A pharmaceutically acceptable salt of a fused ring compound, a crystalline form thereof, and uses thereof

Abstract

The present disclosure relates to a pharmaceutically acceptable salt of a fused ring compound, a crystalline form thereof and uses. Specifically, the present disclosure provides a pharmaceutically acceptable salt of 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline, a crystalline form thereof and a preparation method thereof, and the corresponding salt has good stability and can be better used for clinical treatment.

Description

Technical Field

[0001] This disclosure pertains to the field of pharmaceutical technology and relates to a pharmaceutically acceptable salt of a fused-ring compound, its crystalline form, and its uses. Background Technology

[0002] RAS (Rapid Acid Spectroscopy) genes are among the most frequently mutated oncogenes in tumors, with approximately 30% of human malignancies associated with RAS gene mutations. The RAS family includes KRAS, NRAS, and HRAS, with KRAS mutations being the most common, accounting for about 85%. KRAS mutations are frequently found in solid tumors, exhibiting high frequency in the three leading causes of cancer death in humans—lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). In KRAS gene mutations, 97% involve mutations at amino acid residues 12 or 13, with G12D being a significant mutation. Data analysis of populations in Europe and America shows that G12D mutations account for 36%, 12%, and 4% of patients with pancreatic cancer, colorectal cancer, and non-small cell lung cancer, respectively.

[0003] Once activated, KRAS regulates various functions of cell proliferation, survival, migration, and metabolism through numerous downstream signaling pathways, including RAF-MEK-ERK, PI3K-AKT-mTOR, and TIAM1-RAc. Mutations in the KRAS gene result in a persistently activated protein, leading to continued activation of downstream signaling pathways and promoting tumorigenesis.

[0004] PCT / CN2023 / 109598 provides a KRAS G12D inhibitor with the chemical name 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridged naphtho[1,8-ab]heptan-2-yl)-4-(trifluoromethyl)aniline, having the structure shown in Formula 1.

[0005]

[0006] Salt formation can improve certain undesirable physicochemical or biological properties of drugs. Developing salts with superior physicochemical or pharmaceutical properties compared to 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptan-2-yl)-4-(trifluoromethyl)aniline is of great significance. Given the importance of solid drug crystal forms and their stability in clinical treatment, in-depth research on the polymorphs of pharmaceutically acceptable salts of compound 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptan-2-yl)-4-(trifluoromethyl)aniline is of great significance for developing drugs suitable for industrial production and with good biological activity. Summary of the Invention

[0007] This disclosure provides a pharmaceutically acceptable salt of the compound shown in Formula 1, wherein the pharmaceutically acceptable salt is selected from succinate, malate, fumarate, tartrate, acetate, adipic acidate, benzoate, hydrochloride, sulfate, phosphate, methanesulfonate, citrate, p-toluenesulfonate, maleate, p-hydroxybenzoate, laurate, sorbate, and malonate.

[0008]

[0009] This disclosure also provides a method for preparing a pharmaceutically acceptable salt of a compound of formula 1, comprising the step of reacting the compound of formula 1 with an acid selected from succinic acid, malic acid, fumaric acid, tartaric acid, acetic acid, adipic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, citric acid, p-toluenesulfonic acid, maleic acid, p-hydroxybenzoic acid, lauric acid, sorbic acid, and malonic acid.

[0010] The solvents used in the salt formation of this disclosure are selected from, but are not limited to, acetone, ethyl acetate, and methyl tert-butyl ether.

[0011] Furthermore, in an optional embodiment, the method for preparing the aforementioned pharmaceutically usable salt also includes steps such as crystallization, filtration, washing, or drying.

[0012] In an optional embodiment, the chemical ratio of compound 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptan-2-yl)-4-(trifluoromethyl)aniline to the acid is 3:1 to 1:3, including but not limited to 3:1, 2:1, 1:1, 1:2, and 1:3.

[0013] In another embodiment, the chemical ratio of compound 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptan-2-yl)-4-(trifluoromethyl)aniline to the acid is 2:1 to 1:2.

[0014] In an optional embodiment, the chemical ratio of the compound of Formula 1 to benzoic acid is 1:1.

[0015] In an optional embodiment, the chemical ratio of the compound of Formula 1 to fumaric acid is 1:1.

[0016] In an optional embodiment, the chemical ratio of the compound of Formula 1 to tartaric acid is 1:1 to 1:2.

[0017] In an optional embodiment, the chemical ratio of the compound of Formula 1 to citric acid is 1:1 to 1:2.

[0018] In an optional embodiment, the chemical ratio of the compound of Formula 1 to malic acid is 1:2.

[0019] In an optional embodiment, the chemical ratio of the compound of Formula 1 to succinic acid is 1:1 to 1:2.

[0020] In an optional embodiment, the chemical ratio of the compound of Formula 1 to acetic acid is 1:1 to 1:2.

[0021] In an optional embodiment, the chemical ratio of the compound of Formula 1 to adipic acid is 1:1.

[0022] In an optional embodiment, the chemical ratio of the compound of Formula 1 to hydrochloric acid is 1:1.

[0023] In an optional embodiment, the chemical ratio of the compound of Formula 1 to sulfuric acid is 1:1.

[0024] In an optional embodiment, the chemical ratio of the compound of Formula 1 to phosphoric acid is 1:1.

[0025] In an optional embodiment, the chemical ratio of the compound of Formula 1 to methanesulfonic acid is 1:1.

[0026] In an optional embodiment, the chemical ratio of the compound of Formula 1 to maleic acid is 1:1.

[0027] In an optional embodiment, the chemical ratio of the compound of Formula 1 to p-hydroxybenzoic acid is 1:1.

[0028] In an optional embodiment, the chemical ratio of the compound of Formula 1 to lauric acid is 1:1.

[0029] In an optional embodiment, the chemical ratio of the compound of Formula 1 to sorbic acid is 1:1.

[0030] In an optional embodiment, the chemical ratio of the compound of Formula 1 to malonic acid is 1:1.

[0031] The solvents used in the salt formation of this disclosure are selected from, but are not limited to, acetone, ethyl acetate, and methyl tert-butyl ether.

[0032] This disclosure provides an amorphous form of compound of formula 1, and its X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, as shown below. Figure 1 As shown.

[0033] This disclosure also provides a method for preparing an amorphous form of the compound of formula 1, wherein the method is selected from any of the following methods:

[0034] Method 1: Dissolve the compound of formula 1 in 10% water / methanol and stir;

[0035] Method 2: Dissolve the compound of Formula 1 in solvent I and evaporate the solvent; wherein solvent I is selected from one or more of alcohol solvents, ketone solvents, ester solvents, ether solvents, hydrocarbon solvents, nitrile solvents, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and water;

[0036] The alcohol solvent is selected from methanol, ethanol, n-propanol, and isopropanol;

[0037] The ketone solvent is selected from acetone, 2-butanone, and methyl isobutyl ketone;

[0038] The ester solvent is selected from ethyl acetate and isopropyl acetate;

[0039] The ether solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and isopropyl ether;

[0040] The hydrocarbon solvent is selected from n-heptane and dichloromethane;

[0041] The nitrile solvent is selected from acetonitrile;

[0042] Method 3: Dissolve the compound of Formula 1 in solvent II, add solvent III, and stir. Solvent II is selected from one of methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, isopropyl acetate, 2-butanone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl isobutyl ketone, methyl tert-butyl ether, and dimethyl sulfoxide. Solvent III is selected from one of water and n-heptane.

[0043] The benzoate crystal form α of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.751, 10.627, 11.285, 21.576, 23.385, and 28.637 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0044] In some embodiments, the benzoate crystal form α of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 5.751, 10.627, 10.928, 11.285, 14.703, 18.424, 20.342, 21.576, 23.385, and 28.637.

[0045] In some embodiments, the X-ray powder diffraction pattern of the benzoate crystal form α of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.751, 10.627, 10.928, 11.285, 11.748, 14.703, 16.861, 18.424, 20.342, 21.576, 22.453, 23.385, 26.951, 28.637, and 30.786.

[0046] In some embodiments, the X-ray powder diffraction pattern of the benzoate crystal form α of the compound shown in Formula 1, expressed as a diffraction angle 2θ, is as follows: Figure 2 As shown.

[0047] This disclosure also provides a method for preparing the benzoate crystal form α of the compound of Formula 1, comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding benzoic acid or benzoic acid ethanol solution, heating and stirring, and then cooling and stirring.

[0048] In some embodiments, the method for preparing the benzoate crystal form α of the compound of Formula 1 includes dissolving the compound of Formula 1 in acetone or methyl tert-butyl ether, adding an ethanol solution of benzoic acid, and stirring.

[0049] In some embodiments, the fumarate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0050] This disclosure also provides a method for preparing the amorphous fumarate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding a fumaric acid ethanol solution, and stirring.

[0051] The fumarate crystal form α of the compound of Formula 1 provided in this disclosure has characteristic peaks at 7.880, 10.606, 17.878, 19.468, and 23.546 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0052] In some embodiments, the fumarate crystal form α of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 7.880, 10.606, 14.856, 15.019, 17.878, 19.468, 23.546, and 24.386.

[0053] In some embodiments, the fumarate crystal form α of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 7.880, 10.606, 11.202, 14.856, 15.019, 15.680, 17.878, 19.468, 23.546, and 24.386 in its X-ray powder diffraction pattern.

[0054] In some embodiments, the X-ray powder diffraction pattern of the fumarate crystal form α of the compound shown in Formula 1, expressed as a diffraction angle 2θ, is as follows: Figure 3 As shown.

[0055] This disclosure also provides a method for preparing the fumarate crystal form α of the compound shown in Formula 1, said method being selected from any of the following methods:

[0056] Method 1: Dissolve the compound of formula 1 in acetone or ethyl acetate, add fumaric acid, and stir;

[0057] Method 2: Add the amorphous fumarate of Formula 1 to acetonitrile and slurry.

[0058] The fumarate crystal form β of the compound of Formula 1 provided in this disclosure has characteristic peaks at 7.371, 10.693, 15.730, 19.643, 21.261, and 22.198 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0059] In some embodiments, the fumarate crystal form β of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 7.371, 10.693, 15.730, 16.661, 19.643, 21.261, 22.198, 25.100, and 26.106 in its X-ray powder diffraction pattern.

[0060] In some embodiments, the X-ray powder diffraction pattern of the fumarate crystal form β of the compound shown in Formula 1, expressed as a diffraction angle 2θ, is as follows: Figure 4 As shown.

[0061] This disclosure also provides a method for preparing the fumarate crystal form β of the compound shown in Formula 1, comprising the step of adding the amorphous fumarate of the compound shown in Formula 1 to ethanol and then slurrying it.

[0062] In some embodiments, the tartrate salt of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0063] This disclosure provides a method for preparing an amorphous tartrate salt of a compound of Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding a tartaric acid ethanol solution, and stirring.

[0064] The tartrate crystal form a of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.155, 10.259, 15.345, 18.873, 21.599, and 25.552 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0065] In some embodiments, the tartrate crystal form a of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 5.155, 10.259, 15.345, 18.873, 21.599, 24.932, 25.552, 28.371, 30.837, and 33.388.

[0066] In some embodiments, the X-ray powder diffraction pattern of the tartrate crystal form a of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 5 As shown.

[0067] This disclosure also provides a method for preparing tartrate crystal form a of the compound shown in Formula 1, the method comprising the step of adding the amorphous tartrate of the compound shown in Formula 1 to ethyl acetate and then slurrying.

[0068] The tartrate crystal form b of the compound of Formula 1 provided in this disclosure has characteristic peaks at 8.025, 10.659, 15.229, 22.948, and 23.897 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0069] In some embodiments, the tartrate crystal form b of the compound shown in Formula 1 has characteristic peaks at 8.025, 10.659, 14.561, 15.229, 18.060, 21.445, 22.948, 23.897, and 28.256 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0070] In some embodiments, the tartrate crystal form b of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 8.025, 10.659, 14.561, 14.882, 15.229, 18.060, 18.562, 21.445, 22.948, 23.897, 28.256, 29.323, and 38.475.

[0071] In some embodiments, the X-ray powder diffraction pattern of the tartrate crystal form b of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 6 As shown.

[0072] This disclosure also provides a method for preparing tartrate crystal form b of the compound shown in Formula 1, the method comprising the step of adding the amorphous tartrate acid of the compound shown in Formula 1 to water and slurrying.

[0073] This disclosure also provides a method for preparing tartrate crystal form b of the compound shown in Formula 1, the method comprising the steps of dissolving the compound shown in Formula 1 in acetone or ethyl acetate, adding tartaric acid ethanol solution, and stirring.

[0074] In some embodiments, the citrate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0075] This disclosure provides a method for preparing an amorphous citrate of a compound of formula 1, the method comprising dissolving the compound of formula 1 in one of ethyl acetate, acetone, or methyl tert-butyl ether, adding a citric acid ethanol solution, and stirring.

[0076] The citrate crystal form A of the compound shown in Formula 1, as provided in this disclosure, has a characteristic peak at 8.952, 12.390, 14.868, 18.543, 20.194, and 22.376 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0077] In some embodiments, the X-ray powder diffraction pattern of the citrate crystal form A of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 7 As shown.

[0078] This disclosure also provides a method for preparing citrate crystal form A of the compound shown in Formula 1, the method comprising the step of adding the amorphous citrate of the compound shown in Formula 1 into 2-methyltetrahydrofuran and then pulping it.

[0079] In some embodiments, the malate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0080] This disclosure provides a method for preparing an amorphous malate of a compound of formula 1, the method comprising the steps of dissolving the compound of formula 1 in ethyl acetate, adding a malic acid ethanol solution, and stirring.

[0081] The present disclosure also provides the malate crystal form I of the compound shown in Formula 1, and the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 7.996, 10.523, 14.960, 18.839, 19.731, and 21.455.

[0082] In some embodiments, the X-ray powder diffraction pattern of the malate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 7.996, 10.523, 11.050, 13.325, 14.960, 15.383, 16.769, 17.132, 17.998, 18.839, 19.731, 21.455, 23.642, and 26.054.

[0083] In some embodiments, the malate crystal form I of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 7.996, 10.074, 10.523, 11.050, 13.325, 14.960, 15.383, 16.769, 17.132, 17.998, 18.839, 19.731, 20.864, 21.166, 21.455, 23.642, and 26.054 in its X-ray powder diffraction pattern.

[0084] In some embodiments, the X-ray powder diffraction pattern of the malate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 8 As shown.

[0085] This disclosure also provides a method for preparing the compound malate crystal form I shown in Formula 1, the method comprising the step of adding the amorphous compound malate of Formula 1 to acetonitrile and then pulping it.

[0086] This disclosure also provides a method for preparing the malate crystal form I of the compound shown in Formula 1, the method comprising dissolving the compound shown in Formula 1 in acetone or methyl tert-butyl ether, adding a malic acid ethanol solution, and stirring.

[0087] The malate crystal form II of the compound of Formula 1 provided in this disclosure has characteristic peaks at 7.921, 9.853, 10.908, 18.904, 21.892, and 23.750 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0088] In some embodiments, the malate crystal form II of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has characteristic peaks at 7.921, 9.853, 10.908, 13.531, 14.668, 15.606, 18.904, 21.892, and 23.750.

[0089] In some embodiments, the malate crystal form II of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 7.921, 9.853, 10.908, 13.531, 14.668, 15.606, 18.904, 21.892, 22.351, 23.750, and 26.996.

[0090] In some embodiments, the X-ray powder diffraction pattern of the malate crystal form II of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 9 As shown.

[0091] This disclosure also provides a method for preparing the malate crystal form II of the compound of Formula 1, the method comprising the step of adding the amorphous malate of the compound of Formula 1 to methanol and slurrying.

[0092] The succinate crystal form b of the compound of Formula 1 provided in this disclosure has characteristic peaks at 9.907, 11.153, 13.630, 14.910, 17.441, 19.599, and 22.411 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0093] In some embodiments, the succinate crystal form b of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 9.143, 9.525, 9.907, 10.831, 11.153, 13.630, 14.910, 17.441, 19.599, 21.660, 22.411, 24.949, and 26.981.

[0094] In some embodiments, the succinate crystal form b of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, exhibits characteristic peaks at 8.507, 9.143, 9.525, 9.907, 10.831, 11.153, 12.457, 13.630, 14.368, 14.910, 16.948, 17.441, 18.501, 19.005, 19.599, 20.554, 21.660, 22.411, 22.938, 23.324, 24.949, and 26.981.

[0095] In some embodiments, the X-ray powder diffraction pattern of the succinate crystal form b of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 10 As shown.

[0096] This disclosure also provides a method for preparing succinate crystal form b of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in solvent IV, adding succinic acid ethanol solution, and stirring, wherein solvent IV is selected from one or more of methyl tert-butyl ether, ethyl acetate, methanol, and ethanol.

[0097] The succinate crystal form a of the compound of Formula 1 provided in this disclosure has characteristic peaks at 10.415, 10.680, 14.960, 17.377, 19.314, 21.870, and 23.920 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0098] In some embodiments, the succinate crystal form a of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 8.040, 10.415, 10.680, 11.181, 14.960, 17.377, 19.314, 21.870, 23.920, 24.880, and 26.719.

[0099] In some embodiments, the X-ray powder diffraction pattern of the succinate crystal form a of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 11 As shown.

[0100] This disclosure also provides a method for preparing succinate crystal form a of the compound shown in Formula 1, comprising the step of adding succinate crystal form b of Formula 1 to ethyl acetate and slurrying.

[0101] This disclosure also provides a method for preparing succinate crystal form a of the compound shown in Formula 1, the method comprising dissolving the compound shown in Formula 1 in ethyl acetate, adding succinic acid, and stirring.

[0102] The acetate crystal form a of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.073, 10.296, 14.899, 18.695, 22.406, and 27.164 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0103] In some embodiments, the acetate crystal form a of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 5.073, 10.296, 13.559, 14.899, 15.803, 18.695, 22.406, 23.376, 24.536, 25.560, and 27.164.

[0104] In some embodiments, the X-ray powder diffraction pattern of the acetate crystal form a of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.073, 9.804, 10.296, 10.694, 13.559, 14.899, 15.803, 18.695, 22.406, 23.376, 24.536, 25.560, and 27.164.

[0105] In some embodiments, the X-ray powder diffraction pattern of the acetate crystal form a of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 12 As shown.

[0106] This disclosure also provides a method for preparing the acetate crystal form a of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone, adding an acetic acid-ethanol solution, and stirring.

[0107] The acetate crystal form b of the compound of Formula 1 provided in this disclosure has characteristic peaks at 10.443, 14.793, 18.734, 19.826, 21.191, 23.410, and 27.164 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0108] In some embodiments, the X-ray powder diffraction pattern of the acetate crystal form b of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 13 As shown.

[0109] This disclosure also provides a method for preparing the acetate crystal form b of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in acetone or ethyl acetate, adding an acetic acid-ethanol solution and isopropyl ether, and stirring.

[0110] The adipate crystal form a of the compound of Formula 1 provided in this disclosure has characteristic peaks at 4.505, 8.985, 13.376, 18.973, 21.730, 22.625, and 26.413 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0111] In some embodiments, the adipate crystal form a of the compound shown in Formula 1, expressed in terms of a diffraction angle 2θ, is shown in the following X-ray powder diffraction pattern. Figure 14 As shown.

[0112] This disclosure also provides a method for preparing the crystal form of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in acetone or ethyl acetate, adding solid adipic acid, and stirring.

[0113] The adipate crystal form b of the compound of Formula 1 provided in this disclosure has characteristic peaks at 9.789, 14.461, 19.139, 20.609, 21.944, 23.406, and 24.987 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0114] In some embodiments, the adipate crystal form b of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 9.789, 10.979, 14.461, 17.710, 19.139, 19.963, 20.609, 21.944, 23.406, and 24.987.

[0115] In some embodiments, the X-ray powder diffraction pattern of the adipate crystal form b of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 15 As shown.

[0116] This disclosure also provides a method for preparing adipate crystal form b of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in methyl tert-butyl ether, adding solid adipic acid, and stirring.

[0117] The arginine complex crystal form I of the compound of Formula 1 provided in this disclosure has characteristic peaks at 15.856, 18.756, 19.840, 23.322, and 26.625 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0118] In some embodiments, the arginine complex I of the compound shown in Formula 1 has characteristic peaks at 15.856, 18.051, 18.756, 19.840, 20.816, 21.362, 23.322, 25.526, 26.625, and 32.352 in its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ.

[0119] In some embodiments, the X-ray powder diffraction pattern of the arginine complex I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, is as follows: Figure 16 As shown.

[0120] This disclosure also provides a method for preparing arginine complex crystal form I of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in acetone, adding arginine, and stirring.

[0121] The arginine complex crystal form II of the compound shown in Formula 1 provided in this disclosure has characteristic peaks at 14.901, 19.316, 23.175, 27.643, 28.671, and 29.810 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0122] In some embodiments, the arginine complex crystal form II of the compound shown in Formula 1 has characteristic peaks at 11.241, 14.901, 16.583, 18.082, 19.316, 23.175, 24.521, 27.643, 28.671, and 29.810 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0123] In some embodiments, the arginine complex crystal form II of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, exhibits characteristic peaks at 11.241, 14.901, 16.583, 18.082, 19.316, 20.751, 22.656, 23.175, 24.521, 27.643, 28.671, 29.810, 31.576, 32.533, 33.534, and 34.226.

[0124] In some embodiments, the X-ray powder diffraction pattern of the arginine complex II of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 17 As shown.

[0125] This disclosure also provides a method for preparing crystal form II of the arginine complex of Formula 1, the method comprising placing crystal form I of the arginine complex of Formula 1 at 25°C / 92.5% RH.

[0126] The crystalline form I of the o-benzoylsulfonylimide complex of the compound shown in Formula 1 provided in this disclosure has characteristic peaks at 8.120, 11.601, 13.479, 15.048, 18.085, and 20.372 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0127] In some embodiments, the X-ray powder diffraction pattern of the o-benzoylsulfonylimide complex I of Formula 1, expressed in terms of diffraction angle 2θ, is as follows: Figure 18 As shown.

[0128] This disclosure also provides a method for preparing the crystalline form I of the benzoylsulfonylimide complex of Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone, adding benzoylsulfonylimide solid, and stirring.

[0129] In some embodiments, the hydrochloride salt of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0130] This disclosure also provides a method for preparing the amorphous hydrochloride salt of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone, ethyl acetate, or methyl tert-butyl ether, adding hydrochloric acid ethanol solution and isopropyl ether, and stirring.

[0131] In some embodiments, the sulfate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0132] This disclosure also provides a method for preparing the amorphous sulfate of the compound of Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone, ethyl acetate, or methyl tert-butyl ether, adding a sulfuric acid ethanol solution, and stirring.

[0133] In some embodiments, the phosphate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0134] This disclosure also provides a method for preparing the amorphous phosphate of the compound of Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone, ethyl acetate or methyl tert-butyl ether, adding a phosphoric acid ethanol solution and isopropyl ether, and stirring.

[0135] In some embodiments, the methanesulfonate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0136] This disclosure also provides a method for preparing the amorphous methanesulfonate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone, ethyl acetate, or methyl tert-butyl ether, adding a methanesulfonic acid ethanol solution and isopropyl ether, and stirring.

[0137] In some embodiments, the maleate salt of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0138] This disclosure also provides a method for preparing the amorphous maleate salt of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone, ethyl acetate or methyl tert-butyl ether, adding maleic acid ethanol solution and isopropyl ether, and stirring.

[0139] In some embodiments, the p-hydroxybenzoate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0140] This disclosure also provides a method for preparing the amorphous form of p-hydroxybenzoate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone or ethyl acetate, adding an ethanol solution of p-hydroxybenzoic acid and isopropyl ether, and stirring.

[0141] In some embodiments, the laurate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0142] This disclosure also provides a method for preparing the amorphous laurate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone or methyl tert-butyl ether or ethyl acetate, adding lauric acid ethanol solution and isopropyl ether, and stirring.

[0143] In some embodiments, the sorbate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0144] This disclosure also provides a method for preparing the amorphous sorbate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in methyl tert-butyl ether or acetone or ethyl acetate, adding solid sorbic acid and isopropyl ether, and stirring.

[0145] In some embodiments, the malonate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0146] This disclosure also provides a method for preparing the amorphous malonate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone, adding a malonate ethanol solution and isopropyl ether, and stirring.

[0147] In some embodiments, the preparation method described in this disclosure further includes any one of the following steps: stirring to dissolve or heating to dissolve, crystallization, filtration, washing, or drying.

[0148] This disclosure also provides a pharmaceutical composition comprising, optionally, an amorphous form of the aforementioned compound of Formula 1, a succinate, malate, fumarate, tartrate, acetate, adipic acidate, benzoate, hydrochloride, sulfate, phosphate, methanesulfonate, citrate, p-toluenesulfonate, maleate, p-hydroxybenzoate, laurate, sorbate, malonate, or a corresponding crystal form thereof, and a pharmaceutical excipient optionally selected from pharmaceutically acceptable excipients.

[0149] This disclosure also provides a pharmaceutical composition prepared from the amorphous, succinate, malate, fumarate, tartrate, acetate, adipic acid, benzoate, hydrochloride, sulfate, phosphate, methanesulfonate, citrate, p-toluenesulfonate, maleate, p-hydroxybenzoate, laurate, sorbate, malonate or their respective crystal forms, and optionally a pharmaceutically acceptable excipient.

[0150] This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned optional Formula 1 compound in its amorphous form, succinate, malate, fumarate, tartrate, acetate, adipic acidate, benzoate, hydrochloride, sulfate, phosphate, methanesulfonate, citrate, p-toluenesulfonate, maleate, p-hydroxybenzoate, laurate, sorbate, malonate, or their respective crystal forms, with a pharmaceutically acceptable excipient.

[0151] This disclosure also provides the use of the aforementioned compounds of Formula 1 in amorphous form, succinate, malate, fumarate, tartrate, acetate, adipic acidate, benzoate, hydrochloride, sulfate, phosphate, methanesulfonate, citrate, p-toluenesulfonate, maleate, p-hydroxybenzoate, laurate, sorbate, malonate, or their respective crystal forms, or the use of the aforementioned compositions in the preparation for the prevention and / or treatment of cancer.

[0152] The uses described in this disclosure, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, epithelial cancer, esophageal cancer, neuroblastoma, glioma, bone cancer, nasopharyngeal carcinoma, oral cancer, thyroid cancer, skin cancer, and squamous cell carcinoma; preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, and lung cancer.

[0153] The "2θ or 2θ angle" mentioned in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case where the number has more than one decimal place after rounding), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0154] The numerical values ​​in this disclosure, such as those relating to the content of certain substances, are calculated data and inevitably contain a certain degree of error. Generally, ±10% is within the reasonable error range. The error may vary to some extent depending on the context in which it is used, but this variation shall not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0155] The starting material used in the crystal form preparation method disclosed herein can be any form of compound, including but not limited to: amorphous, arbitrary crystal form, hydrate, solvate, etc.

[0156] The drying temperature described in this disclosure is generally 25℃-100℃, preferably 40℃-70℃, and can be dried under normal pressure or reduced pressure.

[0157] The crystallization methods described in this disclosure include room temperature crystallization, cooling crystallization, solvent evaporation crystallization, and seed crystallization induction. The cooling temperature is selected from below 65°C, preferably from -10°C to 60°C. Stirring can also be performed during the crystallization process.

[0158] The “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0159] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "Guiding Principles on Hygroscopicity of Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia,

[0160] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0161] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0162] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0163] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0164] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0165] The “excipients” described in this disclosure include, but are not limited to, any adjuvants, carriers, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock. Attached Figure Description

[0166] Figure 1 The image shows the XRPD spectrum of compound 1 in its amorphous form.

[0167] Figure 2 The image shows the XRPD spectrum of benzoate α of compound 1.

[0168] Figure 3 The image shows the XRPD spectrum of the fumarate crystal form α of compound 1.

[0169] Figure 4 The image shows the XRPD spectrum of the fumarate crystal form β of compound 1.

[0170] Figure 5 The image shows the XRPD spectrum of tartrate crystal form a of compound 1.

[0171] Figure 6 The image shows the XRPD spectrum of tartrate crystal form b of compound 1.

[0172] Figure 7 The image shows the XRPD spectrum of citrate form A of compound 1.

[0173] Figure 8 The image shows the XRPD spectrum of compound 1, malate crystal form I.

[0174] Figure 9 The image shows the XRPD spectrum of compound 1, malate crystal form II.

[0175] Figure 10 The image shows the XRPD spectrum of succinate crystal form b of compound 1.

[0176] Figure 11 The image shows the XRPD spectrum of succinate crystal form a of compound 1.

[0177] Figure 12The image shows the XRPD spectrum of the acetate crystal form a of compound 1.

[0178] Figure 13 The image shows the XRPD spectrum of the acetate crystal form b of compound 1.

[0179] Figure 14 The image shows the XRPD spectrum of compound 1 adipate crystal form a.

[0180] Figure 15 The image shows the XRPD spectrum of compound 1 adipate crystal form b.

[0181] Figure 16 The image shows the XRPD spectrum of compound 1, arginine cocrystal form I.

[0182] Figure 17 The image shows the XRPD spectrum of compound 1, arginine cocrystal form II.

[0183] Figure 18 The image shows the XRPD spectrum of compound 1, o-benzoylsulfonylimide co-crystal form I. Detailed Implementation

[0184] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and are not intended to limit the substance and scope of the present disclosure.

[0185] Test conditions of the instruments used in the experiment:

[0186] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0187] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0188] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0189] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0190] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0191] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0192] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0193] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0194] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0195] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0196] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0197] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0198] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0199] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0200] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0201] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0202] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0203] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0204] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0205] When the compounds in the examples contain two or more chiral centers, their relative stereochemistry is identified by NMR studies and / or X-ray diffraction. In these cases, the compounds are identified using the prefix "rel" followed by R / S nomenclature, where the R / S provides only relative stereochemical information and does not indicate absolute stereochemistry.

[0206] XRPD (X-ray Powder Diffraction) was used for analysis: measurements were performed using a BRUKER D8 X-ray diffractometer. Specific data collected included: Cu anode (40 kV, 40 mA), Cu-Kα1 rays. Kα2 rays Kβ rays Scanning range (2q range): 3–45°, scanning step size 0.02, scanning speed 0.1s / step, slit width (collimator) 1.0mm. Alternatively, a step-by-step scanning method can be used, with 2 scanning steps, each step having a scanning range of 19°, a starting degree of 10°, an ending degree of 48°, and a step duration of 45s.

[0207] DSC stands for Differential Scanning Calorimetry: Measurements were performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10℃ / min. The specific temperature range was referenced from the corresponding spectra (mostly 25-300 or 25-350℃). Nitrogen purging rate was 50mL / min.

[0208] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA2 thermogravimetric analyzer, with a heating rate of 10℃ / min, and the specific temperature range was referenced from the corresponding spectrum (mostly 25-350℃). The nitrogen purging rate was 50mL / min.

[0209] DVS stands for Dynamic Moisture Adsorption: The detection method is SMSDVS Advantage. At 25℃, the humidity changes from 50% to 95% to 0% to 95% to 50%, with a step of 10% (the last step is 5%). (The specific humidity range is subject to the corresponding spectrum. The methods listed here are the most commonly used methods.) The judgment standard is that dm / dt is not greater than 0.002%.

[0210] Example 1

[0211] 3-Chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptan-2-yl)-4-(trifluoromethyl)aniline

[0212]

[0213] first step

[0214] 4-(fluoromethyl)piperidine-1-carboxylic acid tert-butyl ester 1b

[0215] 2-((fluoromethyl)sulfonyl)pyridine (4.2 g, 23.97 mmol) was dissolved in tetrahydrofuran (50 mL). A 1 M solution of bis(trimethylsilyl)amino potassium in tetrahydrofuran (30 mL) was added at -78 °C. After reacting for 30 minutes, N-tert-butoxycarbonyl-4-piperidinone 1a (5 g, 25.09 mmol, Shanghai Shaoyuan) was added. The reaction was maintained at 3 hours, then allowed to return to room temperature for 1 hour. Saturated ammonium chloride was added to quench the reaction mixture, followed by the addition of 3N hydrochloric acid (100 mL). After stirring for 1 hour, the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 1b (2 g, yield: 37%).

[0216] Step 2

[0217] 4-(Fluoromethyl)piperidine hydrochloride 1c

[0218] Compound 1b (1 g, 4.64 mmol) was dissolved in 20 mL of 4 M hydrogen chloride solution of 1,4-dioxane and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude title compound 1c (700 mg). The product was used directly in the next step of the reaction without purification.

[0219] MS m / z(ESI): 116.1 [M+1].

[0220] Step 3

[0221] 2,5,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine-4-phenol 1e

[0222] The crude compound 1d (2 g, 8 mmol, prepared according to the method in PCT / CN2023 / 109598) was dissolved in phosphorus oxychloride (25 mL), and N,N-diisopropylethylamine (5.16 g, 40 mmol) was added. The mixture was stirred at 110 °C for 14 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane, and the pH was adjusted to 2-3 by adding 20% ​​potassium carbonate solution. After stirring for 2 hours, the mixture was filtered, the filter cake was washed with water, and dried to obtain the crude title compound 1e (1.5 g). The product was used directly in the next step without purification.

[0223] MS m / z(ESI):267.8[M+1].

[0224] Step 4

[0225] (1S,2S,5R)-2-((S)-1-((2,7-dichloro-8-fluoro-4-hydroxypyridino[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo

[0226] [3.2.1] 1g of tert-butyl octane-8-carboxylate

[0227] (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 1f (370 mg, 1.44 mmol, prepared by the method disclosed in Intermediate 29 on page 164 of patent application "WO2022173678A1")) was dissolved in tetrahydrofuran (10 mL), sodium hydride (201 mg, 5.2 mmol, 60% purity) was added under ice bath, and after reacting for 30 minutes, compound 1e (353 mg, 1.31 mmol) was added, and the reaction was stirred for 2 hours. The reaction solution was quenched with water and concentrated under reduced pressure to obtain crude title compound 1 g (600 mg). The product was used directly in the next step without purification.

[0228] MS m / z(ESI):488.2[M+1].

[0229] Step 5

[0230] (5S,5aS,6S,9R)-2,12-dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentazaze

[0231] -6,9-methyl-naphtho[1,8-ab]heptan-14-carboxylic acid tert-butyl ester 1h

[0232] 1 g (78 mg, 159.7 μmol) of the compound was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (61.9 mg, 478.9 μmol) and phosphorus oxychloride (122.4 mg, 798.2 μmol) were added under ice bath conditions. The mixture was stirred for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate solution. The reaction was then combined with dichloromethane (10 mL × 2). The organic phases were dried with anhydrous sodium sulfate. After filtration to remove the desiccant, the mixture was concentrated under reduced pressure to obtain the crude title compound 1h (75 mg). The product was used directly in the next reaction without purification.

[0233] MS m / z(ESI): 470.2 [M+1].

[0234] Step 6

[0235] (5S,5aS,6S,9R)-12-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-chloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptan-14-carboxylic acid tert-butyl

[0236] 1j base ester

[0237] Dissolve 1.4 g (6.4 mmol) of (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol 1i in tetrahydrofuran (15 mL), add 2 M sodium bis(trimethylsilyl)amino in tetrahydrofuran under ice bath, and stir for 30 minutes while maintaining the temperature. Then add 20 mL of tetrahydrofuran solution of crude compound 1h (2.3 g, 4.9 mmol) under ice bath, and stir for 1 hour while maintaining the temperature. Quench the reaction solution with saturated ammonium chloride solution, extract with ethyl acetate (30 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter to remove the desiccant, concentrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to give title compound 1j (2 g, yield: 62.8%).

[0238] MS m / z(ESI): 650.2 [M+1].

[0239] Step 7

[0240] (5S,5aS,6S,9R)-2-chloro-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa

[0241] -3,10a,11,13,14-pentazaza-6,9-methyl-naphtho[1,8-ab]heptan-4-carboxylic acid tert-butyl ester 1k

[0242] Compound 1j (100 mg, 153.8 μmol) was dissolved in tetrahydrofuran (4 mL), and a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (187 μL) was added. The mixture was stirred for 2 hours, and the reaction solution was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1k (82 mg). The product was used directly in the next reaction without purification. MS m / z (ESI): 536.2 [M+1].

[0243] Step 8

[0244] (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((1-((methanesulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridged naphtho[1,8-ab]heptan-14-carboxylic acid tert-butyl ester

[0245] 1l

[0246] The crude compound 1k (83 mg, 154.9 μmol) and N,N-diisopropylethylamine (60 mg, 464.2 μmol) were dissolved in dichloromethane (3 mL). Methanesulfonyl chloride (25 mg, 218.2 μmol) was added under ice bath conditions. The reaction was allowed to return to room temperature for 30 minutes. The reaction solution was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed successively with water and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1l (95 mg). The product was used directly in the next reaction without purification.

[0247] MS m / z(ESI): 614.2 [M+1].

[0248] Step 9

[0249] (5S,5aS,6S,9R)-2-chloro-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptan-14-carboxylic acid tert-butyl

[0250] Ester 1m

[0251] The crude compound 1l (95 mg, 154.7 μmol) and compound 1c (35.5 mg, 234.5 μmol) were dissolved in acetonitrile (4 mL), and anhydrous potassium carbonate (64 mg, 463 μmol) and sodium iodide (70 mg, 467 μmol) were added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1m (80 mg, yield: 81.6%).

[0252] MS m / z(ESI): 633.2 [M+1].

[0253] Step 10

[0254] (5S,5aS,6S,9R)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-12-((1-(4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]

[0255] tert-butyl 1-heptane-14-carboxylic acid ester 1o

[0256] Compound 1m (20 mg, 31.6 μmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-4-(trifluoromethyl)aniline 1m (15 mg, 46.6 μmol, prepared by the method disclosed in Example 80 on page 257 of patent application "WO2022148422"), tetra(triphenylphosphine)palladium (7 mg, 6.1 μmol), and cesium carbonate (31 mg, 95.1 μmol) were mixed with 1,4-dioxane (1 mL) and water (0.2 mL), purged with nitrogen, and reacted at 100 °C for 1 hour. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, dried with anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 1o (20 mg). The product was used directly in the next reaction without purification.

[0257] MS m / z(ESI): 792.2 [M+1].

[0258] Step 11

[0259] 3-Chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptan-2-yl)-4-(trifluoromethyl)aniline

[0260] The crude compound 1o (15 mg, 18.9 μmol) was dissolved in dichloromethane (1 mL), and 4 M hydrochloric acid 1,4-dioxane solution (0.5 mL) was added under ice bath conditions. After reacting at the same temperature for 0.5 hours, the mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give title compound 1 (4 mg, yield: 30.5%).

[0261] MS m / z(ESI): 690.3 [M-1].

[0262] 1 H NMR (500MHz, CD3OD): δ6.90(s,1H),6.58(d,1H),6.42(s,1H),5.37(dd,1H),4.58–4.39(m,3H),4.07(t,1H),3.70(d,1H),3.60(d ,1H),3.20–3.14(m,1H),2.61–2.42(m,6H),2.33(s,2H),2.08(s,3H),1.92–1.74(m,3H),1.58(d,3H),0.74(s,2H),0.52(s,2H).

[0263] Biological evaluation of the GP2d and AGS cell 3D proliferation inhibition experiment in Test Example 1.

[0264] I. Purpose of the Test

[0265] The inhibitory effect of the disclosed compound on the KRAS target was evaluated by testing its 3D proliferation inhibitory effect on GP2d and AGS cells.

[0266] II. Experimental Methods

[0267] GP2d cells were cultured in complete medium, namely DMEM / high glucose medium (Hyclone, SH30243.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, GP2d cells were seeded at a density of 1000 cells / well in 96-well low-absorption plates (Corning, CLS7007-24EA) using complete medium, with 90 μL of cell suspension per well. After centrifugation at 2000 rpm for 5 minutes at room temperature, the cells were incubated overnight at 37°C in a 5% CO2 cell culture incubator.

[0268] AGS cells were cultured in complete medium, namely RPMI 1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, AGS cells were seeded at a density of 1000 cells / well in 96-well low-absorption plates (Corning, CLS7007-24EA) using complete medium, with 90 μL of cell suspension per well. After centrifugation at 2000 rpm for 5 minutes at room temperature, the cells were incubated overnight at 37°C in a 5% CO2 cell culture incubator.

[0269] On the second day, 10 μL of serially diluted test compounds prepared with complete culture medium was added to each well. For GP2d cells, the final concentrations were determined by nine 5-fold serial dilutions starting from 1 μM; for AGS cells, the final concentrations were determined by nine 5-fold serial dilutions starting from 10 μM. A blank control containing 0.5% DMSO was included in both wells. The plates were incubated at 37°C in a 5% CO2 incubator for 5 days. On the seventh day, the 96-well cell culture plate was removed, and 50 μL of the test compound was added to each well. The 3D Cell Viability Assay reagent (Promega, G9682) was shaken at room temperature in the dark for 25 minutes, then mixed by pipetting and aspiration. 100 μL was taken from each well and transferred to a white, opaque 96-well plate (PerkinElmer, 6005290). The luminescence signal value was read using a multi-functional microplate reader (PerkinElmer, EnVision2105).

[0270] III. Data Analysis

[0271] The IC50 of the compound's inhibitory activity was calculated using Graphpad Prism software. 50 The values ​​are shown in Table 2 below.

[0272] Table 1. Data on the inhibitory activity of AGS and GP2d cells on 3D proliferation.

[0273]

[0274] Conclusion: The compound disclosed herein has a good inhibitory effect on the 3D proliferation of AGS and GP2d cells.

[0275] Test Example 2: Biological Evaluation of the 3D Proliferation Inhibition Experiment of AsPC-1 Cells

[0276] On day 1 of the experiment, AsPC-1 cells that had grown well and reached 70%-80% confluence were digested and resuspended in RPMI 1640 (Hyclone, SH30809.01) medium containing 10% FBS, and the cell density was adjusted to the desired level. 90 μL of cell suspension was added to each well of a U-shaped, low-adsorption 96-well plate (Corning, CLS7007-24EA), resulting in a cell density of 1500 cells / well. The cell plates were centrifuged at 2500 rpm for 5 minutes and then incubated overnight at 37°C in a 5% CO2 incubator. On day 2, the 20 mM test compound dissolved in DMSO was diluted to an initial concentration of 2 mM with DMSO, and then serially diluted 5-fold for a total of 9 concentration points. The control wells contained DMSO. The serially diluted compounds were then further diluted 20-fold with medium. 10 μL of the diluted test compound was added to each well of the cell plate, resulting in a final concentration of 10 μM, representing the 9 concentration points of the 5-fold serial dilutions. Cell culture wells containing 0.5% DMSO were set up as solvent control wells, and wells containing only culture medium and 0.5% DMSO were set as blank control wells. Each compound concentration and control well was replicated, with a final DMSO concentration of 0.5% in each well. The cell culture plates were centrifuged at 2500 rpm for 3 minutes and then incubated at 37°C in a 5% CO2 incubator for 5 days. On the seventh day, the 96-well cell culture plates were removed, and 50 μL of luminescent cell viability assay reagent was added to each well. In the 3D Cell Viability Assay (Promega, G9683), after shaking at room temperature in the dark for 25 minutes, mix thoroughly by pipetting up and down, then transfer 100 μL to each well into a white, opaque OptiPlate. TM -96-well plates (PerkinElmer, 6005290) were used to read the luminescence signal values ​​using a multi-functional microplate reader (PerkinElmer, EnVision2105).

[0277] Calculate the inhibition rate using the following formula: Inhibition rate = (Luminous value) / (Emitting value) 溶媒对照孔 -Luminescence value 受试化合物 ) / (luminous value) 溶媒对照孔 -Luminescence value 空白对照孔 ()×100%. Using GraphPad Prism software, curves were plotted based on the compound concentration and corresponding inhibition rate, and the IC50 of the compound was calculated. 50 value.

[0278] Table 2. Data on the 3D proliferation inhibition activity of AsPC-1 cells.

[0279] Example number <![CDATA[AsPC-1 / IC 50 (nM)]]> 1 0.2

[0280] Conclusion: The compound disclosed herein has a good inhibitory effect on the 3D proliferation of AsPC-1 cells.

[0281] Example 2: Preparation of the amorphous form of compound 1

[0282] 5 mg of the compound shown in Formula 1 was dissolved in 0.05 mL of 10% water / methanol, stirred at room temperature to precipitate, centrifuged, and dried under vacuum to obtain a solid. X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD spectrum is shown below. Figure 1 TGA spectra showed a weight loss of 1.13% between 32℃ and 118℃. DVS analysis showed that under normal storage conditions (25℃, 60% RH), the sample gained approximately 2.10% weight due to moisture absorption; under accelerated experimental conditions (70% RH), the weight gain was approximately 2.6%; and under extreme conditions (90% RH), the weight gain was approximately 4.5%. Re-testing of the crystal form after DVS analysis showed that it remained amorphous.

[0283] Example 3: Preparation of the amorphous form of compound 1

[0284] Dissolve 5 mg of the compound shown in Formula 1 in the solvents listed in Table 3, and evaporate the solvents at room temperature to obtain the title product.

[0285] Table 3

[0286]

[0287]

[0288] Example 4: Preparation of the amorphous form of compound 1

[0289] Dissolve 5 mg of the compound shown in Formula 1 in solvent 1 in Table 4, add solvent 2, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product.

[0290] Table 4

[0291]

[0292] Example 5 Preparation of benzoate crystal form α

[0293] The compound shown in Formula 1 (2.5 g, 3.61 mmol) was dissolved in ethyl acetate (35 mL), benzoic acid (486 mg, 3.98 mmol) was added, and the mixture was stirred until clear. The mixture was heated to 50 °C and stirred for 1 hour. After natural cooling, the mixture was stirred for 72 hours. The precipitated solid was collected by filtration and dried under vacuum at 35 °C for 4 hours to obtain the title product.

[0294] X-ray powder diffraction analysis determined it to be benzoate crystal form α, and the XRPD spectrum is shown below. Figure 2The characteristic peak positions are shown in Table 5. The DSC spectrum shows an endothermic peak at 210℃. The TGA spectrum shows a weight loss of 0.61% from 40℃ to 75℃ and 8.46% from 140℃ to 200℃. DVS analysis shows that under normal storage conditions (25℃, 60% humidity), the sample's weight gain due to moisture absorption is approximately 1.075%; under accelerated testing conditions (70% humidity), the weight gain is approximately 1.151%; and under extreme conditions (90% humidity), the weight gain is approximately 1.342%. During humidity changes from 0% to 95%, the desorption and adsorption processes of the sample overlapped; retesting of the crystal form after DVS analysis showed no change in crystal form. Ion detection results showed a benzoate content of 15.27%.

[0295] through 1 1H NMR analysis showed that the salt ratio of compound 1 to benzoic acid was 1:1.

[0296] 1 H NMR(500MHz,CD3OD)δ7.95–7.90(m,2H),7.48–7.43(m,1H),7.39–7.33(m,2H),6.88(d,1H) ,6.66(s,1H),6.49(s,1H),5.33(d,1H),4.46(dd,6.4Hz,1H),4.42(s,2H),4.08–4.04(m,1H ),3.75(d,1H),3.66(d,1H),3.16(d,1H),2.84(s,4H),2.76(s,2H),2.45(s,2H),2.22(s,2H ),2.10–2.04(m,1H),1.87(d,1H),1.77(t,2H),1.56(d,H),0.84–0.78(m,2H),0.63(d,2H).

[0297] Table 5

[0298]

[0299]

[0300] Example 6 Preparation of benzoate crystal form α

[0301] Dissolve 8 mg of compound 1 in 0.1 mL of acetone, add 6.4 μL of 2 M benzoic acid ethanol solution, stir at room temperature to crystallize, centrifuge, and vacuum dry to obtain a solid. X-ray powder diffraction analysis showed that the product is benzoate crystal form α.

[0302] Example 7 Preparation of benzoate crystal form α

[0303] Dissolve 8 mg of compound 1 in 0.1 mL of methyl tert-butyl ether, add 6.4 μL of 2 M benzoic acid ethanol solution, stir at room temperature to crystallize, centrifuge, and vacuum dry to obtain a solid. X-ray powder diffraction analysis showed that the product was benzoate crystal form α.

[0304] Example 8 Preparation of fumarate

[0305] The compound shown in Formula 1 (2.5 g, 3.6 mmol) was added to ethyl acetate (50 mL), stirred until completely dissolved, heated to 50 °C and stirred for 5 minutes. Fumaric acid ethanol solution (0.3 M, 12.0 mL) was added dropwise, causing a solid to precipitate. Stirring continued for 1 hour, until most of the solid dissolved. The mixture was slowly cooled to room temperature and stirred for 16 hours, resulting in a large amount of solid precipitation. The solid was filtered, and the filter cake was washed with 20 mL of ethyl acetate. The filter cake was collected and dried under vacuum to obtain the title product. X-ray powder diffraction analysis showed that it was an amorphous fumarate salt, with no obvious characteristic peaks in the X-ray powder diffraction pattern.

[0306] Example 9 Preparation of fumarate crystal form α

[0307] 8 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of acetone, and 1.5 mg of solid fumaric acid was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and the solid was dried under vacuum to obtain the title product. X-ray powder diffraction analysis identified this product as fumarate crystal form α. The XRPD spectrum is shown below. Figure 3 The characteristic peak positions are shown in Table 6. The DSC spectrum shows the endothermic peaks at 109.46℃ and 219.39℃. The TGA spectrum shows a weight loss of 5.84% between 40℃ and 210℃. Ion detection results show a fumarate content of 14.51%. DVS detection shows that under normal storage conditions (25℃, 60% RH), the sample gains approximately 3.3% weight through moisture absorption; under accelerated experimental conditions (70% RH), the weight gain is approximately 3.6%; and under extreme conditions (90% RH), the weight gain is approximately 4.5%. Re-testing of the crystal form after DVS detection showed no change in crystal form.

[0308] through 1 1H NMR analysis showed that the salt ratio of compound 1 to fumaric acid was 1:1.

[0309] 1H NMR(500MHz,CD3OD)δ6.89(d,1H),6.74(s,0.5H),6.62(s,2H),6.56(d,1H ),6.41(s,0.5H),5.39(dd,1H),4.58(s,1H),4.45(q,2H),4.16(d,1H),3. 90(d,1H),3.82(s,1H),3.10(s,4H),3.01(s,2H),2.57(s,2H),2.34(t,2H ),2.14(s,1H),1.98–1.86(m,3H),1.58(d,3H),0.90(d,2H),0.74(d,2H).

[0310] Table 6

[0311]

[0312] Example 10 Preparation of fumarate crystal form α

[0313] The amorphous fumarate of Formula 1 (100 mg, 123.7 μmol) was added to 6 mL of acetonitrile, stirred for 72 h, filtered, and the filter cake was collected and dried under vacuum to obtain a solid. X-ray powder diffraction analysis showed that the product was fumarate crystal form α.

[0314] Example 11 Preparation of fumarate crystal form α

[0315] Dissolve 8 mg of the compound shown in Formula 1 in 0.1 mL of ethyl acetate, add 1.5 mg of solid fumaric acid, stir at room temperature to crystallize, centrifuge, and vacuum dry to obtain a solid. X-ray powder diffraction analysis showed that the product was fumarate crystal form α.

[0316] Example 12 Preparation of fumarate crystal form β

[0317] 1.8 g (2.6007 mmol) of amorphous fumarate (Formula 1) was added to 45 mL of ethanol, stirred for 4 days, filtered, and the filter cake was collected and dried under vacuum to obtain a solid. X-ray powder diffraction analysis identified the product as fumarate crystal form β. The XRPD spectrum is shown below. Figure 4 The positions of its characteristic peaks are shown in Table 7. The DSC spectrum shows that the endothermic peaks are at 69.65℃, 173.12℃, and 192.64℃. The TGA spectrum shows a weight loss of 2.99% between 40℃ and 100℃.

[0318] through 1 1H NMR analysis showed that the salt ratio of compound 1 to fumaric acid was 1:1.

[0319] 1H NMR(500MHz,CD3OD)δ6.88(d,1H),6.73(s,0.5H),6.58(s,2H),6.56(s,1H ),6.42(s,0.5H),5.40(dd,1H),4.58(t,1H),4.44(q,2H),4.18(d,1H),3. 93(dd,1H),3.85(d,1H),3.10(d,4H),3.01(s,2H),2.57(t,2H),2.35(t,2 H),2.16(d,1H),2.00–1.88(m,3H),1.58(d,3H),0.89(t,2H),0.73(s,2H).

[0320] Table 7

[0321]

[0322] Example 13 Preparation of tartrate

[0323] The compound shown in Formula 1 (500 mg, 722.4 μmol) was added to ethyl acetate (10 mL), stirred until completely dissolved, heated to 50 °C and stirred for 5 minutes. A 5 mL ethanol solution of L-tartaric acid (434 mg, 2.8917 mmol) was added dropwise, causing a solid to precipitate. Ethyl acetate (5 mL) was then added, and stirring continued for 1 hour. The solid did not dissolve. The mixture was then cooled to room temperature and stirred for 2 hours. The mixture was filtered, and the filter cake was collected and dried under vacuum to obtain the solid. X-ray powder diffraction analysis showed that it was an amorphous tartrate salt, and the X-ray powder diffraction pattern showed no obvious characteristic peaks. 1 H NMR analysis showed that the compound of formula 1 formed a salt with L-tartaric acid in a ratio of 1:2.

[0324] 1 H NMR(500MHz,CD3OD)δ6.88(d,1H),6.70(d,1H),6.50(d,1H),5.45(d,1H),4.68(t,1H),4.47(s,3H),4.39(s,4H),4.33–4.23(m,1H),4.18( s,1H),3.58(d,1H),3.38(s,3H),3.28(d,2H),2.69(s,2H),2.49(d,2 H),2.24(s,1H),2.10(d,3H),1.60(d,3H),0.97(s,2H),0.84(s,2H).

[0325] Example 14 Preparation of tartrate crystal form a

[0326] An amorphous sample (60 mg, 60.5 μmol) of compound L-tartrate (Formula 1) was added to 6 mL of ethyl acetate, stirred at room temperature for 72 h, filtered, and the filter cake was collected and dried under vacuum to obtain a solid. X-ray powder diffraction analysis identified this crystal form as L-tartrate crystal form a, and the X-ray powder diffraction pattern is shown below. Figure 5 The positions of its characteristic peaks are shown in Table 8. The DSC spectrum shows that the endothermic peaks have a peak value of 66.82℃ and a peak value of 211.50℃. The TGA spectrum shows a weight loss of 3.39% from 30℃ to 100℃. 1H NMR analysis shows that the compound of formula 1 forms a salt with L-tartaric acid in a 1:1 ratio.

[0327] 1H NMR(500MHz,CD3OD)δ6.89(d,1H),6.68(d,1H),6.48(d,1H),5.41(d,1H),4. 64(q,1H),4.45(q,2H),4.38(s,2H),4.32(d,1H),4.09(d,1H),4.01(d,1H),3 .46–3.39(m,1H),3.29–3.19(m,3H),3.15(d,2H),2.64(d,2H),2.42(d,2H), 2.18(d,1H),2.09–1.90(m,3H),1.59(d,3H),1.03–0.90(m,2H),0.80(d,2H).

[0328] Table 8

[0329]

[0330] Example 15 Preparation of tartrate crystal form a

[0331] Dissolve 8 mg of the compound shown in Formula 1 in 0.1 mL of acetone (the solvent can be 0.1 mL of ethyl acetate), add 6.4 μL of 2M tartaric acid ethanol solution, stir at room temperature to induce crystallization, centrifuge, and dry the solid under vacuum to obtain the title product.

[0332] Example 16 Preparation of tartrate crystal form b

[0333] An amorphous sample (60 mg, 60.5 μmol) of compound L-tartrate (Formula 1) was added to 6 mL of water, stirred at room temperature for 72 h, filtered, and the filter cake was collected and vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as L-tartrate crystal form b. The X-ray powder diffraction pattern is shown below. Figure 6The positions of its characteristic peaks are shown in Table 9. The DSC spectrum shows that the endothermic peaks have peak values ​​of 78.81℃ and 218.77℃. The TGA spectrum shows a weight loss of 3.22% from 30℃ to 100℃. 1H NMR analysis shows that the compound of formula 1 forms a salt with L-tartaric acid in a 1:1 ratio.

[0334] 1H NMR(500MHz,CD3OD)δ6.89(d,1H),6.68(d,1H),6.48(d,1H),5.42(d,1H),4 .64(s,1H),4.45(q,2H),4.38(s,2H),4.32(d,1H),4.09(d,1H),4.01(s,1H ),3.42(t,1H),3.24(s,3H),3.18–3.06(m,2H),2.63(s,2H),2.41(s,2H),2 .19(d,1H),2.12-1.90(m,3H),1.59(d,3H),1.01-0.87(m,2H),0.80(d,2H).

[0335] Table 9

[0336]

[0337]

[0338] Example 17 Preparation of Citrate

[0339] The compound shown in Formula 1 (500 mg, 722.4181 μmol) was dissolved in ethyl acetate (20 mL), heated to 50 °C, and stirred until dissolved. Anhydrous citric acid (556 mg, 2.8940 mmol) was dissolved in ethanol (5 mL) and added dropwise to the reaction solution at 50 °C. A white solid immediately precipitated. Stirring continued at 50 °C for 1 hour. The solid partially dissolved but not completely. The temperature was slowly lowered to room temperature, and stirring continued for 16 hours. The mixture was filtered, and the solid was collected and dried under vacuum to obtain the target solid. X-ray powder diffraction analysis showed it to be an amorphous citrate salt, and the XRPD spectrum showed no obvious characteristic peaks. 1 1H NMR analysis showed that the compound of formula 1 formed a salt with citric acid in a ratio of 1:2.

[0340] 1H NMR(500MHz,CD3OD)δ6.88(s,1H),6.70(d,1H),6.58(s,1H),5.47(dd,1H),4.71(s,1 H),4.56(t,1H),4.47(s,1H),4.35(s,1H),4.25(s,1H),4.16(d,1H),3.53(s,1H),3. 38(s,4H),3.26–3.17(m,1H),2.76(dd,4H),2.72–2.63(m,6H),2.48(s,2H),2.25(s, 1H), 2.18–2.03 (m, 3H), 2.00 (d, 1H), 1.60 (d, 3H), 0.96 (d, J = 8.4Hz, 2H), 0.84 (s, 2H).

[0341] Example 18 Preparation of citrate crystal form A

[0342] The amorphous citrate of Formula 1 (50 mg, 46.4526 μmol) was added to 0.5 mL of 2-methyltetrahydrofuran, stirred for 72 h, filtered, and the solid was collected and dried under vacuum to obtain a solid. X-ray powder diffraction analysis identified the product as citrate crystal form A. The XRPD spectrum is shown below. Figure 7 The positions of its characteristic peaks are shown in Table 10. 1 1H NMR analysis showed that the compound of formula 1 formed a salt with citric acid in a ratio of 1:1.5.

[0343] 1 H NMR(500MHz,CD3OD)δ6.88(s,1H),6.70(d,1H),6.58(s,1H),5.47(dd,1H),4.71(s,1 H),4.56(t,1H),4.47(s,1H),4.35(s,1H),4.25(s,1H),4.16(d,1H),3.53(s,1H),3. 38(s,4H),3.26–3.17(m,1H),2.76(dd,4H),2.72–2.63(m,6H),2.48(s,2H),2.25(s, 1H), 2.18–2.03 (m, 3H), 2.00 (d, 1H), 1.60 (d, 3H), 0.96 (d, J = 8.4Hz, 2H), 0.84 (s, 2H).

[0344] Table 10

[0345]

[0346]

[0347] Example 19 Preparation of malate

[0348] The compound shown in Formula 1 (500 mg, 722.4 μmol) was added to ethyl acetate (10 mL), stirred to dissolve, heated to 50 °C and stirred for 5 minutes. A 5 mL ethanol solution of L-malic acid (388 mg, 2.89 mmol) was added dropwise, causing a solid to precipitate. The precipitate was then dissolved by stirring, and ethyl acetate (5 mL) was added again. Stirring continued for 1 hour until completely dissolved. The solution was cooled to room temperature and stirred for 16 hours. The solution was then concentrated under reduced pressure to obtain a solid. X-ray powder diffraction analysis showed that the solid was an amorphous L-malate, and the XRPD spectrum showed no obvious characteristic peaks.

[0349] Example 20 Preparation of Malate Crystal Form I

[0350] 60 mg (48.9 μmol) of amorphous L-malate (Formula 1) was added to 4 mL of acetonitrile, stirred for 72 h, filtered, and the solid was collected and dried under vacuum. X-ray powder diffraction analysis identified the product as L-malate crystal form I. The XRPD spectrum is shown below. Figure 8 The characteristic peak positions are shown in Table 11. The DSC spectrum shows endothermic peaks at 76.81℃, 188.79℃, and 216.12℃, and an exothermic peak at 208.13℃. The TGA spectrum shows a weight loss of 3.1% between 40℃ and 100℃. DVS analysis shows that under normal storage conditions (25℃, 60% RH), the sample gains approximately 3.3% weight through moisture absorption; under accelerated storage conditions (70% RH), the weight gain is approximately 3.6%; and under extreme conditions (90% RH), the weight gain is approximately 4.3%. Re-testing of the crystal form after DVS analysis showed no change in crystal form. Ion detection results show that the malate ion content is 27.57%. 1 1H NMR analysis showed that the compound of formula 1 formed a salt with malic acid in a ratio of 1:2.

[0351] 1 H NMR(500MHz,CD3OD)δ6.89(d,1H),6.76(s,0.5H),6.57(d,1H),6.40(s,0.5H),5.4 1(dd,1H),4.61(d,1H),4.46(q,3H),4.31(dd,2H),4.22(d,1H),3.97(d,1H),3.89( t,1H),3.24–3.13(m,4H),3.08(s,2H),2.77(dd,2H),2.60(d,2H),2.54(dd,2H),2 .38(t,2H),2.15(q,1H),2.00–1.89(m,3H),1.59(d,3H),0.92(d,2H),0.76(s,2H).

[0352] Table 11

[0353]

[0354]

[0355] Example 21 Preparation of Malate Crystal Form I

[0356] Dissolve 8 mg of the compound shown in Formula 1 in 0.1 mL of acetone, add 6.4 μL of 2 M malic acid ethanol solution, stir at room temperature to induce crystallization, centrifuge, and dry the solid under vacuum to obtain the title product.

[0357] Example 22 Preparation of Malate Crystal Form II

[0358] 60 mg (48.9 μmol) of L-malate crystal form II was added to 1 mL of methanol, stirred for 72 h, filtered, and the solid was collected and dried under vacuum. X-ray powder diffraction analysis identified the product as L-malate crystal form II. The X-ray powder diffraction pattern is shown below. Figure 9 The characteristic peak positions are shown in Table 12. The DSC spectrum shows that the endothermic peaks are at 65.48℃, 147.46℃, 183.42℃, and 210.25℃, and the exothermic peak is at 208.13℃. The TGA spectrum shows a weight loss of 2.1% from 40℃ to 100℃. 1 1H NMR analysis showed that the compound of formula 1 formed a salt with malic acid in a ratio of 1:2.

[0359] 1H NMR(500MHz,CD3OD)δ6.89(d,1H),6.77(s,0.5H),6.57(d,1H),6.40(s,0.5H),5.4 2(d,1H),4.61(s,1H),4.46(q,2H),4.33(dd,2H),4.23(d,1H),3.99(s,1H),3.91( s,1H),3.21(s,4H),3.11(s,2H),2.77(dd,2H),2.61(s,2H),2.55(dd,2H),2.40(d ,2H),2.19–2.13(m,1H),2.04–1.89(m,3H),1.59(d,3H),0.92(t,2H),0.77(s,2H).

[0360] Table 12

[0361]

[0362]

[0363] Example 23 Preparation of succinate crystal form b

[0364] The compound shown in Formula 1 (500 mg, 722.4 μmol) was added to methyl tert-butyl ether (15 mL), stirred to dissolve, and then heated to 50 °C and stirred for 5 minutes. Succinic acid ethanol solution (0.3 M, 4.8 mL) was added dropwise; no solid precipitated. Ethyl acetate (5 mL) was then added, and stirring continued for 1 hour. The mixture was then cooled to room temperature and stirred for 16 hours, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed with 5 mL of ethyl acetate, filtered again, and the filter cake was collected and vacuum dried to obtain the solid. X-ray powder diffraction analysis identified it as succinate crystal form b. The X-ray powder diffraction pattern is shown below. Figure 10 The positions of its characteristic peaks are shown in Table 13. 1 1H NMR analysis showed that the compound of formula 1 formed a salt with succinic acid in a ratio of 1:2.

[0365] 1 H NMR(500MHz,CD3OD)δ6.89(d,1H),6.71(s,0.5H),6.54(s,1H),6.41(s,0.5H ),5.40(dd,1H),4.58(d,1H),4.45(q,2H),4.19(d,1H),3.91(d,1H),3.83(d, 1H),3.03(q,4H),2.99–2.90(m,2H),2.54(d,2H),2.51(s,8H),2.31(t,2H),2 .14(dt,1H),1.98–1.84(m,3H),1.58(d,3H),0.87(t,2H),0.75–0.67(m,2H).

[0366] Table 13

[0367]

[0368]

[0369] Example 24 Preparation of succinate crystal form b

[0370] The compound shown in Formula 1 (2.5 g, 3.6 mmol) was added to ethyl acetate (50 mL), stirred to dissolve, heated to 50 °C and stirred for 5 minutes. Succinic acid ethanol solution (0.3 M, 12.0 mL) was added dropwise; no solid precipitated. Stirring continued for 1 hour, then slowly cooled to room temperature and stirred for 16 hours. A large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with 10 mL of ethyl acetate. The filter cake was collected and vacuum dried. X-ray powder diffraction analysis showed that the product was succinate crystal form b. The DSC spectrum showed endothermic peaks at 137.99 °C, 145.17 °C, and 164.09 °C. The TGA spectrum showed a weight loss of 4.12% from 110 °C to 170 °C. 11H NMR analysis showed that the compound of formula 1 formed a salt with succinic acid in a ratio of 1:2.

[0371] 1 H NMR(500MHz,CD3OD)δ6.89(d,1H),6.72(s,0.5H),6.55(s,1H),6.41(s,0.5H) ,5.46–5.36(m,1H),4.61(d,1H),4.44(dd,2H),4.23(d,1H),3.96(d,1H),3.89 (s,1H),3.08(q,4H),3.03–2.93(m,2H),2.55(t,2H),2.50(s,8H),2.33(t,2H) ,2.20–2.12(m,1H),2.01–1.87(m,3H),1.58(d,3H),0.88(t,2H),0.72(s,2H).

[0372] Example 25 Preparation of succinate crystal form b

[0373] Dissolve 8 mg of the compound shown in Formula 1 in 0.1 mL of acetone, add 1.5 mg of succinic acid solid and 1 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product.

[0374] Example 26 Preparation of succinate crystal form a

[0375] Succinate crystal form b (60 mg, 64.6 μmol) of Formula 1 was added to 6 mL of ethyl acetate, stirred for 5 days, filtered, and the filter cake was collected and dried under vacuum to obtain a solid. X-ray powder diffraction analysis identified this product as succinate crystal form a. The X-ray powder diffraction pattern is shown below. Figure 11 The characteristic peak positions are shown in Table 14. The DSC spectrum shows the endothermic peaks at 73.31℃ and 171.34℃. The TGA spectrum shows a weight loss of 4.04% between 40℃ and 140℃. 1 1H NMR analysis showed that the compound of formula 1 formed a salt with citric acid in a ratio of 1:1.3.

[0376] 1H NMR(500MHz,CD3OD)δ6.88(d,1H),6.69(s,0.5H),6.53(d,1H),6.40(s,0.5H),5.3 7(dd,1H),4.58–4.51(m,1H),4.43(d,2H),4.12(t,1H),3.80(d,1H),3.72(d,1H), 3.22(d,1H),2.91(q,4H),2.86–2.78(m,2H),2.53(s,5.2H),2.48(t,2H),2.28–2. 22(m,2H),2.10(dd,1H),1.94–1.79(m,3H),1.58(d,3H),0.84(d,2H),0.66(s,2H).

[0377] Table 14

[0378]

[0379]

[0380] Example 27 Preparation of acetate crystal form a

[0381] Dissolve 8 mg of compound 1 in 0.1 mL of acetone, add 12.8 μL of 2M acetic acid-ethanol solution and 1 mL of isopropyl ether, stir at room temperature to induce crystallization, centrifuge, and dry under vacuum to obtain the title product. X-ray powder diffraction analysis identified this product as acetate crystal form a, and the XRPD spectrum is shown below. Figure 12 The positions of its characteristic peaks are shown in Table 15. The DSC spectrum shows that the endothermic peak has a peak value of 107.14℃. The TGA spectrum shows that the weight loss is 15.82% from 33℃ to 153℃.

[0382] Table 15

[0383]

[0384]

[0385] Example 28 Preparation of acetate crystal form b

[0386] Dissolve 8 mg of compound 1 in 0.1 mL of acetone, add 6.4 μL of 2 M acetic acid-ethanol solution and 1 mL of isopropyl ether, stir at room temperature to crystallize, centrifuge, and dry under vacuum to obtain the title product. X-ray powder diffraction analysis identified this product as acetate crystal form b, and the XRPD spectrum is shown below. Figure 13 The positions of its characteristic peaks are shown in Table 16. The DSC spectrum shows that the endothermic peaks are at 95.98℃ and 107.15℃. The TGA spectrum shows a weight loss of 15.68% between 32℃ and 163℃.

[0387] Table 16

[0388]

[0389] Example 29 Preparation of acetate crystal form b

[0390] Dissolve 8 mg of compound 1 in 0.1 mL of ethyl acetate, add 6.4 μL of 2 M acetic acid-ethanol solution and 1 mL of isopropyl ether, stir at room temperature to crystallize, centrifuge, and dry the solid under vacuum to obtain the title product.

[0391] Example 30 Preparation of adipate crystal form a

[0392] 8 mg of compound 1 was dissolved in 0.1 mL of acetone, and 2.1 mg of solid adipic acid was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and the solid was dried under vacuum to obtain the title product. X-ray powder diffraction analysis identified this product as adipic acid salt crystal form a. The XRPD spectrum is shown below. Figure 14 The positions of its characteristic peaks are shown in Table 17. The DSC spectrum shows that the exothermic peak has a peak value of 130.25℃, and the endothermic peaks have peak values ​​of 156.89℃ and 163.93℃, respectively. The TGA spectrum shows a weight loss of 5.67% between 34℃ and 155℃.

[0393] Table 17

[0394]

[0395]

[0396] Example 31 Preparation of adipate crystal form a

[0397] Dissolve 8 mg of compound 1 in 0.1 mL of ethyl acetate, add 2.1 mg of solid adipic acid, stir at room temperature to crystallize, centrifuge, and dry the solid under vacuum to obtain the title product.

[0398] Example 32 Preparation of adipate crystal form b

[0399] 15 mg of compound 1 was dissolved in 0.2 mL of methyl tert-butyl ether, and 4.1 mg of solid adipic acid was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and the solid was dried under vacuum to obtain the title product. X-ray powder diffraction analysis identified this product as adipic acid salt crystal form b. The XRPD spectrum is shown below. Figure 15The characteristic peak positions are shown in Table 18. The DSC spectrum shows endothermic peaks at 62.16℃ and 154.27℃. The TGA spectrum shows a weight loss of 6.78% between 32℃ and 145℃. Ion detection results show an adipic acid content of 17.76%. DVS detection shows that under normal storage conditions (25℃, 60% RH), the sample gains approximately 7.4% weight through moisture absorption; under accelerated experimental conditions (70% RH), the weight gain is approximately 7.8%; and under extreme conditions (90% RH), the weight gain is approximately 8.6%. Re-testing of the crystal form after DVS detection showed no change in crystal form.

[0400] Table 18

[0401]

[0402]

[0403] Example 33 Preparation of Arginine Complex Crystal Form I

[0404] 8 mg of compound 1 was dissolved in 0.1 mL of acetone, and 2.4 mg of solid arginine was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and the solid was dried under vacuum to obtain the title product. X-ray powder diffraction analysis identified this product as arginine complex crystal form I. The XRPD spectrum is shown below. Figure 16 The positions of its characteristic peaks are shown in Table 19. The DSC spectrum shows endothermic peaks at 55.81℃, 222.29℃, and 232.97℃. The TGA spectrum shows a weight loss of 4.50% between 33℃ and 185℃.

[0405] Table 19

[0406]

[0407] Example 34 Preparation of Arginine Complex Crystal Form II

[0408] The arginine complex crystal form I from Example 31 was placed at 25°C / 92.5% RH for 5 days to obtain the title product.

[0409] X-ray powder diffraction analysis identified the product as arginine complex crystal form II, and the XRPD spectrum is shown below. Figure 17 The positions of its characteristic peaks are shown in Table 20.

[0410] Table 20

[0411]

[0412]

[0413] Example 35 Preparation of o-benzoylsulfonylimide complex crystal form I

[0414] 8 mg of compound 1 was dissolved in 0.1 mL of acetone, and 2.5 mg of o-benzoylsulfonylimide solid was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and dried under vacuum to obtain the solid. X-ray powder diffraction analysis identified the product as crystal form I of the o-benzoylsulfonylimide complex. The XRPD spectrum is shown below. Figure 18 The positions of its characteristic peaks are shown in Table 21. The DSC spectrum shows endothermic peaks at 42.82℃ and 188.12℃. The TGA spectrum shows a weight loss of 3.25% between 32℃ and 96℃, and a weight loss of 3.52% between 98℃ and 199℃.

[0415] Table 21

[0416]

[0417] Example 36 Preparation of hydrochloride

[0418] Dissolve 8 mg of compound 1 in 0.1 mL of methyl tert-butyl ether, add 6.4 μL of 2 M hydrochloric acid-ethanol solution, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD spectrum showed no obvious characteristic peaks.

[0419] Example 37 Preparation of hydrochloride

[0420] Dissolve 8 mg of compound 1 in 0.1 mL of solvent 1 (Table 22), add 6.4 μL of 2M hydrochloric acid-ethanol solution, then add 1 mL of solvent 2 (Table 22), stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD spectrum showed no obvious characteristic peaks.

[0421] Table 22

[0422] Solvent 1 Solvent 2 result acetone Isopropyl ether amorphous hydrochloride Ethyl acetate Isopropyl ether amorphous hydrochloride

[0423] Example 38 Preparation of Sulfate

[0424] Dissolve 8 mg of compound 1 in 0.1 mL of one of the 23 solvents listed in Table 2, add 6.4 μL of 2M sulfuric acid ethanol solution, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD spectrum showed no obvious characteristic peaks. The sulfate content was 12.63%.

[0425] Table 23

[0426] solvent result acetone Sulfate amorphous Ethyl acetate Sulfate amorphous Methyl tert-butyl ether Sulfate amorphous

[0427] Example 38 Preparation of Phosphate

[0428] Dissolve 8 mg of compound 1 in 0.1 mL of methyl tert-butyl ether, add 6.4 μL of 2 M phosphate ethanol solution, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD spectrum showed no obvious characteristic peaks.

[0429] Example 39 Preparation of Phosphate

[0430] Dissolve 8 mg of compound 1 in 0.1 mL of solvent 1 from Table 24, add 6.4 μL of 2M phosphate ethanol solution, then add 1 mL of solvent 2 from Table 24. Stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD spectrum showed no obvious characteristic peaks.

[0431] Table 24

[0432] Solvent 1 Solvent 2 result acetone Isopropyl ether Phosphate amorphous Ethyl acetate Isopropyl ether Phosphate amorphous

[0433] Example 40 Preparation of Methanesulfonate

[0434] Dissolve 8 mg of compound 1 in 0.1 mL of methyl tert-butyl ether, add 6.4 μL of 2 M methanesulfonic acid in ethanol, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD spectrum showed no obvious characteristic peaks.

[0435] Example 41 Preparation of methanesulfonate

[0436] Dissolve 8 mg of compound 1 in 0.1 mL of solvent 1 (Table 25), add 6.4 μL of 2M methanesulfonic acid ethanol solution, then add 1 mL of solvent 2 (Table 25), stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD spectrum showed no obvious characteristic peaks.

[0437] Table 25

[0438] Solvent 1 Solvent 2 result acetone Isopropyl ether amorphous methanesulfonate Ethyl acetate Isopropyl ether amorphous methanesulfonate

[0439] Example 42 Preparation of maleate

[0440] Dissolve 8 mg of compound 1 in 0.1 mL of ethyl acetate, add 6.4 μL of 2 M maleic acid ethanol solution and 1 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous and the XRPD spectrum showed no obvious characteristic peaks.

[0441] Example 43 Preparation of p-hydroxybenzoate

[0442] Dissolve 8 mg of compound 1 in 0.1 mL of acetone, add 6.4 μL of 2 M p-hydroxybenzoic acid ethanol solution and 1 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous and the XRPD spectrum showed no obvious characteristic peaks.

[0443] Example 44 Preparation of Laurate

[0444] Dissolve 8 mg of compound 1 in 0.1 mL of ethyl acetate, add 6.4 μL of 2M lauric acid ethanol solution and 1 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous and the XRPD spectrum showed no obvious characteristic peaks.

[0445] Example 45 Preparation of sorbate

[0446] Dissolve 8 mg of compound 1 in 0.1 mL of methyl tert-butyl ether, add 1.5 mg of solid sorbic acid and 1 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous and the XRPD spectrum showed no obvious characteristic peaks.

[0447] Example 46 Preparation of malonate

[0448] Dissolve 8 mg of compound 1 in 0.1 mL of acetone, add 6.4 μL of 2 M malonic acid ethanol solution and 1 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous and the XRPD spectrum showed no obvious characteristic peaks.

[0449] Example 47 Stability Study I

[0450] The free-state amorphous samples were laid flat in an open container and the stability of the samples was investigated under high temperature (40℃ and 60℃) and high humidity (RH 75% and RH 92.5%) conditions. The sampling period was 30 days.

[0451] Table 26

[0452]

[0453] Conclusion: The influencing factor experiment shows that the free amorphous state has good physical stability after 30 days under high temperature (40℃, 60℃) and high humidity (75%RH, 92.5%RH) conditions.

[0454] Example 48 Stability Study II

[0455] Succinate crystal form a, fumarate crystal form α, malate crystal form I, adipate / eutectic crystal form b, and benzoate crystal form α were laid out in open positions and their stability was investigated under high temperature (40℃ and 60℃), high humidity (RH 75% and RH 92.5%), and light conditions. The sampling period was 30 days.

[0456] Table 27

[0457]

[0458]

[0459]

[0460]

[0461] Conclusion: Experiments on influencing factors show that benzoate crystal form α is physically and chemically stable for one month under high temperature (40℃, 60℃) and high humidity (75%RH, 92.5%RH) conditions. Succinate crystal form a, fumarate crystal form α, and malate crystal form I exhibit good physical and chemical stability for one month under various influencing factors. Adipate / eutectic crystal form b shows good physical and chemical stability for one month under high humidity (75%RH), high temperature, and light exposure conditions.

[0462] Example 49 Long-term / Accelerated Stability Study I

[0463] The free amorphous state was placed under conditions of 25℃ / 60%RH and 40℃ / 75%RH to investigate its stability.

[0464] Table 28

[0465]

[0466] Conclusion: Long-term accelerated experiments show that the free amorphous state exhibits good physical and chemical stability under conditions of 25℃ / 60%RH and 40℃ / 75%RH for 3 months.

[0467] Example 50 Long-term / Accelerated Stability Study II

[0468] The stability of succinate crystal form a, fumarate crystal form α, malate crystal form I, adipate / eutectic crystal form b, and benzoate crystal form α was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH, respectively.

[0469] Table 29

[0470]

[0471]

[0472] Conclusion: Long-term accelerated experiments show that benzoate crystal form α, succinate crystal form a, adipate / eutectic crystal form b, fumarate crystal form α, and malate crystal form I have good physical and chemical stability under long-term (25℃ / 60%RH) and accelerated (40℃ / 75%RH) conditions for 3 months.

Claims

1. A fumarate α-crystal form of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction peaks, expressed as diffraction angle 2θ, have characteristic peaks at 7.880, 10.606, 17.878, 19.468, and 23.

546. The structural formula of Equation 1 is...

2. The fumarate α-crystal form of the compound of Formula 1 according to claim 1, characterized in that, The X-ray powder diffraction peaks, expressed as diffraction angle 2θ, have characteristic peaks at 7.880, 10.606, 14.856, 15.019, 17.878, 19.468, 23.546, and 24.

386.

3. The fumarate α-crystal form of the compound of Formula 1 according to claim 1, characterized in that, The X-ray powder diffraction peaks, expressed as diffraction angle 2θ, have characteristic peaks at 7.880, 10.606, 11.202, 14.856, 15.019, 15.680, 17.878, 19.468, 23.546, and 24.

386.

4. The fumarate α-crystal form of the compound of Formula 1 according to claim 1, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 3.

5. A method for preparing the fumarate α-crystal form of the compound of Formula 1 as described in any one of claims 1-4, wherein the method is selected from any one of the following methods: Method 1: Dissolve the compound of formula 1 in acetone or ethyl acetate, add fumaric acid, and stir; Method 2: Add the amorphous fumarate of Formula 1 to acetonitrile and slurry.

6. An adipate crystal form b of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction peaks, expressed as diffraction angle 2θ, have characteristic peaks at 9.789, 14.461, 19.139, 20.609, 21.944, 23.406, and 24.

987. Equation 1 is...

7. The adipate crystal form b of the compound of formula 1 according to claim 6, characterized in that, The X-ray powder diffraction peaks, expressed as diffraction angle 2θ, have characteristic peaks at 9.789, 10.979, 14.461, 17.710, 19.139, 19.963, 20.609, 21.944, 23.406, and 24.

987.

8. The adipate crystal form b of the compound of formula 1 according to claim 6, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 15.

9. A method for preparing the adipate crystal form b of the compound of Formula 1 as described in any one of claims 6-8, the method comprising the steps of dissolving the compound of Formula 1 in methyl tert-butyl ether, adding solid adipic acid, and stirring.

10. The crystal form according to any one of claims 1-4, 6-8, wherein the 2θ angle error range is ±0.

20.

11. An amorphous form of the compound represented by Formula 1, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 1. Equation 1 is...

12. A method for preparing an amorphous form of the compound of formula 1 as described in claim 11, wherein the method is selected from any of the following methods: Method 1: Dissolve the compound of formula 1 in 10% water / methanol and stir; Method 2: Dissolve the compound of Formula 1 in solvent I and evaporate the solvent; wherein solvent I is selected from one or more of alcohol solvents, ketone solvents, ester solvents, ether solvents, hydrocarbon solvents, nitrile solvents, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and water; The alcohol solvent is selected from methanol, ethanol, n-propanol, and isopropanol; The ketone solvent is selected from acetone, 2-butanone, and methyl isobutyl ketone; The ester solvent is selected from ethyl acetate and isopropyl acetate; The ether solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and isopropyl ether; The hydrocarbon solvent is selected from n-heptane and dichloromethane; The nitrile solvent is selected from acetonitrile; Method 3: Dissolve the compound of formula 1 in solvent II, add solvent III, and stir. Solvent II is selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, isopropyl acetate, 2-butanone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl isobutyl ketone, methyl tert-butyl ether, and dimethyl sulfoxide. Solvent III is selected from water and n-heptane. Formula 1 is...

13. A complex of a compound represented by Formula 1, wherein the ligand of the complex is selected from arginine and o-benzoylsulfonylimide, wherein Formula 1 is...

14. A pharmaceutical composition comprising the fumarate α-form of the compound of Formula 1 according to any one of claims 1-4, or the adipate α-form of the compound of Formula 1 according to any one of claims 6-8, or the amorphous form of the compound of Formula 1 according to claim 11, or the complex of the compound of Formula 1 according to claim 13, and optionally a pharmaceutically acceptable excipient.

15. A method for preparing a pharmaceutical composition, comprising the following steps: The step of mixing the fumarate α crystal form of the compound of Formula 1 according to any one of claims 1-4, or the adipate crystal form b of the compound of Formula 1 according to any one of claims 6-8, or the amorphous form of the compound of Formula 1 according to claim 11, or the complex of the compound of Formula 1 according to claim 13, with a pharmaceutically acceptable excipient.

16. Use of the fumarate α-crystal form of the compound of Formula 1 according to any one of claims 1-4 in the preparation of a medicament for treating and / or preventing diseases or conditions mediated by KRAS G12D.

17. Use of the adipate crystal form b of the compound of Formula 1 according to any one of claims 6-8 in the preparation of a medicament for treating and / or preventing diseases or conditions mediated by KRAS G12D.

18. The use of the amorphous form of the compound of Formula 1 as claimed in claim 11, or the complex of the compound of Formula 1 as claimed in claim 13, or the pharmaceutical composition of claim 14 in the preparation of a medicament for treating and / or preventing diseases or conditions mediated by KRAS G12D.

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