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

Abstract

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

Description

TECHNICAL FIELD

[0001] The present disclosure belongs to the technical field of medicine, and relates to a pharmaceutically acceptable salt of a fused ring compound, a crystalline form thereof and a use thereof. BACKGROUND

[0002] RAS is one of the oncogenes with the highest mutation rate in tumors, and about 30% of human malignancies 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 three of the most deadly cancers in humans: lung cancer (17%), colorectal cancer (33%) and pancreatic cancer (61%). Among the genetic mutations of KRAS, 97% are mutations in the 12th or 13th amino acid residues, and G12D is an important mutation. Analysis of data on European and American populations shows that G12D mutations account for 36%, 12% and 4% of patients with pancreatic cancer, colorectal cancer and non-small cell lung cancer, respectively.

[0003] After KRAS is activated, it regulates cell proliferation, survival, migration and metabolism and other functions through a large number of downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc. After KRAS gene mutation, the protein is continuously in an activated state, leading to continuous activation of downstream signaling pathways and promoting tumor occurrence.

[0004] PCT / CN2023 / 109598 provides a KRAS G12D inhibitor, which has the chemical name 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptacyclic ring-2-yl)-4-(trifluoromethyl)aniline, which has the structure shown in formula 1,

[0005]

[0006] The salt formation can improve some undesirable physical, chemical or biological properties of the drug. It is of great significance to develop a salt of 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline which has more excellent properties in terms of physical and chemical properties or pharmaceutical properties. In view of the importance of solid drug crystal form and its stability in clinical treatment, it is of great significance to further study the polymorphs of the pharmaceutically acceptable salt of the compound 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline for the development of a drug suitable for industrial production and good biological activity. SUMMARY

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

[0010] The solvent used for salt formation in the present disclosure is selected from, but not limited to, acetone, ethyl acetate, methyl tert-butyl ether.

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

[0012] In an alternative embodiment, the chemical ratio of the compound of Formula 1, 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9- methanonaphtho[1,8-ab]heptacycl-2-yl)-4-(trifluoromethyl)aniline, to 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-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9- methanonaphtho[1,8-ab]heptacycl-2-yl)-4-(trifluoromethyl)aniline, to the acid is 2:1-1:2.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0030] In an alternate 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 disclosure is selected from, but not limited to, acetone, ethyl acetate, methyl tert-butyl ether.

[0032] The present disclosure provides an amorphous form of a compound of formula 1 having an X-ray powder diffraction pattern, as expressed in terms of diffraction angles 2Q, as shown in Figure 1

[0033] The present disclosure also provides a process for preparing an amorphous form of a compound of formula 1, said process is selected from any one of the following processes:

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

[0035] Process 2: Dissolve the compound of formula 1 in solvent I, evaporate the solvent; said solvent I is selected from one or more of an alcohol solvent, a ketone solvent, an ester solvent, an ether solvent, a hydrocarbon solvent, a nitrile solvent, N-methyl pyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, water;

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

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

[0038] said ester solvent is selected from ethyl acetate, isopropyl acetate;

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

[0040] said hydrocarbon solvent is selected from n-heptane, dichloromethane; ​

[0041] the nitrile solvent is selected from acetonitrile;

[0042] Method three: dissolving the compound of formula 1 in solvent II selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, isopropyl acetate, 2-butanone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl isobutyl ketone, methyl tert-butyl ether, dimethyl sulfoxide, and adding solvent III selected from water, n-heptane, and stirring.

[0043] The benzoic acid salt crystal form α of the compound of formula 1 provided by the present disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ angle, and has characteristic peaks at 5.751, 10.627, 11.285, 21.576, 23.385, 28.637.

[0044] In some embodiments, the benzoic acid salt crystal form α of the compound of formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ angle, and has characteristic peaks at 5.751, 10.627, 10.928, 11.285, 14.703, 18.424, 20.342, 21.576, 23.385, 28.637.

[0045] In some embodiments, the benzoic acid salt crystal form α of the compound of formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ angle, 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, 30.786.

[0046] In some embodiments, the benzoic acid salt crystal form α of the compound of formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ angle, and has characteristic peaks at 5.751, 10.627, 10.928, 11.285, 14.703, 18.424, 20.342, 21.576, 23.385, 28.637. Figure 2 The benzoic acid salt crystal form α of the compound of formula 1 provided by the present disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ angle, and has characteristic peaks at 5.751, 10.627, 11.285, 21.576, 23.385, 28.637.

[0047] The present disclosure also provides a method for preparing the benzoic acid salt crystal form α of the compound of formula 1, which comprises the steps of dissolving the compound of formula 1 in ethyl acetate, adding benzoic acid or a benzoic acid ethanol solution, and stirring after heating and then cooling.

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

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

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

[0051] The fumarate salt crystalline form a of the compound of Formula 1 provided by the present disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2 theta angles at 7.880, 10.606, 17.878, 19.468, 23.546.

[0052] In some embodiments, the fumarate salt crystalline form a of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2 theta angles at 7.880, 10.606, 14.856, 15.019, 17.878, 19.468, 23.546, 24.386.

[0053] In some embodiments, the fumarate salt crystalline form a of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2 theta angles at 7.880, 10.606, 11.202, 14.856, 15.019, 15.680, 17.878, 19.468, 23.546, 24.386.

[0054] In some embodiments, the fumarate salt crystalline form a of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2 theta angles as shown in Figure 3 .

[0055] The present disclosure also provides a method for preparing the compound of Formula 1 fumarate salt crystalline form a, which is selected from any one of the following methods:

[0056] Method one: dissolving the compound of Formula 1 in acetone or ethyl acetate, adding fumaric acid, and stirring;

[0057] Method two: adding the compound of Formula 1 fumarate amorphous into acetonitrile, and beating.

[0058] The fumarate salt crystalline form b of the compound of Formula 1 provided by the present disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2 theta angles at 7.371, 10.693, 15.730, 19.643, 21.261, 22.198.

[0059] In some embodiments, the fumarate salt crystalline form b of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2 theta angles at 7.371, 10.693, 15.730, 16.661, 19.643, 21.261, 22.198, 25.100, 26.106.

[0060] In some embodiments, the fumarate salt of the compound of Formula 1 in crystalline Form β has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ as shown in Figure 4 .

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

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

[0063] The present disclosure provides a method for preparing the tartrate salt of the compound of Formula 1 in amorphous form, which comprises the steps of dissolving the compound of Formula 1 in ethyl acetate, adding an ethanolic solution of tartaric acid, and stirring.

[0064] The tartrate salt of the compound of Formula 1 provided by the present disclosure in crystalline Form a has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 5.155, 10.259, 15.345, 18.873, 21.599, 25.552.

[0065] In some embodiments, the tartrate salt of the compound of Formula 1 in crystalline Form a has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 5.155, 10.259, 15.345, 18.873, 21.599, 24.932, 25.552, 28.371, 30.837, 33.388.

[0066] In some embodiments, the tartrate salt of the compound of Formula 1 in crystalline Form a has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ as shown in Figure 5 .

[0067] The present disclosure also provides a method for preparing the tartrate salt of the compound of Formula 1 in crystalline Form a, which comprises the step of adding the tartrate salt of the compound of Formula 1 in amorphous form into ethyl acetate, and beating.

[0068] The tartrate salt of the compound of Formula 1 provided by the present disclosure in crystalline Form b has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 8.025, 10.659, 15.229, 22.948, 23.897.

[0069] In some embodiments, the tartrate salt Form B of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, having characteristic peaks at 8.025, 10.659, 14.561, 15.229, 18.060, 21.445, 22.948, 23.897, 28.256.

[0070] In some embodiments, the tartrate salt Form B of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, having 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, 38.475.

[0071] In some embodiments, the tartrate salt Form B of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, having 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, 38.475. Figure 6

[0072] The present disclosure also provides a method for preparing the tartrate salt Form B of the compound of Formula 1, which comprises the steps of adding the tartrate amorphous of the compound of Formula 1 into water, and beating.

[0073] The present disclosure also provides a method for preparing the tartrate salt Form B of the compound of Formula 1, which comprises the steps of dissolving the compound of Formula 1 in acetone or ethyl acetate, adding the ethanol solution of tartaric acid, and stirring.

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

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

[0076] The present disclosure also provides the citrate salt Form A of the compound of Formula 1, which has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, having characteristic peaks at 8.952, 12.390, 14.868, 18.543, 20.194, 22.376.

[0077] In some embodiments, the citrate salt Form A of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, as shown in Figure 7

[0078] ​​The present disclosure also provides a method for preparing the compound of formula 1 malate crystalline form I, the method comprising the steps of adding the compound of formula 1 malate amorphous into acetonitrile, and slurry.

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

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

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

[0082] In some embodiments, the compound of formula 1 malate crystalline form I has the X-ray powder diffraction pattern expressed by diffraction angle 2θ, and the X-ray powder diffraction pattern 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 compound of formula 1 malate crystalline form I has the X-ray powder diffraction pattern expressed by diffraction angle 2θ, and the X-ray powder diffraction pattern 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 compound of formula 1 malate crystalline form I has the X-ray powder diffraction pattern expressed by diffraction angle 2θ as shown in Figure 8 .

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

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

[0087] The malate salt crystalline form II of the compound of Formula 1 provided by the present disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ angles at 7.921, 9.853, 10.908, 18.904, 21.892, 23.750.

[0088] In some embodiments, the malate salt crystalline form II of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ angles at 7.921, 9.853, 10.908, 13.531, 14.668, 15.606, 18.904, 21.892, 23.750.

[0089] In some embodiments, the malate salt crystalline form II of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ angles at 7.921, 9.853, 10.908, 13.531, 14.668, 15.606, 18.904, 21.892, 22.351, 23.750, 26.996.

[0090] In some embodiments, the malate salt crystalline form II of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ angles as shown in Figure 9 .

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

[0092] The succinate salt crystalline form b of the compound of Formula 1 provided by the present disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ angles at 9.907, 11.153, 13.630, 14.910, 17.441, 19.599, 22.411.

[0093] In some embodiments, the succinate salt crystalline form b of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ angles 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, 26.981.

[0094] In some embodiments, the succinate salt Form b of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, having 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, 26.981.

[0095] In some embodiments, the succinate salt Form b of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, as shown in Figure 10

[0096] The present disclosure also provides a method of preparing the succinate salt Form a of the compound of Formula 1, comprising the steps of dissolving the compound of Formula 1 in a solvent IV selected from one or more of methyl tert-butyl ether, ethyl acetate, methanol, ethanol, adding an ethanolic solution of succinic acid, and stirring.

[0097] The present disclosure provides the succinate salt Form a of the compound of Formula 1, which has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, having characteristic peaks at 10.415, 10.680, 14.960, 17.377, 19.314, 21.870, 23.920.

[0098] In some embodiments, the succinate salt Form a of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, having characteristic peaks at 8.040, 10.415, 10.680, 11.181, 14.960, 17.377, 19.314, 21.870, 23.920, 24.880, 26.719.

[0099] In some embodiments, the succinate salt Form a of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, as shown in Figure 11

[0100] The present disclosure also provides a method of preparing the succinate salt Form a of the compound of Formula 1, comprising the steps of adding the succinate salt Form b of the compound of Formula 1 to ethyl acetate, and beating.

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

[0102] ​​The present disclosure provides a compound of Formula 1 acetate salt Form a, which has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, having characteristic peaks at 5.073, 10.296, 14.899, 18.695, 22.406, 27.164.

[0103] In some embodiments, the compound of Formula 1 acetate salt Form a, which has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, having characteristic peaks at 5.073, 10.296, 13.559, 14.899, 15.803, 18.695, 22.406, 23.376, 24.536, 25.560, 27.164.

[0104] In some embodiments, the compound of Formula 1 acetate salt Form a, which has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, having 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, 27.164.

[0105] In some embodiments, the compound of Formula 1 acetate salt Form a, which has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, having 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, 27.164. Figure 12

[0106] The present disclosure also provides a method for preparing the compound of Formula 1 acetate salt Form a, which comprises the steps of dissolving the compound of Formula 1 in acetone, adding an ethanolic solution of acetic acid, and stirring.

[0107] The present disclosure provides a compound of Formula 1 acetate salt Form b, which has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, having characteristic peaks at 10.443, 14.793, 18.734, 19.826, 21.191, 23.410, 27.164.

[0108] In some embodiments, the compound of Formula 1 acetate salt Form b, which has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, having characteristic peaks at 10.443, 14.793, 18.734, 19.826, 21.191, 23.410, 27.164. Figure 13

[0109] The present disclosure also provides a method for preparing the compound of Formula 1 acetate salt Form b, which comprises the steps of dissolving the compound of Formula 1 in acetone or ethyl acetate, adding an ethanolic solution of acetic acid, isopropyl ether, and stirring.

[0110] ​​The adipate salt Form a of the compound of Formula 1 provided by the present disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 4.505, 8.985, 13.376, 18.973, 21.730, 22.625, 26.413.

[0111] In some embodiments, the adipate salt Form a of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ as shown in Figure 14 .

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

[0113] The adipate salt Form b of the compound of Formula 1 provided by the present disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 9.789, 14.461, 19.139, 20.609, 21.944, 23.406, 24.987.

[0114] In some embodiments, the adipate salt Form b of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 9.789, 10.979, 14.461, 17.710, 19.139, 19.963, 20.609, 21.944, 23.406, 24.987.

[0115] In some embodiments, the adipate salt Form b of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ as shown in Figure 15 .

[0116] The present disclosure also provides a method for preparing the compound of Formula 1 in adipate salt Form b, which comprises the steps of dissolving the compound of Formula 1 in methyl tert-butyl ether, adding adipic acid solid, and stirring.

[0117] The arginine complex Form I of the compound of Formula 1 provided by the present disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 15.856, 18.756, 19.840, 23.322, 26.625.

[0118] In some embodiments, the arginine complex Form I of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 15.856, 18.051, 18.756, 19.840, 20.816, 21.362, 23.322, 25.526, 26.625, 32.352.

[0119] In some embodiments, the arginine complex crystalline Form I of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, as shown in Figure 16 .

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

[0121] The present disclosure provides the arginine complex crystalline Form II of the compound of Formula 1, which has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, with characteristic peaks at 14.901, 19.316, 23.175, 27.643, 28.671, 29.810.

[0122] In some embodiments, the arginine complex crystalline Form II of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, with characteristic peaks at 11.241, 14.901, 16.583, 18.082, 19.316, 23.175, 24.521, 27.643, 28.671, 29.810.

[0123] In some embodiments, the arginine complex crystalline Form II of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, with 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, 34.226.

[0124] In some embodiments, the arginine complex crystalline Form II of the compound of Formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, as shown in Figure 17 .

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

[0126] The present disclosure provides the o-benzoylsulfonamide complex crystalline Form I of the compound of Formula 1, which has an X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, with characteristic peaks at 8.120, 11.601, 13.479, 15.048, 18.085, 20.372.

[0127] In some embodiments, the o-benzoylsulfonamide complex crystal form I of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ angles as shown in FIG. 1. Figure 18

[0128] The present disclosure also provides a method for preparing the o-benzoylsulfonamide complex crystal form I of the compound of Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone, adding o-benzoylsulfonamide solid, and stirring.

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

[0130] The present disclosure also provides a method for preparing the amorphous hydrochloride salt of the compound of Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone or ethyl acetate or methyl tert-butyl ether, adding an ethanol solution of hydrochloric acid, 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 the X-ray powder diffraction pattern thereof has no obvious characteristic peaks in the range of 3-50° of diffraction angle 2θ angle.

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

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

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

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

[0136] The present disclosure also provides a method for preparing the amorphous methanesulfonic acid salt of the compound of Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone or ethyl acetate or methyl tert-butyl ether, adding an ethanol solution of methanesulfonic acid, 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 the X-ray powder diffraction pattern thereof has no obvious characteristic peaks in the range of 3-50° of diffraction angle 2θ.

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

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

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

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

[0142] The present disclosure also provides a method for preparing the 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 an ethanol solution of lauric acid, 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 the X-ray powder diffraction pattern thereof has no obvious characteristic peaks in the range of 3-50° of diffraction angle 2θ.

[0144] The present disclosure also provides a method for preparing the amorphous sorbate salt of the compound of Formula 1, comprising the steps of dissolving the compound of Formula 1 in methyl tert-butyl ether or acetone or ethyl acetate, adding solid sorbic acid, 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 X-ray powder diffraction pattern thereof has no obvious characteristic peaks in the range of 3-50° of diffraction angle 2θ.

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

[0147] In certain embodiments, the method of preparation of the present disclosure further comprises any one of stirring, dissolving or heating, crystallization, filtration, washing, or drying.

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

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

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

[0151] The present disclosure also provides the use of the amorphous, succinate, malate, fumarate, tartrate, acetate, adipate, benzoate, hydrochloride, sulfate, phosphate, mesylate, citrate, p-toluenesulfonate, maleate, p-hydroxybenzoate, laurate, sorbate, malonate salt of the foregoing compound of Formula 1, or a corresponding crystalline form thereof, or a composition thereof, for the preparation of a medicament for the prevention and / or treatment of cancer.

[0152] The present disclosure also provides the use of the amorphous, succinate, malate, fumarate, tartrate, acetate, adipate, benzoate, hydrochloride, sulfate, phosphate, mesylate, citrate, p-toluenesulfonate, maleate, p-hydroxybenzoate, laurate, sorbate, malonate salt of the foregoing compound of Formula 1, or a corresponding crystalline form thereof, or a composition thereof, for the preparation of a medicament for the prevention and / or treatment of cancer.

[0153] The "2θ or 2θ angle" described 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 more than 1 decimal number after rounding), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0154] In the present disclosure, the numerical values such as the content of the related substances are data measured and calculated, and there is inevitably a certain degree of error. Generally, ±10% is within a reasonable error range. There is a certain degree of error variation depending on the context in which it is used, and the error variation is not more than ±10%, which can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

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

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

[0157] The method of crystallization described in the present disclosure includes room temperature crystallization, cooling crystallization, solvent evaporation crystallization, and crystallization induced by adding seeds, etc. The cooling temperature is selected from 65°C or lower, preferably -10 to 60°C, and the crystallization process can also be stirred.

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

[0159] According to the description of the hygroscopicity characteristics and the definition of the hygroscopicity weight gain in "9103 Drug Hygroscopicity Guiding Principle" in the fourth part of "Chinese Pharmacopoeia" 2015 edition,

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

[0161] Highly hygroscopic: the hygroscopic weight gain is not less than 15%.

[0162] Slightly hygroscopic: moisture gain less than 2% but not less than 0.2%;

[0163] Slightly hygroscopic: moisture gain less than 2% but not less than 0.2%;

[0164] Non- or almost non-hygroscopic: moisture gain less than 0.2%.

[0165] As used herein, "excipient" includes, but is not limited to, any adjuvant, carrier, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, or emulsifying agent that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or in animals. BRIEF DESCRIPTION OF DRAWINGS

[0166] Figure 1 XRPD pattern for Compound 1 amorphous.

[0167] Figure 2 XRPD pattern for Compound 1 benzoate Form a.

[0168] Figure 3 XRPD pattern for Compound 1 fumarate Form a.

[0169] Figure 4 XRPD pattern for Compound 1 fumarate Form b.

[0170] Figure 5 XRPD pattern for Compound 1 tartrate Form a.

[0171] Figure 6 XRPD pattern for Compound 1 tartrate Form b.

[0172] Figure 7 XRPD pattern for Compound 1 citrate Form A.

[0173] Figure 8 XRPD pattern for Compound 1 malate Form I.

[0174] Figure 9 XRPD pattern for Compound 1 malate Form II.

[0175] Figure 10 XRPD pattern for Compound 1 succinate Form b.

[0176] Figure 11 XRPD pattern for Compound 1 succinate Form a.

[0177] Figure 12XRPD pattern of Compound 1 acetate Form a.

[0178] Figure 13 XRPD pattern of Compound 1 acetate Form b.

[0179] Figure 14 XRPD pattern of Compound 1 adipate Form a.

[0180] Figure 15 XRPD pattern of Compound 1 adipate Form b.

[0181] Figure 16 XRPD pattern of Compound 1 arginine co-crystal Form I.

[0182] Figure 17 XRPD pattern of Compound 1 arginine co-crystal Form II.

[0183] Figure 18 XRPD pattern of Compound 1 o-benzoylsulfonamide co-crystal Form I. DETAILED DESCRIPTION

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

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

[0186] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The determination of NMR is measured by Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0187] MS determination Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry instrument (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), THERMO Ultimate3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0188] High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

[0189] Chiral HPLC analysis determination uses Agilent 1260DAD high performance liquid chromatograph.

[0190] High performance liquid preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

[0191] Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.

[0192] CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

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

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

[0195] Known starting materials of the present application can be synthesized or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Daejung Chemicals, etc. according to methods known in the art.

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

[0197] Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon of about 1 L volume.

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

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

[0200] The hydrogenation reaction was usually carried out by repeatedly vacuuming and filling hydrogen for 3 times.

[0201] The microwave reaction used 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, which is 20-30°C.

[0204] The reaction progress in the examples was monitored by thin layer chromatography (TLC), and the developing agent used in the reaction, the eluent used in the column chromatography for purifying the compounds, and the developing agent used in the thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate, the volume ratio of the solvents was adjusted according to the polarity of the compounds, and a small amount of triethylamine and acetic acid or other basic or acidic reagents were also added for adjustment.

[0205] When the compounds in the examples contain two or more chiral centers, the relative stereochemistry of these compounds was identified by NMR studies and / or X-ray diffraction. In these cases, the prefix "rel" was used, followed by the R / S nomenclature to identify the compounds, and at this time, R / S only provides relative stereochemical information, not absolute stereochemistry.

[0206] XRPD refers to X-ray powder diffraction detection: the measurement was performed using a BRUKER D8 X-ray diffractometer, and the specific acquisition information was as follows: Cu anode (40 kV, 40 mA), Cu-Kα1 ray Kα2 ray Kβ ray Scanning range (2q range): 3-45°, scanning step 0.02, scanning speed 0.1 s / step, slit width (collimator) 1.0 mm. Or using step scanning method, scanning step number is 2, each scanning range is 19°, starting degree 10°, ending degree 48°, each step time length 45 s.

[0207] DSC is Differential Scanning Calorimetry: measured using a METTLER TOLEDO DSC 3+ differential scanning calorimeter, heating rate 10 °C / min, temperature range as specified in the respective graph (mostly 25-300 or 25-350 °C), nitrogen purge rate 50 mL / min.

[0208] TGA is Thermogravimetric Analysis: measured using a METTLER TOLEDO TGA2 thermogravimetric analyzer, heating rate 10 °C / min, temperature range as specified in the respective graph (mostly 25-350 °C), nitrogen purge rate 50 mL / min.

[0209] DVS is Dynamic Vapor Sorption: measured using a SMDVS Advantage, at 25 °C, humidity change 50%-95%-0%-95%-50%, steps of 10% (last step 5%)(humidity range as specified in the respective graph, here listed as mostly used method), judgement criteria dm / dt not more 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-methanonaphtho[1,8-ab]heptalen-2-yl)-4- (trifluoromethyl)aniline 1

[0212]

[0213] First step

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

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

[0216] Second step

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

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

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

[0220] Third step

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

[0222] To a solution of crude compound 1d (2 g, 8 mmol, prepared according to the method in PCT / CN2023 / 109598) in phosphorus oxychloride (25 mL) was added N,N-diisopropylethylamine (5.16 g, 40 mmol) at 110 °C. The reaction was stirred for 14 h, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane, then 20% potassium carbonate solution was added dropwise to adjust the pH to 2-3. The reaction was stirred for 2 h, then filtered. The filter cake was washed with water, dried, and concentrated under reduced pressure to give the crude title compound 1e (1.5 g). The product was used directly in the next step without purification. MS m / z (ESI): 267.8 [M+1].

[0223] Fourth step

[0224] (1S,2S,5R)-2-((S)-1-((2,7-dichloro-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo

[0225] [3.2.1]octane-8-carboxylic acid tert-butyl ester 1g

[0226] (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 the specification of patent application “WO2022173678A1” on page 164, Intermediate 29) was dissolved in tetrahydrofuran (10 mL), sodium hydride (201 mg, 5.2 mmol, 60% purity) was added under ice bath, after 30 minutes, compound 1e (353 mg, 1.31 mmol) was added, the reaction was stirred for 2 hours, after the reaction solution was quenched by adding water, it was concentrated under reduced pressure to obtain the crude title compound 1g (600 mg), which was used directly in the next step without purification.

[0227] MS m / z (ESI): 488.2 [M+1].

[0228] Fifth step

[0229] (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-6,9-methanonaphtho[1,8-ab]heptacyclodecane-14-carboxylic acid tert-butyl ester 1h

[0230] Compound 1g (78 mg, 159.7 μmol) was dissolved in dichloromethane (2 mL), N,N-diisopropylethylamine (61.9 mg, 478.9 μmol) was added under ice bath, phosphorus oxychloride (122.4 mg, 798.2 μmol) was added, the reaction was stirred for 2 hours, the reaction solution was quenched by adding saturated sodium bicarbonate solution, dichloromethane (10 mL x 2) was added, the organic phase was combined, dried over anhydrous sodium sulfate, after removing the drying agent by filtration, it was concentrated under reduced pressure to obtain the crude title compound 1h (75 mg), which was used directly in the next step without purification.

[0231] MS m / z (ESI): 470.2 [M+1].

[0232] Sixth step

[0233] (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-methanonaphtho[1,8-ab]heptacyclodecane-14-carboxylic acid tert-butyl ester 1j

[0234] (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-methanonaphtho[1,8-ab]heptacyclodecane-14-carboxylic acid tert-butyl ester 1j

[0235] Compound 1i (1.4 g, 6.4 mmol) was dissolved in tetrahydrofuran (15 mL), 2M sodium bis(trimethylsilyl)amide in tetrahydrofuran was added under ice bath, after stirring for 30 minutes at the same temperature, tetrahydrofuran solution (20 mL) of crude compound 1h (2.3 g, 4.9 mmol) was added under ice bath, the reaction was stirred for 1 hour at the same temperature, saturated ammonium chloride solution was added to quench the reaction, ethyl acetate (30 mL x 2) was used to extract, the organic phase was combined and dried over anhydrous sodium sulfate, after removing the drying agent by filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1j (2 g, yield: 62.8%).

[0236] MS m / z (ESI): 650.2 [M+1].

[0237] Seventh step (5S, 5aS, 6S, 9R)-2-chloro-1-fluoro-12-((1- (hydroxymethyl)cyclopropyl)methoxy)-5-methyl-5a, 6, 7, 8, 9, 10- hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methano naphtho[1, 8-ab] azulene-4-carboxylic acid tert-butyl ester 1k

[0238] Compound 1j (100 mg, 153.8 μmol) was dissolved in tetrahydrofuran (4 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (187 μL) was added, the reaction was stirred for 2 hours, saturated ammonium chloride aqueous solution was added to quench the reaction, ethyl acetate (15 mL x 3) was used to extract, the organic phase was combined and washed with water, saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, after removing the drying agent by filtration, the filtrate was concentrated under reduced pressure to obtain the crude title compound 1k (82 mg), which was used directly in the next step without purification. MS m / z (ESI): 536.2 [M+1].

[0239] Eighth step

[0240] (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-methano naphtho[1, 8-ab] azulene-14 carboxylic acid tert-butyl ester 1l

[0241] ester 1l

[0242] The crude compound 1k (83 mg, 154.9 μmol), N,N-diisopropylethylamine (60 mg, 464.2 μmol) were dissolved in dichloromethane (3 mL), and methane sulfonyl chloride (25 mg, 218.2 μmol) was added under ice-bath cooling, and the reaction was allowed to proceed naturally at room temperature for 30 minutes. The reaction solution was quenched by adding saturated ammonium chloride aqueous solution, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure after removing the drying agent by filtration. The crude title compound 1l (95 mg) was obtained, which was used directly in the next reaction without purification.

[0243] MS m / z (ESI): 614.2 [M+1].

[0244] Ninth step

[0245] (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-methanonaphtho[1,8-ab]perhydro-1H-isoquinoline-14-carboxylic acid tert-butyl ester 1m

[0246] Ester 1m

[0247] The crude compound 1l (95 mg, 154.7 μmol), 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, and the reaction 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 obtain the title compound 1m (80 mg, yield: 81.6%).

[0248] MS m / z (ESI): 633.2 [M+1].

[0249] Tenth step

[0250] (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-methanonaphtho[1,8-ab]perhydro-1H-isoquinoline-14-carboxylic acid tert-butyl ester 1o

[0251] Ester 1o

[0252] 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 of the specification of 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, and reacted at 100 °C for 1 hour. After the reaction solution was cooled to room temperature, ethyl acetate was added for dilution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain the crude title compound 1o (20 mg). The product was used directly in the next reaction without purification.

[0253] MS m / z (ESI): 792.2 [M+1].

[0254] Tenth step

[0255] 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4- (trifluoromethyl)aniline 1

[0256] The crude compound 1o (15 mg, 18.9 μmol) was dissolved in dichloromethane (1 mL), and 4 M hydrochloric acid in 1,4-dioxane (0.5 mL) was added under ice bath. After the reaction was maintained for 0.5 hour, the reaction solution was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to obtain the title compound 1 (4 mg, yield: 30.5%). MS m / z (ESI): 690.3 [M-1].

[0257] 1H NMR (500 MHz, CD3OD): δ 6.90 (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).

[0258] Biological evaluation of test example 1 GP2d, AGS cell 3D proliferation inhibition experiment

[0259] I. Purpose of the test

[0260] By testing the 3D proliferation inhibition effect of the compounds of the present disclosure on GP2d, AGS cells, the inhibitory effect of the compounds of the present disclosure on KRAS target is evaluated.

[0261] II. Experimental method

[0262] 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-attachment plate (Corning, CLS7007-24EA) at a density of 1000 cells / well using complete medium, 90 μL of cell suspension per well, and centrifuged at 2000 rpm for 5 minutes at room temperature, then placed in a 37°C, 5% CO2 cell incubator overnight.

[0263] 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-attachment plate (Corning, CLS7007-24EA) at a density of 1000 cells / well using complete medium, 90 μL of cell suspension per well, and centrifuged at 2000 rpm for 5 minutes at room temperature, then placed in a 37°C, 5% CO2 cell incubator overnight.

[0264] The next day, 10 μL of the test compound diluted in complete medium was added to each well, and the final concentration of the compound was 9 concentration points diluted by 5 times from 1 μM for GP2d cells and 9 concentration points diluted by 5 times from 10 μM for AGS cells, and a blank control containing 0.5% DMSO was set. The plate was placed in a 37°C, 5% CO2 cell incubator for 5 days. On the seventh day, the 96-well cell culture plate was taken out, 50 μL of CellTiter-Glo® 3D Cell Viability Assay reagent (Promega, G9682) was added to each well, and the plate was shaken at room temperature in the dark for 25 minutes, then mixed by blowing and sucking, and 100 μL was taken from each well and transferred to a white opaque 96-well plate (PerkinElmer, 6005290). The luminescence signal value was read using a multifunctional microplate reader (PerkinElmer, EnVision2105). 3D Cell Viability Assay reagent (Promega, G9682) was added to each well, and the plate was shaken at room temperature in the dark for 25 minutes, then mixed by blowing and sucking, and 100 μL was taken from each well and transferred to a white opaque 96-well plate (PerkinElmer, 6005290). The luminescence signal value was read using a multifunctional microplate reader (PerkinElmer, EnVision2105).

[0265] III. Data Analysis

[0266] The IC50 value of the compound was calculated using Graphpad Prism software 50 The results are shown in Table 2 below.

[0267] Table 1 AGS, GP2d cell 3D proliferation inhibition activity data

[0268]

[0269] Conclusion: The compound of the present disclosure has good inhibition effect on the 3D proliferation of AGS and GP2d cells.

[0270] Test Example 2 AsPC-1 cell 3D proliferation inhibition experiment biological evaluation

[0271] On the first day of the experiment, AsPC-1 cells, which were in good growth condition and reached 70%-80% confluence, were digested, resuspended with RPMI 1640 (Hyclone, SH30809.01) medium containing 10% FBS, and adjusted to the required cell density. 90 μL of the cell suspension was added to each well of a U-shaped low-adsorption 96-well plate (Corning, CLS7007-24EA) at a cell density of 1500 cells / well. After centrifugation of the cell plate at 2500 r / min for 5 min, the plate was incubated in a 37°C, 5% CO2 incubator overnight. On the second day, 20 mM of the test compound dissolved in DMSO was diluted with DMSO to a first concentration of 2 mM, and then diluted at a 5-fold gradient, a total of 9 concentration points, and the control well was DMSO. Then the gradient-diluted compound was further diluted 20 times with the medium. 10 μL of the test compound diluted with the medium was added to each well of the cell plate, and the final concentration of the compound was 10 μM at the first concentration, and 9 concentration points at a 5-fold gradient. The cell well containing 0.5% DMSO was set as the solvent control well, and the well containing only the medium and 0.5% DMSO was set as the blank control well. Each concentration of the compound and the control well was set in duplicate, and the final DMSO concentration in each well was 0.5%. After centrifugation of the cell plate at 2500 r / min for 3 min, the plate was incubated in a 37°C, 5% CO2 incubator for 5 days. On the seventh day, the 96-well cell culture plate was taken out, 50 μL of luminescent cell viability detection reagent 3D Cell Viability Assay (Promega, G9683) was added to each well, and the plate was shaken at room temperature in the dark for 25 min. After mixing the contents of each well up and down with a pipette, 100 μL of the mixture was transferred to a white non-bottom OptiPlate TM 96-well plate (PerkinElmer, 6005290), and the luminescent signal value was read using a multifunctional microplate reader (PerkinElmer, EnVision2105).

[0272] The inhibition rate was calculated using the following formula: inhibition rate = (luminescent value 溶媒对照孔 - luminescent value 受试化合物 ) / (luminescent value 溶媒对照孔 - luminescent value 空白对照孔 ) x 100%. The curve of each concentration of the compound and the corresponding inhibition rate was plotted using GraphPad Prism software, and the IC 50 value of the compound was calculated.

[0273] Table 2 3D proliferation inhibition activity data of AsPC-1 cells

[0274] Example number AsPC-1 / IC 50 (nM) 1 0.2

[0275] Conclusion: The compound of the present disclosure has good inhibition effect on the 3D proliferation of AsPC-1 cells.

[0276] Preparation of amorphous form of the compound of formula 1

[0277] The compound of formula 1 (5 mg) was dissolved in 0.05 mL of 10% water / methanol, stirred at room temperature to precipitate, centrifuged, and dried under vacuum to obtain a solid. The product was determined to be amorphous by X-ray powder diffraction, and the XRPD pattern is shown in Figure 1. Figure 1 The TGA pattern showed a weight loss of 1.13% from 32°C to 118°C. DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample gained about 2.10% in weight by moisture absorption; under accelerated experimental conditions (i.e., 70% RH), the sample gained about 2.6% in weight by moisture absorption; under extreme conditions (90% RH), the sample gained about 4.5% in weight by moisture absorption; and after DVS testing, the sample was retested for crystalline form and was still amorphous.

[0278] Preparation of amorphous form of the compound of formula 1

[0279] The compound of formula 1 (5 mg) was dissolved in the solvent in Table 3, and the solvent was evaporated at room temperature to obtain the title product.

[0280] Table 3

[0281]

[0282]

[0283] Preparation of amorphous form of the compound of formula 1

[0284] The compound of formula 1 (5 mg) was dissolved in solvent 1 in Table 4, solvent 2 was added, and the mixture was stirred at room temperature to precipitate, centrifuged, and the solid was dried under vacuum to obtain the title product.

[0285] Table 4

[0286]

[0287] Preparation of benzoate salt Form α

[0288] The compound of formula 1 (2.5 g, 3.61 mmol) was dissolved in ethyl acetate (35 mL), benzoic acid (486 mg, 3.98 mmol) was added, and the mixture was stirred until clear, warmed to 50°C, and stirred for 1 hour, allowed to cool 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.

[0289] The product was determined to be benzoate salt Form α by X-ray powder diffraction, and the XRPD pattern is shown in Figure 2. Figure 2The characteristic peak position is shown in Table 5. The DSC spectrum shows that the endothermic peak has a peak value of 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 absorbs moisture and increases in weight by about 1.075%; under accelerated test conditions (i.e. humidity 70%), the moisture absorption and weight increase is about 1.151%; under extreme conditions (i.e. humidity 90%), the moisture absorption and weight increase is about 1.342%. During the humidity change process of 0%-95%, the desorption process of the sample coincides with the adsorption process; after the DVS test, the crystal form is retested and the crystal form is not converted. The ion detection result shows that the benzoate content is 15.27%.

[0290] The compound of formula 1 is dissolved in acetone, and 2M benzoic acid ethanol solution is added. The mixture is stirred at room temperature to obtain a solid. The solid is centrifuged and dried under vacuum to obtain a product. The product is detected by X-ray powder diffraction, and the product is benzoate salt crystal form α. 1 HNMR nuclear magnetic test shows that the salt formation ratio of the compound of formula 1 and benzoic acid is 1:1.

[0291] 1 H NMR (500 MHz, CD3OD) δ 7.95-7.90 (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, 6.4 Hz, 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).

[0292] Table 5

[0293]

[0294]

[0295] Example 6 Preparation of benzoate salt crystal form α

[0296] The compound of formula 1 8 mg is dissolved in 0.1 mL of acetone, and 6.4 μL of 2M benzoic acid ethanol solution is added. The mixture is stirred at room temperature to obtain a solid. The solid is centrifuged and dried under vacuum to obtain a product. The product is detected by X-ray powder diffraction, and the product is benzoate salt crystal form α.

[0297] Example 7 Preparation of benzoate salt crystal form α

[0298] Dissolve 8 mg of compound 1 in 0.1 mL of methyl tert-butyl ether, add 6.4 μL of 2 M benzoic acid ethanol solution, stir at room temperature to crystallize, centrifuge, and vacuum dry to obtain a solid. X-ray powder diffraction analysis showed that the product was benzoate crystal form α.

[0299] Example 8 Preparation of fumarate

[0300] The compound shown in Formula 1 (2.5 g, 3.6 mmol) was added to ethyl acetate (50 mL), stirred until completely dissolved, heated to 50 °C and stirred for 5 minutes. Fumaric acid ethanol solution (0.3 M, 12.0 mL) was added dropwise, causing a solid to precipitate. Stirring continued for 1 hour, until most of the solid dissolved. The mixture was slowly cooled to room temperature and stirred for 16 hours, resulting in a large amount of solid precipitation. The solid was filtered, and the filter cake was washed with 20 mL of ethyl acetate. The filter cake was collected and dried under vacuum to obtain the title product. X-ray powder diffraction analysis showed that it was an amorphous fumarate salt, with no obvious characteristic peaks in the X-ray powder diffraction pattern.

[0301] Example 9 Preparation of fumarate crystal form α

[0302] 8 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of acetone, and 1.5 mg of solid fumaric acid was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and the solid was dried under vacuum to obtain the title product. X-ray powder diffraction analysis identified this product as fumarate crystal form α. The XRPD spectrum is shown below. Figure 3 The characteristic peak positions are shown in Table 6. The DSC spectrum shows the endothermic peaks at 109.46℃ and 219.39℃. The TGA spectrum shows a weight loss of 5.84% between 40℃ and 210℃. Ion detection results show a fumarate content of 14.51%. DVS detection shows that under normal storage conditions (25℃, 60% RH), the sample gains approximately 3.3% weight through moisture absorption; under accelerated experimental conditions (70% RH), the weight gain is approximately 3.6%; and under extreme conditions (90% RH), the weight gain is approximately 4.5%. Re-testing of the crystal form after DVS detection showed no change in crystal form.

[0303] through 1 1H NMR analysis showed that the salt ratio of compound 1 to fumaric acid was 1:1.

[0304] 1H NMR (500 MHz, CD3OD) δ 6.89 (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).

[0305] Table 6

[0306]

[0307] Example 10 Preparation of Formic Acid Salt Form Alpha

[0308] The Formic Acid Salt Amorphous of Formula 1 (100 mg, 123.7 μmol) was added to 6 mL of acetonitrile, slurried with stirring for 72 h, filtered, and the filter cake was collected and dried under vacuum to give a solid. The product was defined as Formic Acid Salt Form Alpha by X-ray powder diffraction.

[0309] Example 11 Preparation of Formic Acid Salt Form Alpha

[0310] The Formic Acid Salt Amorphous of Formula 1 (8 mg) was dissolved in 0.1 mL of ethyl acetate, 1.5 mg of Formic Acid solid was added, and the mixture was stirred at room temperature to crystallize, centrifuged, and dried under vacuum to give a solid. The product was defined as Formic Acid Salt Form Alpha by X-ray powder diffraction.

[0311] Example 12 Preparation of Formic Acid Salt Form Beta

[0312] The Formic Acid Salt Amorphous of Formula 1 (1.8 g, 2.6007 mmol) was added to ethanol (45 mL), slurried with stirring for 4 days, filtered, and the filter cake was collected and dried under vacuum to give a solid. The product was defined as Formic Acid Salt Form Beta by X-ray powder diffraction. Figure 4 , and the characteristic peak positions are shown in Table 7. The DSC spectrum showed an endothermic peak with a peak value of 69.65 °C, 173.12 °C, 192.64 °C. The TGA spectrum showed a weight loss of 2.99% at 40 °C-100 °C.

[0313] The Formic Acid Salt Amorphous of Formula 1 (1.8 g, 2.6007 mmol) was added to ethanol (45 mL), slurried with stirring for 4 days, filtered, and the filter cake was collected and dried under vacuum to give a solid. The product was defined as Formic Acid Salt Form Beta by X-ray powder diffraction. 1 H NMR nuclear magnetic resonance test showed that the salt-forming ratio of the compound of Formula 1 and formic acid was 1:1.

[0314] 1H NMR (500 MHz, CD3OD) δ 6.88 (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, 2H), 2.16 (d, 1H), 2.00 - 1.88 (m, 3H), 1.58 (d, 3H), 0.89 (t, 2H), 0.73 (s, 2H).

[0315] Table 7

[0316]

[0317] Example 13 Preparation of tartrate salt

[0318] The compound of Formula 1 (500 mg, 722.4 μmol) was added to ethyl acetate (10 mL) and stirred to dissolve completely, warmed to 50 °C and stirred for 5 min, then a solution of L-tartaric acid (434 mg, 2.8917 mmol) in 5 mL of ethanol was added dropwise, solid precipitated, ethyl acetate (5 mL) was added, and stirring was continued for 1 h, the solid did not dissolve, then it was cooled to room temperature, stirred for 2 h, filtered, and the filter cake was collected and dried under vacuum to give a solid. X-ray powder diffraction showed that it was amorphous tartrate salt, and the X-ray powder diffraction spectrum had no obvious characteristic peaks. The compound of Formula 1 was confirmed by H NMR test. 1 H NMR test showed that the compound of Formula 1 was salted with L-tartaric acid in a ratio of 1:2.

[0319] 1 1H NMR (500 MHz, CD3OD) δ 6.88 (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, 2H), 2.16 (d, 1H), 2.00 - 1.88 (m, 3H), 1.58 (d, 3H), 0.89 (t, 2H), 0.73 (s, 2H).

[0320] Example 14 Preparation of tartrate salt crystal form a

[0321] The amorphous sample of the compound of Formula 1 L-tartrate salt (60 mg, 60.5 μmol) was slurried in 6 mL of ethyl acetate at room temperature with stirring for 72 h, filtered, and the filter cake was collected and dried under vacuum to give a solid. The crystal form was defined as L-tartrate salt Form a by X-ray powder diffraction, and the X-ray powder diffraction pattern is shown in Figure 8. Figure 5 with characteristic peak positions shown in Table 8. The DSC pattern showed an endothermic peak with a peak value of 66.82 °C, 211.50 °C. The TGA pattern showed a weight loss of 3.39% from 30 °C to 100 °C. The ratio of the compound of Formula 1 to L-tartaric acid was 1:1 by 1H NMR nuclear magnetic test.

[0322] 1H NMR (500 MHz, CD3OD) δ 6.89 (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).

[0323] Table 8

[0324]

[0325] Example 15 Preparation of tartrate salt Form a

[0326] The compound of Formula 1 (8 mg) was dissolved in 0.1 mL of acetone (the solvent can be 0.1 mL of ethyl acetate), 6.4 μL of 2M tartaric acid ethanol solution was added, and the mixture was stirred at room temperature to crystallize, centrifuged, and the solid was dried under vacuum to give the title product.

[0327] Example 16 Preparation of tartrate salt Form b

[0328] The amorphous sample of the compound of Formula 1 L-tartrate salt (60 mg, 60.5 μmol) was slurried in 6 mL of water at room temperature with stirring for 72 h, filtered, and the filter cake was collected and dried under vacuum to give a solid. The product was defined as L-tartrate salt Form b by X-ray powder diffraction, and the X-ray powder diffraction pattern is shown in Figure 9. Figure 6The characteristic peak position is shown in Table 9. The DSC spectrum shows that the endothermic peak has a peak value of 78.81 °C and 218.77 °C. The TGA spectrum shows that the weight loss is 3.22% at 30-100 °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.

[0329] 1H NMR (500 MHz, CD3OD) δ 6.89 (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).

[0330] Table 9

[0331]

[0332]

[0333] Example 17 Preparation of citrate salt

[0334] The compound of formula 1 (500 mg, 722.4181 μmol) was dissolved in ethyl acetate (20 mL) and heated to 50 °C and stirred until the solution was clear, then a solution of anhydrous citric acid (556 mg, 2.8940 mmol) in ethanol (5 mL) was added dropwise to the reaction solution at 50 °C, and white solids immediately precipitated. The stirring was continued at 50 °C for 1 h, and the solid part was dissolved but not completely clear. The temperature was slowly reduced to room temperature and stirred for 16 h. The solid was collected by filtration and dried in vacuum to obtain a solid. The X-ray powder diffraction test showed that it was amorphous citrate salt, and the XRPD spectrum had no obvious characteristic peaks. The 1H NMR nuclear magnetic test showed that the salt ratio of the compound of formula 1 and citric acid was 1:2. 1 H NMR nuclear magnetic test showed that the salt ratio of the compound of formula 1 and citric acid was 1:2.

[0335] 1H NMR (500 MHz, CD3OD) δ 6.88 (s, 1H), 6.70 (d, 1H), 6.58 (s, 1H), 5.47 (dd, 1H), 4.71 (s, 1H), 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 = 8.4 Hz, 2H), 0.84 (s, 2H).

[0336] Preparation of citrate salt Form A

[0337] Formula 1 citrate salt amorphous (50 mg, 46.4526 pmol) was added to 0.5 mL 2-methyltetrahydrofuran, slurry stirred for 72 h, filtered, the solid was collected and dried under vacuum to get a solid, which was defined as citrate salt Form A by X-ray powder diffraction, the XRPD spectrum is as follows Figure 7 , and the characteristic peak positions are shown in Table 10. The H NMR test showed that the salt formation ratio of the compound of Formula 1 and citric acid was 1:1.5. 1 H NMR test showed that the salt formation ratio of the compound of Formula 1 and citric acid was 1:1.5.

[0338] 1 H NMR (500 MHz, CD3OD) δ 6.88 (s, 1H), 6.70 (d, 1H), 6.58 (s, 1H), 5.47 (dd, 1H), 4.71 (s, 1H), 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 = 8.4 Hz, 2H), 0.84 (s, 2H).

[0339] Table 10

[0340]

[0341]

[0342] Example 19 Preparation of malate salt

[0343] The compound of Formula 1 (500 mg, 722.4 μmol) was added to ethyl acetate (10 mL) and stirred to dissolve. The solution was warmed to 50 °C and stirred for 5 min. A solution of L-malic acid (388 mg, 2.89 mmol) in 5 mL of ethanol was added dropwise. The solid was allowed to precipitate and then stirred to dissolve. Additional ethyl acetate (5 mL) was added and the solution was stirred for 1 h. The solution was allowed to cool to room temperature and stirred for 16 h. The solution was concentrated under reduced pressure to give a solid. The product was defined as L-malate amorphous by X-ray powder diffraction, and the XRPD pattern showed no significant peaks.

[0344] Example 20 Preparation of malate salt Form I

[0345] The L-malate salt Form I amorphous (60 mg, 48.9 μmol) was slurried in 4 mL of acetonitrile and stirred for 72 h. The solid was collected by filtration and dried under vacuum. The product was defined as L-malate salt Form I by X-ray powder diffraction, and the XRPD pattern is shown in Figure 20. Figure 8 The characteristic peak positions are shown in Table 11. The DSC pattern showed endothermic peaks with peak values at 76.81 °C, 188.79 °C, and 216.12 °C, and an exothermic peak at 208.13 °C. The TGA pattern showed a weight loss of 3.1% from 40 °C to 100 °C. The DVS test showed that the sample gained about 3.3% in weight under normal storage conditions (i.e., 25 °C, 60% RH), about 3.6% under accelerated experimental conditions (i.e., 70% RH), and about 4.3% under extreme conditions (90% RH). The Form was rechecked after the DVS test and was not converted. The ion test showed that the content of malate ion was 27.57%. The product was defined as L-malate salt Form I by X-ray powder diffraction, and the XRPD pattern is shown in Figure 20. 1 H NMR nuclear magnetic resonance test showed that the compound of Formula 1 was salted with malic acid in a ratio of 1:2.

[0346] 1 H NMR (500 MHz, CD3OD) δ 6.89 (d, 1H), 6.76 (s, 0.5H), 6.57 (d, 1H), 6.40 (s, 0.5H), 5.41 (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).

[0347] Table 11

[0348]

[0349]

[0350] Example 21 Preparation of Malate salt Form I

[0351] To a solution of 8 mg of the compound of Formula 1 in 0.1 mL of acetone was added 6.4 μL of 2 M malic acid in ethanol. The solution was stirred at room temperature and crystals were formed. The solution was centrifuged and the solid was dried under vacuum to give the title product.

[0352] Example 22 Preparation of Malate salt Form II

[0353] To a solution of 60 mg of the compound of Formula 1 L-malate salt Form amorphous in 1 mL of methanol was added. The solution was stirred for 72 h. The solid was collected by filtration and dried under vacuum. The product was defined as L-malate salt Form II by X-ray powder diffraction. The X-ray powder diffraction pattern is shown in Figure 2. Figure 9 The characteristic peak positions are shown in Table 12. The DSC pattern showed an endothermic peak with a peak value of 65.48 °C, 147.46 °C, 183.42 °C, 210.25 °C and an exothermic peak of 208.13 °C. The TGA pattern showed a weight loss of 2.1% from 40 °C to 100 °C. The product was further characterized by 1 H NMR nuclear magnetic test showed that the compound of Formula 1 was salted with malic acid in a ratio of 1:2.

[0354] 1H NMR (500 MHz, CD3OD) δ 6.89 (d, 1H), 6.77 (s, 0.5H), 6.57 (d, 1H), 6.40 (s, 0.5H), 5.42 (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).

[0355] Table 12

[0356]

[0357]

[0358] Example 23 Preparation of Succinate salt Form b

[0359] The compound of Formula 1 (500 mg, 722.4 μmol) was added into methyl tert-butyl ether (15 mL) and stirred to dissolve, then warmed to 50 °C and stirred for 5 min, succinic acid ethanolic solution (0.3 M, 4.8 mL) was added dropwise, no solid precipitated, then ethyl acetate (5 mL) was added and stirred for 1 h, then cooled to room temperature and stirred for 16 h, a large amount of solid precipitated, filtered, the filter cake was rinsed with 5 mL of ethyl acetate, filtered, and the filter cake was collected and dried under vacuum to give a solid. The product was defined as succinate Form b by X-ray powder diffraction. The X-ray powder diffraction pattern is shown in Figure 2. Figure 10 The characteristic peak positions are shown in Table 13. The product was defined as succinate Form b by X-ray powder diffraction. 1 H NMR nuclear magnetic resonance test showed that the compound of Formula 1 was salified with succinic acid in a ratio of 1:2.

[0360] 1 H NMR (500 MHz, CD3OD) δ 6.89 (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).

[0361] Table 13

[0362]

[0363]

[0364] Example 24 Preparation of succinate Form b

[0365] The compound of Formula 1 (2.5 g, 3.6 mmol) was added into ethyl acetate (50 mL) and stirred to dissolve, then warmed to 50 °C and stirred for 5 min, succinic acid ethanolic solution (0.3 M, 12.0 mL) was added dropwise, no solid precipitated, then stirred for 1 h, then slowly cooled to room temperature and stirred for 16 h, a large amount of solid precipitated, filtered, the filter cake was rinsed with 10 mL of ethyl acetate, the filter cake was collected and dried under vacuum, the product was defined as succinate Form b by X-ray powder diffraction. The DSC pattern showed: endothermic peak peak value was 137.99 °C, 145.17 °C, 164.09 °C. The TGA pattern showed: weight loss was 4.12% at 110 °C-170 °C. The product was defined as succinate Form b by X-ray powder diffraction. 1H NMR nuclear magnetic test showed that the salt formation ratio of the compound of formula 1 and succinic acid was 1:2.

[0366] 1 H NMR (500 MHz, CD3OD) δ 6.89 (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).

[0367] Example 25 Preparation of succinate salt crystal form b

[0368] The compound of formula 1 8 mg was dissolved in 0.1 mL of acetone, 1.5 mg of succinic acid solid was added, 1 mL of isopropyl ether was added, and stirring was performed at room temperature to precipitate, centrifugation was performed, and the solid was dried under vacuum to obtain the title product.

[0369] Example 26 Preparation of succinate salt crystal form a

[0370] The succinate salt crystal form b of formula 1 (60 mg, 64.6 μmol) was added to 6 mL of ethyl acetate, and stirring was performed for 5 days. The filter cake was collected and dried under vacuum to obtain a solid. The product was defined as succinate salt crystal form a by X-ray powder diffraction. The X-ray powder diffraction spectrum is shown in FIG. 6, and the characteristic peak positions are shown in Table 14. The DSC spectrum showed that the endothermic peak had a peak value of 73.31 °C, 171.34 °C. The TGA spectrum showed that the weight loss was 4.04% at 40 °C-140 °C. The product was further characterized by single crystal X-ray diffraction. Figure 11 1 H NMR nuclear magnetic test showed that the salt formation ratio of the compound of formula 1 and citric acid was 1:1.3.

[0371] 1 ​H NMR (500 MHz, CD3OD) δ 6.88 (d, 1 H), 6.69 (s, 0.5 H), 6.53 (d, 1 H), 6.40 (s, 0.5 H), 5.37 (dd, 1 H), 4.58 - 4.51 (m, 1 H), 4.43 (d, 2 H), 4.12 (t, 1 H), 3.80 (d, 1 H), 3.72 (d, 1 H), 3.22 (d, 1 H), 2.91 (q, 4 H), 2.86 - 2.78 (m, 2 H), 2.53 (s, 5.2 H), 2.48 (t, 2 H), 2.28 - 2.22 (m, 2 H), 2.10 (dd, 1 H), 1.94 - 1.79 (m, 3 H), 1.58 (d, 3 H), 0.84 (d, 2 H), 0.66 (s, 2 H).

[0372] Table 14

[0373]

[0374]

[0375] Preparation of acetate salt Form a

[0376] The compound of Formula 1, 8 mg, was dissolved in 0.1 mL of acetone, 12.8 μL of 2 M acetic acid in ethanol was added, 1 mL of isopropyl ether was added, and the mixture was stirred at room temperature to crystallize, centrifuged, and the solid was dried under vacuum to give the title product. The product was defined as acetate salt Form a by X-ray powder diffraction, and the XRPD pattern is shown in Figure 12 with characteristic peak positions shown in Table 15. The DSC pattern showed an endothermic peak with a peak value of 107.14 °C. The TGA pattern showed a weight loss of 15.82% from 33 °C to 153 °C.

[0377] Table 15

[0378]

[0379] Preparation of acetate salt Form b

[0380] The compound of Formula 1, 8 mg, was dissolved in 0.1 mL of acetone, 6.4 μL of 2 M acetic acid in ethanol was added, 1 mL of isopropyl ether was added, and the mixture was stirred at room temperature to crystallize, centrifuged, and the solid was dried under vacuum to give the title product. The product was defined as acetate salt Form b by X-ray powder diffraction, and the XRPD pattern is shown in Figure 13 with characteristic peak positions shown in Table 16. The DSC pattern showed endothermic peaks with peak values of 95.98 °C and 107.15 °C. The TGA pattern showed a weight loss of 15.68% from 32 °C to 163 °C.

[0381] Table 16

[0382]

[0383] Example 29 Preparation of acetate salt Form b

[0384] Dissolve 8 mg of the compound of Formula 1 in 0.1 mL of ethyl acetate, add 6.4 μL of 2 M acetic acid in ethanol, 1 mL of isopropyl ether, stir at room temperature to crystallize, centrifuge, and dry the solid in vacuum to obtain the title product.

[0385] Example 30 Preparation of adipate salt Form a

[0386] Dissolve 8 mg of the compound of Formula 1 in 0.1 mL of acetone, add 2.1 mg of adipic acid solid, stir at room temperature to crystallize, centrifuge, and dry the solid in vacuum to obtain the title product. The product is defined as adipate salt Form a by X-ray powder diffraction, and the XRPD pattern is shown in Figure 6. Figure 14 The characteristic peak positions are shown in Table 17. The DSC pattern shows an exothermic peak with a peak value of 130.25 °C, and endothermic peaks with peak values of 156.89 °C and 163.93 °C. The TGA pattern shows a weight loss of 5.67% from 34 °C to 155 °C.

[0387] Table 17

[0388]

[0389] Example 31 Preparation of adipate salt Form a

[0390] Dissolve 8 mg of the compound of Formula 1 in 0.1 mL of ethyl acetate, add 2.1 mg of adipic acid solid, stir at room temperature to crystallize, centrifuge, and dry the solid in vacuum to obtain the title product.

[0391] Example 32 Preparation of adipate salt Form b

[0392] Dissolve 15 mg of the compound of Formula 1 in 0.2 mL of methyl tert-butyl ether, add 4.1 mg of adipic acid solid, stir at room temperature to crystallize, centrifuge, and dry the solid in vacuum to obtain the title product. The product is defined as adipate salt Form b by X-ray powder diffraction, and the XRPD pattern is shown in Figure 7. Figure 15 The characteristic peak positions are shown in Table 18. The DSC pattern shows endothermic peaks with peak values of 62.16 °C and 154.27 °C. The TGA pattern shows a weight loss of 6.78% from 32 °C to 145 °C. The ion detection result shows that the content of adipate is 17.76%. The DVS detection shows that under normal storage conditions (i.e., 25 °C, 60% RH), the sample absorbs moisture and increases in weight by about 7.4%; under accelerated experimental conditions (i.e., 70% RH), the moisture absorption is about 7.8%; under extreme conditions (90% RH), the moisture absorption is about 8.6%; and after DVS detection, the crystal form is rechecked and is not converted.

[0393] Table 18

[0394]

[0395] Example 33 Preparation of Arginine Complex Form I

[0396] The compound of Formula 1, 8 mg, was dissolved in 0.1 mL of acetone, 2.4 mg of arginine solid was added, and the mixture was stirred at room temperature to crystallize, centrifuged, and the solid was dried under vacuum to yield the title product. The product was defined as Arginine Complex Form I by X-ray powder diffraction, and the XRPD pattern is shown in Figure 8. Figure 16 The characteristic peak positions are shown in Table 19. The DSC pattern showed endothermic peaks with peak values of 55.81 °C, 222.29 °C, and 232.97 °C. The TGA pattern showed a weight loss of 4.50% from 33 °C to 185 °C.

[0397] Table 19

[0398]

[0399] Example 34 Preparation of Arginine Complex Form II

[0400] The Arginine Complex Form I of Example 31 was placed at 25 °C / 92.5% RH for 5 days to yield the title product.

[0401] The product was defined as Arginine Complex Form II by X-ray powder diffraction, and the XRPD pattern is shown in Figure 9. Figure 17 The characteristic peak positions are shown in Table 20.

[0402] Table 20

[0403]

[0404]

[0405] Example 35 Preparation of o-Toluoyl Sulfimide Complex Form I

[0406] The compound of Formula 1, 8 mg, was dissolved in 0.1 mL of acetone, 2.5 mg of o-toluoyl sulfimide solid was added, and the mixture was stirred at room temperature to crystallize, centrifuged, and dried under vacuum to yield the solid. The product was defined as o-Toluoyl Sulfimide Complex Form I by X-ray powder diffraction, and the XRPD pattern is shown in Figure 10. Figure 18 The characteristic peak positions are shown in Table 21. The DSC pattern showed endothermic peaks with peak values of 42.82 °C, 188.12 °C. The TGA pattern showed a weight loss of 3.25% from 32 °C to 96 °C, and 3.52% from 98 °C to 199 °C.

[0407] Table 21

[0408]

[0409] Preparation of hydrochloride salt of Example 36

[0410] Dissolve 8 mg of the compound of Formula 1 in 0.1 mL of methyl tert-butyl ether, add 6.4 μL of 2 M hydrochloric acid in ethanol, stir at room temperature, centrifuge, and dry the solid in vacuo to give the title product. The product is amorphous by X-ray powder diffraction, and the XRPD pattern has no significant peaks.

[0411] Preparation of hydrochloride salt of Example 37

[0412] Dissolve 8 mg of the compound of Formula 1 in 0.1 mL of solvent 1 in Table 22, add 6.4 μL of 2 M hydrochloric acid in ethanol, and then add 1 mL of solvent 2 in Table 22, stir at room temperature, centrifuge, and dry the solid in vacuo to give the title product. The product is amorphous by X-ray powder diffraction, and the XRPD pattern has no significant peaks.

[0413] Table 22

[0414] Solvent 1 Solvent 2 Result Acetone Isopropyl ether Hydrochloride amorphous Ethyl acetate Isopropyl ether Hydrochloride amorphous

[0415] Preparation of sulfate salt of Example 38

[0416] Dissolve 8 mg of the compound of Formula 1 in 0.1 mL of a solvent in Table 23, add 6.4 μL of 2 M sulfuric acid in ethanol, stir at room temperature, centrifuge, and dry the solid in vacuo to give the title product. The product is amorphous by X-ray powder diffraction, and the XRPD pattern has no significant peaks. The sulfate content is 12.63%.

[0417] Table 23

[0418] Solvent Result Acetone Sulfate amorphous Ethyl acetate Sulfate amorphous Methyl t-butyl ether Sulfate amorphous

[0419] Preparation of phosphate salt of Example 38

[0420] Dissolve 8 mg of the compound of Formula 1 in 0.1 mL of methyl tert-butyl ether, add 6.4 μL of 2 M phosphoric acid in ethanol, stir at room temperature, centrifuge, and dry the solid in vacuo to give the title product. The product is amorphous by X-ray powder diffraction, and the XRPD pattern has no significant peaks.

[0421] Preparation of phosphate salt of Example 39

[0422] Dissolve 8 mg of the compound of Formula 1 in 0.1 mL of solvent 1 in Table 24, add 6.4 μL of 2 M phosphoric acid in ethanol, and then add 1 mL of solvent 2 in Table 24, stir at room temperature, centrifuge, and dry the solid in vacuo to give the title product. The product is amorphous by X-ray powder diffraction, and the XRPD pattern has no significant peaks.

[0423] Table 24

[0424] Solvent 1 Solvent 2 Result Acetone Isopropyl ether Phosphate amorphous Ethyl acetate Isopropyl ether Phosphate amorphous

[0425] Preparation of the methanesulfonate salt of Example 40

[0426] The compound of Formula 1, 8 mg, was dissolved in 0.1 mL of methyl tert-butyl ether, 6.4 μL of 2 M methanesulfonic acid in ethanol was added, and the mixture was stirred at room temperature until it precipitated. The solid was centrifuged, and the solid was dried under vacuum to yield the title product. The product was amorphous as determined by X-ray powder diffraction, and the XRPD pattern had no significant characteristic peaks.

[0427] Preparation of the methanesulfonate salt of Example 41

[0428] The compound of Formula 1, 8 mg, was dissolved in 0.1 mL of solvent 1 in Table 25, 6.4 μL of 2 M methanesulfonic acid in ethanol was added, and 1 mL of solvent 2 in Table 25 was added. The mixture was stirred at room temperature until it precipitated. The solid was centrifuged, and the solid was dried under vacuum to yield the title product. The product was amorphous as determined by X-ray powder diffraction, and the XRPD pattern had no significant characteristic peaks.

[0429] Table 25

[0430] Solvent 1 Solvent 2 Result Acetone Isopropyl ether Mesylate amorphous Ethyl acetate Isopropyl ether Mesylate amorphous

[0431] Preparation of the maleate salt of Example 42

[0432] The compound of Formula 1, 8 mg, was dissolved in 0.1 mL of ethyl acetate, 6.4 μL of 2 M maleic acid in ethanol was added, and 1 mL of isopropyl ether was added. The mixture was stirred at room temperature until it precipitated. The solid was centrifuged, and the solid was dried under vacuum to yield the title product. The product was amorphous as determined by X-ray powder diffraction, and the XRPD pattern had no significant characteristic peaks.

[0433] Preparation of the p-hydroxybenzoic acid salt of Example 43

[0434] The compound of Formula 1, 8 mg, was dissolved in 0.1 mL of acetone, 6.4 μL of 2 M p-hydroxybenzoic acid in ethanol was added, and 1 mL of isopropyl ether was added. The mixture was stirred at room temperature until it precipitated. The solid was centrifuged, and the solid was dried under vacuum to yield the title product. The product was amorphous as determined by X-ray powder diffraction, and the XRPD pattern had no significant characteristic peaks.

[0435] Preparation of the lauric acid salt of Example 44

[0436] The compound of Formula 1, 8 mg, was dissolved in 0.1 mL of ethyl acetate, 6.4 μL of 2 M lauric acid in ethanol was added, and 1 mL of isopropyl ether was added. The mixture was stirred at room temperature until it precipitated. The solid was centrifuged, and the solid was dried under vacuum to yield the title product. The product was amorphous as determined by X-ray powder diffraction, and the XRPD pattern had no significant characteristic peaks.

[0437] Example 45 Preparation of sorbate salt

[0438] The compound of Formula 1, 8 mg, was dissolved in 0.1 mL of methyl tert-butyl ether, 1.5 mg of sorbic acid solid was added, 1 mL of isopropyl ether was added, and the mixture was stirred at room temperature to precipitate, centrifuged, and the solid was dried under vacuum to obtain the title product. The product was amorphous as determined by X-ray powder diffraction, and the XRPD pattern had no distinct peaks.

[0439] Example 46 Preparation of malonate salt

[0440] The compound of Formula 1, 8 mg, was dissolved in 0.1 mL of acetone, 6.4 μL of 2M malonic acid in ethanol solution was added, 1 mL of isopropyl ether was added, and the mixture was stirred at room temperature to precipitate, centrifuged, and the solid was dried under vacuum to obtain the title product. The product was amorphous as determined by X-ray powder diffraction, and the XRPD pattern had no distinct peaks.

[0441] Example 47 Stability Study I

[0442] The amorphous free form was left open and flat to investigate the stability of the sample under the conditions of high temperature (40 °C and 60 °C) and high humidity (RH 75%, RH 92.5%), respectively, and the sampling observation period was 30 days.

[0443] Table 26

[0444]

[0445]

[0446] Conclusion: The influence factor experiment showed that the amorphous free form had good physical stability under the conditions of high temperature (40 °C, 60 °C) for 30 days, and good physical and chemical stability under the conditions of high humidity (75% RH, 92.5% RH) for 30 days.

[0447] Example 48 Stability Study II

[0448] The succinate salt Form a, fumarate salt Form a, malate salt Form I, adipate salt / eutectic Form b, and benzoate salt Form a were left open and flat to investigate the stability of the sample under the conditions of high temperature (40 °C and 60 °C), high humidity (RH 75%, RH 92.5%), and light, respectively, and the sampling observation period was 30 days.

[0449] Table 27

[0450]

[0451]

[0452]

[0453] Conclusion: The stress testing indicated that benzoate Form a was physically and chemically stable at high temperature (40 °C, 60 °C) and high humidity (75% RH, 92.5% RH) for 1 month. Succinate Form a, fumarate Form a, and malate Form I were physically and chemically stable under all stress conditions for 1 month. Adipate / co-crystal Form b was physically and chemically stable under high humidity (75% RH), high temperature, and light conditions for 1 month.

[0454] Example 49 Long-term / Accelerated Stability Study I

[0455] The free amorphous was placed at 25 °C / 60% RH and 40 °C / 75% RH, respectively, to investigate the stability.

[0456] Table 28

[0457]

[0458] Conclusion: The long-term accelerated experiment indicated that the free amorphous was physically and chemically stable at 25 °C / 60% RH and 40 °C / 75% RH for 3 months.

[0459] Example 50 Long-term / Accelerated Stability Study II

[0460] Succinate Form a, fumarate Form a, malate Form I, adipate / co-crystal Form b, and benzoate Form a were placed at 25 °C / 60% RH and 40 °C / 75% RH, respectively, to investigate the stability.

[0461] Table 29

[0462]

[0463]

[0464] Conclusion: The long-term accelerated experiment indicated that benzoate Form a, succinate Form a, adipate / co-crystal Form b, fumarate Form a, and malate Form I were physically and chemically stable at long-term (25 °C / 60% RH) and accelerated (40 °C / 75% RH) conditions for 3 months.

Claims

1. A pharmaceutically acceptable salt of 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4- (fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10- hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)- 4-(trifluoromethyl)aniline represented by Formula 1: ###0001### Formula 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of succinate, malate, fumarate, tartrate, acetate, adipate, benzoate, hydrochloride, sulfate, phosphate, mesylate, citrate, p-toluenesulfonate, maleate, p-hydroxybenzoate, laurate, sorbate, malonate, 2. The pharmaceutically acceptable salt of claim 1, wherein, the chemical ratio of 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4- (fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10- hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)- 4-(trifluoromethyl)aniline to acid is 3:1-1:

3.

3. The pharmaceutically acceptable salt of claim 2, wherein, the chemical ratio of 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4- (fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10- hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)- 4-(trifluoromethyl)aniline to acid is 2:1-1:

2.

4. The pharmaceutically acceptable salt of claim 2, wherein, the chemical ratio of 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4- (fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10- hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)- 4-(trifluoromethyl)aniline to acid is 1:1-1:

2.

5. A method of preparing the pharmaceutically acceptable salt according to any one of claims 1 to 4, comprising the step of reacting a compound represented by Formula 1 with an acid selected from the group consisting of 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, malonic acid.

6. A benzoic acid salt of the compound of formula 1 according to claim 1, characterized by an α crystal form, wherein ###0001### X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ angle, having characteristic peaks at 5.751, 10.627, 11.285, 21.576, 23.385, 28.

637. ​ 7. The benzoic acid salt alpha crystalline form of the compound of Formula 1 according to claim 6, characterized in that, X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ has characteristic peaks at 5.751, 10.627, 10.928, 11.285, 14.703, 18.424, 20.342, 21.576, 23.385, 28.

637.

8. The benzoic acid salt of the compound of Formula 1 according to claim 6, characterized in that, X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ has characteristic peaks at 5.751, 10.627, 10.928, 11.285, 11.748, 14.703, 16.861, 18.424, 20.342, 21.576, 22.453, 23.385, 26.951, 28.637, 30.

786.

9. The benzoic acid salt alpha crystalline form of claim 6, characterized by, X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ is shown in Figure 2.

10. A method for preparing the benzoic acid salt a crystalline form according to any one of claims 6-9, which method is selected from any one of the following methods: Method one: dissolving the compound of formula 1 in ethyl acetate, adding benzoic acid or benzoic acid ethyl alcohol solution, and stirring; Method two: dissolving the compound of formula 1 in acetone or methyl tert-butyl ether, adding benzoic acid ethyl alcohol solution, and stirring.

11. The crystalline form according to any one of claims 6-9, wherein the 2θ angle error range is ±0.

20.

12. A pharmaceutical composition comprising a pharmaceutically acceptable salt of 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline according to any one of claims 1-4, or the crystalline form according to any one of claims 6-9 and optionally a pharmaceutically acceptable excipient.

13. A method of preparing a pharmaceutical composition comprising the steps of: The step of mixing a pharmaceutically acceptable salt of 3-chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline according to any one of claims 1-4, or the crystalline form according to any one of claims 6-9 and a pharmaceutically acceptable excipient.

14. Use of a pharmaceutically acceptable salt of 3-chloro-5-((5S,5aS,6S,9R)-1- fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5- methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9- methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline according to any one of claims 1 to 4, or a crystalline form according to any one of claims 6 to 9, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the treatment and / or prevention of a disease or disorder mediated by KRAS G12D.

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