Medicinal salt of fused ring compound, crystal form and application thereof

Abstract

The invention relates to a pharmaceutically acceptable salt of a fused ring compound, and a crystal form and application thereof. Specifically, the present disclosure provides a pharmaceutically acceptable salt of 3-chloro-5-((5S, 5aS, 6S, 9R)-1-fluoro-12-((1-((4-(fluoromethylsubunit) piperidine-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-methylbridged naphtho [1, 8-ab] heptan-2-yl)-4-(trifluoromethyl) aniline, a crystal form, and a preparation method thereof, and a preparation method thereof. Corresponding salts have good stability and can be better used for clinical treatment. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a pharmaceutically acceptable salt of a condensed ring compound, a crystal form thereof and uses thereof. Background Art

[0002] RAS is one of the oncogenes with the highest mutation rate in tumors, and about 30% of human malignant tumors are related to mutations in the RAS gene. The RAS family includes KRAS, NRAS, and HRAS, among which KRAS mutations are the most common, accounting for about 85%. KRAS mutations are common in solid tumors, and high-frequency mutations exist in the three major fatal human cancers: lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). Among the KRAS gene mutations, 97% are mutations in the 12th or 13th amino acid residues, among which G12D is an important mutation. Data analysis of European and American populations shows that in pancreatic cancer, colorectal cancer, and non-small cell lung cancer, G12D mutations account for 36%, 12%, and 4% of patients, respectively.

[0003] After KRAS is activated, it regulates cell proliferation, survival, migration, metabolism and other functions through numerous downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc. After the KRAS gene mutates, the protein remains in an activated state, resulting in the continuous activation of downstream signaling pathways and promoting tumorigenesis.

[0004] PCT / CN2023 / 109598 provides a KRAS G12D inhibitor, whose chemical name is 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-methylnaphtho[1,8-ab]heptyl-2-yl)-4-(trifluoromethyl)aniline, having a structure shown in Formula 1,

[0005]

[0006] Salt formation can improve some undesirable physicochemical or biological properties of drugs. It is of great significance to develop salts with better physicochemical or pharmaceutical properties than 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-methano[1,8-ab]heptyl-2-yl)-4-(trifluoromethyl)aniline. In view of the importance of solid drug crystal forms and their stability in clinical treatment, in-depth research on the polymorphic forms of pharmaceutically acceptable salts of the 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-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-4-(trifluoromethyl)aniline is of great significance for the development of drugs suitable for industrial production and with good biological activity. Summary of the invention

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

[0008]

[0009] The present 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, wherein the acid is 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 solvent used for salt formation in the present invention is selected from but not limited to acetone, ethyl acetate, and methyl tert-butyl ether.

[0011] Furthermore, in an optional embodiment, the method for preparing the aforementioned pharmaceutically acceptable salt further comprises the steps of crystallization, filtering, washing or drying.

[0012] In an optional embodiment, the chemical ratio of the compound of Formula 1, 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-methylnaphtho[1,8-ab]heptyl-2-yl)-4-(trifluoromethyl)aniline and the acid is 3:1-1:3, including but not limited to 3:1, 2:1, 1:1, 1:2, 1:3.

[0013] In another embodiment, the chemical ratio of the compound of Formula 1, 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-methanaphtho[1,8-ab]heptyl-2-yl)-4-(trifluoromethyl)aniline and the acid is 2:1-1:2.

[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 1:1-1:2.

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

[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 1:1-1:2.

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

[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 solvent used for salt formation in the present invention is selected from but not limited to acetone, ethyl acetate, and methyl tert-butyl ether.

[0032] The present disclosure provides an amorphous form of a compound of formula 1, wherein the X-ray powder diffraction pattern represented by a diffraction angle 2θ is as follows: Figure 1 shown.

[0033] The present disclosure also provides a method for preparing an amorphous compound of Formula 1, wherein the method is selected from any one of the following methods:

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

[0035] Method 2: dissolving the compound of formula 1 in solvent I, and volatilizing the solvent; the 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: dissolving the compound of formula 1 in solvent II, adding solvent III, and stirring, wherein the 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, and the solvent III is selected from one of water and n-heptane.

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

[0044] In some embodiments, the benzoate salt form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with 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 benzoate salt form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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 benzoate salt form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Figure 2 shown.

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

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

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

[0050] The present disclosure also provides a method for preparing an amorphous fumarate of a compound of 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 crystalline form α of the compound represented by Formula 1 provided in the present disclosure has characteristic peaks at 7.880, 10.606, 17.878, 19.468 and 23.546 in an X-ray powder diffraction pattern represented by a diffraction angle 2θ.

[0052] In some embodiments, the fumarate salt form α of the compound represented by Formula 1 has characteristic peaks at 7.880, 10.606, 14.856, 15.019, 17.878, 19.468, 23.546, and 24.386 in an X-ray powder diffraction pattern represented by a diffraction angle 2θ.

[0053] In some embodiments, the fumarate salt form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.880, 10.606, 11.202, 14.856, 15.019, 15.680, 17.878, 19.468, 23.546, and 24.386.

[0054] In some embodiments, the fumarate salt crystalline form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Figure 3 shown.

[0055] The present disclosure also provides a method for preparing a fumarate crystalline form α of the compound represented by Formula 1, wherein the method is selected from any one 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 the compound of formula 1 into acetonitrile and slurry.

[0058] The fumarate crystalline form β of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 7.371, 10.693, 15.730, 19.643, 21.261, and 22.198.

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

[0060] In some embodiments, the fumarate salt crystalline form β of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Figure 4 shown.

[0061] The present disclosure also provides a method for preparing the crystalline form β of the fumarate salt of the compound shown in Formula 1, comprising the steps of adding the amorphous fumarate salt of the compound shown in Formula 1 into ethanol and slurrying.

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

[0063] The present 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 represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 5.155, 10.259, 15.345, 18.873, 21.599, and 25.552.

[0065] In some embodiments, the tartrate salt form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with 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 tartrate salt form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Figure 5 shown.

[0067] The present disclosure also provides a method for preparing tartrate crystal form a of the compound shown in Formula 1, the method comprising the steps of adding tartaric acid amorphous form of the compound shown in Formula 1 into ethyl acetate and slurrying.

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

[0069] In some embodiments, the tartrate salt form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 8.025, 10.659, 14.561, 15.229, 18.060, 21.445, 22.948, 23.897, and 28.256.

[0070] In some embodiments, the tartrate salt form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and 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 tartrate salt form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Figure 6 shown.

[0072] The present disclosure also provides a method for preparing tartrate crystal form b of the compound shown in Formula 1, the method comprising the steps of adding tartaric acid amorphous form of the compound shown in Formula 1 into water and slurrying.

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

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

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

[0076] The present disclosure also provides a citrate crystalline form A of the compound represented by Formula 1, and an X-ray powder diffraction pattern represented by a diffraction angle 2θ, having characteristic peaks at 8.952, 12.390, 14.868, 18.543, 20.194, and 22.376.

[0077] In some embodiments, the citrate salt form A of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Figure 7 shown.

[0078] The present disclosure also provides a method for preparing a crystalline form A of a citrate of the compound of Formula 1, the method comprising the steps of adding an amorphous citrate of the compound of Formula 1 into 2-methyltetrahydrofuran and slurrying.

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

[0080] The present 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 a malate crystalline form I of the compound represented by Formula 1, and an X-ray powder diffraction pattern represented by a diffraction angle 2θ, having characteristic peaks at 7.996, 10.523, 14.960, 18.839, 19.731, and 21.455.

[0082] In some embodiments, the malate crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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 crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and 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.

[0084] In some embodiments, the malate crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Figure 8 shown.

[0085] The present disclosure also provides a method for preparing a crystalline form I of a malate salt of the compound of Formula 1, the method comprising the steps of adding an amorphous malate salt of the compound of Formula 1 into acetonitrile and slurrying.

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

[0087] The malate crystalline form II of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 7.921, 9.853, 10.908, 18.904, 21.892, and 23.750.

[0088] In some embodiments, the malate crystalline form II of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with 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 crystalline form II of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with 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 malate crystalline form II of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig. 9 shown.

[0091] The present disclosure also provides a method for preparing a crystalline form II of a malate salt of the compound of Formula 1, the method comprising the steps of adding an amorphous malate salt of the compound of Formula 1 into methanol and slurrying.

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

[0093] In some embodiments, the succinate salt form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with 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 salt form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has 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 succinate salt form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.10 shown.

[0096] The present disclosure also provides a method for preparing a succinate crystal form b of the compound represented by formula 1, comprising the steps of dissolving the compound represented by formula 1 in a solvent IV, adding a succinic acid ethanol solution, and stirring, wherein the 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 represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 10.415, 10.680, 14.960, 17.377, 19.314, 21.870, and 23.920.

[0098] In some embodiments, the succinate salt form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with 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 succinate salt form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.11 shown.

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

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

[0102] The acetate crystalline form a of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 5.073, 10.296, 14.899, 18.695, 22.406, and 27.164.

[0103] In some embodiments, the acetate salt form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with 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 acetate salt form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with 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 acetate salt form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.12 shown.

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

[0107] The acetate salt crystalline form b of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 10.443, 14.793, 18.734, 19.826, 21.191, 23.410, and 27.164.

[0108] In some embodiments, the acetate salt form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.13 shown.

[0109] The present disclosure also provides a method for preparing acetate crystal form b of the compound represented by formula 1, the method comprising the steps of dissolving the compound represented by formula 1 in acetone or ethyl acetate, adding ethanol acetic acid solution and isopropyl ether, and stirring.

[0110] The adipate salt crystalline form a of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 4.505, 8.985, 13.376, 18.973, 21.730, 22.625, and 26.413.

[0111] In some embodiments, the adipate salt form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.14 shown.

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

[0113] The adipate salt form b of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 9.789, 14.461, 19.139, 20.609, 21.944, 23.406, and 24.987.

[0114] In some embodiments, the adipate salt form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with 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 adipate salt form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.15 shown.

[0116] The present disclosure also provides a method for preparing adipic acid salt crystalline form b of the compound represented by formula 1, the method comprising the steps of dissolving the compound represented by formula 1 in methyl tert-butyl ether, adding adipic acid solid, and stirring.

[0117] The arginine complex crystalline form I of the compound represented by Formula 1 provided in the present disclosure has characteristic peaks at 15.856, 18.756, 19.840, 23.322, and 26.625 in an X-ray powder diffraction pattern represented by a diffraction angle 2θ.

[0118] In some embodiments, the arginine complex form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and 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.

[0119] In some embodiments, the arginine complex crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.16 shown.

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

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

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

[0123] In some embodiments, the arginine complex form II of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has 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 arginine complex crystalline form II of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.17 shown.

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

[0126] The o-benzoylsulfonyl imide complex crystalline form I of the compound represented by formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 8.120, 11.601, 13.479, 15.048, 18.085, and 20.372.

[0127] In some embodiments, the o-benzoylsulfonyl imide complex crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.18 shown.

[0128] The present disclosure also provides a method for preparing the o-benzoylsulfonyl imide complex crystalline form I of the compound represented by formula 1, comprising the steps of dissolving the compound represented by formula 1 in acetone, adding o-benzoylsulfonyl imide solid, and stirring.

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

[0130] The present disclosure also provides a method for preparing an amorphous hydrochloride of a 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 hydrochloric acid ethanol solution and isopropyl ether, and stirring.

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

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

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

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

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

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

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

[0138] The present disclosure also provides a method for preparing an amorphous maleate salt of a compound represented by Formula 1, comprising the steps of dissolving the compound represented by 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 by the present disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peak at a diffraction angle 2θ in the range of 3-50°.

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

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

[0142] The present disclosure also provides a method for preparing an amorphous laurate salt of the compound of 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 salt of the compound of Formula 1 provided by the present disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peak at a diffraction angle 2θ in the range of 3-50°.

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

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

[0146] The present disclosure also provides a method for preparing an amorphous malonate of the compound of 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 certain embodiments, the preparation method disclosed herein further comprises any step of stirring and dissolving or heating and dissolving, crystallizing, filtering, washing or drying.

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

[0149] The present disclosure also provides a pharmaceutical composition, which is prepared from the amorphous form, succinate, malate, fumarate, tartrate, acetate, adipate, benzoate, hydrochloride, sulfate, phosphate, methanesulfonate, citrate, p-toluenesulfonate, maleate, p-hydroxybenzoate, laurate, sorbate, malonate or their corresponding crystalline forms of the aforementioned optionally selected compound of Formula 1, and optionally a pharmaceutically acceptable excipient.

[0150] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing an amorphous form, succinate, malate, fumarate, tartrate, acetate, adipate, benzoate, hydrochloride, sulfate, phosphate, methanesulfonate, citrate, p-toluenesulfonate, maleate, p-hydroxybenzoate, laurate, sorbate, malonate or a corresponding crystalline form of the aforementioned compound of formula 1 with a pharmaceutically acceptable excipient.

[0151] The present disclosure also provides the use of the amorphous form, succinate, malate, fumarate, tartrate, acetate, adipate, benzoate, hydrochloride, sulfate, phosphate, methanesulfonate, citrate, p-toluenesulfonate, maleate, p-hydroxybenzoate, laurate, sorbate, malonate of the aforementioned compound of Formula 1 or its corresponding crystal forms or the aforementioned composition in the preparation for preventing and / or treating cancer.

[0152] The use disclosed herein, 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 cancer, oral cancer, thyroid cancer, skin cancer, 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 the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number exceeding 1 decimal place is rounded off), 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 the present disclosure, such as the data of the measured and calculated content of the relevant substances, inevitably have a certain degree of error. Generally speaking, ±10% is within the reasonable error range. There is a certain degree of error variation depending on the context where it is used, and the error variation does not exceed ±10%, and can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2% or ±1%, preferably ±5%.

[0155] The starting material used in the crystal preparation method of the present invention can be a compound in any form, and specific forms include but are not limited to: amorphous, any crystal form, hydrate, solvate, etc.

[0156] The drying temperature in the present disclosure is generally 25° C.-100° C., preferably 40° C.-70° C., and the drying can be performed under normal pressure or reduced pressure.

[0157] The crystallization methods described in the present disclosure include room temperature crystallization, cooling crystallization, volatile solvent crystallization, adding seed crystals to induce crystallization, etc. The cooling temperature is selected from below 65°C, preferably -10°C to 60°C, and stirring can also be performed during the crystallization process.

[0158] The "differential scanning calorimetry or DSC" described in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0159] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "9103 Drug Hygroscopicity Guidelines" in the fourth volume of the 2015 edition of the Chinese Pharmacopoeia,

[0160] Deliquesce: Absorbs enough water to form a liquid;

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

[0162] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

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

[0164] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0165] The "excipients" described in the present disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals. BRIEF DESCRIPTION OF THE DRAWINGS

[0166] Figure 1 This is the XRPD spectrum of the amorphous form of compound 1.

[0167] Figure 2 This is the XRPD spectrum of Compound 1 benzoate form α.

[0168] Figure 3 This is the XRPD spectrum of compound 1 fumarate form α.

[0169] Figure 4 XRPD spectrum of compound 1 fumarate crystalline form β

[0170] Figure 5 XRPD spectrum of compound 1 tartrate salt form a

[0171] Figure 6 XRPD spectrum of compound 1 tartrate salt form b

[0172] Figure 7 XRPD spectrum of compound 1 citrate form A

[0173] Figure 8 XRPD spectrum of compound 1 malate crystal form I

[0174] Fig. 9 XRPD spectrum of compound 1 malate crystal form II

[0175] Fig.10 XRPD spectrum of compound 1 succinate salt form b

[0176] Fig.11 XRPD spectrum of compound 1 succinate salt form a

[0177] Fig.12 XRPD spectrum of compound 1 acetate salt form a

[0178] Fig.13 XRPD spectrum of compound 1 acetate salt form b

[0179] Fig.14 XRPD spectrum of compound 1 adipate salt form a

[0180] Fig.15 XRPD spectrum of compound 1 adipate salt form b

[0181] Fig.16 XRPD spectrum of compound 1 arginine cocrystal form I

[0182] Fig.17 XRPD spectrum of compound 1 arginine cocrystal form II

[0183] Fig.18 XRPD spectrum of compound 1 o-benzoylsulfonyl imide cocrystal form I DETAILED DESCRIPTION

[0184] The present disclosure will be explained in more detail below in conjunction with 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 essence and scope of the present disclosure.

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

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

[0187] MS was measured using Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

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

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

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

[0191] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0192] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0193] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

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

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

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

[0197] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0198] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

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

[0200] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

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

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

[0203] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0204] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0205] Where the compounds in the examples contain two or more chiral centres, the relative stereochemistry of these compounds is determined by NMR studies and / or X-ray diffraction. In these cases, the prefix "rel" followed by R / S nomenclature is used to identify these compounds, where R / S only provides relative stereochemical information and does not represent absolute stereochemistry.

[0206] XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, and the specific collection information is: Cu anode (40kV, 40mA), Cu-Kα1 ray Kα2 rays Kβ rays Scanning range (2q range): 3-45°, scanning step length 0.02, scanning speed 0.1s / step, slit width (collimator) 1.0mm. Or adopt step scanning method, the scanning steps are 2 steps, each step scanning range is 19°, the starting degree is 10°, the ending degree is 48°, and the duration of each step is 45s.

[0207] DSC is differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter, with a heating rate of 10°C / min, the specific temperature range refers to the corresponding spectrum (mostly 25-300 or 25-350°C), and a nitrogen purge rate of 50 mL / min.

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

[0209] DVS stands for dynamic moisture adsorption: SMSDVS Advantage is used for detection. At 25°C, 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 range of humidity is subject to the corresponding graph, and most of the methods listed here are used). 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-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-4-(trifluoromethyl)aniline 1

[0212]

[0213] first step

[0214] tert-Butyl 4-(fluoromethylidene)piperidin-1-carboxylate 1b

[0215] 2-((Fluoromethyl)sulfonyl)pyridine (4.2 g, 23.97 mmol) was dissolved in tetrahydrofuran (50 mL), and a 1 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (30 mL) was added at -78°C. The temperature was maintained for reaction for 30 minutes, and then N-tert-butoxycarbonyl-4-piperidone 1a (5 g, 25.09 mmol, Shanghai Shaoyuan) was added. The temperature was maintained for reaction for 3 hours, and then the mixture was returned to room temperature for reaction for 1 hour. Saturated ammonium chloride was added to the reaction solution for quenching, and 3N hydrochloric acid (100 mL) was added. 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 with eluent system B to obtain the title compound 1b (2 g, yield: 37%).

[0216] Step 2

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

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

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

[0220] Step 3

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

[0222] The crude compound 1d (2 g, 8 mmol, prepared by referring 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 reaction was stirred at 110°C for 14 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane, and 20% potassium carbonate solution was added dropwise to adjust the pH to 2-3. After stirring for 2 hours, the mixture was filtered, and 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-hydroxypyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo

[0226] [3.2.1] Octane-8-carboxylic acid tert-butyl ester 1g

[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 the specification of the patent application "WO2022173678A1")) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (201 mg, 5.2 mmol, 60% purity) was added under ice bath. After reacting for 30 minutes, compound 1e (353 mg, 1.31 mmol) was added, and the reaction was stirred for 2 hours. Water was added to the reaction solution to quench the reaction solution and then concentrated under reduced pressure to obtain the crude title compound 1g (600 mg). The product was not purified and used directly in the next step.

[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-pentaaza

[0231] -6,9-methylnaphtho[1,8-ab]heptyl-14-carboxylic acid tert-butyl ester 1h

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

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

[0234] Step 6

[0235] tert-Butyl (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-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-14-carboxylate

[0236] Ester 1j

[0237] (1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol 1i (1.4 g, 6.4 mmol) was dissolved in tetrahydrofuran (15 mL), and a 2M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran was added under ice bath. The temperature was maintained and stirred for 30 minutes. Then, a solution of crude compound 1h (2.3 g, 4.9 mmol) in tetrahydrofuran (20 mL) was added under ice bath. The temperature was maintained and stirred for 1 hour. Saturated ammonium chloride solution was added to the reaction solution for quenching, and the solution was extracted with ethyl acetate (30 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered out and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the 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-oxapropane

[0241] -3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-4-carboxylic acid tert-butyl ester 1k

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

[0243] Step 8

[0244] (5S,5aS,6S,9R)-2-Chloro-1-fluoro-5-methyl-12-((1-((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-14carboxylic 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), and methanesulfonyl chloride (25 mg, 218.2 μmol) was added under ice bath. The reaction mixture was naturally restored to room temperature for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1l (95 mg), which was used directly in the next step without purification.

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

[0248] Step 9

[0249] tert-Butyl (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-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-14-carboxylate

[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-pentaaza-6,9-methano[1,8-ab]

[0255] Tert-butyl 14-heptylcarboxylate

[0256] Compound 1m (20 mg, 31.6 μmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline 1m (15 mg, 46.6 μmol, prepared by the method disclosed in Example 80 on page 257 of the specification of the patent application "WO2022148422"), tetrakis(triphenylphosphine)palladium (7 mg, 6.1 μmol), cesium carbonate (31 mg, 95.1 μmol) were mixed in 1,4-dioxane (1 mL) and water (0.2 mL), replaced with nitrogen, reacted at 100 ° C for 1 hour, the reaction solution was cooled to room temperature and diluted with ethyl acetate, dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure to obtain the crude title compound 1o (20 mg), and the product was directly used in the next step 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-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-4-(trifluoromethyl)aniline 1

[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. After maintaining the temperature for 0.5 hour, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 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 the 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] Test Example 1 Biological Evaluation of GP2d and AGS Cell 3D Proliferation Inhibition Experiment

[0264] 1. Test Purpose

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

[0266] 2. Experimental Methods

[0267] GP2d cells were cultured with complete medium, i.e., 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 in a 96-well low-adhesion plate (Corning, CLS7007-24EA) at a density of 1000 cells / well using complete medium, with 90 μL of cell suspension per well, centrifuged at 2000 rpm at room temperature for 5 minutes, and then placed in a 37°C, 5% CO2 cell culture incubator for overnight culture.

[0268] AGS cells were cultured with complete medium, i.e., RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, AGS cells were seeded in a 96-well low-adhesion plate (Corning, CLS7007-24EA) at a density of 1000 cells / well using complete medium, with 90 μL of cell suspension per well, centrifuged at 2000 rpm for 5 minutes at room temperature, and then placed in a 37°C, 5% CO2 cell culture incubator for overnight culture.

[0269] On the second day, 10 μL of the compound to be tested prepared with complete medium was added to each well. The final concentration of the compound for GP2d cells was 9 concentration points of 5-fold gradient dilution starting from 1 μM, and the final concentration of the compound for AGS cells was 9 concentration points of 5-fold gradient dilution starting from 10 μM. A blank control containing 0.5% DMSO was set. The well plate was placed in a cell culture incubator at 37°C and 5% CO2 for 5 days. On the seventh day, the 96-well cell culture plate was taken out and 50 μL of the compound to be tested was added to each well. 3D Cell Viability Assay reagent (Promega, G9682) was shaken at room temperature in the dark for 25 minutes, then pipetted to mix and 100 μL was taken out from each well and transferred to a white opaque 96-well plate (PerkinElmer, 6005290), and the luminescent signal value was read using a multi-function microplate reader (PerkinElmer, EnVision2105).

[0270] 3. Data Analysis

[0271] The IC of the inhibitory activity of the compounds was calculated using Graphpad Prism software 50 The results are shown in Table 2 below.

[0272] Table 1 AGS, GP2d cell 3D proliferation inhibitory activity data

[0273]

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

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

[0276] On the first day of the experiment, AsPC-1 cells that grew 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 required level. 90 μL of cell suspension was added to each well of a U-shaped low-adsorption 96-well plate (Corning, CLS7007-24EA), and the cell density was 1500 cells / well. After the cell plate was centrifuged at 2500 rpm for 5 minutes, it was placed in a 37°C, 5% CO2 incubator and cultured overnight. On the second day, the 20mM test compound dissolved in DMSO was diluted with DMSO to a first concentration of 2mM, and then diluted 5-fold gradients for a total of 9 concentration points, and the control well was DMSO. The gradient diluted compound was then further diluted 20 times with culture medium. 10 μL of the test compound diluted with culture medium was added to each well of the cell plate, and the final concentration of the compound was the first concentration of 10 μM and the 9 concentration points of the 5-fold gradient dilution. The cell wells containing 0.5% DMSO were set as the solvent control wells, and the wells containing only the culture medium and 0.5% DMSO were set as blank control wells. The compound concentrations and control wells were set in duplicate, and the final DMSO concentration in each well was 0.5%. After centrifugation at 2500 rpm for 3 minutes, the cell plate was placed in a 37°C, 5% CO2 incubator for 5 days. On the seventh day, the 96-well cell culture plate was removed and 50 μL of luminescent cell activity detection reagent was added to each well. 3D Cell Viability Assay (Promega, G9683), shake at room temperature in the dark for 25 minutes, pipette up and down to mix, and transfer 100 μL per well to the white opaque OptiPlate TM -96-well plate (PerkinElmer, 6005290), and the luminescent signal value was read using a multi-function microplate reader (PerkinElmer, EnVision2105).

[0277] The inhibition rate was calculated using the following formula: Inhibition rate = (luminescence 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%. GraphPad Prism software was used to draw a curve based on the concentration of the compound and the corresponding inhibition rate, and the IC of the compound was calculated. 50 value.

[0278] Table 2 AsPC-1 cell 3D proliferation inhibition activity data

[0279] Example No. <![CDATA[AsPC-1 / IC 50 (nM)]]> 1 0.2

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

[0281] Example 2 Preparation of amorphous compound of formula 1

[0282] 5 mg of the compound of formula 1 was dissolved in 0.05 mL of 10% water / methanol, stirred at room temperature to precipitate, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis showed that the product was amorphous, with an XRPD spectrum as shown below: Figure 1 . The TGA spectrum shows that the weight loss is 1.13% at 32℃-118℃. The DVS test shows that under normal storage conditions (i.e. 25℃, 60%RH), the sample has a moisture absorption weight gain of about 2.10%; under accelerated experimental conditions (i.e. 70%RH), the moisture absorption weight gain is about 2.6%; under extreme conditions (90%RH), the moisture absorption weight gain is about 4.5%; after DVS test, the crystal form is retested and it is still amorphous.

[0283] Example 3 Preparation of amorphous compound of formula 1

[0284] 5 mg of the compound represented by Formula 1 was dissolved in a solvent listed in Table 3, and the solvent was evaporated at room temperature to obtain the title product.

[0285] Table 3

[0286]

[0287]

[0288] Example 4 Preparation of amorphous compound of formula 1

[0289] 5 mg of the compound of formula 1 was dissolved in solvent 1 in Table 4, and solvent 2 was added. The mixture was stirred at room temperature to precipitate, and the mixture was centrifuged. The solid was dried in vacuum to obtain the title product.

[0290] Table 4

[0291]

[0292] Example 5 Preparation of Benzoate Crystalline Form α

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

[0294] The X-ray powder diffraction test revealed that the benzoate crystal form α was obtained. The XRPD spectrum was as follows: Figure 2 , and the positions of its characteristic peaks are shown in Table 5. The DSC spectrum shows that the peak value of the endothermic peak is 210°C. The TGA spectrum shows that the weight loss is 0.61% at 40°C-75°C and 8.46% at 140°C-200°C. The DVS test shows that under normal storage conditions (i.e. 25°C, humidity 60%), the sample has a moisture absorption weight gain of about 1.075%; under accelerated test conditions (i.e. humidity 70%), the moisture absorption weight gain is about 1.151%; under extreme conditions (i.e. humidity 90%), the moisture absorption weight gain is about 1.342%. During the humidity change process from 0% to 95%, the desorption process of the sample coincides with the adsorption process; the crystal form was retested after DVS detection, and the crystal form did not change. The ion detection results show that the benzoate content is 15.27%.

[0295] through 1 H NMR test showed that the salt ratio of the compound of formula 1 and 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 Crystalline Form α

[0301] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, and 6.4 μL of 2M benzoic acid ethanol solution was added. The mixture was stirred at room temperature for crystallization, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis showed that the product was benzoate crystal form α.

[0302] Example 7 Preparation of Benzoate Crystalline Form α

[0303] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of methyl tert-butyl ether, and 6.4 μL of 2M benzoic acid ethanol solution was added. The mixture was stirred at room temperature for crystallization, centrifuged, and vacuum dried 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 with ethyl acetate (50 mL), stirred until completely dissolved, heated to 50 °C and stirred for 5 minutes, and fumaric acid ethanol solution (0.3 M, 12.0 mL) was added dropwise to precipitate solids. Stirring was continued for 1 hour until most of the solids dissolved. The mixture was slowly cooled to room temperature and stirred for 16 hours until a large amount of solids precipitated. The mixture 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 the fumarate was amorphous, and the X-ray powder diffraction spectrum had no obvious characteristic peaks.

[0306] Example 9 Preparation of Fumarate Crystalline Form α

[0307] 8 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of acetone, 1.5 mg of solid fumaric acid was added, and the mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain the title product. The product was defined as fumarate crystal form α by X-ray powder diffraction detection, and the XRPD spectrum was as follows: Figure 3 , and the positions of its characteristic peaks are shown in Table 6. The DSC spectrum shows that the peak values ​​of the endothermic peaks are 109.46°C and 219.39°C. The TGA spectrum shows that the weight loss is 5.84% at 40°C-210°C. The ion detection results show that the fumarate content is 14.51%. The DVS test shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 3.3%; under accelerated experimental conditions (i.e. 70% RH), the moisture absorption weight gain is about 3.6%; under extreme conditions (90% RH), the moisture absorption weight gain is about 4.5%; after DVS detection, the crystal form is retested and the crystal form has not changed.

[0308] through 1 H NMR test showed that the salt ratio of the compound of formula 1 and 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 Crystalline Form α

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

[0314] Example 11 Preparation of Fumarate Crystalline Form α

[0315] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of ethyl acetate, 1.5 mg of solid fumaric acid was added, the mixture was stirred at room temperature for crystallization, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis showed that the product was fumarate crystal form α.

[0316] Example 12 Preparation of Fumarate Crystalline Form β

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

[0318] through 1 H NMR test showed that the salt ratio of the compound of formula 1 and 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 to dissolve completely, heated to 50 ° C and stirred for 5 minutes, 5 mL of ethanol solution of L-tartaric acid (434 mg, 2.8917 mmol) was added dropwise, solid was precipitated, ethyl acetate (5 mL) was added, and stirring continued for 1 h. The solid did not dissolve, then cooled to room temperature, stirred for 2 h, filtered, and the filter cake was collected and vacuum dried to obtain a solid. X-ray powder diffraction detection showed that it was an amorphous tartrate salt, and the X-ray powder diffraction spectrum had no obvious characteristic peaks. 1 H NMR test showed that the salt ratio of the compound of formula 1 and L-tartaric acid was 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 Crystalline Form a

[0326] The amorphous L-tartrate sample (60 mg, 60.5 μmol) of the compound of 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 vacuum dried to obtain a solid. The crystal form was defined as L-tartrate crystal form a by X-ray powder diffraction detection. The X-ray powder diffraction spectrum is as follows: Figure 5 , and the characteristic peak positions are shown in Table 8. The DSC spectrum shows that the endothermic peaks are 66.82°C and 211.50°C. The TGA spectrum shows that the weight loss is 3.39% at 30°C-100°C. The 1H NMR nuclear magnetic test shows that the salt ratio of the compound of formula 1 and L-tartaric acid is 1:1.

[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] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone (the solvent may be 0.1 mL of ethyl acetate), 6.4 μL of 2M tartaric acid ethanol solution was added, the mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain the title product.

[0332] Example 16 Preparation of Tartrate Crystalline Form B

[0333] The amorphous L-tartrate sample (60 mg, 60.5 μmol) of the compound of 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. The product was defined as L-tartrate crystal form b by X-ray powder diffraction detection. The X-ray powder diffraction spectrum is as follows: Figure 6, and the characteristic peak positions are shown in Table 9. The DSC spectrum shows that the endothermic peaks are 78.81°C and 218.77°C. The TGA spectrum shows that the weight loss is 3.22% at 30°C-100°C. The 1H NMR nuclear magnetic test shows that the salt ratio of the compound of formula 1 and L-tartaric acid is 1:1.

[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 to dissolve, then 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 was immediately precipitated. The mixture was stirred at 50 ° C for 1 hour. The solid was partially dissolved but not completely dissolved. The mixture was slowly cooled to room temperature and stirred for 16 hours. The solid was filtered and vacuum dried to obtain the solid. X-ray powder diffraction analysis showed that the citrate was amorphous and the XRPD spectrum had no obvious characteristic peaks. 1 H NMR test showed that the salt ratio of the compound of formula 1 and citric acid was 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, and the mixture was stirred for 72 h. The mixture was filtered, and the solid was collected and dried under vacuum to obtain a solid. The product was defined as citrate crystal form A by X-ray powder diffraction detection. The XRPD spectrum is shown in Figure 7 , and the characteristic peak positions are shown in Table 10. 1 H NMR test showed that the salt ratio of the compound of formula 1 to citric acid was 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] Example 19 Preparation of malate

[0347] 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, and a 5 mL ethanol solution of L-malic acid (388 mg, 2.89 mmol) was added dropwise to precipitate a solid, which was dissolved after stirring, and then ethyl acetate (5 mL) was added and stirred for 1 h. After all the solid was dissolved, the mixture was cooled to room temperature and stirred for 16 h. The solid was concentrated under reduced pressure to obtain a solid. X-ray powder diffraction detection showed that the L-malate was amorphous, and the XRPD spectrum had no obvious characteristic peaks.

[0348] Example 20 Preparation of Malate Crystalline Form I

[0349] The amorphous L-malate salt of formula 1 (60 mg, 48.9 μmol) was added with 4 mL of acetonitrile, stirred for 72 h, filtered, and the solid was collected and dried under vacuum. The product was defined as L-malate salt form I by X-ray powder diffraction detection. The XRPD spectrum is shown in Figure 8 , and the positions of its characteristic peaks are shown in Table 11. The DSC spectrum shows that the endothermic peaks are 76.81°C, 188.79°C, and 216.12°C, and the exothermic peak is 208.13°C. The TGA spectrum shows that the weight loss at 40°C-100°C is 3.1%. The DVS test shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample absorbs moisture and gains weight by about 3.3%; under accelerated experimental conditions (i.e. 70% RH), the moisture absorption and weight gain are about 3.6%; under extreme conditions (90% RH), the moisture absorption and weight gain are about 4.3%; after the DVS test, the crystal form was retested and the crystal form did not change. The ion detection results show that the malate ion content is 27.57%. 1 H NMR test showed that the salt ratio of the compound of formula 1 and malic acid was 1:2.

[0350] 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).

[0351] Table 11

[0352]

[0353]

[0354] Example 21 Preparation of Malate Crystal Form I

[0355] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, and 6.4 μL of 2M malic acid ethanol solution was added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain the title product.

[0356] Example 22 Preparation of Malate Crystalline Form II

[0357] The amorphous L-malate salt of formula 1 (60 mg, 48.9 μmol) was added with 1 mL of methanol, slurried and stirred for 72 h, filtered, and the solid was collected and dried in vacuo. The product was defined as L-malate salt form II by X-ray powder diffraction detection. The X-ray powder diffraction spectrum is shown in Fig. 9 The characteristic peak positions are shown in Table 12. The DSC spectrum shows that the endothermic peaks are 65.48°C, 147.46°C, 183.42°C, and 210.25°C, and the exothermic peak is 208.13°C. The TGA spectrum shows that the weight loss is 2.1% at 40°C-100°C. 1 H NMR test showed that the salt ratio of the compound of formula 1 and malic acid was 1:2.

[0358] 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).

[0359] Table 12

[0360]

[0361]

[0362] Example 23 Preparation of Succinate Form B

[0363] The compound shown in formula 1 (500 mg, 722.4 μmol) was added with methyl tert-butyl ether (15 mL), stirred and dissolved, then heated to 50 ° C and stirred for 5 minutes, and succinic acid ethanol solution (0.3 M, 4.8 mL) was added dropwise. No solid was precipitated, and ethyl acetate (5 mL) was added. Stirring continued for 1 hour, cooled to room temperature, stirred for 16 hours, and a large amount of solid was precipitated. Filter, rinse the filter cake with 5 mL of ethyl acetate, filter, collect the filter cake, and vacuum dry to obtain a solid. After X-ray powder diffraction detection, it was defined as succinate crystal form b. The X-ray powder diffraction spectrum is shown as follows: Fig.10 , and the characteristic peak positions are shown in Table 13. 1 H NMR test showed that the salt ratio of the compound of formula 1 to succinic acid was 1:2.

[0364] 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).

[0365] Table 13

[0366]

[0367]

[0368] Example 24 Preparation of Succinate Form B

[0369] Add ethyl acetate (50 mL) to the compound shown in Formula 1 (2.5 g, 3.6 mmol), stir to dissolve, heat to 50 ° C and stir for 5 minutes, add succinic acid ethanol solution (0.3 M, 12.0 mL) dropwise, no solid is precipitated, continue stirring for 1 hour, slowly cool to room temperature, stir for 16 hours, a large amount of solid is precipitated, filter, rinse the filter cake with 10 mL of ethyl acetate, collect the filter cake and vacuum dry, and X-ray powder diffraction test shows that the product is succinate crystal form b. DSC spectrum shows: endothermic peaks are 137.99 ° C, 145.17 ° C, 164.09 ° C. TGA spectrum shows: 110 ° C-170 ° C weight loss of 4.12%. 1H NMR test showed that the salt ratio of the compound of formula 1 to succinic acid was 1:2.

[0370] 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).

[0371] Example 25 Preparation of Succinate Form B

[0372] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, and 1.5 mg of solid succinic acid and 1 mL of isopropyl ether were added. The mixture was stirred at room temperature to precipitate, and the mixture was centrifuged. The solid was dried in vacuum to obtain the title product.

[0373] Example 26 Preparation of Succinate Crystalline Form a

[0374] The succinate salt form b (60 mg, 64.6 μmol) of formula 1 was added with 6 mL of ethyl acetate, stirred for 5 days, filtered, and the filter cake was collected and vacuum dried to obtain a solid. The product was defined as succinate salt form a by X-ray powder diffraction detection. The X-ray powder diffraction spectrum is shown in Fig.11 The characteristic peak positions are shown in Table 14. The DSC spectrum shows that the endothermic peaks are 73.31°C and 171.34°C. The TGA spectrum shows that the weight loss is 4.04% at 40°C-140°C. 1 H NMR test showed that the salt ratio of the compound of formula 1 to citric acid was 1:1.3.

[0375] 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).

[0376] Table 14

[0377]

[0378]

[0379] Example 27 Preparation of Acetate Crystalline Form a

[0380] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, and 12.8 μL of 2M acetic acid ethanol solution and 1 mL of isopropyl ether were added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain the title product. The product was defined as acetate salt form a by X-ray powder diffraction detection. The XRPD spectrum is shown in Fig.12 The characteristic peak positions are shown in Table 15. The DSC spectrum shows that the endothermic peak value is 107.14°C. The TGA spectrum shows that the weight loss is 15.82% from 33°C to 153°C.

[0381] Table 15

[0382]

[0383] Example 28 Preparation of Acetate Crystalline Form B

[0384] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, 6.4 μL of 2M acetic acid ethanol solution and 1 mL of isopropyl ether were added, and the mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain the title product. The product was defined as acetate salt form b by X-ray powder diffraction detection, and the XRPD spectrum was as follows: Fig.13 The characteristic peak positions are shown in Table 16. The DSC spectrum shows that the endothermic peaks are 95.98°C and 107.15°C. The TGA spectrum shows that the weight loss is 15.68% at 32°C-163°C.

[0385] Table 16

[0386]

[0387] Example 29 Preparation of Acetate Crystalline Form B

[0388] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of ethyl acetate, and 6.4 μL of 2M ethanolic acetic acid solution and 1 mL of isopropyl ether were added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was dried in vacuo to obtain the title product.

[0389] Example 30 Preparation of adipate salt crystal form a

[0390] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, and 2.1 mg of adipic acid solid was added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain the title product. The product was defined as adipic acid salt crystal form a by X-ray powder diffraction detection. The XRPD spectrum is shown in Fig.14 The characteristic peak positions are shown in Table 17. The DSC spectrum shows that the exothermic peak has a peak value of 130.25°C, and the endothermic peak has a peak value of 156.89°C and 163.93°C. The TGA spectrum shows that the weight loss is 5.67% at 34°C-155°C.

[0391] Table 17

[0392]

[0393] Example 31 Preparation of adipate salt crystal form a

[0394] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of ethyl acetate, and 2.1 mg of solid adipic acid was added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was dried in vacuo to obtain the title product.

[0395] Example 32 Preparation of adipate salt crystal form b

[0396] 15 mg of the compound of formula 1 was dissolved in 0.2 mL of methyl tert-butyl ether, 4.1 mg of adipic acid solid was added, and the mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain the title product. The product was defined as adipic acid salt crystal form b by X-ray powder diffraction detection, and the XRPD spectrum was as follows: Fig.15 , and the positions of its characteristic peaks are shown in Table 18. The DSC spectrum shows that the endothermic peaks are 62.16°C and 154.27°C. The TGA spectrum shows that the weight loss is 6.78% at 32°C-145°C. The ion detection results show that the adipate content is 17.76%. The DVS test shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 7.4%; under accelerated experimental conditions (i.e. 70% RH), the moisture absorption weight gain is about 7.8%; under extreme conditions (90% RH), the moisture absorption weight gain is about 8.6%; after DVS detection, the crystal form was retested and the crystal form did not change.

[0397] Table 18

[0398]

[0399] Example 33 Preparation of Arginine Complex Crystalline Form I

[0400] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, and 2.4 mg of arginine solid was added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain the title product. The product was defined as arginine complex crystal form I by X-ray powder diffraction detection. The XRPD spectrum is shown in Fig.16 The characteristic peak positions are shown in Table 19. The DSC spectrum shows that the endothermic peaks are 55.81°C, 222.29°C and 232.97°C. The TGA spectrum shows that the weight loss is 4.50% from 33°C to 185°C.

[0401] Table 19

[0402]

[0403] Example 34 Preparation of Arginine Complex Crystalline Form II

[0404] The arginine complex crystal form I in Example 31 was placed at 25°C / 92.5% RH for 5 days to obtain the title product.

[0405] The product was defined as arginine complex crystal form II by X-ray powder diffraction detection. The XRPD spectrum is as follows: Fig.17 , and the positions of its characteristic peaks are shown in Table 20.

[0406] Table 20

[0407]

[0408]

[0409] Example 35 Preparation of o-benzoylsulfonyl imide complex crystal form I

[0410] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, 2.5 mg of solid o-benzoylsulfonyl imide was added, and the mixture was stirred at room temperature for crystallization, centrifuged, and vacuum dried to obtain a solid. The product was defined as o-benzoylsulfonyl imide complex crystal form I by X-ray powder diffraction detection, and the XRPD spectrum was as follows: Fig.18 The characteristic peak positions are shown in Table 21. The DSC spectrum shows that the endothermic peaks are 42.82°C and 188.12°C. The TGA spectrum shows that the weight loss is 3.25% at 32°C-96°C and 3.52% at 98°C-199°C.

[0411] Table 21

[0412]

[0413] Example 36 Preparation of Hydrochloride

[0414] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of methyl tert-butyl ether, and 6.4 μL of 2M hydrochloric acid ethanol solution was added. The mixture was stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous and had no obvious characteristic peaks in the XRPD spectrum.

[0415] Example 37 Preparation of Hydrochloride

[0416] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of solvent 1 in Table 22, 6.4 μL of 2M hydrochloric acid ethanol solution was added, and then 1 mL of solvent 2 in Table 22 was added, stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction detection showed that the product was amorphous and the XRPD spectrum had no obvious characteristic peaks.

[0417] Table 22

[0418] Solvent 1 Solvent 2 result acetone Isopropyl ether Hydrochloride amorphous Ethyl acetate Isopropyl ether Hydrochloride amorphous

[0419] Example 38 Preparation of sulfate

[0420] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of the solvents in Table 23, 6.4 μL of 2M sulfuric acid ethanol solution was added, stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous and had no obvious characteristic peaks in the XRPD spectrum. The sulfate content was 12.63%.

[0421] Table 23

[0422] Solvents result acetone Sulfate amorphous Ethyl acetate Sulfate amorphous Methyl tert-butyl ether Sulfate amorphous

[0423] Example 38 Preparation of Phosphate

[0424] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of methyl tert-butyl ether, and 6.4 μL of 2M ethanolic phosphoric acid solution was added. The mixture was stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous and had no obvious characteristic peaks in the XRPD spectrum.

[0425] Example 39 Preparation of Phosphate

[0426] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of solvent 1 in Table 24, 6.4 μL of 2M ethanolic phosphoric acid solution was added, and then 1 mL of solvent 2 in Table 24 was added, stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction detection showed that the product was amorphous and the XRPD spectrum had no obvious characteristic peaks.

[0427] Table 24

[0428] Solvent 1 Solvent 2 result acetone Isopropyl ether Phosphate Amorphous Ethyl acetate Isopropyl ether Phosphate Amorphous

[0429] Example 40 Preparation of Methanesulfonate

[0430] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of methyl tert-butyl ether, and 6.4 μL of 2M methanesulfonic acid ethanol solution was added. The mixture was stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous and had no obvious characteristic peaks in the XRPD spectrum.

[0431] Example 41 Preparation of Methanesulfonate

[0432] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of solvent 1 in Table 25, 6.4 μL of 2M methanesulfonic acid ethanol solution was added, and 1 mL of solvent 2 in Table 25 was added, stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction detection showed that the product was amorphous and the XRPD spectrum had no obvious characteristic peaks.

[0433] Table 25

[0434] Solvent 1 Solvent 2 result acetone Isopropyl ether Methanesulfonate amorphous Ethyl acetate Isopropyl ether Methanesulfonate amorphous

[0435] Example 42 Preparation of maleate salt

[0436] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of ethyl acetate, 6.4 μL of 2M maleic acid ethanol solution and 1 mL of isopropyl ether were added, stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous and had no obvious characteristic peaks in the XRPD spectrum.

[0437] Example 43 Preparation of p-Hydroxybenzoate

[0438] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, 6.4 μL of 2M p-hydroxybenzoic acid ethanol solution and 1 mL of isopropyl ether were added, stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction analysis showed that the product was amorphous and had no obvious characteristic peaks in the XRPD spectrum.

[0439] Example 44 Preparation of laurate

[0440] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of ethyl acetate, 6.4 μL of 2M lauric acid ethanol solution and 1 mL of isopropyl ether were added, stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction detection showed that the product was amorphous and the XRPD spectrum had no obvious characteristic peaks.

[0441] Example 45 Preparation of sorbate

[0442] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of methyl tert-butyl ether, 1.5 mg of sorbic acid solid and 1 mL of isopropyl ether were added, stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction detection showed that the product was amorphous and the XRPD spectrum had no obvious characteristic peaks.

[0443] Example 46 Preparation of Malonate

[0444] 8 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, 6.4 μL of 2M malonic acid ethanol solution and 1 mL of isopropyl ether were added, stirred at room temperature to precipitate, centrifuged, and the solid was vacuum dried to obtain the title product. X-ray powder diffraction detection showed that the product was amorphous and the XRPD spectrum had no obvious characteristic peaks.

[0445] Example 47 Stability Study I

[0446] The free amorphous material was laid out in an open position, and the stability of the sample was investigated under high temperature (40°C and 60°C) and high humidity (RH 75%, RH 92.5%) conditions, and the sampling period was 30 days.

[0447] Table 26

[0448]

[0449]

[0450] Conclusion: The influencing factor experiment shows that the free amorphous state has good physical stability for 30 days under the influencing factor high temperature conditions (40℃, 60℃); and has good physical and chemical stability for 30 days under high humidity conditions (75%RH, 92.5%RH).

[0451] Example 48 Stability Study II

[0452] The succinate form a, fumarate form α, malate form I, adipate / cocrystal form b and benzoate form α were spread out in the open, and the stability of the samples was investigated under high temperature (40°C and 60°C), high humidity (RH 75%, RH 92.5%) and light conditions, and the sampling period was 30 days.

[0453] Table 27

[0454]

[0455]

[0456]

[0457] Conclusion: The influencing factor experiment shows that the benzoate salt form α is physically and chemically stable under high temperature (40℃, 60℃) and high humidity (75%RH, 92.5%RH) conditions for 1 month. The succinate salt form a, fumarate salt form α and malate salt form I have good physical and chemical stability under the influencing factor conditions for 1 month. The adipate salt / cocrystal form b has good physical and chemical stability under high humidity (75%RH), high temperature and light conditions for 1 month.

[0458] Example 49 Long-term / accelerated stability study I

[0459] The free amorphous state was placed under 25°C / 60%RH and 40°C / 75%RH conditions to investigate the stability.

[0460] Table 28

[0461]

[0462] Conclusion: Long-term accelerated experiments show that the free amorphous state has good physical and chemical stability under 25℃ / 60%RH and 40℃ / 75%RH conditions for 3 months.

[0463] Example 50 Long-term / accelerated stability study II

[0464] The succinate form a, fumarate form α, malate form I, adipate / cocrystal form b and benzoate form α were placed at 25°C / 60% RH and 40°C / 75% RH, respectively, to investigate their stability.

[0465] Table 29

[0466]

[0467]

[0468] Conclusion: Long-term accelerated experiments show that the benzoate form α, succinate form a, adipate / cocrystal form b, fumarate form α and malate form I have good physical and chemical stability under long-term (25°C / 60% RH) and accelerated (40°C / 75% RH) conditions for 3 months.

Claims

1. A succinate crystalline form 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-methylnaphtho[1,8-ab]heptyl-2-yl)-4-(trifluoromethyl)aniline as shown in Formula 1 a, an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, having characteristic peaks at 10.415, 10.680, 14.960, 17.377, 19.314, 21.870, and 23.920, preferably at 8.040, 10.415, 10.680, 11.181, 14.960, 17.377, 19.314, 21.870, 23.920, 24.880, and 26.719, 2. The succinate salt form a according to claim 1, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG11 .

3. A method for preparing the succinate salt form a as claimed in claim 1 or 2, comprising the steps of dissolving the compound represented by formula 1 in ethyl acetate, adding succinic acid, and stirring.

4. A malate crystalline form I of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.996, 10.523, 14.960, 18.839, 19.731, and 21.455, preferably at 7.996, 10.523, 11.050, 13.325, 14.960, 15.383, 16.769, 17.132, 17.998, 18.839, 19.731, and 21.

455. The characteristic peaks are at 455, 23.642, and 26.054, and more preferably 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.

5. The malate crystalline form I according to claim 4, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG8 .

6. A method for preparing the malate crystalline form I according to claim 4 or 5, wherein the method is selected from any one of the following methods: Method 1: Dissolve the compound of formula 1 in acetone or methyl tert-butyl ether, add malic acid ethanol solution, and stir; Method 2: Add the amorphous malate of the compound of formula 1 into acetonitrile and slurry.

7. According to the crystal form according to any one of claims 1-2, 4-5, the 2θ angle error range is ±0.

20.

8. A pharmaceutical composition comprising 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-methanaphtho[1,8-ab]heptyl-2-yl)-4-(trifluoromethyl)aniline in a crystalline form and optionally a pharmaceutically acceptable excipient.

9. A method for preparing a pharmaceutical composition, comprising the following steps: 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl The invention further comprises the step of mixing a crystalline form of -5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-2-yl)-4-(trifluoromethyl)aniline with a pharmaceutically acceptable excipient.

10. Use of a crystalline form 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-methanaphtho[1,8-ab]heptyl-2-yl)-4-(trifluoromethyl)aniline according to any one of claims 1-2 and 4-5, or a pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing a disease or condition mediated by KRAS G12D.

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