Salt and crystalline forms of 5,6-dihydrothieno[3,4-h]quinazoline compounds and their preparation methods

Abstract

The present invention discloses salts and crystalline forms of 5,6-dihydrothieno[3,4-h]quinazolines and methods for their preparation, and the use of said salts and crystalline forms in the preparation of drugs for treating colorectal cancer and other solid tumors. [Formula 1] TIFF2025528116000033.tif37170

Description

[Technical Field]

[0001] Citation of Related Applications This application claims priority to the following:

[0002] CN202210948349.2, filing date: August 8, 2022.

[0003] Technical Field The present invention relates to salts and crystalline forms of 5,6-dihydrothieno[3,4-h]quinazolines and methods for their preparation, and to the use of said salts and crystalline forms in the preparation of medicaments for treating colorectal cancer and other solid tumors. [Background technology]

[0004] Polo-like kinases (PLKs) are a class of highly conserved serine / threonine kinases. Their N-terminal domains all share a highly homologous serine / threonine kinase domain, while their C-terminal domains all contain a distinctive polobox domain (PBD) that regulates PLK activity and dynamic subcellular localization. The PLKs family contains many members, including four subtypes in the human body: PLK1, PLK2, PLK3, and PLK4. Each plays a crucial role in regulating various phases of the cell cycle. Of these four family members, PLK1 has been studied most extensively. Therefore, PLK1 is a promising target for tumor diagnosis and therapy.

[0005] Onvansertib (PCM-075; NMS-P937; nms-1286937; NMS-937), an oral Polo-kinase (Plk)-1 inhibitor, is being developed by Cardiff Oncology (formerly Trovagene) under license from Nerviano. Onvansertib, as the fumarate salt, is a potential oral cancer treatment indicated for metastatic colorectal cancer (mCRC), solid tumors, acute myeloid leukemia (AML), and metastatic castration-resistant prostate cancer. PLK1 is overexpressed in many cancers and is an effective therapeutic target. Onvansertib is a novel, highly selective PLK1 inhibitor.

[0006] [ka] Onvansertib (NMS-1286937), a highly selective PLK1 inhibitor currently in clinical development, has potent inhibitory effects on the PLK1 kinase protein. It is currently being evaluated in phase I and II clinical studies for the treatment of recurrent small cell lung cancer (SCLC) as a single agent and in combination with SOC for the treatment of solid tumors such as KRAS-mutated metastatic colorectal cancer (mCRC), metastatic pancreatic cancer (mPDAC), and metastatic castration-resistant prostate cancer (mCRPC). Compared with KRASG12C inhibitors, PLK1 inhibitors have a higher response rate in CRC patients and are effective against all KRAS mutation subtypes. CRC is the third most common malignancy after lung cancer and breast cancer, with a global market of approximately $25 billion in 2018. Therefore, there is a need to develop highly active, highly selective, and metabolically stable small molecule PLK1 inhibitors for tumor treatment. Summary of the Invention

[0007] The present invention provides succinate, fumarate, benzenesulfonate, sulfate, phosphate, maleate, L-tartrate, methanesulfonate, L-malate, hydrochloride, citrate and L-aspartate salts of the compound of formula (I).

[0008] [ka] In some aspects of the invention, the salt of the compound is [ka] [ka] Selected from; Here, m, n, p, q, r, s, t, u, v, w, x, and y are each independently selected from 0.5 to 3.0.

[0009] In some embodiments of the present invention, the salt of the above compound, wherein m, n, p, q, r, s, t, u, v, w, x, and y are each independently selected from 0.8 to 2.0.

[0010] In some embodiments of the invention, a salt of the above compound, wherein m, n, p, q, r, s, t, u, v, w, x, and y are each independently selected from 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0.

[0011] In some embodiments of the present invention, a salt of the above compound, wherein m is 1.0, n is 1.0, p is 1.0, q is 1.0, r is 1.0, s is 1.0, t is 1.0, u is 1.0, v is 1.0, w is 1.0, x is 1.0, and y is 1.0.

[0012] In some embodiments of the invention, the salt of the above compound, wherein m, n, p, q, r, s, t, u, v, w, x, and y are each independently selected from 1.0.

[0013] The present invention provides crystalline form A of the compound of formula (I), characterized in that its powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 6.305±0.200°, 9.140±0.200°, 12.661±0.200°, and 19.637±0.200°.

[0014] [ka] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form A has characteristic diffraction peaks at 2θ angles of 6.305±0.200°, 9.140±0.200°, 9.681±0.200°, 12.661±0.200°, 19.637±0.200°, 23.281±0.200°, and 24.892±0.200°.

[0015] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form A has characteristic diffraction peaks at 2θ angles of 6.305±0.200°, 9.140±0.200°, 9.681±0.200°, 12.661±0.200°, 14.139±0.200°, 19.637±0.200°, 23.281±0.200°, and 24.892±0.200°.

[0016] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form A has characteristic diffraction peaks at 2θ angles of 6.305±0.200°, 9.140±0.200°, 9.681±0.200°, 12.661±0.200°, 13.479±0.200°, 19.637±0.200°, 23.281±0.200°, and 24.892±0.200°.

[0017] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form A has characteristic diffraction peaks at 2θ angles of 6.305±0.200°, 9.140±0.200°, 9.681±0.200°, 12.661±0.200°, 13.479±0.200°, 14.139±0.200°, 16.523±0.200°, 18.385±0.200°, 19.637±0.200°, 21.161±0.200°, 23.281±0.200°, and 24.892±0.200°.

[0018] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form A has characteristic diffraction peaks at 2θ angles of 6.305±0.200°, 9.140±0.200°, 9.681±0.200°, 11.138±0.200°, 12.661±0.200°, 13.479±0.200°, 14.139±0.200°, 15.175±0.200°, 16.523±0.200°, 18.385±0.200°, 19.637±0.200°, 21.161±0.200°, 22.159±0.200°, 23.281±0.200°, 24.892±0.200°, and 26.582±0.200°.

[0019] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form A is 6.305±0.200°, 9.140±0.200°, 19.637±0.200°, and / or 9.681±0.200°, and / or 11.138±0.200°, and / or 12.661±0.200°, and / or 13.479±0.200°, and / or 14.139±0.200°, and / or 15.175±0.200°, and / or 16.523±0.200°, and / or 18.385±0.200°, and / or 18.710±0.200°, and / or 19.904±0.200°, and / or 20.692±0.200°, and / or 21.161±0.200°, and / or 21.915±0.200°, and / or 22.159±0.200°, and / or 23.281±0.200°, and / or 24.892±0.200°, and / or 25.491±0.200°, and / or 26.582±0.200°, and / or 32.389±0.200°.

[0020] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form A is 6.305±0.200°, 9.140±0.200°, 19.637±0.200°, and / or 9.681±0.200°, and / or 11.138±0.200°, and / or 12.661±0.200°, and / or 13.479±0.200°, and / or 14.139±0.200°, and / or 15.175±0.200°, and / or 16.523±0.200°, and / or 18.385±0.200°, and / or 18.710±0.200°, and / or 19.094±0.200°, and / or 19.904±0.200°, and / or 20.692±0.200°, and / or 21.161±0.200°, and / or 21.915±0.200°, and / or 22.159±0.200°, and / or 23.281±0.200°, and / or 23.630±0.200°, and / or 24.892±0.200°, and / or 25.491±0.200°, and / or 26.582±0.200°, and / or 32.389±0.200°.

[0021] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form A has characteristic diffraction peaks at 2θ angles of 6.305°, 9.140°, 9.681°, 11.138°, 12.661°, 13.479°, 14.139°, 16.523°, 18.385°, 19.637°, 19.904°, 21.161°, 22.159°, 23.281°, 24.892°, and 26.582°.

[0022] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form A has characteristic diffraction peaks at 2θ angles of 6.305°, 9.140°, 9.681°, 11.138°, 12.661°, 13.479°, 14.139°, 15.175°, 16.523°, 18.385°, 18.710°, 19.094°, 19.637°, 19.904°, 20.692°, 21.161°, 21.915°, 22.159°, 23.281°, 23.630°, 24.892°, 25.491°, 26.582°, and 32.389°.

[0023] In some embodiments of the present invention, the XRPD spectrum of crystalline Form A above will be essentially as shown in FIG.

[0024] In some embodiments of the present invention, the analytical data of the XRPD spectrum of Crystalline Form A is as shown in Table 1.

[0025] [Table 1]

[0026] In some embodiments of the present invention, the differential scanning calorimetry curve for crystalline Form A has an endothermic peak onset at 222.64±3.0°C.

[0027] In some embodiments of the present invention, the DSC spectrum of the crystalline form A is as shown in FIG.

[0028] In some embodiments of the present invention, the thermogravimetric analysis curve for the crystalline form A reaches a weight loss of 1.220% at 242±3° C.

[0029] In some embodiments of the present invention, the TGA spectrum of crystalline form A is as shown in FIG.

[0030] The present invention provides crystalline form B of the compound of formula (II), wherein m is selected from 0.8, 0.9, 1.0, 1.1, and 1.2, and characterized in that its powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 13.855±0.200°, 17.861±0.200°, 19.915±0.200°, and 24.154±0.200°.

[0031] [ka] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline form B has characteristic diffraction peaks at 2θ angles of 13.855±0.200°, 17.861±0.200°, 18.764±0.200°, 19.915±0.200°, 20.651±0.200°, and 24.154±0.200°.

[0032] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline form B has characteristic diffraction peaks at 2θ angles of 7.333±0.200°, 13.855±0.200°, 17.861±0.200°, 18.764±0.200°, 19.915±0.200°, 20.651±0.200°, 24.154±0.200°, and 27.518±0.200°.

[0033] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline form B has characteristic diffraction peaks at 2θ angles of 13.855±0.200°, 17.861±0.200°, 18.764±0.200°, 19.915±0.200°, 20.651±0.200°, 23.449±0.200°, 24.154±0.200°, and 27.518±0.200°.

[0034] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form B has characteristic diffraction peaks at 2θ angles of 7.333±0.200°, 11.034±0.200°, 13.855±0.200°, 14.350°±0.200°, 16.116±0.200°, 17.861±0.200°, 18.764±0.200°, 19.915±0.200°, 20.651±0.200°, 21.157±0.200°, 24.154±0.200°, and 27.518±0.200°.

[0035] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline form B has characteristic diffraction peaks at 2θ angles of 7.333±0.200°, 11.034±0.200°, 13.855±0.200°, 16.116±0.200°, 17.861±0.200°, 18.764±0.200°, 19.915±0.200°, 20.651±0.200°, 21.157±0.200°, 23.449±0.200°, 24.154±0.200°, and 27.518±0.200°.

[0036] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form B is 7.333±0.200°, 11.034±0.200°, 12.635±0.200°, 13.855±0.200°, 14.350±0.200°, 16.116±0.200°, 17.861±0.200°, 18.764±0.200°, 19.864±0.200°, 20.864±0.200°, 21.864±0.200°, 22.864±0.200°, 23.864±0.200°, 24.864±0.200°, 25.864±0.200°, 26.864±0.200°, 27.864±0.200°, 28.864±0.200°, 29.864±0.200°, 30.864±0.200°, 31.864±0.200°, 32.864±0.200°, 33.864±0.200°, 34.864±0.200°, 35.864±0.200°, 36.864±0.200°, 37.864±0.200°, 38.864±0.200°, 39.864±0.200°, 40.864±0.200°, 41.864±0.200°, 42.864±0.200°, 43.864±0.2 It has characteristic diffraction peaks at 2θ angles of 0.200°, 19.915±0.200°, 20.651±0.200°, 21.157±0.200°, 24.154±0.200°, 24.702±0.200°, 26.884±0.200°, 27.518±0.200°, and 31.071±0.200°.

[0037] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form B is 7.333±0.200°, 11.034±0.200°, 12.635±0.200°, 13.855±0.200°, 14.350±0.200°, 16.116±0.200°, 17.861±0.200°, 18.764±0.200°, 19.864±0.200°, 20.864±0.200°, 21.864±0.200°, 22.864±0.200°, 23.864±0.200°, 24.864±0.200°, 25.864±0.200°, 26.864±0.200°, 27.864±0.200°, 28.864±0.200°, 29.864±0.200°, 30.864±0.200°, 31.864±0.200°, 32.864±0.200°, 33.864±0.200°, 34.864±0.200°, 35.864±0.200°, 36.864±0.200°, 37.864±0.200°, 38.864±0.200°, 39.864±0.200°, 40.864±0.200°, 41.864±0.200°, 42.864±0.200°, 43.864±0.2 It has characteristic diffraction peaks at 2θ angles of 0.200°, 19.915±0.200°, 20.651±0.200°, 21.157±0.200°, 23.449±0.200°, 24.154±0.200°, 24.702±0.200°, 27.518±0.200°, and 31.071±0.200°.

[0038] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form B is 13.855±0.200°, 17.861±0.200°, and / or 7.333±0.200°, and / or 11.034±0.200°, and / or 12.635±0.200°, and / or 13.534±0.200°, and / or 14.350±0.200°, and / or 16.116±0.200°, and / or 17.483±0.200°, and / or 18.764±0.200°, and / or 19.764±0.200°. and / or 24.154±0.200°, and / or 24.702±0.200°, and / or 26.884±0.200°, and / or 27.518±0.200°, and / or 31.071±0.200°.

[0039] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form B has characteristic diffraction peaks at 2θ angles of 7.333°, 11.034°, 13.534°, 13.855°, 14.350°, 16.116°, 17.483°, 17.861°, 18.764°, 19.915°, 20.651°, 21.157°, 23.449°, 23.806°, 24.154°, and 27.518°.

[0040] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form B has characteristic diffraction peaks at 2θ angles of 7.333°, 11.034°, 12.635°, 13.534°, 13.855°, 14.350°, 16.116°, 17.483°, 17.861°, 18.764°, 19.658°, 19.915°, 20.651°, 21.157°, 23.449°, 23.806°, 24.154°, 24.702°, 26.884°, 27.518°, and 31.071°.

[0041] In some embodiments of the present invention, the XRPD spectrum of crystalline Form B is essentially as shown in FIG.

[0042] In some embodiments of the present invention, the analytical data of the XRPD spectrum of the crystalline form B is as shown in Table 2.

[0043] [Table 2]

[0044] In some embodiments of the present invention, the differential scanning calorimetry curve for crystalline Form B has an endothermic peak onset at 193.63±3.0°C.

[0045] In some embodiments of the present invention, the DSC spectrum of the crystalline form B is as shown in FIG.

[0046] In some embodiments of the present invention, the thermogravimetric analysis curve of the crystalline form B reaches a weight loss of 0.867% at 92±3°C.

[0047] In some embodiments of the present invention, the TGA spectrum of crystalline form B is as shown in FIG.

[0048] In some embodiments of the present invention, m in the crystalline form B is selected from 1.1.

[0049] The present invention provides crystalline form C of the compound of formula (III), wherein n is selected from 0.8, 0.9, 1.0, 1.1, and 1.2, and whose powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 13.637±0.200°, 14.138±0.200°, 17.076±0.200°, and 24.866±0.200°.

[0050] [ka] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the crystalline form C has characteristic diffraction peaks at 2θ angles of 11.412±0.200°, 13.637±0.200°, 14.138±0.200°, 17.076±0.200°, 19.310±0.200°, 23.654±0.200°, 24.214±0.200°, and 24.866±0.200°.

[0051] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the crystalline form C has characteristic diffraction peaks at 2θ angles of 11.412±0.200°, 13.637±0.200°, 14.138±0.200°, 15.555±0.200°, 17.076±0.200°, 18.016±0.200°, 18.907±0.200°, 19.310±0.200°, 20.811±0.200°, 23.654±0.200°, 24.214±0.200°, and 24.866±0.200°.

[0052] In some embodiments of the present invention, the powder X-ray diffraction spectrum of crystalline Form C is 13.637±0.200°, 17.076±0.200°, 24.866±0.200°, and / or 5.677±0.200°, and / or 7.086±0.200°, and / or 11.412±0.200°, and / or 11.627±0.200°, and / or 13.200±0.200°, and / or 13.429 ± 0.200°, and / or 14.138 ± 0.200°, and / or 14.499 ± 0.200°, and / or 15.167 ± 0.200°, and / or 15.555 ± 0.200°, and / or 15.763 ± 0.200°, and / or 17.272 ± 0.200°, and / or 18.016 ± 0.200°, and / or 18.171 ± 0.200°, and and / or 18.614 ± 0.200°, and / or 18.907 ± 0.200°, and / or 19.310 ± 0.200°, and / or 19.656 ± 0.200°, and / or 20.016 ± 0.200°, and / or 20.811 ± 0.200°, and / or 21.765 ± 0.200°, and / or 22.748 ± 0.200°, and / or 23.443 ± 0.200°, and / or 23.654±0.200°, and / or 23.880±0.200°, and / or 24.214±0.200°, and / or 24.577±0.200°, and / or 25.987±0.200°, and / or 26.493±0.200°, and / or 27.011±0.200°, and / or 27.537±0.200°.

[0053] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the crystalline form C has characteristic diffraction peaks at 2θ angles of 11.412°, 13.637°, 14.138°, 15.555°, 17.076°, 18.016°, 18.907°, 19.310°, 20.811°, 23.654°, 24.214°, and 24.866°.

[0054] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the C crystalline form has the following angles: 5.677°, 7.086°, 11.412°, 11.627°, 13.200°, 13.429°, 13.637°, 14.138°, 14.499°, 15.167°, 15.555°, 15.763°, 17.076°, 17.272°, 18.016°, 18.171°, 18.182°, 18.183°, 18.184°, 18.185°, 18.186°, 18.187°, 18.188°, 18.189 ... It has characteristic diffraction peaks at 2θ angles of 8.614°, 18.907°, 19.310°, 19.656°, 20.016°, 20.811°, 21.765°, 22.748°, 23.443°, 23.654°, 23.880°, 24.214°, 24.577°, 24.866°, 25.987°, 26.493°, 27.011°, and 27.537°.

[0055] In some embodiments of the present invention, the XRPD spectrum of crystalline Form C is essentially as shown in FIG.

[0056] In some embodiments of the present invention, the analytical data of the XRPD spectrum of the above crystalline form C is as shown in Table 3.

[0057] [Table 3]

[0058] In some embodiments of the present invention, the differential scanning calorimetry curve for the crystalline form C has an endothermic peak at 237.14±3.0°C.

[0059] In some embodiments of the present invention, the DSC spectrum of the C crystalline form is as shown in FIG.

[0060] In some embodiments of the present invention, the thermogravimetric analysis curve of the C crystalline form reaches a weight loss of 0.469% at 100±3°C.

[0061] In some embodiments of the present invention, the TGA spectrum of the C crystalline form is as shown in FIG.

[0062] In some embodiments of the present invention, n in the C crystalline form is selected from 1.0.

[0063] The present invention provides crystalline form D of the compound of formula (IV), wherein p is selected from 0.8, 0.9, 1.0, 1.1 and 1.2, and characterized in that its powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 6.859±0.200°, 8.784±0.200°, 16.420±0.200° and 18.965±0.200°.

[0064] [ka] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the crystalline form D has characteristic diffraction peaks at 2θ angles of 6.859±0.200°, 8.784±0.200°, 10.922±0.200°, 13.238±0.200°, 16.420±0.200°, 18.965±0.200°, 20.400±0.200°, and 24.069±0.200°.

[0065] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the crystalline form D has characteristic diffraction peaks at 2θ angles of 6.859±0.200°, 8.784±0.200°, 10.922±0.200°, 11.644±0.200°, 13.238±0.200°, 16.420±0.200°, 17.596±0.200°, 18.965±0.200°, 19.390±0.200°, 20.400±0.200°, 21.416±0.200°, and 24.069±0.200°.

[0066] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the D crystalline form is 6.859±0.200°, 8.784±0.200°, and / or 10.922±0.200°, and / or 11.644±0.200°, and / or 13.238±0.200°, and / or 13.741±0.200°, and / or 16.420±0.200°, and / or 16.720±0.200°, and / or 17.596±0.200°, and / or 17.930±0.200°. and / or 26.587±0.200°, and / or 27.661±0.200°.

[0067] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the D crystalline form has characteristic diffraction peaks at 2θ angles of 6.859°, 8.784°, 10.922°, 11.644°, 13.238°, 16.420°, 17.596°, 17.930°, 18.965°, 19.390°, 20.400°, and 24.069°.

[0068] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the D crystalline form has characteristic diffraction peaks at 2θ angles of 6.859°, 8.784°, 10.922°, 11.644°, 13.238°, 13.741°, 16.420°, 16.720°, 17.596°, 17.930°, 18.965°, 19.390°, 20.400°, 21.416°, 22.630°, 23.473°, 24.069°, 24.832°, 26.587°, and 27.661°.

[0069] In some embodiments of the present invention, the XRPD spectrum of crystalline Form D is essentially as shown in FIG.

[0070] In some embodiments of the present invention, the analytical data for the XRPD spectrum of crystalline form D is as shown in Table 4.

[0071] [Table 4]

[0072] In some embodiments of the present invention, the differential scanning calorimetry curve for crystalline Form D has an endothermic peak onset at 240.70±3.0°C.

[0073] In some embodiments of the present invention, the DSC spectrum of the crystalline form D is as shown in FIG.

[0074] In some embodiments of the present invention, the thermogravimetric analysis curve for the D crystalline form reaches a weight loss of 0.295% at 120±3°C.

[0075] In some embodiments of the present invention, the TGA spectrum of crystalline form D is as shown in FIG.

[0076] In some embodiments of the present invention, p in the D crystalline form is selected from 0.9.

[0077] The present invention further provides the use of the above salt forms, crystalline form A of the compound of formula (I), crystalline form B of the compound of formula (II), crystalline form C of the compound of formula (III) and crystalline form D of the compound of formula (IV) in the preparation of a medicament for treating solid tumors.

[0078] In some aspects of the present invention, the drug for treating solid tumors is a drug for treating colorectal cancer.

[0079] Effect of the invention The crystalline form of the present invention has good stability, good moisture absorption, and good prospects for drug formulation. The compound of the present invention has a relatively good inhibitory effect on PLK1, good pharmacokinetic properties, and good oral bioavailability.

[0080] Definitions and Explanations Unless otherwise specified, the following terms and phrases used herein are intended to include the following meanings. Unless a particular term or phrase is specifically defined, it should not be considered indefinite or unclear, but should be understood in its general sense. When trade names are mentioned herein, it is intended to refer to the corresponding product or its active ingredient.

[0081] The intermediate compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitution forms known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0082] The chemical reactions in specific embodiments of the present invention are carried out in suitable solvents appropriate for the chemical transformations of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it may be necessary to modify or select synthetic steps or reaction flows based on conventional embodiments.

[0083] The present invention will be described in more detail below with reference to examples, but these examples do not imply any limitations on the present invention.

[0084] All solvents used in this invention are commercially available and can be used without further purification.

[0085] The present invention employs the following abbreviations: rt represents room temperature; THF represents tetrahydrofuran; NMP represents N-methylpyrrolidone; MeSO3H represents methanesulfonic acid; DME represents ethylene glycol dimethyl ether; DCM represents dichloromethane; Xphos represents 2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl; EtOAc represents ethyl acetate; MeOH represents methanol; acetone represents acetone; 2-Me-THF represents 2-methyltetrahydrofuran; IPA represents isopropanol.

[0086] Compounds are named manually or using ChemDraw® software, and commercially available compounds are taken from supplier catalogs.

[0087] The X-ray powder diffractometer (XRPD) method of the present invention Instrument model: Brook D2 PHASER X-ray diffractometer Test method: Approximately 5-10 mg of sample was used for XRPD measurement.

[0088] The detailed parameters of the XRPD are as follows:

[0089] Target: Cu, kα, (λ=1.54184Å).

[0090] Tube voltage: 30 kV, tube current: 10 mA Divergence slit: 0.60 mm Probe slit: 0.075 mm Anti-scatter slit: 0 mm Scanning range: 3-40deg Step width: 0.02 deg Dwell time per step: 0.2 seconds Differential Scanning Calorimetry (DSC) Method of the Present Invention Instrument model number: TA Instruments DSC250 Differential Scanning Calorimeter Test method: 1 to 3 mg of sample was weighed on a sample dish, weighed accurately, and the weight was recorded. After drilling a hole using an aluminum crucible, the sample was measured. The temperature was increased from 25°C to the final temperature at a rate of 10°C / min.

[0091] The Thermal Gravimetric Analysis (TGA) Method of the Present Invention Instrument model number: TA Instruments TGA550 Thermogravimetric Analyzer Test method: 2 to 5 mg of sample was placed on a sample dish (Al2O3), the opening was measured, and the temperature was raised from 25°C to the specified temperature at a rate of 10°C / min.

[0092] Dynamic Vapor Sorption (DVS) Method of the Present Invention Instrument model number: SMS DVS Intrinsic Dynamic Vapor Sorption Meter Test conditions: A sample (10-30 mg) was taken and placed in a DVS sample dish for measurement.

[0093] The detailed parameters of DVS are as follows:

[0094] Temperature: 25℃ Balance: dm / dt = 0.002% / min (min: 10 min, max: 180 min) RH (%) measurement steps: 10% (90%RH-0%RH-90%RH), 5% (95%RH-90%RH and 90%RH-95%RH) RH (%) measurement range: 0%RH-95%RH-0%RH The moisture absorption rating classification is shown in Table 5.

[0095] [Table 5] [Brief explanation of the drawings]

[0096] [Figure 1] FIG. 1 shows an XRPD spectrum of Cu-Kα radiation for crystalline form A of compound of formula (I). [Figure 2] FIG. 1 shows a DSC spectrum of crystalline form A of the compound of formula (I). [Figure 3] FIG. 1 shows the TGA spectrum of crystalline form A of the compound of formula (I). [Figure 4] FIG. 1 shows the DVS spectrum of crystalline form A of the compound of formula (I). [Figure 5] FIG. 1 shows an XRPD spectrum of Cu-Kα radiation for crystalline form B of compound of formula (II). [Figure 6] FIG. 2 shows a DSC spectrum of crystalline form B of the compound of formula (II). [Figure 7] FIG. 1 shows a TGA spectrum of crystalline form B of compound of formula (II). [Figure 8] FIG. 1 shows the DVS spectrum of crystalline form B of compound of formula (II). [Figure 9] FIG. 1 shows an XRPD spectrum of Cu-Kα radiation for the C crystalline form of compound of formula (III). [Figure 10] FIG. 1 shows a DSC spectrum of the C crystalline form of the compound of formula (III). [Figure 11] FIG. 1 shows a TGA spectrum of crystalline form C of compound of formula (III). [Figure 12] FIG. 1 shows the DVS spectrum of crystalline form C of compound of formula (III). [Figure 13] FIG. 1 shows an XRPD spectrum of Cu-Kα radiation for the D crystalline form of compound of formula (IV). [Figure 14] FIG. 1 shows a DSC spectrum of the D crystalline form of the compound of formula (IV). [Figure 15] FIG. 1 shows a TGA spectrum of crystalline form D of the compound of formula (IV). DETAILED DESCRIPTION OF THE INVENTION

[0097] The present invention will be described in detail below with reference to examples, but these examples are not intended to limit the present invention in any way. The present invention has been described in detail in this specification, and specific embodiments thereof have also 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.

[0098] Example 1: Preparation of compounds of formula (I) [ka] Step 1: Synthesis of Compound 1-2 Compound 1-1 (60 g) was dissolved in tetrahydrofuran (600 mL), and tert-butoxybis(dimethylamine)methane (77.35 g) was added at 20°C. After the addition was complete, the mixture was heated to 80°C and reacted for 12 hours. The temperature was lowered to 20°C, and water (200 mL) was added to the reaction mixture. The mixture was then concentrated under reduced pressure. Water (400 mL) was added again to the reaction mixture, and the mixture was stirred for 3 hours. The mixture was then filtered, the solid matter was collected, and air-dried to obtain a crude product. 2-Methyltetrahydrofuran (160 mL) and methyl tert-butyl ether (480 mL) were added to the crude product, and the mixture was stirred at 20°C for 3 hours. The mixture was then filtered, the solid matter was collected, and air-dried to obtain compound 1-2. LCMS: m / z (ESI) = 326.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ:7.59 (s, 1H), 4.35 - 4.29 (m, 2H), 3.19 - 3.16 (t, 2H, J =6.8 Hz), 3.12 (s, 6H), 2.89 - 2.86 (t, 2H, J =6.8 Hz), 2.58 (s, 3H), 1.39 - 1.35 (t, 3H, J =7.0 Hz).

[0099] Step 2: Synthesis of Compounds 1-4 Compound 1-3 (78 g) was dissolved in dimethyl sulfoxide (640 mL), compound 1-2 (80 g) was added, and the mixture was heated to 110 ° C. and reacted for 48 hours. The temperature was lowered to 30 ° C., and the mixture was diluted with water (3 L). After stirring for 0.5 hours, the mixture was filtered and rinsed with water (200 mL). The cake was collected, acetonitrile (750 mL) was added to the cake, and the mixture was stirred at 50 ° C. for 2 hours. The cake was filtered, rinsed with acetonitrile (200 mL), and acetonitrile (400 mL) was added to the cake. The mixture was stirred at 25 ° C. for 16 hours. The cake was filtered, rinsed with acetonitrile (80 mL), and the cake was collected and dried under reduced pressure to give compound 1-4. LCMS: m / z (ESI) = 580.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ:8.55 (s, 1H), 8.34 (s, 1H), 7.49 - 7.46 (m, 1H), 7.19 - 7.17 (m, 1H), 6.73 - 6.71 (m, 1H), 4.31 - 4.25 (m, 2H), 3.32 - 3.15 (m, 6H), 2.79 - 2.76 (m 2H), 2.57 - 2.44 (m 7H), 2.22 (s, 3H), 1.32 - 1.28 (m, 3H).

[0100] Step 3: Synthesis of Compounds 1-5 Compound 1-4 (86.8 g) was dissolved in anhydrous tetrahydrofuran (520 mL), and a solution of lithium hydroxide monohydrate (18.9 g) in water (780 mL) was added to the mixture. Methanol (87 mL) was then added, and the mixture was heated to 36.5 °C and reacted for 16 hours. The reaction mixture was concentrated under reduced pressure, and the organic solvent was removed by distillation to obtain a crude product. Water (780 mL) and 2-methyltetrahydrofuran (78 mL) were added to the crude product, and the pH was adjusted to 7 with concentrated hydrochloric acid while stirring, followed by adjustment to 6.5 with 1N diluted hydrochloric acid. The mixture was filtered and the cake was collected. Acetone (800 mL) was added to the cake, and the mixture was refluxed with stirring for 2 hours. The temperature was then lowered to 25 °C, filtered, rinsed with acetone (300 mL), and the cake was collected and dried under reduced pressure to obtain compound 1-5. LCMS: m / z (ESI) = 552.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ:8.49 (s, 1H), 8.32 (s, 1H), 7.49 - 7.48 (m, 1H), 6.74 - 6.72 (m, 1H), 6.72 - 6.70 (m, 1H), 3.32 - 3.17 (m, 6H), 2.77 - 2.75 (m, 2H), 2.55 - 2.50 (m, 7H), 2.27 (s, 3H).

[0101] Step 4: Synthesis of Compounds of Formula (I) Dimethyl sulfoxide (100 mL) was added to compound 1-5 (10 g), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphonate (13.79 g), diisopropylethylamine (7.03 g), and ammonium bicarbonate (4.3 g) and stirring at 30 °C for 16 hours. The reaction mixture was slowly poured into water (0.5 L) and stirred at 25 °C for 16 hours. The mixture was then filtered and the cake was collected to give a crude product. Water (100 mL) was added to the crude product, and the mixture was stirred at 25 °C for 16 hours. The cake was then filtered and the residual solvent was removed with a nitrogen stream to give compound of formula (I). LCMS: m / z (ESI) = 551.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ:8.45 (s, 1H), 8.32 (s, 1H), 7.52 - 7.51 (m, 1H), 7.34 (s, 2H), 7.18 - 7.15 (m, 1H), 6.72 - 6.68 (m, 1H), 3.17 - 3.10 (m, 6H), 2.75 - 2.71 (m, 2H), 2.54 - 2.46 (m, 7H), 2.23 (s, 3H).

[0102] Example 2: Preparation of crystalline form A of the compound of formula (I) [ka] 200 mg of compound of formula (I) was weighed and added to a glass vial containing 3 mL of ethanol to form a suspension. After adding a stir bar, the suspension sample was placed on a magnetic heating stirrer and stirred at 60°C overnight. The temperature was then lowered to room temperature, filtered, and the solid sample was concentrated under reduced pressure using a vacuum pump to obtain crystalline form A of compound of formula (I). The XRPD spectrum was shown in Figure 1, the DSC spectrum was shown in Figure 2, and the TGA spectrum was shown in Figure 3.

[0103] 200 mg of the compound of formula (I) was weighed and added to a glass vial containing 3 mL of acetone to form a suspension. After adding a stir bar, the suspension sample was placed on a magnetic heating stirrer and stirred at 60°C overnight. After that, the temperature was lowered to room temperature, filtered, and the solid sample was concentrated under reduced pressure using a vacuum pump to obtain crystalline form A of the compound of formula (I).

[0104] 200 mg of the compound of formula (I) was weighed and added to a glass vial containing 3 mL of methanol to form a suspension. After adding a stir bar, the suspension sample was placed on a magnetic heating stirrer and stirred at 60°C overnight. After that, the temperature was lowered to room temperature, filtered, and the solid sample was concentrated under reduced pressure using a vacuum pump to obtain crystalline form A of the compound of formula (I).

[0105] 200 mg of the compound of formula (I) was weighed and added to a glass vial containing 1.5 mL of ethanol and 1.5 mL of water to form a suspension. After adding a stir bar, the suspension sample was placed on a magnetic heating stirrer and stirred at 60°C overnight. After that, the temperature was lowered to room temperature, filtered, and the solid sample was concentrated under reduced pressure using a vacuum pump to obtain crystalline form A of the compound of formula (I).

[0106] 200 mg of the compound of formula (I) was weighed and added to a glass vial containing 1.5 mL of acetone and 1.5 mL of water to form a suspension. After adding a stir bar, the suspension sample was placed on a magnetic heating stirrer and stirred at 60°C overnight. After that, the temperature was lowered to room temperature, filtered, and the solid sample was concentrated under reduced pressure using a vacuum pump to obtain crystalline form A of the compound of formula (I).

[0107] 200 mg of the compound of formula (I) was weighed and added to a glass vial containing 3 mL of ethyl acetate to form a suspension. After adding a stir bar, the suspension sample was placed on a magnetic heating stirrer and stirred at 60°C overnight. After that, the temperature was lowered to room temperature, filtered, and the solid sample was concentrated under reduced pressure using a vacuum pump to obtain crystalline form A of the compound of formula (I). 1H NMR (400 MHz, D2O) δ:7.90 (s, 1 H), 7.30 (d, J =8.8 Hz, 1 H), 7.14 (d, J =3.2 Hz, 1 H), 7.00 (dd, J =8.8, 3.2 Hz, 1 H), 3.74 -3.77 (m, 2 H), 3.47 - 3.50 (m, 2 H), 2.99 - 3.15 (m, 4 H), 2.74 - 2.83 (m, 5 H), 2.51 - 2.59 (m, 2 H), 2.07 (s, 3 H).

[0108] Example 3: Preparation of crystalline form B of the compound of formula (II) [ka] Approximately 50 mg of crystalline form A of compound of formula (I) was weighed out and placed in 1.0 mL of ethanol and stirred at 50° C. 11.38 mg of the weighed amount of succinic acid was diluted with 1 mL of ethanol, and the diluted succinic acid solution was slowly added dropwise to the above solvent and stirred at 50° C. for 20 hours, then the temperature was lowered to 25° C. and stirred for 4 days. After filtration, the mixture was dried at 50° C. for approximately 18 hours to obtain crystalline form B of compound of formula (II), whose XRPD spectrum is shown in FIG. 5, DSC spectrum is shown in FIG. 6, and TGA spectrum is shown in FIG. 7.

[0109] 45 mg of succinic acid was weighed and added to a glass vial containing 3 mL of ethanol, and 200 mg of the compound of formula (I) was weighed and added to the above solution. The reaction solution was placed on a magnetic heating stirrer and stirred at 60°C overnight, then cooled to room temperature, filtered, and the solid sample was concentrated under reduced pressure using a vacuum pump to obtain crystalline form B of the compound of formula (II).

[0110] 45 mg of succinic acid was weighed and added to a glass vial containing 3 mL of methanol, and 200 mg of the compound of formula (I) was weighed and added to the above solution. The reaction solution was placed on a magnetic heating stirrer and stirred at 60°C overnight, then cooled to room temperature, filtered, and the solid sample was concentrated under reduced pressure using a vacuum pump to obtain crystalline form B of the compound of formula (II).

[0111] 45 mg of succinic acid was weighed and added to a glass vial containing 1.5 mL of methanol and 1.5 mL of water, and dissolved. 200 mg of the compound of formula (I) was weighed and added to the solution. The reaction solution was placed on a magnetic heating stirrer and stirred at 60°C overnight. The temperature was then lowered to room temperature, filtered, and the solid sample was concentrated under reduced pressure using a vacuum pump to obtain crystalline form B of the compound of formula (II).

[0112] 45 mg of succinic acid was weighed and added to a glass vial containing 1.5 mL of ethanol and 1.5 mL of water, and dissolved. 200 mg of the compound of formula (I) was weighed and added to the above solution. The reaction solution was placed on a magnetic heating stirrer and stirred at 60°C overnight. The temperature was then lowered to room temperature, filtered, and the solid sample was concentrated under reduced pressure using a vacuum pump to obtain crystalline form B of the compound of formula (II).

[0113] 45 mg of succinic acid was weighed and added to a glass vial containing 3 mL of acetone, and dissolved. 200 mg of the compound of formula (I) was weighed and added to the above solution. The reaction solution was placed on a magnetic stirrer and stirred at 60 °C overnight. The temperature was then lowered to room temperature, filtered, and the solid sample was concentrated under reduced pressure using a vacuum pump to obtain crystalline form B of the compound of formula (II). Analysis based on nuclear magnetic spectrum showed that m was 1.1. 1 H NMR (400 MHz, D2O) δ:7.95 (s, 1 H), 7.35 (d, J =9.2 Hz, 1 H), 7.18 (d, J =2.4 Hz, 1 H), 7.04 (dd, J =9.2, 2.4 Hz, 1 H), 3.80 (m, 2 H), 3.53 (m, 2 H), 3.01 - 3.20 (m, 4 H), 2.81 - 2.90 (m, 5 H), 2.58 - 2.67 (m, 2 H), 2.53 (s, 4.4 H), 2.18 (s, 3 H).

[0114] Example 4: Preparation of crystalline form C of the compound of formula (III) [ka] 155 mg of the crude product from Step 4 of Example 1 was weighed, added to 1.5 mL of water, and concentrated hydrochloric acid (1.5 mL) was added to dissolve the crude product and clarify the solution. Then, solid sodium hydroxide was added to adjust the pH to greater than 14. The mixture was filtered, the cake was collected, and water (1 mL) was added thereto. The mixture was stirred at 25°C for 6 hours, filtered, the cake was collected, and the mixture was dried in an oven at 50°C for 16 hours to obtain 150 mg of the crude product. The mixture was then placed in a 4.0 mL glass vial with 33.2 mg of fumaric acid and 2 mL of ethyl acetate was added to form a suspension. After adding a stir bar, the suspension sample was placed on a magnetic heating stirrer (50°C) for testing. After stirring overnight at 50°C, the temperature was lowered, and the temperature was lowered to 25°C while stirring. The mixture was then filtered, and the cake was collected to obtain crystalline form C of the compound of formula (III).

[0115] 520 mg of the crude product from Step 4 of Example 1 was weighed, added to water (5.2 mL), and concentrated hydrochloric acid (5.2 mL) was added to dissolve the crude product and clarify the solution. Then, solid sodium hydroxide was added to increase the pH to greater than 14. The mixture was filtered, the cake was collected, water (3.7 mL) was added thereto, and the mixture was stirred at 25°C for 6 hours. The mixture was filtered, the cake was collected, and the mixture was dried in an oven at 50°C for 16 hours to obtain 500 mg. The mixture was then placed in a 40.0 mL glass vial, and 5 mL of a mixed solution of dichloromethane and methanol (dichloromethane:methanol = 2:1) was added. A stir bar was added, and the mixture was stirred at 50°C to dissolve the product and clarify the solution. Then, 110.7 mg of fumaric acid was dissolved in 10 mL of a mixed solution of dichloromethane and methanol (dichloromethane:methanol=2:1), and the solution was dropped into a glass vial. The reaction solution sample was placed on a magnetic heating stirrer (50°C) for testing. After stirring at 50°C for 3 hours, the temperature was reduced and the mixture was cooled to 20°C while stirring. After filtering, the cake was collected to obtain the C crystalline form of compound of formula (III). Analysis based on nuclear magnetic spectrum showed that n was 1.0, and the XRPD spectrum was as shown in Figure 9, the DSC spectrum was as shown in Figure 10, and the TGA spectrum was as shown in Figure 11. 1H NMR (400 MHz, DMSO- d6) δ:8.48 (s, 1 H), 8.32 (s, 1 H), 7.55 - 7.50 (m, 1 H), 7.44 (s, 2 H), 7.22 - 7.15 (m, 1 H), 6.76 - 6.69 (m, 1 H) , 6.60 (s, 2 H) , 3.23 - 3.16 (m, 4 H) , 3.15 - 3.08 (m, 2 H) , 2.79 - 2.70 (m, 2 H), 2.60 - 2.55 (m, 4 H), 2.54 (s, 3 H) ,2.30 (s, 3 H).

[0116] Example 5: Preparation of crystalline form D of the compound of formula (IV) [ka] Approximately 50 mg of crystalline form A of compound of formula (I) was weighed and added to 1.0 mL of ethanol and stirred at 50° C. A weighed amount of 15.28 mg of benzenesulfonic acid was diluted with 1 mL of ethanol solvent, and the diluted benzenesulfonic acid solution was slowly added dropwise to the above solvent and stirred at 50° C. for 20 hours, then the temperature was lowered to 25° C. and stirred for 4 days. After filtration, the mixture was dried at 50° C. for approximately 18 hours to obtain crystalline form D of compound of formula (IV). Analysis based on nuclear magnetic spectrum showed that p was 0.9, with an XRPD spectrum as shown in FIG. 13, a DSC spectrum as shown in FIG. 14, and a TGA spectrum as shown in FIG. 15. 1H NMR (400 MHz, DMSO-d6) δ:9.37 - 9.69 (m, 0.9 H), 8.59 (s, 1 H), 8.33 (s, 1 H), 7.56 - 7.65 (m, 1.8 H), 7.54 (d, J =3.2 Hz, 1 H), 7.44 - 7.56 (m, 2 H), 7.27 - 7.36 (m, 2.7 H), 7.24 (d, J =8.4 Hz, 1 H), 6.80 (dd, J =8.4, 3.2 Hz, 1 H), 3.40 - 3.96 (m, 4 H), 2.92 - 3.26 (m, 6 H), 2.86 (s, 3 H), 2.74 (m, 2 H), 2.54 (s, 3 H).

[0117] Example 6: Crystalline Form Screening Experiment 6.1 Phase transition of crystals due to suspension The process for crystalline phase transition by suspension involves weighing a certain amount of crystalline Form A of compound of formula (I), adding a certain amount of solvent, stirring the system at a certain temperature to maintain the suspension, and filtering and analyzing the solid after a certain period of time. The specific conditions are shown in Table 6.

[0118] [Table 6]

[0119] 6.2 Crystallization by cooling The cooling crystallization procedure was as follows: a certain amount of crystalline Form A of compound of formula (I) was dissolved in a certain amount of solvent at a high temperature, stirred at a high temperature for a certain period of time, and then cooled to a relatively low temperature at a constant rate. After cooling to a low temperature, a solid precipitated out, which was filtered and subjected to solid analysis. The specific conditions are shown in Table 7.

[0120] [Table 7]

[0121] 6.3 Solvent-Based Crystallization The solvent crystallization procedure was as follows: a certain amount of crystalline Form A of compound of formula (I) was dissolved in a solvent to obtain a drug substance solution, which was then slowly added to an anti-solvent at a constant temperature, and the solid precipitated was filtered and analyzed. The specific conditions are shown in Table 8.

[0122] [Table 8]

[0123] Experimental conclusion: Crystalline form A of compound of formula (I) has certain stability in different solvents and temperatures.

[0124] Example 7: Hygroscopicity study of crystalline form A of the compound of formula (I) Test materials: SMS DVS Intrinsic Dynamic Vapor Sorption Meter Experimental Method: 10 to 30 mg of crystalline form A of the compound of formula (I) was taken and placed on a DVS sample dish for measurement.

[0125] Test Results: The DVS spectrum of crystalline form A of the compound of formula (I) was shown in FIG. 4, and when the humidity was increased to 80%, ΔW was 0.1671%.

[0126] Testing conclusion: Crystalline form A of the compound of formula (I) showed a weight gain of 0.1671% after absorbing moisture at 25°C and 80% RH, and the sample was not hygroscopic.

[0127] Example 8: Hygroscopicity study of crystalline form B of compound of formula (II) Test materials: SMS DVS Intrinsic Dynamic Vapor Sorption Meter Experimental Method: 10 to 30 mg of crystalline form B of the compound of formula (II) was taken and placed on a DVS sample dish for measurement.

[0128] Test Results: The DVS spectrum of crystalline form B of the compound of formula (II) was shown in FIG. 8, and when the humidity was increased to 80%, ΔW was 2.078%.

[0129] Testing conclusion: Crystalline form B of the compound of formula (II) was hygroscopic, with a weight gain of 2.078% after absorbing moisture at 25°C and 80% RH.

[0130] Example 9: Hygroscopicity study of crystalline form C of compound of formula (III) Test materials: SMS DVS Intrinsic Dynamic Vapor Sorption Meter Experimental Method: 10 to 30 mg of crystalline form C of the compound of formula (III) was taken and placed on a DVS sample dish for measurement.

[0131] Test Results: The DVS spectrum of the C crystalline form of the compound of formula (III) was shown in FIG. 12, and ΔW was 2.919% when the humidity was increased to 80%.

[0132] Testing conclusion: The C crystalline form of the compound of formula (III) was hygroscopic, with a weight gain of 2.919% after absorbing moisture at 25°C and 80% RH.

[0133] Example 10: Testing the solid state stability of crystalline form A of the compound of formula (I) and crystalline form B of the compound of formula (II) Objective of the experiment: Based on the "Guideline for Stability Testing of Drug Substances and Preparations" (Chinese Pharmacopoeia 2020 Edition, Part 4 General Principle 9001), the stability of crystalline form A of compound of formula (I) and crystalline form B of compound of formula (II) under high temperature and humidity conditions (40°C / 75% RH, open) (60°C / 75% RH, open) is considered.

[0134] Experimental Procedure: 10-30 mg of crystalline form A of formula (I) and crystalline form B of formula (II) were weighed and placed in the bottom of a glass vial and spread thinly. The samples were placed in the open to ensure sufficient contact with ambient air. Samples were stored under different conditions and analyzed (XRPD) on days 10, 30, and 60. The results were compared with the initial results on day 0. The results are shown in Table 9.

[0135] [Table 9]

[0136] Experimental conclusion: Crystalline form A of compound of formula (I) and crystalline form B of compound of formula (II) have good stability under high temperature and high humidity conditions.

[0137] Test Example 1: Pharmacokinetic study of test compound after oral administration in male beagle dogs Objective of the experiment: The purpose of this experiment was to study the pharmacokinetic profile of the test compound in the plasma of male beagle dogs after oral administration.

[0138] Experimental Procedure: Oral administration group: The appropriate amount of test compound (calculated in the free state) was weighed and dissolved in a 0.5% MC aqueous solution. The solution was subjected to ultrasonic vortexing for 10 minutes until the compound became milky white and uniformly suspended. A 1.0 mg / mL preliminary homogeneous suspension was prepared. Male beagle dogs weighing approximately 11 kg were selected and orally administered the test compound. Samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours.

[0139] Approximately 1 mL of whole blood was drawn from the forelimb vein at each time point, and plasma was prepared. Concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). Plasma concentrations were processed using the non-atrial model in WinNonlin 8.2.0 (Pharsight, Mountain View, CA) pharmacokinetic analysis software, and pharmacokinetic parameters were calculated using the linear-logarithmic trapezoidal method. The experimental results are shown in Table 10.

[0140] [Table 10]

[0141] Experimental conclusion: Crystalline form A of the compound of formula (I), crystalline form B of the compound of formula (II) and crystalline form C of the compound of formula (III) were all well absorbed when orally administered to male beagle dogs.

[0142] Test Example 2: In vitro evaluation of PLK1 kinase activity 33 IC using a P isotope-labeled kinase activity assay (Reaction Biology Corp). 50 The value is measured to evaluate the inhibitory ability of the test compound against human PLK1 protein kinase.

[0143] Buffer conditions: 20mM HEPES (pH 7.5), 10mM MgCl2, 1mM EGTA, 0.01% Brij35, 0.02 mg / ml BSA, 0.1mM Na3VO4, 2mM DTT, 1% DMSO Test step: Test compounds were dissolved in DMSO at room temperature to prepare a 10 mM solution for preliminary use. The substrate, Casein, was dissolved in a freshly prepared buffer solution (final concentration: 20 μM), to which PLK1 kinase (final concentration: 12 nM) to be measured was added and mixed uniformly. Using the Echo 550 ultrasonic pipette system, the mother solution of the test compound dissolved in DMSO was added to the above uniformly mixed reaction solution at a gradient of set final concentrations (the highest final concentration was 1 μM, 3-fold dilution, 10 gradients). After incubating at room temperature for 20 minutes, 33P-ATP (final concentration 0.01 μCi / μL) was added, and the reaction mixture was incubated at room temperature for 120 minutes. The reaction mixture was then spotted onto P81 ion-exchange filter paper (Whatman # 3698-915). After repeatedly washing the filter paper with 0.75% phosphoric acid solution, the level of radioactive phosphorylated substrate remaining on the filter paper was measured. % kinase activity = kinase activity test compound / kinase activity blank group (DMSO) × 100%, and IC was calculated by curve fitting using Prism4 software (GraphPad). 50 The values ​​were obtained and the experimental results are shown in Table 11.

[0144] [Table 11]

[0145] Experimental conclusion: Crystalline form A of compound of formula (I) exhibits relatively good inhibitory activity against PLK1.

Claims

1. Salts of the compound of formula (I), which are succinate, fumarate, benzenesulfonate, sulfate, phosphate, maleate, L-tartrate, methanesulfonate, L-malate, hydrochloride, citrate and L-aspartate salts of the compound. 【Chemical 1】

2. The salt is 【Chemistry 2】 wherein m, n, p, q, r, s, t, u, v, w, x, and y are each independently selected from 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.

0.

3. 3. The salt of claim 2, wherein m, n, p, q, r, s, t, u, v, w, x, and y are each independently selected from 1.

0.

4. Crystalline form A of the compound of formula (I), characterized in that its powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 6.305±0.200°, 9.140±0.200°, 12.661±0.200°, and 19.637±0.200°. 【Chemistry 3(1)】 【Chemistry 3(2)】

5. 5. Crystalline Form A according to claim 4, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 6.305±0.200°, 9.140±0.200°, 9.681±0.200°, 12.661±0.200°, 13.479±0.200°, 19.637±0.200°, 23.281±0.200°, and 24.892±0.200°.

6. 6. Crystalline Form A of claim 5, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 6.305±0.200°, 9.140±0.200°, 9.681±0.200°, 12.661±0.200°, 13.479±0.200°, 14.139±0.200°, 16.523±0.200°, 18.385±0.200°, 19.637±0.200°, 21.161±0.200°, 23.281±0.200°, and 24.892±0.200°.

7. 7. Crystalline Form A of claim 6, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 6.305°, 9.140°, 9.681°, 11.138°, 12.661°, 13.479°, 14.139°, 15.175°, 16.523°, 18.385°, 18.710°, 19.094°, 19.637°, 19.904°, 20.692°, 21.161°, 21.915°, 22.159°, 23.281°, 23.630°, 24.892°, 25.491°, 26.582°, and 32.389°.

8. Crystalline Form A according to any one of claims 4 to 7, having an XRPD spectrum essentially as shown in Figure 1.

9. Crystalline Form A according to any one of claims 4 to 7, wherein the differential scanning calorimetry curve has an endothermic peak onset at 222.64±3.0°C.

10. 10. Crystalline form A of claim 9, having a DSC spectrum as shown in Figure 2.

11. Crystalline form A according to any one of claims 4 to 7, wherein the thermogravimetric analysis curve reaches a weight loss of 1.220% at 242±3°C.

12. 12. Crystalline form A of claim 11, having a TGA spectrum as shown in Figure 3.

13. Crystalline form B of the compound of formula (II), wherein m is selected from 0.8, 0.9, 1.0, 1.1 and 1.2, and whose powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 13.855±0.200°, 17.861±0.200°, 19.915±0.200°, and 24.154±0.200°. 【Chemistry 4】

14. 14. Crystalline form B according to claim 13, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 7.333±0.200°, 13.855±0.200°, 17.861±0.200°, 18.764±0.200°, 19.915±0.200°, 20.651±0.200°, 24.154±0.200°, and 27.518±0.200°.

15. Crystalline form B according to claim 14, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 7.333±0.200°, 11.034±0.200°, 13.855±0.200°, 14.350°±0.200°, 16.116±0.200°, 17.861±0.200°, 18.764±0.200°, 19.915±0.200°, 20.651±0.200°, 21.157±0.200°, 24.154±0.200°, and 27.518±0.200°.

16. 16. Crystalline form B according to claim 15, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 7.333°, 11.034°, 12.635°, 13.534°, 13.855°, 14.350°, 16.116°, 17.483°, 17.861°, 18.764°, 19.658°, 19.915°, 20.651°, 21.157°, 23.449°, 23.806°, 24.154°, 24.702°, 26.884°, 27.518°, and 31.071°.

17. Crystalline Form B according to any one of claims 13 to 16, having an XRPD spectrum essentially as shown in Figure 5.

18. Crystalline form B according to any one of claims 13 to 16, wherein the differential scanning calorimetry curve has an endothermic peak onset at 193.63±3.0°C.

19. Crystalline form B of claim 18, having a DSC spectrum as shown in Figure 6.

20. Crystalline form B according to any one of claims 13 to 16, wherein the thermogravimetric analysis curve reaches a weight loss of 0.867% at 92±3°C.

21. Crystalline form B of claim 20, having a TGA spectrum as shown in Figure 7.

22. Crystalline form C of the compound of formula (III), wherein n is selected from 0.8, 0.9, 1.0, 1.1, and 1.2, and whose powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 13.637±0.200°, 14.138±0.200°, 17.076±0.200°, and 24.866±0.200°. 【Chemistry 5】

23. 23. Crystalline Form C according to claim 22, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 11.412±0.200°, 13.637±0.200°, 14.138±0.200°, 17.076±0.200°, 19.310±0.200°, 23.654±0.200°, 24.214±0.200°, and 24.866±0.200°.

24. 24. Crystalline Form C according to claim 23, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 11.412±0.200°, 13.637±0.200°, 14.138±0.200°, 15.555±0.200°, 17.076±0.200°, 18.016±0.200°, 18.907±0.200°, 19.310±0.200°, 20.811±0.200°, 23.654±0.200°, 24.214±0.200°, and 24.866±0.200°.

25. The powder X-ray diffraction spectrum shows the following: 5.677°, 7.086°, 11.412°, 11.627°, 13.200°, 13.429°, 13.637°, 14.138°, 14.499°, 15.167°, 15.555°, 15.763°, 17.076°, 17.272°, 18.016°, 18.171°, 18.614°, 18.907°, 19.

25. Crystalline Form C according to claim 24, having characteristic diffraction peaks at 2θ angles of 310°, 19.656°, 20.016°, 20.811°, 21.765°, 22.748°, 23.443°, 23.654°, 23.880°, 24.214°, 24.577°, 24.866°, 25.987°, 26.493°, 27.011°, and 27.537°.

26. Crystalline Form C according to any one of claims 22 to 25, having an XRPD spectrum essentially as shown in Figure 9.

27. Crystalline form C according to any one of claims 22 to 25, wherein a differential scanning calorimetry curve has an endothermic peak onset at 237.14±3.0°C.

28. 28. Crystalline form C of claim 27, having a DSC spectrum as shown in Figure 10.

29. Crystalline form C according to any one of claims 22 to 25, wherein the thermogravimetric analysis curve reaches a weight loss of 0.469% at 100±3°C.

30. 30. Crystalline form C of claim 29, having a TGA spectrum as shown in Figure 11.

31. A D crystalline form of the compound of formula (IV), wherein p is selected from 0.8, 0.9, 1.0, 1.1 and 1.2, and characterized in that its powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 6.859±0.200°, 8.784±0.200°, 16.420±0.200° and 18.965±0.200°. 【Chemistry 6】

32. Crystalline form D of claim 31, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 6.859±0.200°, 8.784±0.200°, 10.922±0.200°, 13.238±0.200°, 16.420±0.200°, 18.965±0.200°, 20.400±0.200°, and 24.069±0.200°.

33. Crystalline form D of claim 32, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 6.859±0.200°, 8.784±0.200°, 10.922±0.200°, 11.644±0.200°, 13.238±0.200°, 16.420±0.200°, 17.596±0.200°, 18.965±0.200°, 19.390±0.200°, 20.400±0.200°, 21.416±0.200°, and 24.069±0.200°.

34. Crystalline form D of claim 33, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 6.859°, 8.784°, 10.922°, 11.644°, 13.238°, 13.741°, 16.420°, 16.720°, 17.596°, 17.930°, 18.965°, 19.390°, 20.400°, 21.416°, 22.630°, 23.473°, 24.069°, 24.832°, 26.587°, and 27.661°.

35. Crystalline Form D according to any one of claims 31 to 34, having an XRPD spectrum essentially as shown in Figure 13.

36. Crystalline form D according to any one of claims 31 to 34, wherein a differential scanning calorimetry curve has an endothermic peak onset at 240.70±3.0°C.

37. Crystalline form D of claim 36, having a DSC spectrum as shown in Figure 14.

38. Crystalline form D according to any one of claims 31 to 34, wherein the thermogravimetric analysis curve reaches a weight loss of 0.295% at 120±3°C.

39. Crystalline form D of claim 38, having a TGA spectrum as shown in Figure 15.

40. Use of the salt form of any one of claims 1 to 3, the crystalline form A of any one of claims 4 to 12, the crystalline form B of any one of claims 13 to 21, the crystalline form C of any one of claims 22 to 30 or the crystalline form D of any one of claims 31 to 39 in the preparation of a medicament for treating solid tumors.

41. 41. The use of claim 40, wherein the drug for treating solid tumors is a drug for treating colorectal cancer.

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