IC) equipment The molar ratio test in the test was performed using an Agilent 1260 high performance liquid chromatograph and ion chromatograph, and the analytical conditions are shown in Tables 22 and 23.

[0192] [Table 22]

[0193] [Table 23] [Brief explanation of the drawings]

[0194] [Figure 1] 1 is an XRPD pattern of crystalline form B of compound of formula (I). [Figure 2] 1 is a DSC pattern of crystalline form B of the compound of formula (I). [Figure 3] 1 is a TGA pattern of crystalline form B of compound of formula (I). [Figure 4] 1 is an XRPD pattern of crystalline form C of compound of formula (I). [Figure 5] 1 is a DSC pattern of crystalline form C of the compound of formula (I). [Figure 6] 1 is a TGA pattern of crystalline form C of compound of formula (I). [Figure 7] 1 is an XRPD pattern of crystalline form A1 of compound of formula (I). [Figure 8] 1 is an XRPD pattern of crystalline form D of compound of formula (I). [Figure 9] 1 is a DSC pattern of crystalline form D of the compound of formula (I). [Figure 10] 1 is a TGA pattern of crystalline form D of the compound of formula (I). [Figure 11] 1 is an XRPD pattern of crystalline form E of compound of formula (I). [Figure 12] 1 is a DSC pattern of crystalline form E of the compound of formula (I). [Figure 13] 1 is a TGA pattern of crystalline form E of the compound of formula (I). [Figure 14] 1 is an XRPD pattern of crystalline form F of compound of formula (I). [Figure 15] 1 is a DSC pattern of crystalline form F of the compound of formula (I). [Figure 16] 1 is a TGA pattern of crystalline form F of compound of formula (I). [Figure 17] 1 is an XRPD pattern of crystalline form G of compound of formula (I). [Figure 18] 1 is an XRPD pattern of crystalline form H of compound of formula (I). [Figure 19] 1 is an XRPD pattern of crystalline form S1 of compound of formula (II-1). [Figure 20] 1 is a 1H NMR spectrum of the crystalline form S1 of the compound of formula (II-1). [Figure 21] 1 is an XRPD pattern of crystalline form S2 of compound of formula (III-1). [Figure 22] 1 is an XRPD pattern of crystalline form S3 of compound of formula (III-1). [Figure 23] 1 is an XRPD pattern of crystalline form S4 of compound of formula (IV-1). [Figure 24] 1H NMR spectrum of crystalline form S4 of compound of formula (IV-1). [Figure 25] 1 is an XRPD pattern of crystalline form S5 of compound of formula (IV-2). [Figure 26] 1H NMR spectrum of crystalline form S5 of compound of formula (IV-2). [Figure 27] 1 is an XRPD pattern of crystalline form A2 of compound of formula (I). [Figure 28] 1 is an XRPD pattern of crystalline form A3 of compound of formula (I). [Figure 29]1 is an XRPD pattern of crystalline form A4 of compound of formula (I). [Figure 30] 1 is an XRPD pattern of crystalline form A5 of compound of formula (I). [Figure 31] 1 is an XRPD pattern of crystalline form A6 of compound of formula (I). [Figure 32] 1 is an XRPD pattern of crystalline form A7 of compound of formula (I). [Figure 33] 1 is a DVS pattern of crystalline form B of the compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0195] The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. Although the present invention is described in detail and specific examples are disclosed herein, it will be apparent to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0196] Reference example 1: Intermediate BB-1 [ka]

[0197] Compound B-1 (2 g, 7.95 mmol, hydrochloride salt) was dissolved in tetrahydrofuran (20 mL) and water (10 mL) and potassium carbonate (1.65 g, 11.92 mmol) was added. Phenyl chloroformate (2.49 g, 15.89 mmol) was added dropwise at 5-10 °C. The reaction mixture was stirred at 5-10 °C for 1 hour. 50 mL of water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL each time). The 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 triturated at 30 °C for 30 minutes. The filter cake was then dried under reduced pressure to obtain compound BB-1. The calculated MS-ESI values ​​were [M+H]. +The measured value was 336.1.

[0198] Reference example 2: Intermediate BB-2 [ka]

[0199] 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 solution of acetic anhydride (4.04 g, 39.57 mmol) in dichloromethane (5 mL). The mixture was warmed to 25°C and stirred at 25°C for 4 hours. The reaction mixture 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 phase was washed with saturated aqueous sodium bicarbonate solution (10 mL x 2) and saturated brine (10 mL x 2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate compound BB-2. 1 H NMR (400MHz, CDCl3) δ = 4.18-4.25 (m, 2H), 3.44-3.51 (m, 2H), 2.15-2.23 (m, 2H), 2.07 (s, 3H).

[0200] Example 1: Preparation of compounds of formula (I) [ka]

[0201] Step 1 Lithium diisopropylamide (166.53 mL, concentration: 2 mol / L) was added dropwise to a solution of compound 1-1 (3,4-difluoroanisole, 40 g, 277.5 mmol) in tetrahydrofuran (400 mL) at -70°C, and the reaction mixture was stirred at -70°C for 0.5 hours. A solution of N,N-dimethylformamide (25.62 mL, 333.06 mmol) in tetrahydrofuran (24 mL) was added dropwise to the reaction mixture at -70°C to -60°C, and the reaction mixture was stirred at -70°C for 1 hour. Acetic acid (25 mL) and water (100 mL) were added to the reaction mixture at -65°C, and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed sequentially with water (100 mL x 3) and saturated brine (100 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-2.

[0202] Step 2 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 gradually 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 mixture, and the mixture was warmed to 40°C and stirred at 40°C for 2 hours. The layers were separated, and the aqueous phase was extracted with dichloromethane (300 mL x 2). The combined organic phase was 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 phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-3. 1 H NMR (400 MHz, CDCl3) δ = 11.13 (s, 1H), 10.29 (s, 1H), 7.37 (q, J = 9.3 Hz, 1H), 6.77 - 6.68 (m, 1H).

[0203] Step 3 To a solution of compound 1-3 (1.5 g, 9.49 mmol) in N,N-dimethylformamide (20 mL), sodium iodide (284.42 mg, 1.90 mmol) and potassium carbonate (1.97 g, 14.23 mmol) were added. The mixture was stirred at 25°C for 0.5 h. Compound BB-2 (2.06 g, 11.39 mmol) was then added, and the mixture was heated to 60°C and stirred at 60°C for 12 h. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (50 mL x 5). The combined organic phase was 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 give compound 1-4. 1 H NMR (400 MHz, CDCl3) δ = 10.45 - 10.38 (m, 1H), 7.37 - 7.28 (m, 1H), 6.74 - 6.65 (m, 1H), 4.28 (t, J = 6.2 Hz, 2H), 4.16 - 4.13 (m, 2H), 2.22 - 2.16 (m, 2H), 2.06 (s, 3H).

[0204] Step 4 At 0°C, a solution of compound 1-4 (3.25 g, 12.59 mmol) in tetrahydrofuran (30 mL) was added with an aqueous solution (3 mL) of sodium borohydride (490 mg, 12.95 mmol), and the reaction mixture was stirred at 0°C for 0.5 hours. At 0°C, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with water (10 mL x 2) and saturated brine (10 mL x 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-5.

[0205] Step 5 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), tri-n-butylphosphorus (3.71 g, 18.33 mmol) was added and stirred for 0.1 hours. Then, at 0 ° C, a solution of azodicarboxylic acid dipiperidine (4.62 g, 18.33 mmol) in tetrahydrofuran (5 mL) was added dropwise. The mixture was warmed to 25 ° C and stirred at 25 ° C for 12 hours. The reaction mixture was poured into 10 mL of water and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with water (10 mL × 3) and brine (10 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1 / 0 to 20 / 1) to give compound 1-6. 1 H NMR (400 MHz, CDCl3) δ = 10.31 (d, J = 3.2 Hz, 1H), 7.49 (dd, J = 3.2, 8.4 Hz, 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 = 2.8 Hz, 2H), 4.19 (t, J = 6.2 Hz, 2H), 4.06 (t, J = 6.2 Hz, 2H), 2.09 - 2.06 (m, 2H), 2.04 (s, 3H).

[0206] Step 6 To a solution of compound 1-6 (1.04 g, 2.72 mmol) in dichloromethane (10 mL) was added m-chloroperbenzoic acid (1.66 g, 85% purity, 8.16 mmol) at 0° C. The mixture was warmed to 25° C. and stirred at 25° C. for 12 hours. 2 mL of saturated aqueous sodium sulfite solution and 10 mL of water were added to the reaction mixture, followed by extraction with ethyl acetate (30 mL × 3). The combined organic phase was washed with water (10 mL × 2), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting crude product was purified by preparative chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 1-7. 1 H NMR (400 MHz, CDCl3) δ = 8.19 (s, 1H), 7.18 - 7.08 (m, 2H), 7.00 - 6.93 (m, 1H), 6.89 (dd, J = 3.2, 8.4 Hz, 1H), 6.63 - 6.57 (m, 1H), 5.14 - 5.09 (m, 2H), 4.23 (t, J = 6.2 Hz, 2H), 4.04 (t, J = 6.2 Hz, 2H), 2.14 - 2.09 (m, 2H), 2.06 (s, 3H).

[0207] Step 7 To a solution of compound 1-7 (1 g, 2.51 mmol) in 10 mL of methanol was added an aqueous solution of potassium hydroxide (1 mL, 20% purity, 489.03 μmol), and the mixture was stirred for 6 hours at 25° C. The reaction mixture was poured into 10 mL of water and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with water (10 mL × 2) and saturated brine (10 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 5 / 1 to 3 / 1) to obtain compound 1-8. 1H NMR (400 MHz, CDCl3) δ = 7.15 (q, J = 9.2 Hz, 1H), 7.00 (dd, J = 5.2, 8.8 Hz, 1H), 6.91 (s, 1H), 6.69 - 6.62 (m, 2H), 6.53 (dt, J = 3.0, 8.6 Hz, 1H), 5.17 (d, J = 2.0 Hz, 2H), 4.22 (t, J = 5.8 Hz, 2H), 3.88 (q, J = 5.0 Hz, 2H), 2.49 (br s, 1H), 2.15 - 2.05 (m, 2H).

[0208] Step 8 Sodium hydride (135.04 mg, 60% purity, 3.38 mmol) was added to a tetrahydrofuran (400 mL) solution of compound 1-8 (421 mg, 1.28 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 0.5 hours. A tetrahydrofuran solution (5 mL) of p-toluenesulfonyl chloride (244.50 mg, 1.28 mmol) 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 × 3). The combined organic phase was washed with water (10 mL × 2), washed with saturated brine (10 mL × 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 obtain compound 1-9.

[0209] Step 9 Nitric acid (1.46 mL, 60% purity, 19.51 mmol) was added dropwise to a solution of compound 1-9 (53 mg, 170.82 μmol) in acetic acid (1 mL) at 80° C., and the mixture was stirred for 2 hours at 80° C. The reaction mixture 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 × 5). The combined organic phase was washed with water (30 mL × 3), washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-10. 1 H NMR (400 MHz, CDCl3) δ = 7.92 (d, J = 7.6 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.76 - 6.73 (d, J = 12.0 Hz, 1H), 6.57 - 6.12 (m, 1H), 5.20 (d, J = 1.2 Hz, 2H), 4.48 - 4.42 (m, 2H), 4.37 - 4.31 (m, 2H), 2.17 - 2.14 (m, 2H).

[0210] Step 10 To a solution of compound 1-10 (46 mg, 129.48 μmol) in ethyl acetate (10 mL), wet palladium on carbon (10 mg, 10% purity) was added, and the mixture was purged with hydrogen gas three times. The mixture was stirred under a hydrogen gas atmosphere (15 psi) at 24 °C for 12 hours. The reaction mixture was filtered with celite filtration aid, and the filtrate was concentrated to give compound 1-11. Calculated ESI values ​​were [M+H] + The measured value was 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).

[0211] Step 11 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 mixture was poured into 10 mL of water and extracted with ethyl acetate (30 mL × 5). The combined organic phase was washed with water (10 mL × 3), washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative chromatography (petroleum ether: ethyl acetate = 2 / 1) to obtain compound 1-12. The calculated MS-ESI value was [M + H] + The measured value was 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).

[0212] Step 12 A solution of compound 1-12 (22 mg, 28.57 μmol, 73.57% purity) in tetrahydrofuran (2 mL) and methanol (1 mL) was added with aqueous lithium hydroxide monohydrate (5.99 mg, 142.85 μmol) (1 mL), and the mixture was stirred at 26 °C for 2 hours. The reaction mixture was adjusted to pH 6 with 1 mol / L dilute hydrochloric acid, extracted with ethyl acetate (5 mL x 5), and the combined organic phase was washed with water (5 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative chromatography (dichloromethane:methanol = 10 / 1) to obtain compound of formula (I). The calculated value of MS-ESI was [M + H] + The calculated value was 521.0, and the actual measured value was 521.1.

[0213] Example 2: Preparation of crystalline form A1 of the compound of formula (I) [ka]

[0214] The compound of formula (I) (25 g) was suspended in ethyl acetate (80 mL) at 45-50°C, and n-heptane (40 mL) was added with stirring. The mixture was then naturally cooled to 15-20°C and stirred for 0.5 hours. The mixture was filtered, and the filter cake was washed 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 revealed that the crystalline form was Form A1 of the compound of formula (I), and the XRPD pattern is shown in Figure 7. The calculated MS-ESI value was [M+H]. + The calculated value was 521.0, and the actual measured value was 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).

[0215] Example 3: Preparation of crystalline form B of the compound of formula (I) [ka]

[0216] In Method 1, crystalline form A1 of the compound of formula (I) (1 gram) was weighed, suspended in water (10 milliliters) at 90°C for 14 hours with stirring, and then filtered. The filter cake was dried under reduced pressure at 50°C to obtain a solid. XRPD confirmed that the solid was crystalline form B of the compound of formula (I). The XRPD pattern is shown in Figure 1, the DSC pattern in Figure 2, and the TGA pattern in Figure 3.

[0217] In Method 2, crystalline form A1 of compound of formula (I) (0.3 grams) was weighed, suspended in a mixed solvent of acetonitrile (1 milliliter) and water (5 milliliters) at 70°C for 12 hours with stirring, and then filtered. The filter cake was dried under reduced pressure at 50°C to obtain a solid, which was detected by XRPD as crystalline form B of compound of formula (I).

[0218] Example 4: Preparation of crystalline form C of the compound of formula (I) [ka]

[0219] Crystalline form A1 of the compound of formula (I) (24.8 mg) was weighed out, suspended in acetonitrile (0.5 mL) at room temperature (25±3°C) for 3 days with stirring, and then centrifuged to obtain a wet sample, which was then dried at room temperature to obtain a solid. XRPD confirmed that the crystal was form C of the compound of formula (I). The XRPD pattern is shown in Figure 4, the DSC pattern in Figure 5, and the TGA pattern in Figure 6.

[0220] Example 5: Preparation of crystalline form D of the compound of formula (I) [ka]

[0221] Crystalline form A1 of the compound of formula (I) (24.5 mg) was weighed, added to dichloromethane (0.5 mL), and suspended and stirred at room temperature (25±3°C) for 3 days. The mixture was then centrifuged to obtain a wet sample, which was then dried at room temperature to obtain a solid. XRPD revealed that the crystal was form D of the compound of formula (I). The XRPD pattern is shown in Figure 8, the DSC pattern in Figure 9, and the TGA pattern in Figure 10.

[0222] Example 6: Preparation of crystalline form E of the compound of formula (I) [ka]

[0223] Crystalline form A1 of the compound of formula (I) (25.1 mg) was weighed and suspended in 0.5 mL of tetrahydrofuran / n-heptane (volume ratio 1:4) at room temperature (25±3°C) for 3 days with stirring. The suspension was then centrifuged to obtain a wet sample, which was then dried at room temperature to obtain a solid. XRPD confirmed that the crystalline form A1 was form E of the compound of formula (I). The XRPD pattern is shown in Figure 11, the DSC pattern in Figure 12, and the TGA pattern in Figure 13.

[0224] Example 7: Preparation of crystalline form F of the compound of formula (I) [ka]

[0225] Crystalline form A1 of the compound of formula (I) (52.3 mg) was weighed and suspended in 0.75 mL of dimethyl sulfoxide / water (volume ratio 1:4) at room temperature (25±3°C) for 5 days with stirring. The suspension was then centrifuged to obtain a wet sample, which was then 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 confirmed that the crystalline form A1 was form F of the compound of formula (I). The XRPD pattern is shown in Figure 14, the DSC pattern in Figure 15, and the TGA pattern in Figure 16.

[0226] Example 8: Preparation of crystalline form G of the compound of formula (I) [ka]

[0227] Crystalline form A1 of the compound of formula (I) (24.4 mg) was weighed and suspended in 0.5 mL of methanol / water (volume ratio 69:31) at room temperature (25±3°C) for 3 days with stirring, then centrifuged to obtain a wet sample, which was then dried at room temperature to obtain a solid. XRPD confirmed that the crystalline form A1 was form G of the compound of formula (I). The XRPD pattern is shown in Figure 17.

[0228] Example 9: Preparation of crystalline form H of the compound of formula (I) [ka]

[0229] Form G of the compound of formula (I) was heated to 180° C. and then cooled to room temperature to obtain a solid, which was detected by XRPD as form H of the compound of formula (I). The XRPD pattern is shown in FIG.

[0230] Example 10: Preparation of crystalline form S1 of the compound of formula (II) [ka]

[0231] Crystalline form A1 of the compound of formula (I) (25.0 mg) and 11.7 mg of choline were suspended and stirred in 2-methyltetrahydrofuran (0.5 mL) at room temperature (25±3°C) for 3 days, then transferred to 5°C and stirred for 1 day, then transferred to -20°C and stirred for 2 days, centrifuged, and dried under vacuum at room temperature to obtain a solid. XRPD detected that the solid was crystalline form S1 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 pattern is shown in Figure 19. 1 The 1 H NMR spectrum is shown in FIG.

[0232] Example 11: Preparation of crystalline form S2 of the compound of formula (III) [ka]

[0233] Crystalline form A1 of compound of formula (I) (25.0 mg) and 2.0 mg of sodium hydroxide were suspended in acetonitrile (0.5 mL) at room temperature (25±3°C) for 4 days with stirring, centrifuged, and dried under vacuum at room temperature to obtain a solid. XRPD confirmed that the solid was crystalline form S2 of compound of formula (III), and HPLC / IC confirmed that the base-acid molar ratio was 1.0. The XRPD pattern is shown in Figure 21.

[0234] Example 12: Preparation of crystalline form S3 of the compound of formula (III) [ka]

[0235] Crystalline Form A1 of the compound of Formula (I) (25.1 mg) and 2.0 mg of sodium hydroxide were suspended in tetrahydrofuran (0.5 mL) at room temperature (25±3°C) for 4 days with stirring, centrifuged, and dried under vacuum at room temperature to obtain a solid. XRPD confirmed that the solid was crystalline Form S3 of the compound of Formula (III), and HPLC / IC showed a base-acid molar ratio of 1.2. The XRPD pattern is shown in Figure 22.

[0236] Example 13: Preparation of crystalline form S4 of the compound of formula (IV-1) [ka]

[0237] Crystalline form A1 of the compound of formula (I) (25.1 mg) and 11.5 mg of dibenzylethylenediamine were suspended and stirred in isopropanol (0.5 mL) at room temperature (25±3°C) for 3 days, centrifuged, and then vacuum dried at room temperature to obtain a solid. XRPD detected that the solid was crystalline form S4 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 pattern is shown in Figure 23. 1 The 1 H NMR spectrum is shown in Figure 24.

[0238] Example 14: Preparation of crystalline form S5 of the compound of formula (IV-2) [ka]

[0239] Crystalline form A1 of compound of formula (I) (25.0 mg) and 11.5 mg of dibenzylethylenediamine were suspended and stirred in acetonitrile (0.5 mL) at room temperature (25±3°C) for 3 days, centrifuged, and then vacuum dried at room temperature to obtain a solid. XRPD detected that the solid was crystalline form S5 of 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 pattern is shown in Figure 25. 1 The 1 H NMR spectrum is shown in Figure 26.

[0240] Example 15: Preparation of crystalline form A2 of the compound of formula (I) [ka]

[0241] Crystalline form A1 of the compound of formula (I) (24.7 grams) was weighed and suspended in 0.5 milliliters of dimethyl sulfoxide / water (volume ratio 1:4) at room temperature (25±3°C) for 3 days with stirring, then centrifuged to obtain a wet sample, which was then dried at room temperature to obtain a solid. XRPD confirmed that the crystalline form was form A2 of the compound of formula (I). The XRPD pattern is shown in Figure 27.

[0242] Example 16: Preparation of crystalline form A3 of the compound of formula (I) [ka]

[0243] Crystalline form A1 of the compound 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, which was then dried at room temperature to obtain a solid. XRPD confirmed that the crystalline form was form A3 of the compound of formula (I). The XRPD pattern is shown in Figure 28.

[0244] Example 17: Preparation of crystalline form A4 of the compound of formula (I) [ka]

[0245] Crystalline form A1 of the compound of formula (I) (24.6 mg) was weighed and dissolved in 0.2 mL of acetone, followed by the addition of 1.5 mL of n-heptane. The mixture was stirred at 5°C for 1 day, transferred to -20°C and stirred for 2 days, centrifuged to obtain a wet sample, and dried at room temperature to obtain a solid. XRPD confirmed that the crystalline form A1 was form A4 of the compound of formula (I). The XRPD pattern is shown in Figure 29.

[0246] Example 18: Preparation of crystalline form A5 of the compound of formula (I) [ka]

[0247] Crystalline form A1 of the compound 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 solution was centrifuged to obtain a wet sample, which was then dried at room temperature to obtain a solid. XRPD confirmed that the crystalline form A5 of the compound of formula (I) was obtained. The XRPD pattern is shown in Figure 30.

[0248] Example 19: Preparation of crystalline form A6 of the compound of formula (I) [ka]

[0249] Crystalline form A1 of the compound of formula (I) (25.6 mg) was weighed and suspended in 0.5 mL of methanol / methyl tert-butyl ether (volume ratio 1:4) at room temperature (25±3°C) for 3 days with stirring, then centrifuged to obtain a wet sample, which was then dried at room temperature to obtain a solid. XRPD confirmed that the crystalline form A6 of the compound of formula (I) was obtained. The XRPD pattern is shown in Figure 31.

[0250] Example 20: Preparation of crystalline form A7 of the compound of formula (I) [ka]

[0251] Crystalline form A1 of the compound of formula (I) (52.3 mg) was weighed and suspended in 0.75 mL of dimethyl sulfoxide / water (volume ratio 1:4) at room temperature (25±3°C) for 5 days with stirring, then centrifuged to obtain a wet sample, which was then dried at room temperature to obtain a solid. XRPD confirmed that the crystalline form was form A7 of the compound of formula (I). The XRPD pattern is shown in Figure 32.

[0252] Example 21: Solid-state stability test of crystalline form B of the compound of formula (I) In accordance with the "Guiding Principles for Stability Testing of Drug Substances and Preparations" (Chinese Pharmacopoeia, 2020 Edition, Part 4 General Rule 9001), to evaluate the solid-state stability of crystalline form B of compound of formula (I), crystalline form B was tested for stability under influencing factors (high temperature, high humidity, and light exposure), accelerated (40°C / 75%RH), and long-term (25°C / 60%RH) conditions. For the influencing factor test, unless otherwise specified, each sample was placed in an open weighing bottle and placed in the corresponding storage container to test for stability at 5 and 10 days. For the light stability test, in accordance with the requirements of ICH Q1B, the light-exposed samples were irradiated under visible and ultraviolet light, with static conditions of 5000±500 lux (visible light) and 90W / cm². 2 The samples were irradiated for 5 and 10 days under the conditions of ultraviolet light. The total irradiance received by the samples during the 10 days was 1.2 × 10 6 Lux·h or more, and near-ultraviolet energy is 200w·h / m 2 The above was the result. The irradiated samples were placed in clean weighing bottles, flattened into a single layer, and placed uncovered in a light box with the opening exposed to light. The control samples were packaged in the same manner as the irradiated samples, but the outside of the weighing bottle was coated with an aluminum film. For the long-term accelerated test, each sample was placed in a double-layered LDPE bag, each LDPE bag sealed with a buckle, and then placed in an aluminum foil bag and heat-sealed. The accelerated test was held for 1, 2, and 3 months, while the long-term test was held for 3 months. XRPD tests were performed on all stability samples to detect changes in crystalline form.

[0253] Approximately 25 mg of sample was precisely weighed and placed in a 10 mL volumetric flask. 6 mL of acetonitrile was added and dissolved using ultrasound. After allowing to cool to room temperature, water was added to the appropriate level and the flask was shaken uniformly to dissolve the sample, yielding a solution with a concentration of approximately 2.5 mg / mL. Liquid-phase sample injection analysis was performed, and the detection results were compared with the initial detection results on day 0. The specific test results are shown in Table 24 below. The HPLC test equipment and analysis conditions are listed in Table 25.

[0254] [Table 24]

[0255] [Table 25]

[0256] Conclusion: The crystalline form B of compound of formula (I) has good chemical stability, with no significant changes in purity and crystalline form under all stability conditions (high temperature, high humidity, light exposure, long-term and accelerated).

[0257] Example 22: Hygroscopicity study of crystalline form B of compound of formula (I) The test was carried out using an SMS DVS intrinsic plus dynamic moisture sorption apparatus. Crystalline Form B of the compound of formula (I) (10-20 mg) was placed in a DVS sample disk.

[0258] Experimental Results: The DVS pattern of crystalline form B of compound of formula (I) is shown in Figure 33, and the ΔW% was 0.535%.

[0259] Experimental conclusion: Crystalline form B of compound of formula (I) was slightly hygroscopic, with a water adsorption of 2%>ΔW%≧0.2% at 25° C. / 80% RH. Bioassay Data

[0260] Experimental Example 1: Testing the activity of the compounds of the present invention on human gonadotropin-releasing hormone receptors

[0261] Experimental Objective: To detect the inhibitory activity of test compounds on gonadotropin-releasing hormone receptors at the cellular level using FLIPR detection technology.

[0262] Main experimental materials and sources: Fluo-4 Direct® Kit - Invitrogen - F10471 Greiner-781946, a 384-well polylysine-coated cell plate 384-well compound plate: Greiner-781280 Compound Manufacturing ECHO (Sonic Pipetting System) - Labcyte FLIPR (Fluorescence Imaging Plate Reader) - Molecular Devices

[0263] Experimental steps: GnRH / HEK293 (human embryonic kidney 293) cells were cultured in the logarithmic growth phase and washed with DPBS (Dulbecco's phosphate-buffered saline). An appropriate amount of 0.05% EDTA (ethylenediaminetetraacetic acid)-pancreatin was added and the cells were digested in a 37°C carbon dioxide incubator. After 1-2 minutes, the cells were removed and added to the medium to stop the digestion. The cells were dispersed by repeated spraying, then collected by centrifugation. They were seeded into a 384-well polylysine-coated cell plate at a density of 20,000 cells per well in 20 μL of solution and incubated overnight in a 5% CO2, 37°C incubator.

[0264] The next day, 20 μL of 2× Fluo-4 Direct® buffer was added to each well and incubated in a 5% CO2, 37°C incubator for 50 minutes. The cells were then allowed to stand at room temperature for 10 minutes. A 10-point, 4-fold gradient dilution of 0.2 mM leuprolide acetate was performed using ECHO, and 900 nL was transferred to the compound plate. 30 μL of FLIPR buffer salt solution was added to the compound plate, which was then centrifuged at 1000 rpm for 1 minute. The FLIPR instrument software was run, and 10 μL of experimental buffer salt solution was added according to the setup program, and the fluorescent signal was read. Then, an additional 10 μL of the agonist reference compound (leuprolide acetate) was added, and the fluorescent signal was read. ECHO was then used to calculate the ECHO. 80 Calculate 6×EC 80 Concentrations of agonists were prepared.

[0265] 2 mM test compound and appropriate concentration of reference compound (Cetrorelix Acetate) were diluted 4-fold in 10-point gradient in ECHO, and 900 nL was transferred to the compound plate. 30 μL of FLIPR buffered salt solution was added to the compound plate, and the plate was centrifuged at 1000 rpm for 1 minute. The FLIPR instrument software was run, and 10 μL of test compound and reference compound were added to the cell plate according to the set program, and the fluorescent signal was read. Further 6 × ECHO was added. 80 10 μL of agonist at the concentration was added to the cell plate and the fluorescent signal was read.

[0266] IC of compounds for inhibition of calcium flux at the gonadotropin-releasing hormone receptor 50 , i.e., in cells stably expressing the GnRH receptor, Ca 2+ Calculate the drug concentration at which flux is inhibited by half and calculate the IC value of the drug using GraphPad Prism 5.0 software. 50 was calculated.

[0267] Test Results: The inhibitory activity of the compounds of the present invention against human gonadotropin-releasing hormone receptors was measured by the above test method, and the measured IC 50 is shown in Table 26.

[0268] [Table 26]

[0269] Conclusion: The compounds of the present invention have significant inhibitory effects on human gonadotropin-releasing hormone receptors.

[0270] Experimental Example 2 Pharmacokinetic evaluation Experimental objective: To study the pharmacokinetic properties of the compounds of the present invention in mice.

[0271] Testing scheme: Each test compound was mixed with DMAC and vortexed for 2 minutes. The DMAC solution was then mixed with the test compound and vortexed for another 2 minutes to produce a 10 mg / mL clear solution. 0.300 mL of Solutol was added to 0.0600 mL of the 10 mg / mL solution, vortexed for 2 minutes, and 2.400 mL of saline was added and vortexed for 2 minutes to obtain a 0.2 mg / mL clear solution for administration to the PO group. 0.500 mL of the PO group administration solution was vortexed for 2 minutes, 0.0500 mL of DMAC was added, mixed, and vortexed for 2 minutes. 0.0500 mL of Solutol was added, vortexed for 2 minutes, and finally 0.400 mL of saline was added and vortexed for 2 minutes to obtain a 0.1 mg / mL clear solution, which was then filtered through a microfiltration membrane to obtain the IV administration solution. Four male CD-1 mice were divided into two groups. Animals in Group 1 received a single intravenous dose of 0.5 mg / kg of the test compound in a 5 mL / kg volume of 10% DMAC / 10% Solutol / 80% saline. Animals in Group 2 received a single oral intragastric dose of 2 mg / kg of the test compound in a 10 mL / kg volume of 10% DMAC / 10% Solutol / 80% saline. Whole blood samples were collected at 0.033 (intravenous injection only), 0.083, 0.25, 0.5, 1, 2, 4, and 12 hours post-dose. Plasma was obtained by centrifugation at 3200 g for 10 minutes at 2-8°C. Plasma concentrations of the test compound were measured by LC / MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software.

[0272] Test Results: The test results are shown in Table 27. The meaning of each parameter is as follows: IV: Intravenous injection, PO: Oral administration, C0: Initial blood concentration, C max : Maximum drug concentration in the systemic circulation, T max :C max The time it takes to reach 1 / 2 : Half-life, V dss : apparent volume of distribution, Cl: clearance rate, AUC 0-last : Area under the drug-time curve

[0273] [Table 27]

[0274] Conclusion: The compounds of the present invention exhibit excellent pharmacokinetic properties with high plasma exposure, low clearance rate, long half-life, and high oral bioavailability.

Claims

1. Crystalline form B of the compound of formula (I), 【Chemistry 1】 Crystalline form B is characterized by having characteristic diffraction peaks at 2θ angles of 4.62±0.20°, 7.35±0.20°, and 18.34±0.20° in a powder X-ray diffraction pattern using Cu Kα radiation.

2. 2. The crystalline form B of claim 1, having characteristic diffraction peaks in an X-ray powder diffraction pattern at 2θ angles of 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. 3. The crystalline form B of claim 2, having characteristic diffraction peaks in an X-ray powder diffraction pattern at 2θ angles of 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. 4. Crystalline form B according to claim 3, having characteristic diffraction peaks in an X-ray powder diffraction pattern at 2θ angles of 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. 5. Crystalline form B according to claim 4, having characteristic diffraction peaks in an X-ray powder diffraction pattern at 2θ angles of 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. (1) A differential scanning calorimetry curve has an exothermic peak value at 224.4°C ± 3°C; (2) A thermogravimetric analysis curve showing a weight loss of 1.12% at 150°C ± 3°C.

7. Crystalline form C of the compound of formula (I), 【Chemistry 2】 In the powder X-ray diffraction pattern of Cu Kα radiation, the 2θ angle is (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) Crystalline form C, characterized by having characteristic diffraction peaks at any one set of positions selected from the group consisting of 7.18°, 8.47°, 11.55°, 12.80°, 15.80°, 16.96°, 19.23°, 20.12°, 23.30°, and 26.31°.

8. (1) A differential scanning calorimetry curve has an exothermic peak value at 225.1°C ± 3°C; (2) A thermogravimetric analysis curve showing a weight loss of 1.13% at 150°C ± 3°C.

9. A pharmaceutically acceptable salt of a compound of formula (I), 【Transformation 3】 A pharmaceutically acceptable salt of the compound of formula (I), which is a 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. 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), 【Chemistry 4】 10. A pharmaceutically acceptable salt of the compound of formula (I) according to claim 9, 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.

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), and the compound of formula (III) is selected from the compounds of formula (III-1). 【Transformation 5】

12. Crystalline form S1 of the compound of formula (II-1), 【Transformation 6】 In the powder X-ray diffraction pattern of Cu Kα radiation, the 2θ angle is (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) Crystalline form S1, characterized by having characteristic diffraction peaks at any one set of positions selected from the group consisting of 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. A pharmaceutical composition for treating a GnRH receptor-related disease, comprising crystalline form B described in any one of claims 1 to 6, crystalline form C described in claim 7 or 8, crystalline form S1 described in claim 12, or a salt described in any one of claims 9 to 11.

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