Salt of large fused-ring compound, polymorph and use thereof

Abstract

Provided in the present invention are a salt form of a WEE1 / YES dual-target inhibitor compound of formula (I), a polymorph of the salt, and a preparation method therefor and the use thereof. The salt form and the polymorph thereof of the present invention exhibit higher solubility and stability, are easier to separate and purify, show better processability, are convenient for storage, and are more applicable in the preparation of a drug for preventing or treating diseases related to WEE1 or / and YES targets and signaling pathways thereof, e.g., conditions such as tumors, particularly solid tumors, inflammations, and autoimmune diseases.

Description

Salt of a large condensed ring compound, polymorphs thereof and applications thereof TECHNICAL FIELD

[0001] The present application relates to a salt of a large condensed ring compound, polymorphs thereof and applications thereof. BACKGROUND

[0002] MindRank AI Ltd. has developed a class of novel structure small molecule compounds with WEE1 and YES dual target inhibition activity of formula (I) (chemical name: (R, Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl) oxy) phenyl) amino)-7, 10, 11, 12-tetrahydro-5H-13, 17- (azene bridge) pyrimido [4', 5': 3, 4] pyrazolo [1, 2-a] [1, 2] diazacyclotridecine-5-ketone), and applied for a PCT patent (PCT / CN2024 / 092244). Compared with the reference compounds DEBIO0123, ZN-c3, NUV-569 and the like with known structures, the compound of formula (I) has higher in vitro and in vivo antitumor activity.

[0003] The successful development of the pharmaceutical solid form of the compound of formula (I) usually has a solid form that can be easily separated and purified after synthesis, which can be suitable for large-scale manufacturing, can be stored for a long period of time and minimally absorbs moisture, decomposes or converts into other solid forms, and has good solubility, etc., and is suitable for the dosage form that can be rapidly absorbed by individuals after administration (such as being soluble in water and gastric juice) and the like.

[0004] In order to meet the needs of clinical research and marketed drug preparations, it is urgent to develop a pharmaceutical solid form which can be easily separated and purified, suitable for industrial production, has stable physicochemical properties and good solubility. SUMMARY

[0005] In order to solve the problems existing in the prior art, the present application provides a pharmaceutically acceptable salt of a compound of formula (I);

[0006] The pharmaceutically acceptable salt refers to a pharmaceutically non-toxic acid addition salt.

[0007] In an embodiment, the acid addition salt is a salt of the compound of formula (I) with an inorganic or organic acid, including one or more of hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, phosphate, borate, acetate, oxalate, valerate, benzoate, lactate, toluylate, citrate, malate, maleate, fumarate, succinate, tartrate, mesylate, besylate and tosylate, preferably one or more of hydrochloride, sulfate, succinate, fumarate, maleate, tosylate, mesylate and besylate, more preferably one or more of tosylate, mesylate and maleate.

[0008] In an embodiment, the acid addition salt has a ratio of the compound of formula (I) to the acid of 3:1 to 1:3.

[0009] In an embodiment, the application provides a crystalline form of a hydrochloride salt of the compound of formula (I) having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2q) at 4.54±0.2°, 15.92±0.2°, 15.08±0.2° and 17.14±0.2°.

[0010] In an embodiment, the application provides a crystalline form of a hydrochloride salt of the compound of formula (I) further having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2q) at 23.02±0.2°, 9.16±0.2°, 13.67±0.2°, 26.69±0.2°, 18.15±0.2° and 6.85±0.2°.

[0011] In an embodiment, the crystalline form of the hydrochloride salt further has an X-ray powder diffraction pattern having diffraction angles (2q) as shown in Table 1, wherein the error range of the 2q angles is ±0.20°:

[0012] Table 1

[0013] In an embodiment, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern substantially as shown in Figure 1.

[0014] In an embodiment, the crystalline form of the hydrochloride salt has a DSC thermogram having endothermic peaks at temperatures of about 49.69 °C and 287.83 °C.

[0015] In an embodiment, the crystalline form of the hydrochloride salt has a DSC pattern substantially as shown in Figure 2.

[0016] In an embodiment, the crystalline form of the hydrochloride salt has a TGA pattern substantially as shown in Figure 3.

[0017] In one aspect, the present application provides a crystalline form of a sulfate salt of a compound of formula (I), having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) at 6.97±0.2°, 4.58±0.2°, 13.79±0.2° and 14.08±0.2°.

[0018] In one aspect, the present application provides a crystalline form of a sulfate salt of a compound of formula (I), further having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) at 23.05±0.2°, 5.63±0.2°, 6.22±0.2°, 20.75±0.2°, 14.90±0.2° and 17.57±0.2°.

[0019] In one aspect, the crystalline form of a sulfate salt of a compound of formula (I) further has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 2, wherein the error range of the 2θ angles is ±0.20°.

[0020] Table 2

[0021] In one aspect, the crystalline form of a sulfate salt of a compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 4.

[0022] In one aspect, the crystalline form of a sulfate salt of a compound of formula (I) has a DSC thermogram with endothermic peaks at temperatures of about 33.84°C, 177.83°C, 218.04°C and 254.19°C.

[0023] In one aspect, the crystalline form of a sulfate salt of a compound of formula (I) has a DSC thermogram substantially as shown in Figure 5.

[0024] In one aspect, the crystalline form of a sulfate salt of a compound of formula (I) has a TGA pattern substantially as shown in Figure 6.

[0025] In one aspect, the present application provides a crystalline form of a succinate salt of a compound of formula (I), having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) at 4.83±0.2°, 7.25±0.2°, 13.23±0.2° and 10.30±0.2°.

[0026] In one aspect, the crystalline form of a succinate salt of a compound of formula (I) further has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) at 22.23±0.2°, 14.53±0.2°, 18.84±0.2°, 9.31±0.2°, 18.37±0.2° and 6.80±0.2°.

[0027] In an embodiment, the crystalline form of the succinate salt of the compound of formula (I) has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2q) of 5.10 ± 0.2°, 7.03 ± 0.2°, 12.14 ± 0.2°, and 13.11 ± 0.2°.

[0028] Table 3

[0029] In an embodiment, the crystalline form of the succinate salt of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 7.

[0030] In an embodiment, the crystalline form of the succinate salt of the compound of formula (I) has a DSC thermogram with endothermic peaks at temperatures of about 76.43 °C, 153.80 °C and 182.84 °C.

[0031] In an embodiment, the crystalline form of the succinate salt of the compound of formula (I) has a DSC thermogram substantially as shown in Figure 8.

[0032] In an embodiment, the crystalline form of the succinate salt of the compound of formula (I) has a TGA pattern substantially as shown in Figure 9.

[0033] In an embodiment, the present application provides a crystalline form of a fumarate salt of the compound of formula (I), having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2q) of 5.10 ± 0.2°, 7.03 ± 0.2°, 12.14 ± 0.2°, and 13.11 ± 0.2°.

[0034] In an embodiment, the crystalline form of the fumarate salt of the compound of formula (I) has an X-ray powder diffraction pattern (XRPD) further comprising peaks at diffraction angles (2q) of 23.55 ± 0.2°, 17.75 ± 0.2°, 16.01 ± 0.2°, 12.65 ± 0.2°, 16.69 ± 0.2° and 13.36 ± 0.2°.

[0035] In an embodiment, the crystalline form of the fumarate salt of the compound of formula (I) has an X-ray powder diffraction pattern comprising diffraction angles (2q) as shown in Table 4, wherein the error range for the 2q angles is ± 0.20°:

[0036] Table 4

[0037] In an embodiment, the crystalline form of the fumarate salt of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 10.

[0038] In an embodiment, the crystalline form of the fumarate salt of the compound of formula (I) has a DSC thermogram with endothermic peaks at temperatures of about 209.86 °C and 248.89 °C.

[0039] In one aspect, the crystalline form of the fumarate salt of the compound of formula (I) has a DSC pattern substantially as shown in Figure 11.

[0040] In one aspect, the crystalline form of the fumarate salt of the compound of formula (I) has a TGA pattern substantially as shown in Figure 12.

[0041] In one aspect, the present application provides a crystalline form of a p-toluenesulfonic acid salt of a compound of formula (I), having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) at 4.01 ± 0.2°, 22.66 ± 0.2°, 19.99 ± 0.2°, and 15.76 ± 0.2°.

[0042] In one aspect, the crystalline form of the p-toluenesulfonic acid salt of the compound of formula (I) has an X-ray powder diffraction pattern further comprising peaks at diffraction angles (2θ) at 8.07 ± 0.2°, 25.83 ± 0.2°, 16.34 ± 0.2°, 14.75 ± 0.2°, 6.04 ± 0.2°, and 26.05 ± 0.2°.

[0043] In one aspect, the crystalline form of the p-toluenesulfonic acid salt of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction angles (2θ) as shown in Table 5, wherein the error range for the 2θ angles is ± 0.20°:

[0044] Table 5

[0045] In one aspect, the crystalline form of the p-toluenesulfonic acid salt of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 13.

[0046] In one aspect, the crystalline form of the p-toluenesulfonic acid salt of the compound of formula (I) has a DSC thermogram with endothermic peaks at temperatures of about 52.06 °C and 254.23 °C.

[0047] In one aspect, the crystalline form of the p-toluenesulfonic acid salt of the compound of formula (I) has a DSC pattern substantially as shown in Figure 14.

[0048] In one aspect, the crystalline form of the p-toluenesulfonic acid salt of the compound of formula (I) has a TGA pattern substantially as shown in Figure 15.

[0049] In one aspect, the present application provides a methanesulfonic acid salt of a compound of formula (I), having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) at 4.5 ± 0.2°, 6.74 ± 0.2°, 20.16 ± 0.2°, and 22.81 ± 0.2°.

[0050] In one embodiment, the mesylate salt of the compound of formula (I) has an X-ray powder diffraction pattern (XRPD) further comprising peaks at diffraction angles (2Θ) at 13.54 ± 0.2°, 15.90 ± 0.2°, 18.18 ± 0.2°, 16.29 ± 0.2°, 15.55 ± 0.2°, and 22.36 ± 0.2°.

[0051] In one embodiment, the mesylate salt of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction angles (2Θ) as shown in Table 7, wherein the error range of the 2Θ angles is ± 0.20°:

[0052] Table 7

[0053] In one embodiment, the crystalline form of the mesylate salt of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 19.

[0054] In one embodiment, the crystalline form of the mesylate salt of the compound of formula (I) has a DSC thermogram with endothermic peaks at temperatures of about 85.45 °C, 236.03 °C, and 260.99 °C.

[0055] In one embodiment, the crystalline form of the mesylate salt of the compound of formula (I) has a DSC pattern substantially as shown in Figure 20.

[0056] In one embodiment, the crystalline form of the mesylate salt of the compound of formula (I) has a TGA pattern substantially as shown in Figure 21.

[0057] In one embodiment, the present application provides a crystalline form of the besylate salt of the compound of formula (I) having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2Θ) at 4.17 ± 0.2°, 8.30 ± 0.2°, 19.87 ± 0.2°, and 6.23 ± 0.2°.

[0058] In one embodiment, the present application provides a crystalline form of the besylate salt of the compound of formula (I) having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2Θ) at 23.73 ± 0.2°, 15.10 ± 0.2°, 14.57 ± 0.2°, 16.02 ± 0.2°, 23.55 ± 0.2°, and 12.43 ± 0.2°.

[0059] In one embodiment, the crystalline form of the besylate salt has an X-ray powder diffraction pattern having diffraction angles (2Θ) as shown in Table 8, wherein the error range of the 2Θ angles is ± 0.20°:

[0060] Table 8

[0061] In certain embodiments, the crystalline form of the besylate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 22.

[0062] In certain embodiments, the besylate salt has a DSC thermogram with an endothermic peak at a temperature of about 254.84 °C.

[0063] In certain embodiments, the besylate salt has a DSC pattern substantially as shown in FIG. 23.

[0064] In certain embodiments, the besylate salt has a TGA pattern substantially as shown in FIG. 24.

[0065] The present application also provides a method for preparing a pharmaceutically acceptable salt of the compound of formula (I), which comprises reacting the compound of formula (I) with an acid in a solvent to prepare the pharmaceutically acceptable salt of the compound of formula (I).

[0066] In certain embodiments, the acid is selected from an inorganic acid or an organic acid, the inorganic acid is one or more selected from hydrobromic acid, hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid and boric acid; the organic acid is one or more selected from acetic acid, oxalic acid, valeric acid, benzoic acid, lactic acid, toluic acid, citric acid, malic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

[0067] In certain embodiments, the method for preparing further comprises a step of creating supersaturation to precipitate the product after the reaction is completed, the method for creating supersaturation comprises one or more of adding seed crystal, adding volatile solvent, adding anti-solvent or obtaining the acid salt of the compound of formula (I) by cooling.

[0068] In certain embodiments, the solvent can be selected from alcohol, chloroalkane, ketone, ether, cyclic ether, ester, alkane, cycloalkane, benzene, amide, sulfoxide, nitrile organic solvent, a combination of two or more of the solvents, or a mixture of the above solvents or combinations with water respectively.

[0069] In certain embodiments, the ketone can be selected from ketones having 3-10 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, methyl isobutyl ketone, 4-methyl-2-pentanone or a combination thereof; the nitrile can be selected from acetonitrile; the alcohol can be selected from alcohols having 1-8 carbon atoms or halogenated alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, trifluoroethanol or a combination thereof; the ester can be selected from organic formate esters, such as methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate or a combination thereof; the ether can be a linear or branched alkyl ether or a cyclic ether compound, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran or a combination thereof; the chloro can be selected from dichloromethane, trichloromethane, 1,2-dichloroethane.

[0070] In one embodiment, the solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, acetonitrile, water or a mixture thereof.

[0071] In one embodiment, the molar ratio of the compound of formula (I) to the acid can be 1:0.8-1:2, preferably 1:0.9-1:1.8, more preferably 1:1.0-1:1.5.

[0072] In one embodiment, the preparation method further comprises the step of filtering and / or drying after the reaction is completed to prepare the pharmaceutically acceptable salt of the compound of formula (I).

[0073] In one embodiment, the temperature of drying in the preparation method can be selected in a wide range, for example, can be 20-80°C, preferably 30-60°C.

[0074] The application also provides a preparation method of the pharmaceutically acceptable salt of the compound of formula (I):

[0075] Method 1a, comprising: dissolving the compound of formula (I) in isopropyl acetate, adding concentrated hydrochloric acid, stirring at room temperature, filtering, and drying to obtain the hydrochloride salt of the compound of formula (I);

[0076] Method 1b, comprising: dissolving the compound of formula (I) and sulfuric acid in acetone, stirring at room temperature, filtering, and drying to obtain the sulfate salt of the compound of formula (I);

[0077] Method 1c, comprising: dissolving the compound of formula (I) and fumaric acid, maleic acid, p-toluenesulfonic acid monohydrate, methanesulfonic acid or benzenesulfonic acid in isopropanol, stirring at room temperature, filtering, and drying to obtain the fumarate salt, maleate salt, p-toluenesulfonate salt, methanesulfonate salt or benzenesulfonate salt of the compound of formula (I);

[0078] Method 1d, comprising: dissolving the compound of formula (I) and succinic acid in ethanol, stirring at room temperature, filtering, and drying to obtain the succinate salt of the compound of formula (I).

[0079] The application also provides a polymorph of the maleate salt of the compound of formula (I):

[0080] In one embodiment, the ratio of the compound of formula (I) to maleic acid is 3:1-1:3, preferably 2:1-1:2; most preferably 1:1.

[0081] In one embodiment, the polymorph of the maleate salt of the compound of formula (I) is a solvent-free crystal form, a solvate crystal form or a metastable crystal form of the compound of formula (IA).

[0082] The present application also provides a crystalline Form E of the compound of formula (IA), having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.58±0.2°, 14.78±0.2°, 39.60±0.2° and 24.45±0.2°:

[0083] In one aspect, the crystalline Form E of the compound of formula (IA) has an X-ray powder diffraction pattern further comprising peaks at diffraction angles (2θ) of 11.43±0.2°, 22.07±0.2°, 16.31±0.2°, 13.30±0.2° and 10.19±0.2°.

[0084] In one aspect, the crystalline Form E of the compound of formula (IA) has an X-ray powder diffraction pattern further comprising peaks at diffraction angles (2θ) of 21.45±0.2°, 18.90±0.2°, 23.53±0.2°, 20.49±0.2°, 22.75±0.2° and 19.97±0.2°.

[0085] In one aspect, the crystalline Form E of the compound of formula (IA) has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 12, wherein the error range of the 2θ angles is ±0.20°:

[0086] Table 12

[0087] In one aspect, the crystalline Form E of the compound of formula (IA) has an X-ray powder diffraction pattern substantially as shown in Figure 34.

[0088] In one aspect, the crystalline Form E of the compound of formula (IA) has a DSC analysis with an endothermic peak near the peak temperature of 207.03°C.

[0089] In one aspect, the crystalline Form E of the compound of formula (IA) has a DSC pattern substantially as shown in Figure 35.

[0090] In one aspect, the crystalline Form E of the compound of formula (IA) has a TGA pattern substantially as shown in Figure 36.

[0091] The present application also provides a crystalline Form A of the compound of formula (IA), having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 6.49±0.2°, 15.25±0.2°, 15.86±0.2° and 4.32±0.2°.

[0092] In an embodiment, the crystalline Form A of the compound of formula (I) has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2q) of 20.14±0.2°, 17.20±0.2°, 14.91±0.2°, 23.26±0.2°, 21.39±0.2°, and 23.01±0.2°.

[0093] In an embodiment, the crystalline Form A of the compound of formula (IA) has X-ray powder diffraction data as shown in Table 6 below:

[0094] Table 6

[0095] In an embodiment, the crystalline Form A of the compound of formula (IA) has an X-ray powder diffraction pattern substantially as shown in Figure 16.

[0096] In an embodiment, the crystalline Form A of the compound of formula (IA) has a DSC thermogram with endothermic peaks at temperatures of about 83.71 °C and 180.67 °C.

[0097] In an embodiment, the crystalline Form A of the compound of formula (IA) has a DSC pattern substantially as shown in Figure 17.

[0098] In an embodiment, the crystalline Form A of the compound of formula (IA) has a TGA pattern substantially as shown in Figure 18.

[0099] The present application also provides a crystalline Form B of the compound of formula (IA), which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2q) of 4.42±0.2°, 8.89±0.2°, 13.37±0.2° and 17.85±0.2°;

[0100] In an embodiment, the crystalline Form B of the compound of formula (IA) further comprises peaks at diffraction angles (2q) of 23.53±0.2°, 23.40±0.2°, 18.04±0.2°, 22.34±0.2° and 17.18±0.2°.

[0101] In an embodiment, the crystalline Form B of the compound of formula (IA) further comprises peaks at diffraction angles (2q) of 14.94±0.2°, 20.01±0.2°, 21.43±0.2°, 22.62±0.2°, 15.84±0.2° and 14.79±0.2°.

[0102] In an embodiment, the crystalline Form B of the compound of formula (IA) has an X-ray powder diffraction pattern with diffraction angles (2q) as shown in Table 9, wherein the error range of the 2q angles is ±0.20°:

[0103] Table 9

[0104] In one embodiment, the crystal form B of the compound of formula (IA) has an X-ray powder diffraction pattern as shown in Figure 25.

[0105] In one embodiment, DSC analysis of crystal form B of compound (IA) showed an endothermic peak when heated to a peak temperature of around 195.66 °C.

[0106] In one embodiment, the crystal form B of the compound of formula (IA) has a DSC spectrum as shown in Figure 26.

[0107] In one embodiment, the crystal form B of the compound of formula (IA) has a TGA diagram as shown in Figure 27.

[0108] The present invention also provides a crystal form C of the compound of formula (IA) whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 6.45±0.2°, 4.33±0.2°, 12.95±0.2° and 23.73±0.2°.

[0109] In one embodiment, the crystal form C of the compound of formula (IA) further includes peaks at diffraction angles (2θ) of 15.45±0.2°, 16.03±0.2°, 15.06±0.2°, 17.26±0.2° and 23.22±0.2°.

[0110] In one embodiment, the crystal form C of the compound of formula (IA) further includes peaks at diffraction angles (2θ) of 22.85±0.2°, 8.61±0.2°, 18.14±0.2°, 25.08±0.2°, 25.87±0.2° and 20.45±0.2°.

[0111] In one embodiment, the X-ray powder diffraction pattern of crystal form C of compound (IA) has diffraction angles (2θ) as shown in Table 10, wherein the error range of the 2θ angle is ±0.20°.

[0112] Table 10

[0113] In one embodiment, the crystal form C of the compound of formula (IA) has an X-ray powder diffraction pattern as shown in Figure 28.

[0114] In one embodiment, DSC analysis of crystal form C of compound (IA) showed endothermic peaks near peak temperatures of 85.14 °C and 179.58 °C when heated.

[0115] In one embodiment, the crystal form C of the compound of formula (IA) has a DSC spectrum as shown in Figure 29.

[0116] In one aspect, the crystalline Form C of the compound of formula (IA) has a TGA pattern substantially as shown in Figure 30.

[0117] The present application also provides a crystalline Form D of the compound of formula (IA), which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.48±0.2°, 23.03±0.2°, 18.00±0.2° and 15.94±0.2°.

[0118] In one aspect, the crystalline Form D of the compound of formula (IA) further comprises peaks at diffraction angles (2θ) of 18.16±0.2°, 8.96±0.2°, 21.31±0.2°, 14.90±0.2° and 13.46±0.2°.

[0119] In one aspect, the crystalline Form D of the compound of formula (IA) further comprises peaks at diffraction angles (2θ) of 18.16±0.2°, 8.96±0.2°, 21.31±0.2°, 14.90±0.2° and 13.46±0.2°.

[0120] In one aspect, the crystalline Form D of the compound of formula (IA) has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 11, wherein the error range of the 2θ angles is ±0.20°:

[0121] Table 11

[0122] In one aspect, the crystalline Form D of the compound of formula (IA) has an X-ray powder diffraction pattern substantially as shown in Figure 31.

[0123] In one aspect, the crystalline Form D of the compound of formula (IA) has a DSC analysis with an endothermic peak near the peak temperature of 191.66°C.

[0124] In one aspect, the crystalline Form D of the compound of formula (IA) has a DSC pattern substantially as shown in Figure 32.

[0125] In one aspect, the crystalline Form D of the compound of formula (IA) has a TGA pattern substantially as shown in Figure 33.

[0126] The present application provides a dimethyl sulfoxide solvate crystalline Form F of the compound of formula (IA), which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.11±0.2°, 6.08±0.2°, 15.51±0.2° and 17.48±0.2°;

[0127] In an embodiment, the Form F further comprises peaks at diffraction angles (2θ) of 24.08±0.2°, 16.32±0.2°, 15.06±0.2°, 22.02±0.2° and 15.96±0.2°.

[0128] In an embodiment, the Form F further comprises peaks at diffraction angles (2θ) of 25.79±0.2°, 21.21±0.2°, 20.55±0.2°, 17.98±0.2°, 26.94±0.2° and 23.47±0.2°.

[0129] In an embodiment, the Form F has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 13, wherein the error range of the 2θ angles is ±0.20°:

[0130] Table 13

[0131] In an embodiment, the Form F has an X-ray powder diffraction pattern substantially as shown in Figure 37.

[0132] In an embodiment, the Form F has a DSC profile substantially as shown in Figure 38.

[0133] In an embodiment, the Form F has a DSC profile substantially as shown in Figure 38.

[0134] In an embodiment, the Form F has a TGA profile substantially as shown in Figure 39.

[0135] The present application also provides a N-methylpyrrolidone solvate Form G of the compound of Formula (IA), which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.01±0.2°, 6.02±0.2°, 15.43±0.2° and 15.95±0.2°.

[0136] In an embodiment, the Form G further preferably comprises peaks at diffraction angles (2θ) of 23.12±0.2°, 23.98±0.2°, 8.03±0.2°, 17.16±0.2° and 17.65±0.2°.

[0137] In an embodiment, the Form G further preferably comprises peaks at diffraction angles (2θ) of 20.96±0.2°, 20.26±0.2°, 21.59±0.2°, 16.15±0.2°, 18.21±0.2° and 24.31±0.2°.

[0138] In one aspect, the Form G has an X-ray powder diffraction pattern with peaks at diffraction angles (2Θ) as shown in Table 14, wherein the error range for the 2Θ angles is ±0.20°:

[0139] Table 14

[0140] In one aspect, the Form G has an X-ray powder diffraction pattern substantially as shown in Figure 40.

[0141] In one aspect, the Form G has a DSC profile substantially as shown in Figure 41.

[0142] In one aspect, the Form G has a TGA profile substantially as shown in Figure 42.

[0143] In one aspect, the Form G has a TGA profile substantially as shown in Figure 42.

[0144] The present application provides a metastable Form H of the compound of formula (IA), which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) at 4.23 ± 0.2°, 15.68 ± 0.2°, 18.06 ± 0.2° and 17.92 ± 0.2°.

[0145] In one aspect, the Form H further preferably comprises peaks at diffraction angles (2Θ) at 8.53 ± 0.2°, 17.67 ± 0.2°, 16.95 ± 0.2°, 22.56 ± 0.2° and 14.81 ± 0.2°.

[0146] In one aspect, the Form H further comprises peaks at diffraction angles (2Θ) at 12.82 ± 0.2°, 15.84 ± 0.2°, 14.42 ± 0.2°, 20.12 ± 0.2°, 21.00 ± 0.2° and 24.12 ± 0.2°.

[0147] In one aspect, the Form H has an X-ray powder diffraction pattern with peaks at diffraction angles (2Θ) as shown in Table 15, wherein the error range for the 2Θ angles is ±0.20°:

[0148] Table 15

[0149] In one aspect, the Form H has an X-ray powder diffraction pattern substantially as shown in Figure 43.

[0150] The present application provides a metastable Form I of the compound of formula (IA), which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) at 6.43 ± 0.2°, 3.99 ± 0.2°, 4.25 ± 0.2° and 6.02 ± 0.2°.

[0151] In an embodiment, the Form I further comprises peaks at diffraction angles (2θ) of 15.33±0.2°, 13.03±0.2°, 17.34±0.2°, 15.84±0.2° and 24.00±0.2°.

[0152] In an embodiment, the Form I further comprises peaks at diffraction angles (2θ) of 24.33±0.2°, 24.49±0.2°, 22.81±0.2°, 18.20±0.2°, 20.19±0.2° and 14.84±0.2°.

[0153] In an embodiment, the Form I has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 16, wherein the error range of the 2θ angles is ±0.20°:

[0154] Table 16

[0155] In an embodiment, the Form I has an X-ray powder diffraction pattern substantially as shown in Figure 44.

[0156] The present application provides a metastable Form J of the compound of formula (IA), which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 3.94±0.2°, 5.92±0.2°, 15.37±0.2° and 15.88±0.2°;

[0157] In an embodiment, the Form J further comprises peaks at diffraction angles (2θ) of 18.02±0.2°, 7.91±0.2°, 23.79±0.2°, 24.08±0.2° and 17.73±0.2°.

[0158] In an embodiment, the Form J further comprises peaks at diffraction angles (2θ) of 23.20±0.2°, 17.32±0.2°, 6.41±0.2°, 21.66±0.2°, 18.36±0.2° and 25.44±0.2°.

[0159] In an embodiment, the Form J has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 17, wherein the error range of the 2θ angles is ±0.20°:

[0160] Table 17

[0161] In an embodiment, the Form J has an X-ray powder diffraction intensity as shown in Table 17.

[0162] In an embodiment, the Form J has an X-ray powder diffraction pattern substantially as shown in Figure 45.

[0163] The present application also provides a preparation method of the polymorph of the compound of formula (IA) as described above, which comprises the following steps:

[0164] The mixture of the compound of formula (I), maleic acid and solvent is obtained.

[0165] The solvent is one or more of alcohol, chloroalkane, ketone, ether, cyclic ether, ester, alkane, cycloalkane, benzene, amide and sulfoxide organic solvent. The alcohol solvent is preferably ethanol and / or isopropanol. The ester is preferably ethyl acetate.

[0166] In one aspect, the solvent is isopropanol.

[0167] In one aspect, the solvent is a mixture of ethanol and ethyl acetate, preferably a mixture of ethanol and ethyl acetate in a volume ratio of 1:2.

[0168] In one aspect, the volume-mole ratio of the solvent to the compound of formula (I) is 5-50 L / mol, for example, 10 L / mol or 30 L / mol.

[0169] In one aspect, in the preparation method of the polymorph of the compound of formula (IA), the step further comprises stirring and crystallizing the mixture. The stirring and crystallizing temperature is preferably 0-50℃.

[0170] In one aspect, in the preparation method of the polymorph of the compound of formula (IA), the step further comprises mixing the mixture with an anti-solvent after the mixture is clarified. The anti-solvent is one or more of n-hexane, isooctane, pentane, cyclohexane, cyclopentane and methylcyclohexane.

[0171] In one aspect, the polymorph of the compound of formula (IA) is obtained by converting the crystal form A of the compound of formula (IA) by different solvent conditions.

[0172] The present application also provides a pharmaceutical composition comprising at least one of the pharmaceutically acceptable salts of the compounds of formula (I) and formula (IA) and various polymorphs thereof and a pharmaceutically acceptable carrier.

[0173] The present application also provides a use of at least one of the pharmaceutically acceptable salts of the compounds of formula (I) and formula (IA) and various polymorphs thereof in the preparation of a medicament for preventing and / or treating diseases related to WEE1 and / or YES targets, including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and other diseases.

[0174] The application also provides a pharmaceutically acceptable salt of the aforementioned compound of formula (I) and formula (IA) and various polymorphs thereof, which is used as a drug for treating diseases related to WEE1 and / or YES target points, including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis), and other diseases.

[0175] The application also provides a method for treating diseases, which comprises administering to an individual in need thereof a therapeutically effective amount of at least one of the pharmaceutically acceptable salt of the compound of formula (I) and formula (IA) and the polymorphs thereof or the pharmaceutical composition.

[0176] Technical effects

[0177] The various salt types of the compound of formula (I) provided by the application, such as methanesulfonate, maleate, etc., have higher stability and better solubility than the base. Furthermore, the inventors have unexpectedly found that the salt of the compound of formula (I) and the polymorphs thereof, especially the maleate salt and the polymorphs thereof, are mainly distributed in tissues rather than in blood, have tens or even hundreds of times selectivity in main tissues such as gastrointestinal, liver, lung, pancreas, ovary and kidney compared with blood, effectively avoid or reduce the on-target hematological toxicity risk caused by WEE1 target points, and are expected to have better human PK characteristics, higher efficacy and lower hematological toxicity risk, and thus are more suitable for being used as a candidate drug for preventing or treating solid tumor diseases related to WEE1 and / or YES target points or signal pathways. BRIEF DESCRIPTION OF DRAWINGS

[0178] Figure 1 shows the X-ray powder diffraction pattern of the hydrochloride salt of the compound of formula (I) of the application. The abscissa represents the 2θ value (degree), and the ordinate represents the peak intensity.

[0179] Figure 2 shows the DSC graph of the hydrochloride salt of the compound of formula (I) of the application. The abscissa represents the temperature (℃), and the ordinate represents the heat flow (mW).

[0180] Figure 3 shows the TGA graph of the hydrochloride salt of the compound of formula (I) of the application. The abscissa represents the temperature (℃), and the ordinate represents the weight (%).

[0181] Figure 4 shows the X-ray powder diffraction pattern of the sulfate salt of the compound of formula (I) of the application. The abscissa represents the 2θ value (degree), and the ordinate represents the peak intensity.

[0182] Figure 5 shows the DSC graph of the sulfate salt of the compound of formula (I) of the application. The abscissa represents the temperature (℃), and the ordinate represents the heat flow (mW).

[0183] Figure 6 shows a TGA plot of the sulfate salt of the compound of formula (I) of the application. The abscissa indicates the temperature (°C) and the ordinate indicates the weight (%).

[0184] Figure 7 shows an X-ray powder diffractogram of the succinate salt of the compound of formula (I) of the application. The abscissa indicates the 2 theta value (degrees) and the ordinate indicates the peak intensity.

[0185] Figure 8 shows a DSC plot of the succinate salt of the compound of formula (I) of the application. The abscissa indicates the temperature (°C) and the ordinate indicates the heat flow (mW).

[0186] Figure 9 shows a TGA plot of the succinate salt of the compound of formula (I) of the application. The abscissa indicates the temperature (°C) and the ordinate indicates the weight (%).

[0187] Figure 10 shows an X-ray powder diffractogram of the fumarate salt of the compound of formula (I) of the application. The abscissa indicates the 2 theta value (degrees) and the ordinate indicates the peak intensity.

[0188] Figure 11 shows a DSC plot of the fumarate salt of the compound of formula (I) of the application. The abscissa indicates the temperature (°C) and the ordinate indicates the heat flow (mW).

[0189] Figure 12 shows a TGA plot of the fumarate salt of the compound of formula (I) of the application. The abscissa indicates the temperature (°C) and the ordinate indicates the weight (%).

[0190] Figure 13 shows an X-ray powder diffractogram of the p-toluenesulfonic acid salt of the compound of formula (I) of the application. The abscissa indicates the 2 theta value (degrees) and the ordinate indicates the peak intensity.

[0191] Figure 14 shows a DSC plot of the p-toluenesulfonic acid salt of the compound of formula (I) of the application. The abscissa indicates the temperature (°C) and the ordinate indicates the heat flow (mW).

[0192] Figure 15 shows a TGA plot of the p-toluenesulfonic acid salt of the compound of formula (I) of the application. The abscissa indicates the temperature (°C) and the ordinate indicates the weight (%).

[0193] Figure 16 shows an X-ray powder diffractogram of the crystalline Form A of the compound of formula (IA) of the application. The abscissa indicates the 2 theta value (degrees) and the ordinate indicates the peak intensity.

[0194] Figure 17 shows a DSC plot of the crystalline Form A of the compound of formula (IA) of the application. The abscissa indicates the temperature (°C) and the ordinate indicates the heat flow (mW).

[0195] Figure 18 shows a TGA plot of the crystalline Form A of the compound of formula (IA) of the application. The abscissa indicates the temperature (°C) and the ordinate indicates the weight (%).

[0196] Figure 19 shows the X-ray powder diffraction pattern of the mesylate salt of the compound of formula (I) of the present application. The abscissa indicates the 2 theta value in degrees, the ordinate indicates the peak intensity.

[0197] Figure 20 shows the DSC pattern of the mesylate salt of the compound of formula (I) of the present application. The abscissa indicates the temperature in °C, the ordinate indicates the heat flow in mW.

[0198] Figure 21 shows the TGA pattern of the mesylate salt of the compound of formula (I) of the present application. The abscissa indicates the temperature in °C, the ordinate indicates the weight in %.

[0199] Figure 22 shows the X-ray powder diffraction pattern of the besylate salt of the compound of formula (I) of the present application. The abscissa indicates the 2 theta value in degrees, the ordinate indicates the peak intensity.

[0200] Figure 23 shows the DSC pattern of the besylate salt of the compound of formula (I) of the present application. The abscissa indicates the temperature in °C, the ordinate indicates the heat flow in mW.

[0201] Figure 24 shows the TGA pattern of the besylate salt of the compound of formula (I) of the present application. The abscissa indicates the temperature in °C, the ordinate indicates the weight in %.

[0202] Figure 25 shows the X-ray powder diffraction pattern of crystalline Form B of the compound of formula (IA) of the present application. The abscissa indicates the 2 theta value in degrees, the ordinate indicates the peak intensity.

[0203] Figure 26 shows the DSC pattern of crystalline Form B of the compound of formula (IA) of the present application. The abscissa indicates the temperature in °C, the ordinate indicates the heat flow in mW.

[0204] Figure 27 shows the TGA pattern of crystalline Form B of the compound of formula (IA) of the present application. The abscissa indicates the temperature in °C, the ordinate indicates the weight in %.

[0205] Figure 28 shows the X-ray powder diffraction pattern of crystalline Form C of the compound of formula (IA) of the present application. The abscissa indicates the 2 theta value in degrees, the ordinate indicates the peak intensity.

[0206] Figure 29 shows the DSC pattern of crystalline Form C of the compound of formula (IA) of the present application. The abscissa indicates the temperature in °C, the ordinate indicates the heat flow in mW.

[0207] Figure 30 shows the TGA pattern of crystalline Form C of the compound of formula (IA) of the present application. The abscissa indicates the temperature in °C, the ordinate indicates the weight in %.

[0208] Figure 31 shows the X-ray powder diffraction pattern of crystalline Form D of the compound of formula (IA) of the present application. The abscissa indicates the 2 theta value in degrees, the ordinate indicates the peak intensity.

[0209] Figure 32 shows a DSC pattern of crystalline Form D of the compound of formula (IA) of the present application. The abscissa indicates temperature (°C) and the ordinate indicates heat flow (mW).

[0210] Figure 33 shows a TGA pattern of crystalline Form D of the compound of formula (IA) of the present application. The abscissa indicates temperature (°C) and the ordinate indicates weight (%).

[0211] Figure 34 shows an X-ray powder diffraction pattern of crystalline Form E of the compound of formula (IA) of the present application. The abscissa indicates 2 theta values (degrees) and the ordinate indicates peak intensity.

[0212] Figure 35 shows a DSC pattern of crystalline Form E of the compound of formula (IA) of the present application. The abscissa indicates temperature (°C) and the ordinate indicates heat flow (mW).

[0213] Figure 36 shows a TGA pattern of crystalline Form E of the compound of formula (IA) of the present application. The abscissa indicates temperature (°C) and the ordinate indicates weight (%).

[0214] Figure 37 shows an X-ray powder diffraction pattern of dimethyl sulfoxide solvate crystalline Form F of the compound of formula (IA) of the present application. The abscissa indicates 2 theta values (degrees) and the ordinate indicates peak intensity.

[0215] Figure 38 shows a DSC pattern of dimethyl sulfoxide solvate crystalline Form F of the compound of formula (IA) of the present application. The abscissa indicates temperature (°C) and the ordinate indicates heat flow (mW).

[0216] Figure 39 shows a TGA pattern of dimethyl sulfoxide solvate crystalline Form F of the compound of formula (IA) of the present application. The abscissa indicates temperature (°C) and the ordinate indicates weight (%).

[0217] Figure 40 shows an X-ray powder diffraction pattern of N-methyl pyrrolidone solvate crystalline Form G of the compound of formula (IA) of the present application. The abscissa indicates 2 theta values (degrees) and the ordinate indicates peak intensity.

[0218] Figure 41 shows a DSC pattern of N-methyl pyrrolidone solvate crystalline Form G of the compound of formula (IA) of the present application. The abscissa indicates temperature (°C) and the ordinate indicates heat flow (mW).

[0219] Figure 42 shows a TGA pattern of N-methyl pyrrolidone solvate crystalline Form G of the compound of formula (IA) of the present application. The abscissa indicates temperature (°C) and the ordinate indicates weight (%).

[0220] Figure 43 shows an X-ray powder diffraction pattern of metastable crystalline Form H of the compound of formula (IA) of the present application. The abscissa indicates 2 theta values (degrees) and the ordinate indicates peak intensity.

[0221] Figure 44 shows the X-ray powder diffraction pattern of the metastable crystalline Form I of the compound of formula (IA) of the present application. The abscissa indicates the 2 theta values in degrees, the ordinate indicates the peak intensities.

[0222] Figure 45 shows the X-ray powder diffraction pattern of the metastable crystalline Form J of the compound of formula (IA) of the present application. The abscissa indicates the 2 theta values in degrees, the ordinate indicates the peak intensities.

[0223] Figure 46 shows the DVS plot of the compound of formula (I) of the present application. The abscissa indicates the relative humidity in %, the ordinate indicates the weight change in %.

[0224] Figure 47 shows the DVS plot of the mesylate salt of the compound of formula (I) of the present application. The abscissa indicates the relative humidity in %, the ordinate indicates the weight change in %.

[0225] Figure 48 shows the DVS plot of the crystalline Form A of the compound of formula (IA) of the present application. The abscissa indicates the relative humidity in %, the ordinate indicates the weight change in %.

[0226] Figure 49 shows the DVS plot of the crystalline Form B of the compound of formula (IA) of the present application. The abscissa indicates the relative humidity in %, the ordinate indicates the weight change in %.

[0227] Figure 50 shows the DVS plot of the crystalline Form C of the compound of formula (IA) of the present application. The abscissa indicates the relative humidity in %, the ordinate indicates the weight change in %.

[0228] Figure 51 shows the DVS plot of the crystalline Form D of the compound of formula (IA) of the present application. The abscissa indicates the relative humidity in %, the ordinate indicates the weight change in %.

[0229] Figure 52 shows the DVS plot of the crystalline Form E of the compound of formula (IA) of the present application. The abscissa indicates the relative humidity in %, the ordinate indicates the weight change in %.

[0230] Terminology definitions and explanations

[0231] Unless otherwise indicated, the following terms have the following meanings when used in the specification and claims. A particular phrase or term should not be considered indefinite or unclear unless specifically defined otherwise. When a trade name appears herein, it is intended to designate the product by that name and its active ingredients.

[0232] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption of the active ingredient.

[0233] "Salt", as used herein, refers to a compound prepared by reaction of an organic acid or base with a pharmaceutically acceptable inorganic or organic acid or base.

[0234] "Polymorph", as used herein, refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms and / or ions making up the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement, and can exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and the like. Two polymorphs can be enantiotropic or monotropic with respect to their temperature-stability relationships. For monotropic systems, the relative stabilities of the two solid phases remain the same upon change in temperature. In contrast, in enantiotropic systems, there is a transition temperature at which the stabilities of the two phases are interchanged (Theory and Origin of Polymorphismin "Polymorphismin Pharmaceutical Solids" (1999) ISBN: 0-8247-0237). The phenomenon of a compound existing in different crystal structures is known as polymorphism in pharmaceuticals.

[0235] The various crystalline structures of the present application can be distinguished from one another using various analytical techniques known to those of ordinary skill in the art. Such techniques include, but are not limited to, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA).

[0236] The term "room temperature" or "RT" as used herein refers to ambient temperature of 20 to 25 °C (68-77 °F).

[0237] The term "substantially the same" as used herein with respect to X-ray diffraction peak positions means that typical peak position and intensity variability is taken into account. For example, one of skill in the art will appreciate that peak positions (2 theta) will vary somewhat from measurement to measurement due to differences in XRPD instruments, and sometimes such variations can be as much as 0.2° at times. In addition, one of skill in the art will appreciate that factors such as XRPD sample preparation methods, XRPD instruments, sample crystallinity, sample loading, and crystal preferred orientation will result in changes in relative peak intensities in the XRPD pattern of a sample.

[0238] In the present application, the term "about" means a variation within a range that can be predicted by one of skill in the art.

[0239] The intermediate compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments set forth below with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present application.

[0240] The chemical reactions of the specific embodiments of the present application are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In some instances, the solvent can be changed after a given reaction to facilitate the purification of the products. It is understood that the work-up procedures represented are examples only and do not represent the only procedures by which the products can be recovered.

[0241] The present application will now be described in detail by examples, which are not intended to limit the present application in any manner.

[0242] All solvents used in the present application are commercially available and used without further purification.

[0243] Unless otherwise indicated, all reactions of the present application are conducted under an inert atmosphere at room temperature, in dry solvents, and temperature units are in degrees Celsius (°C).

[0244] Methods and Materials

[0245] The structure of the compounds is determined by nuclear magnetic resonance (NMR). NMR shifts (δ) are given in parts per million (ppm). NMR measurements are performed on a Bruker avance-400MHz NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (MeOD-d4) as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are reported in 10 -6 ppm) as the unit.

[0246] HPLC measurements are performed using an Agilent high performance liquid chromatograph or a high performance liquid chromatograph of equivalent performance (Waters XBridge C18, 4.6 x 150 mm column or a column of equivalent performance).

[0247] The crystalline form of the acid salt of the compound of formula (I) is characterized by an X-ray powder diffraction pattern. The X-ray powder diffraction pattern of the salt is collected on a Bruker D8 Advance powder diffractometer operating in reflection mode using Cu Ka radiation. The instrument is operated using a SSD 160-2 detector at room temperature with Cu Ka illumination (40 kV, 40 mA). The scan range is from 3° to 40° in 2 theta with a scan speed of 0.1 s / step. The diffractograms are analyzed using DIFFRAC.MEA.CENTER software.

[0248] The preparation of the XRPD sample is by placing the sample onto a single crystal silicon wafer and using a glass slide or equivalent to press the sample powder to ensure the surface of the sample is flat and of an appropriate height. The sample holder is then placed into the Bruker D8 Advance instrument and an X-ray powder diffraction pattern is collected using the instrument parameters described above. The measurement discrepancies associated with such X-ray powder diffraction analysis results arise from a variety of factors including: (a) errors in sample preparation (e.g. sample height), (b) instrument errors, (c) calibration discrepancies, (d) operator errors (including those that arise when determining peak positions), and (e) properties of the material (e.g. preferred orientation errors). Calibration errors and sample height errors often result in shifts of all peaks in the same direction. In general, this calibration factor will bring the measured peak positions into agreement with the expected peak positions and can be in the range of ±0.2° of the expected 2 theta value.

[0249] In the present invention, the X-ray powder diffraction X-ray tube uses a copper target (Cu Ka).

[0250] The experimental method for characterizing the crystalline form of the acid salt of the compound of formula (I) by differential scanning calorimetry (DSC) is to take a small amount of the powder of the crystalline acid salt of the compound of formula (I), place it in an aluminum crucible which is matched with the instrument and can be covered with a lid, load the sample and cover it with an aluminum disc, and then send it into the instrument for detection. The instrument used in the present patent for differential scanning calorimetry is METTLER TOLEDO DSC 3, and the scanning parameter setting is to use a nitrogen atmosphere with a heating rate of 10.0 k / min.

[0251] The experimental method for characterizing the crystalline form of the acid salt of the compound of formula (I) by thermal gravimetric analysis (TGA) is to take a small amount of the powder of the crystalline acid salt of the compound of formula (I), place it in an aluminum crucible which is matched with the instrument, load the sample and send it into the instrument for detection. The instrument used in the present patent for differential scanning calorimetry is METTLER TOLEDO TGA 2, and the scanning parameter setting is to use a nitrogen atmosphere with a heating rate of 10.0 k / min.

[0252] The experimental method for characterizing the acid salt of the compound of formula (I) by dynamic water adsorption method (DVS) is as follows: a small amount of the acid salt of the compound of formula (I) powder is taken and placed in a precision sample pan matched with the instrument. After loading the sample, it is sent into the instrument for detection. In the present application, all the instruments used by the dynamic water adsorption method are Intrinsic PLUS. The experimental parameters are set as follows: the constant temperature is set to 25℃, the mass percentage change rate (dm / dt) per unit time is 0.002% / min as the judgment standard for reaching equilibrium, and the program humidity change cycle is set as follows: the initial relative humidity is 0%, and the relative humidity at the end point is 90%. DETAILED DESCRIPTION

[0253] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of the present application.

[0254] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0255] Example 1, Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecin-5-one (compound of formula (I)): 1) Synthesis of 2-allyl-1-(6-(2-hydroxyhex-5-en-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0256] A solution of 2-allyl-6-(methylthio)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (5.00 g, 22.5 mmol), 2-(6-bromopyridin-2-yl)hex-5-en-2-ol (5.75 g, 22.4 mmol), N,N'-dimethylethylenediamine (2.18 g, 24.7 mmol), cuprous iodide (4.25 g, 22.3 mmol) and potassium carbonate (4.34 g, 31.4 mmol) in dioxane (60 mL) was stirred at 90 °C overnight under argon. After cooling, the resulting reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with saturated brine (1 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50%) to give 2-allyl-l-(6-(2-hydroxyhex-5-en-2-yl)pyridin-2-yl)-6-(methylthio)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (5.25 g, yield: 58.7%).

[0257] 2) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azepino)pyrimido[4',5':3,4]pyrazolo[l,2-a][l,2]diazacyclotridecin-5-one

[0258] A solution of 2-allyl-l-(6-(2-hydroxyhex-5-en-2-yl)pyridin-2-yl)-6-(methylthio)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (5.25 g, 13.2 mmol) and Grubbs III (1.17 g, 1.32 mmol) in dichloromethane (1.6 L) was stirred at 40 °C overnight under argon. After cooling, the resulting reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20-65%) to give (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azepino)pyrimido[4',5':3,4]pyrazolo[l,2-a][l,2]diazacyclotridecin-5-one (510 mg, yield: 10.5%).

[0259] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azepino)pyrimido[4',5':3,4]pyrazolo[l,2-a][l,2]diazacyclotridecin-5-one

[0260] A solution of (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H- 13,17-(azenenyl)pyrimido[4',5':3,4]pyrazolo[l,2-a][l,2]diazacyclotridecin-5-one (510 mg, 1.38 mmol) and m-chloroperbenzoic acid (500 mg, 2.46 mmol) in toluene (50 mL) was stirred at room temperature for 3 hours. The resulting reaction solution was concentrated under reduced pressure to give a crude product, which was used directly for the next reaction without further purification.

[0261] 4) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((l-methylpiperidin-4- yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azenenyl)pyrimido[4',5':3,4] pyrazolo[l,2-a][l,2]diazacyclotridecin-5-one (Compound of Formula (I))

[0262] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro- 5H-13,17-(azenenyl)pyrimido[4',5':3,4]pyrazolo[l,2-a][l,2]diazacyclotridecin-5-one (500 mg, 1.24 mmol) and 3-methyl-4-((l-methylpiperidin-4-yl)oxy)aniline (328.3 mg, 1.49 mmol) in dioxane (50 mL) was heated at 100 °C and stirred for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-10%) to give a crude product, which was purified by preparative supercritical fluid chromatography (chromatographic conditions: instrument: SHIMADZU LC-20AP; column: 250*40 mm 10 μm; mobile phase A: n-hexane; mobile phase B: ethanol containing 0.1% ammonia / methanol (7M)) to give (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((l-methylpiperidin-4- yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azenenyl)pyrimido[4',5':3,4] pyrazolo[l,2-a][l,2]diazacyclotridecin-5-one (160 mg, yield: 19.0%). 250*40 mm 10 μm; mobile phase A: n-hexane; mobile phase B: ethanol containing 0.1% ammonia / methanol (7M). 1H NMR (400 MHz, MeOD-d4): δ 8.78 (s, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.34 (dd, J = 8.0, 4.0 Hz, 1H), 6.87 (d, J = 12.0 Hz, 1H), 5.53 - 5.41 (m, 2H), 4.57 (d, J = 8.0 Hz, 2H), 4.40 (s, 1H), 2.73 (s, 2H), 2.44 (s, 2H), 2.34 (s, 3H), 2.20 (s, 3H), 2.19 - 2.16 (m, 1H), 2.16-2.08 (m, 1H), 2.06 - 1.96 (m, 3H), 1.92 - 1.79 (m, 3H), 1.67 (s, 3H).

[0263] Example 2, Preparation of the hydrochloride salt of the compound of formula (I)

[0264] A quantity of 200.11 mg of the compound of formula (I) and 14.82 mg of concentrated hydrochloric acid were weighed into 7 mL of isopropyl acetate and sonicated to form a suspension. After stirring at room temperature for 1 day, an additional 3 mL of isopropyl acetate was added and stirring was continued for 2 days. The filter cake was dried in a 50 °C forced air oven. The hydrochloride salt of the compound of formula (I) was collected and analyzed, including characterization by XRPD (Figure 1), DSC (Figure 2), and TGA (Figure 3). 1 H NMR (400 MHz, DMSO-d6): δ 10.67 (s, 1H), 10.07 (s, 1H), 8.84 (s, 1H), 7.99 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.39 - 7.30 (m, 1H), 6.97 (d, J = 12.0 Hz, 1H), 5.37 - 5.32 (m, 2H), 4.68 - 4.40 (m, 3H), 3.08 - 3.07 (m, 2H), 2.78 (dd, J = 19.8, 4.6 Hz, 3H), 2.23 - 1.91 (m, 10H), 1.56 - 1.53 (m, 1H), 1.51 (s, 3H).

[0265] Example 3, Preparation of the sulfate salt of the compound of formula (I)

[0266] Take 199.84 mg of the compound of formula (I) and 39.84 mg of concentrated sulfuric acid, add 7 mL of acetone to form a suspension, stir at room temperature for 1 day, then add 7 mL of acetone and continue to stir for 2 days. Filter, and the filter cake is placed in a 50°C air oven for drying. The sulfate salt of the compound of formula (I) is obtained. The product is collected and analyzed, including characterization by XRPD (Figure 4), DSC (Figure 5) and TGA (Figure 6). 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.84 (s, 11H), 7.99 (t, J = 7.9 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.7 Hz, 9H), 6.94 (d, J = 8.9 Hz, 1H), 5.33-5.30 (m, 3H), 4.64-4.30 (m, 3H), 2.68 (s, 3H), 2.40 (s, 8H), 2.30 (s, 3H), 2.17 (s, 3H), 2.08-1.87 (m, 5H), 1.74-1.70 (s, 3H), 1.57 (s, 3H).

[0267] Example 4, Preparation of succinate salt of the compound of formula (I)

[0268] Take 199.84 mg of the compound of formula (I) and 39.84 mg of concentrated sulfuric acid, add 7 mL of acetone to form a suspension, stir at room temperature for 1 day, then add 7 mL of acetone and continue to stir for 2 days. Filter, and the filter cake is placed in a 50°C air oven for drying. The sulfate salt of the compound of formula (I) is obtained. The product is collected and analyzed, including characterization by XRPD (Figure 4), DSC (Figure 5) and TGA (Figure 6). 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.84 (s, 11H), 7.99 (t, J = 7.9 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.7 Hz, 9H), 6.94 (d, J = 8.9 Hz, 1H), 5.33-5.30 (m, 3H), 4.64-4.30 (m, 3H), 2.68 (s, 3H), 2.40 (s, 8H), 2.30 (s, 3H), 2.17 (s, 3H), 2.08-1.87 (m, 5H), 1.74-1.70 (s, 3H), 1.57 (s, 3H).

[0269] Example 5, Preparation of fumarate salt of the compound of formula (I)

[0270] Take 200.03 mg of the compound of formula (I) and 42.89 mg of fumaric acid, add 10 mL of isopropyl alcohol to form a suspension under ultrasonic, stir at room temperature for 2 hours, add 5 mL of isopropyl alcohol and continue to stir for 2 days, filter, and the filter cake is placed in a 50°C air oven for drying to obtain the fumarate salt of the compound of formula (I). The product is collected and analyzed, including characterization by XRPD (Figure 10), DSC (Figure 11) and TGA (Figure 12). 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.84 (s, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.9 Hz, 1H), 6.58 (s, 3H), 5.33 (s, 3H), 4.43 (d, J = 27.4 Hz, 3H), 2.77 (s, 3H), 2.37 (s, 3H), 2.17 (s, 3H), 1.98 - 1.95 (m, 5H), 1.75 - 1.73 (m, 3H), 1.57 (s, 3H).

[0271] Example 6, Preparation of p-toluenesulfonic acid salt of the compound of formula (I)

[0272] Take 200.03 mg of the compound of formula (I) and 42.89 mg of fumaric acid, add 10 mL of isopropyl alcohol to form a suspension under ultrasonic, stir at room temperature for 2 hours, add 5 mL of isopropyl alcohol and continue to stir for 2 days, filter, and the filter cake is placed in a 50°C air oven for drying to obtain the fumarate salt of the compound of formula (I). The product is collected and analyzed, including characterization by XRPD (Figure 10), DSC (Figure 11) and TGA (Figure 12). 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H), 7.99 (t, J = 7.8 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 6.8 Hz, 2H), 7.41 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 7.7 Hz, 2H), 6.97 (dd, J = 17.8, 9.0 Hz, 1H), 5.35 - 5.33 (m, 3H), 4.73 - 4.32 (m, 3H), 3.50 (d, J = 11.8 Hz, 2H), 3.12 - 3.10 (m, 2H), 2.84 (dd, J = 19.8, 4.2 Hz, 3H), 2.36 - 1.82 (m, 14H), 1.74 - 1.70 (m, 2H), 1.57 (s, 3H).

[0273] Example 7, Preparation of crystalline Form A of the compound of formula (IA)

[0274] A sample of 199.95 mg of the compound of formula (I) and 47.20 mg of maleic acid was weighed into 7 mL of isopropanol and sonicated to form a suspension. The suspension was stirred at room temperature for 1 day, an additional 2 mL of isopropanol was added and stirring was continued for 2 days. The suspension was filtered and the filter cake was dried in a 50 °C forced air oven. The maleate salt of the compound of formula (I) was collected and analyzed for data, including characterization by XRPD (Figure 16), DSC (Figure 17) and TGA (Figure 18). 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.1 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.02 (s, 2H), 5.41 - 5.26 (m, 3H), 4.48 - 4.46 (m, 3H), 3.15 - 3.10 (m, 2H), 2.82 (s, 3H), 2.26 - 1.89 (m, 10H), 1.74 - 1.71 (m, 1H), 1.56 (s, 3H).

[0275] Example 8, Preparation of the mesylate salt of the compound of formula (I)

[0276] Take 199.85 mg of the compound of formula (I) and 39.03 mg of methanesulfonic acid, add 7 mL of isopropyl alcohol to form a suspension, stir at room temperature for 1 day, supplement with 2 mL of isopropyl alcohol and continue to stir for 2 days, suction filter, and place the filter cake in a 50°C air oven for drying to obtain the methanesulfonic acid salt of the compound of formula (I). Collect the product for analysis data, including characterization by XRPD (Figure 19), DSC (Figure 20), and TGA (Figure 21). 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.32 (s, 1H), 8.85 (s, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.82 - 7.74 (m, 1H), 7.67 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 18.1, 9.0 Hz, 1H), 5.36 - 5.32 (m, 2H), 4.75 - 4.32 (m, 3H), 3.50 (d, J = 13.7 Hz, 2H), 3.21 - 3.02 (m, 2H), 2.83 (dd, J = 19.4, 4.8 Hz, 3H), 2.32 (s, 3H), 2.25 - 1.90 (m, 10H), 1.74 - 1.72 (m, 2H), 1.56 (s, 3H).

[0277] Example 9, Preparation of the benzenesulfonic acid salt of the compound of formula (I)

[0278] Take 199.85 mg of the compound of formula (I) and 39.03 mg of methanesulfonic acid, add 7 mL of isopropyl alcohol to form a suspension, stir at room temperature for 1 day, supplement with 2 mL of isopropyl alcohol and continue to stir for 2 days, suction filter, and place the filter cake in a 50°C air oven for drying to obtain the methanesulfonic acid salt of the compound of formula (I). Collect the product for analysis data, including characterization by XRPD (Figure 19), DSC (Figure 20), and TGA (Figure 21). 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.65 - 7.57 (m, 3H), 7.40 (d, J = 8.8 Hz, 1H), 7.37 - 7.26 (m, 3H), 6.97 (dd, J = 17.9, 8.9 Hz, 1H), 5.52 - 5.20 (m, 3H), 4.79 - 4.27 (m, 3H), 3.50 (d, J = 12.1 Hz, 1H), 3.23 - 2.99 (m, 2H), 2.83 (dd, J = 19.8, 4.6 Hz, 3H), 2.33 - 1.89 (m, 10H), 1.78-1.72 (m, 2H), 1.56 (s, 3H).

[0279] Preparation of polymorphs of the compound of formula (IA)

[0280] Preparation of crystalline Form B of the compound of formula (IA)

[0281] About 200 mg of crystalline Form A of the compound of formula (IA) was weighed into 10 mL of 2-butanone / isopropyl acetate (1 : 1), stirred at 50 °C for 2 hours, then cooled to 5 °C and stirred for 2 hours, filtered under suction, and the filter cake was placed in a 50 °C air-draft drying oven to obtain crystalline Form B of the compound of formula (IA), which was characterized by XRPD (Figure 25), DSC (Figure 26) and TGA (Figure 27) analysis. 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.65 - 7.57 (m, 3H), 7.40 (d, J = 8.8 Hz, 1H), 7.37 - 7.26 (m, 3H), 6.97 (dd, J = 17.9, 8.9 Hz, 1H), 5.52 - 5.20 (m, 3H), 4.79 - 4.27 (m, 3H), 3.50 (d, J = 12.1 Hz, 1H), 3.23 - 2.99 (m, 2H), 2.83 (dd, J = 19.8, 4.6 Hz, 3H), 2.33 - 1.89 (m, 10H), 1.78-1.72 (m, 2H), 1.56 (s, 3H).

[0282] Preparation of crystalline Form C of the compound of formula (IA)

[0283] About 200 mg of Form A of the compound of formula (IA) was weighed into 10 mL of methanol / isopropyl acetate (1 :9) and stirred at 25 °C for 4 days. The filter cake was dried at 50 °C under a blast of air. Form C of the compound of formula (IA) was characterized by XRPD (Figure 28), DSC (Figure 29), and TGA (Figure 30). 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.31 (s, 1H), 8.85 (s, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.02 (s, 2H), 5.48 - 5.20 (m, 3H), 4.47 (d, J = 6.2 Hz, 3H), 3.35 - 3.32 (m, 2H), 2.81 (s, 3H), 2.27 - 1.91 (m, 10H), 1.78 - 1.67 (m, 1H), 1.56 (s, 3H).

[0284] Example 10-3, Preparation of Form D of the compound of formula (IA)

[0285] About 200 mg of Form A of the compound of formula (IA) was weighed into 6 mL of acetonitrile / 2-methyltetrahydrofuran (1 : 1) and stirred at 50 °C for 3 days. The filter cake was dried at 60 °C under a blast of air. Form D of the compound of formula (IA) was characterized by XRPD (Figure 31), DSC (Figure 32), and TGA (Figure 33). 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.31 (s, 1H), 8.85 (s, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.02 (s, 2H), 5.48 - 5.20 (m, 3H), 4.47 (d, J = 6.2 Hz, 3H), 3.35 - 3.32 (m, 2H), 2.81 (s, 3H), 2.27 - 1.91 (m, 10H), 1.78 - 1.67 (m, 1H), 1.56 (s, 3H).

[0286] Example 10-4, Preparation of Form E of the compound of formula (IA)

[0287] Take 200 mg of the compound of formula (I), add 1 mL of ethanol, stir at 50°C for 0.5 hours, add 44 mg of maleic acid, after adding, stir at 50°C for 2 hours, add 2 mL of ethyl acetate, and then stir at room temperature for 2 hours, and then stir at 0-10°C for 1 hour, filter, wash the filter cake with ethyl acetate, and dry the filter cake at 50°C under a blast of air to obtain the crystal form E of the compound of formula (IA), and characterize the product by XRPD (Figure 34), DSC (Figure 35) and TGA (Figure 36). 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.52 (s, 1H), 8.89 (s, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.10 (s, 2H), 5.54 - 5.27 (m, 3H), 4.75 - 4.36 (m, 3H), 2.88 (s, 3H), 2.37 - 1.93 (m, 10H), 1.84 - 1.73 (m, 1H), 1.61 (s, 3H).

[0288] Example 10-5, Preparation of the dimethyl sulfoxide solvate crystal form F of the compound of formula (IA)

[0289] Take 200 mg of the crystal form A of the compound of formula (IA), add 5.5 mL of toluene / dimethyl sulfoxide (10:1), stir at 5°C for 16 hours, filter, and dry the filter cake at 50°C under a blast of air to obtain the dimethyl sulfoxide solvate crystal form F of the compound of formula (IA), and characterize the product by XRPD (Figure 37), DSC (Figure 38) and TGA (Figure 39). 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.31 (s, 1H), 8.85 (s, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.03 (s, 2H), 5.57 - 5.13 (m, 3H), 4.47 (d, J = 5.5 Hz, 3H), 3.35-3.33 (m, 2H), 2.83 (s, 3H), 2.54 (s, 6H), 2.28 - 1.88 (m, 10H), 1.78 - 1.67 (m, 1H), 1.56 (s, 3H).

[0290] Example 10-6, Preparation of N-methylpyrrolidone solvate Form G of the compound of Formula (IA)

[0291] A 200 mg sample of Form A of the compound of Formula (IA) was weighed into 5.5 mL of methyl-tert-butyl ether / N-methylpyrrolidone (10:1) and stirred at 5 °C for 16 hours. The filter cake was dried at 50 °C under a blast of air. The N-methylpyrrolidone solvate Form G of the compound of Formula (IA) was characterized by XRPD (Figure 40), DSC (Figure 41), and TGA (Figure 42). 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.32 (s, 1H), 8.85 (s, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 6.03 (s, 2H), 5.37 - 5.21 (m, 3H), 4.47 (d, J = 6.0 Hz, 3H), 3.37 - 3.26 (m, 3H), 2.82 (s, 3H), 2.70 (s, 1H), 2.24 - 1.85 (m, 12H), 1.78 - 1.65 (m, 1H), 1.56 (s, 3H).

[0292] Example 10-7, Preparation of metastable Form H of the compound of Formula (IA)

[0293] A 20 mg sample of Form A of the compound of Formula (IA) was weighed into 1 mL of acetonitrile / 2-methyltetrahydrofuran (1:1) and stirred at 50 °C for 3 days. Metastable Form H of the compound of Formula (IA) was characterized by XRPD (Figure 43). Drying at 50 °C under a blast of air for 16 hours resulted in crystallization to Form D.

[0294] Example 10-8, Preparation of metastable Form I of the compound of Formula (IA)

[0295] A 20 mg sample of Form A of the compound of Formula (IA) was weighed into 1.5 mL of ethanol / isopropyl acetate (2:1) and sonicated to dissolve. The filtrate was stirred at 5 °C for 16 hours. Metastable Form I of the compound of Formula (IA) was characterized by XRPD (Figure 44). Drying at 50 °C under a blast of air for 3 hours resulted in crystallization to Form A.

[0296] Example 10-9, Preparation of metastable Form J of the compound of Formula (IA)

[0297] A sample of 20 mg of crystalline Form A of compound of formula (IA) was stirred in 1.1 mL of diethyl ether / DMF (10:1) at 5°C for 3 days. The metastable Form J of compound of formula (IA) was obtained by centrifugation and characterized by XRPD (Figure 45). The Form J was converted to Form A by drying at 50°C under a blast of air for 16 hours.

[0298] Test Example 1, Equilibrium solubility study of free form and representative salt forms of compound of formula (I) and their polymorphs in biological media

[0299] The equilibrium solubility of free form and representative salt forms of compound of formula (I) and their polymorphs were tested in water (H2O), simulated fasted state simulated gastric fluid (FaSSGF), simulated fasted state simulated intestinal fluid (FaSSIF). In the test, the solid was prepared into suspension (~10 mg / mL) in the corresponding buffer and mixed at 37 ± 2°C. The suspension was sampled after 24 hours and the supernatant was filtered to determine the concentration. The results are shown in the following table:

[0300] From the above experimental results, it can be seen that the solubility of the representative salt forms of compound of formula (I), such as maleate and mesylate, in water (H2O) is significantly improved compared to the free form. The solubility of Form A, B, C, D, E of compound of formula (IA) in simulated fasted state simulated gastric fluid (FaSSGF) and simulated fasted state simulated intestinal fluid (FaSSIF) is significantly better than that of the free form.

[0301] Test Example 2, Solid state stability study of free form and representative salt forms of compound of formula (I) and their polymorphs

[0302] The free form and representative salt forms of compound of formula (I) and their polymorphs were placed under long term (25°C / 60% RH), accelerated (40°C / 75% RH) and high temperature (60°C, RH <30%) conditions for 7 days, respectively, and the HPLC purity and crystal form change were tested to investigate the solid stability. The results are shown in the following table:

[0303] From the purity results of the above experiments, it can be seen that the purity of the free form of compound of formula (I) decreased significantly after being placed under high temperature conditions for 7 days, and there was no significant change in purity after being placed under long term and accelerated conditions for 7 days. The HPLC purity of the mesylate salt of compound of formula (I) did not change significantly under long term, accelerated and high temperature conditions for 7 days, but the crystal form changed under high temperature conditions. The HPLC purity and crystal form of Form A, B, C, D, E of compound of formula (IA) did not change significantly after being placed under long term, accelerated and high temperature conditions for 7 days, and its stability was better than that of the free form.

[0304] Test Example 3, Hygroscopicity test of free form and representative salt forms of compound of formula (I) and their polymorphs

[0305] The inventors of the present patent evaluated the risk of stability of the samples as a function of humidity at 25°C according to the dynamic water sorption method, and performed DVS tests on the free form and representative salt forms of the compound of formula (I) and its polymorphs to evaluate the hygroscopicity of the compound forms, and the results obtained are shown in the following table:

[0306] As can be seen from the above experimental results, in the sorption curve from 0 to 90% RH, the hygroscopicity of the salt form of the compound of formula (I) is reduced compared to the free form under the condition of 80% RH, and the crystal forms A, B, C and E of the compound of formula (IA) are more stable and only slightly hygroscopic, and no crystal form change is observed.

[0307] Test Example 4, Competitive Experiment Study of Polymorphs of the Compound of Formula (IA)

[0308] Suspension competitive tests were performed on the crystal forms A, B, C, D and E of the compound of formula (IA) in isopropanol and ethyl acetate (room temperature and 50°C) respectively to test the crystal form change, and the results are shown in the following table:

[0309] As can be seen from the above experimental results, the crystal forms A, B, C, D and E of the compound of formula (IA) are all converted to crystal form E in isopropanol or ethyl acetate (room temperature and 50°C) system, indicating that crystal form E has higher thermodynamic stability than other crystal forms in the range from room temperature to 50°C.

[0310] Test Example 5, Tissue Distribution Test of the Compound of Formula (IA)

[0311] In addition to high expression on tumors, the WEE1 target site also has high expression on bone marrow and the hematological system, especially on hematopoietic progenitor cells. Therefore, an ideal WEE1 inhibitor for the treatment of solid tumors should mainly distribute in tissues rather than mainly distribute in plasma, so as to reduce or avoid the risk of hematological toxicity. In order to evaluate the risk of hematological toxicity development of the compound of formula (IA), we tested the tissue distribution of the compound of formula (IA) on SD rats.

[0312] 1) Test operation and procedure

[0313] After single oral gavage administration of 20 mg / kg of crystal form E of the compound of formula (IA) (solvent: 5% HP-β-CD aqueous solution) to fasted SD rats (half male and half female), whole blood samples were collected first, and then tissue samples (including brain, heart, lung, liver, stomach, pancreas, spleen, kidney, skeletal muscle, abdominal fat, testis, ovary, uterus, bladder, small intestine and large intestine tissues) were collected at 1, 4, 12 and 24 hours after administration (a total of 4 time points).

[0314] 2) Sample collection and processing procedure

[0315] Whole blood sample: about 1 mL blood was collected by cardiac puncture, and K2EDTA was used as anticoagulant. After blood collection, deionized water was added into the blood sample at a ratio of 1:1, and the sample tube was gently inverted several times to ensure mixing. The sample was placed on wet ice after collection.

[0316] Tissue sample: after collection, the tissue sample was washed with normal saline and dried with filter paper. The tissue sample was weighed and homogenized after adding 10 times volume (10 mL / g tissue) of 50% methanol solution.

[0317] 3) Sample detection and data analysis method

[0318] After the above whole blood and tissue samples were precipitated with methanol containing an internal standard, they were vortexed and centrifuged, and the supernatant was analyzed by LC-MS / MS. The lower limit of quantification of the analysis method was 1 ng / mL. The pharmacokinetic parameters were calculated by non-compartment model using Phoenix 7.0 software. 7.0 software.

[0319] 4) Results and discussion:

[0320] Overall, as shown in Table 5-1, the exposure of the compound of formula (IA) in tissues was much higher than that in plasma. The exposure in all tissues was higher than that in whole blood, except for the brain. The highest drug distribution tissues included small intestine, liver, spleen, stomach, kidney, ovary, lung and pancreas, and the drug exposure in these tissues was about 30-400 times that in whole blood. It is more suitable for the treatment of gastrointestinal cancer, liver cancer, lung cancer, kidney cancer, ovarian cancer and pancreatic cancer.

[0321] The peak time (T max ) in the stomach and abdominal adipose tissue was 1.0 hour after administration, the T max in the testis was 12 hours after administration, and the T max in other tissues was 4 hours after administration. Among them, the ratio of drug exposure in small intestine to whole blood was 418.48, the ratio of drug exposure in liver to whole blood was 145.55, the ratio of drug exposure in spleen to whole blood was 114.03, the ratio of drug exposure in stomach to whole blood was 92.12, the ratio of drug exposure in kidney to whole blood was 75.43, the ratio of drug exposure in ovary to whole blood was 64.13, the ratio of drug exposure in lung to whole blood was 47.50, and the ratio of drug exposure in pancreas to whole blood was 37.85. The results are shown in Table 5-1.

[0322] Table 5-1, main pharmacokinetic parameters of the compound of formula (IA) in whole blood and tissues

[0323] The above has exemplarily described the embodiments of the technical scheme of the present application. It should be understood that the protection scope of the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present application shall be included in the protection scope of the claims of the present application.

Claims

1. A pharmaceutically acceptable salt of a compound of formula (I) and its solvates or polymorphs; The pharmaceutically acceptable salt refers to an acid addition salt which is pharmaceutically non-toxic; The acid addition salt is a salt of the compound of formula (I) with an inorganic or organic acid, including one or more of hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, phosphate, borate, acetate, oxalate, valerate, benzoate, lactate, toluylate, citrate, malate, maleate, fumarate, succinate, tartrate, mesylate, besylate and tosylate, preferably one or more of hydrochloride, sulfate, succinate, fumarate, maleate, tosylate, mesylate and besylate, more preferably one or more of tosylate, mesylate and maleate; The acid addition salt has a ratio of the compound of formula (I) to the acid of preferably 3:1 to 1:

3.

2. A crystalline Form E of a compound of Formula (IA), having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 4.58 ± 0.2°, 14.78 ± 0.2°, 39.60 ± 0.2°, and 24.45 ± 0.2°:

3. The crystalline Form E of the compound of formula (IA) according to claim 2, characterized in that, The X-ray powder diffraction pattern of the crystalline form E of the compound of formula (IA) further includes peaks at diffraction angles (2θ) of 21.45±0.2°, 18.90±0.2°, 23.53±0.2°, 20.49±0.2°, 22.75±0.2° and 19.97±0.2°, preferably has diffraction angles (2θ) as shown in Table 12, wherein the error range of the 2θ angle is ±0.20°: Table 12 4. The crystalline Form E of the compound of formula (IA) according to claim 3, characterized in that, The crystalline form E of the compound of formula (IA) has an X-ray powder diffraction pattern substantially as shown in Figure 34; and / or, the DSC analysis of the crystalline form E of the compound of formula (IA) has an endothermic peak near the peak temperature of 207.03°C, preferably has a DSC pattern substantially as shown in Figure 35; and / or, the crystalline form E of the compound of formula (IA) has a TGA pattern substantially as shown in Figure 36.

5. A crystalline form A of the compound of formula (IA), which X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 6.49±0.2°, 15.25±0.2°, 15.86±0.2° and 4.32±0.2°, preferably further includes peaks at diffraction angles (2θ) of 20.14±0.2°, 17.20±0.2°, 14.91±0.2°, 23.26±0.2°, 21.39±0.2°, and 23.01±0.2°.

6. The crystalline Form A of the compound of formula (IA) according to claim 5, characterized in that, The X-ray powder diffraction pattern of the crystalline form A of the compound of formula (IA) has data as shown in Table 6: Table 6 , preferably has an X-ray powder diffraction pattern substantially as shown in Figure 16; and / or, has a DSC thermogram with endothermic peaks at temperatures of about 83.71°C and 180.67°C, preferably has a DSC pattern substantially as shown in Figure 17; and / or, has a TGA pattern substantially as shown in Figure 18.

7. A method for preparing the crystalline form E of the compound of formula (IA) as claimed in any one of claims 2-4 or the crystalline form A of the compound of formula (IA) as claimed in claim 5 or 6, which comprises the step of mixing the compound of formula (I), maleic acid and a solvent.

8. The production method according to claim 7, wherein The solvent is one or more of alcohol, chloroalkane, ketone, ether, cyclic ether, ester, alkane, cycloalkane, benzene, amide and sulfoxide organic solvent; And / or, the volume molar ratio of the solvent to the compound of formula (I) is 5-50 L / mol; And / or, the step further comprises the operation of stirring the mixture to crystallize.

9. A pharmaceutical composition comprising at least one of the compound of formula (I) or the pharmaceutically acceptable salt of the compound of formula (IA) as claimed in any one of claims 1-6 and various polymorphs thereof and a pharmaceutically acceptable carrier.

10. Use of at least one of the compound of formula (I) or the pharmaceutically acceptable salt of the compound of formula (IA) as claimed in any one of claims 1-6 and various polymorphs thereof in the preparation of a medicament for preventing and / or treating diseases related to WEE1 and / or YES target points, including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis), and other diseases.

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