Crystalline forms of nitrogen-containing tetracyclic compounds and methods for preparing them

Abstract

This disclosure relates to crystalline forms of nitrogen-containing tetracyclic compounds and methods for preparing them. Specifically, this disclosure provides C-type, F-type, G-type, H-type, L-type, M-type, N-type, R-type, and S-type crystals of (S)-4-((S)-10-acryloyl-4-chloro-2-fluoro-14-oxo-8,8a,9,10,11,12-hexahydro-7H,14H-pyrazino[1',2':5,6][1,5]diazosino[3,2,1-hi]indazole-3-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (formula 1), which have good stability and can be used more effectively in clinical treatment. [Formula 1] JPEG2026516635000071.jpg56137

Description

Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical technology and relates to a crystalline form of a nitrogen-containing tetracyclic compound and a method for preparing the same.

Background Art

[0002] The RAS (Rat Sarcoma Viral Oncogene Homolog) family belongs to the low molecular weight GTPase superfamily and is widely expressed in various eukaryotes. There are three RAS genes (HRAS, KRAS and NRAS) in the human body and can be expressed as four highly related RAS low molecular weight GTPases (HRAS, KRAS4A, KRAS4B and NRAS). It functions as a binary switch for GDP-GTP regulation. Generally, they have two forms: the GDP (guanosine diphosphate) -bound form in the inactivated state and the GTP (guanosine triphosphate) -bound form in the activated state. The RAS protein regulates multiple downstream pathways including RAF-MEK-ERK, PI3K / Akt / mTOR by switching between the two active states, thereby affecting cell growth, proliferation and differentiation (Nat Rev Cancer, 2007, 7, 295-308). The RAS gene has a relatively high mutation rate in multiple types of tumors such as pancreatic cancer, colorectal cancer, and non-small cell lung cancer. The activated mutant RAS protein promotes abnormal signal transduction, leading to cancer occurrence, progression, and resistance to targeted drugs. Among them, the KRAS mutation is the gene with the highest mutation rate in human oncogenic genes, accounting for 20% - 30% of all tumors.

[0003] KRAS G12C is attracting the participation of many well-known drug development companies both domestically and internationally. Amgen's sotorasib (AMG510), the fastest-growing small molecule KRAS G12C inhibitor, already received marketing approval from the FDA on May 28, 2021, for non-small cell lung cancer patients with KRAS G12C mutations who have received at least one systemic therapy. However, Eli Lilly's new generation KRAS G12C inhibitor, LY3537982, is attracting even more attention. Eli Lilly reported preclinical data for LY3537982 at the American Association for Cancer Research (AACR) annual meeting in April 2021. The data showed that LY3537982 inhibits cell activity more than 10 times more effectively than sotorasib, and it entered Phase I clinical trials in July 2021. Clinically, there is still a need for highly selective, safe, and effective KRAS G12C inhibitors.

[0004] PCT / CN2022 / 126650 provides a KRAS G12C inhibitor, whose chemical name is (S)-4-((S)-10-acryloyl-4-chloro-2-fluoro-14-oxo-8,8a,9,10,11,12-hexahydro-7H,14H-pyrazino[1',2':5,6][1,5]diazosino[3,2,1-hi]indazole-3-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile, which has the structure shown in formula 1. [ka]

[0005] The crystalline structure of a pharmaceutical active ingredient tends to affect the chemical stability of the drug. Depending on crystallization and storage conditions, the crystalline structure of a compound can change, sometimes leading to the formation of other crystalline forms. Generally, amorphous pharmaceutical products lack a regular crystalline structure and have other drawbacks, such as relatively poor product stability, relatively fine precipitated crystals, difficulty in filtration, tendency to solidify, and poor fluidity. The crystalline polymorphism of a drug presents different requirements for product storage, manufacturing, and scale-up. Therefore, it is necessary to study the crystalline forms of the above compounds in detail and improve various properties of those compounds. [Overview of the project]

[0006] This disclosure provides a novel crystalline form of the compound represented by Formula 1, which has good stability and is more readily applicable in clinical settings. [ka]

[0007] The A-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 8.406, 10.960, 11.530, 18.216, and 22.849 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0008] In some embodiments, the A-type crystals of the compound represented by Equation 1 exhibit characteristic peaks at 7.419, 8.406, 10.960, 11.530, 18.216, 21.298, 22.849, and 28.948 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0009] In some embodiments, the A-type crystals of the compound represented by formula 1 exhibit characteristic peaks at 7.419, 8.406, 10.960, 11.530, 18.216, 21.298, 22.433, 22.849, 28.948, and 30.452 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0010] In some embodiments, the A-type crystal of the compound represented by Equation 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 1.

[0011] This disclosure further provides a method for preparing type A crystals of a compound represented by formula 1, the method comprising adding the compound of formula 1 to solvent a and stirring to crystallize, wherein solvent a is selected from one or more of ethyl acetate and n-heptane.

[0012] The C-type crystals of the compound represented by Formula 1 provided in this disclosure have characteristic peaks at 9.150, 12.034, 17.860, 19.920, 23.604, and 23.997 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0013] In some embodiments, the C-type crystals of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 9.150, 11.840, 12.034, 17.860, 19.920, 23.604, 23.997, 25.803, 27.536, and 28.038.

[0014] In some embodiments, the C-type crystals of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 9.150, 11.840, 12.034, 17.860, 19.920, 23.604, 23.997, 25.803, 27.536, 28.038, 30.743, and 31.353.

[0015] In some embodiments, the C-type crystals of the compound represented by Equation 1 have powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, as shown in Figure 2.

[0016] This disclosure further provides a method for preparing C-type crystals of the compound represented by Formula 1, the method being described above. Method 1 is a method in which the compound of formula 1 is added to solvent I, stirred and crystallized, and the solvent I is selected from one or more of isopropanol, ethanol, and n-propanol. Method 2 is a method in which the compound of formula 1 is dissolved in 1,4-dioxane, solvent II is added and stirred to crystallize, wherein solvent II is selected from one or more of isopropanol, methyl tert-butyl ether, n-heptane, isopropyl acetate, dichloromethane, and cyclohexane. Method 3 comprises dissolving the compound of Formula 1 in solvent III, stirring to crystallize it, wherein solvent III is selected from one or more of acetone, tetrahydrofuran, 1,4-dioxane, isopropyl acetate, dichloromethane, and tetrahydrofuran / ethanol (v / v=2:1).

[0017] The D-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 9.096, 11.735, 12.094, 17.928, and 23.968 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0018] In some embodiments, the D-type crystals of the compound represented by Equation 1 exhibit characteristic peaks at 9.096, 11.735, 12.094, 14.894, 16.002, 17.928, 19.870, 23.397, and 23.968 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0019] In some embodiments, the D-type crystals of the compound represented by Equation 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 9.096, 11.735, 12.094, 14.894, 16.002, 17.928, 19.870, 23.397, 23.968, 24.917, and 29.556.

[0020] In some embodiments, the D-type crystals of the compound represented by Equation 1 exhibit the powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, as shown in Figure 3.

[0021] The present disclosure further provides a method for preparing the D-type crystal of the compound represented by Formula 1, the method comprising adding the compound of Formula 1 to Solvent b and stirring for crystallization, wherein Solvent b is selected from one or more of n-butanol and tert-butyl alcohol.

[0022] The E-type crystal of the compound represented by Formula 1 provided by the present disclosure has characteristic peaks at 7.296, 10.626, 17.905, 23.131 and 25.377 in the powder X-ray diffraction pattern represented by the diffraction angle 2θ.

[0023] In some embodiments, the E-type crystal of the compound represented by Formula 1 has characteristic peaks at 7.296, 10.626, 11.393, 12.647, 17.905, 20.706, 23.131 and 25.377 in the powder X-ray diffraction pattern represented by the diffraction angle 2θ.

[0024] In some embodiments, the E-type crystal of the compound represented by Formula 1 has characteristic peaks at 7.296, 10.626, 11.393, 12.647, 16.030, 17.905, 20.706, 21.483, 23.131, 24.729, 25.377 and 27.267 in the powder X-ray diffraction pattern represented by the diffraction angle 2θ.

[0025] In some embodiments, the E-type crystal of the compound represented by Formula 1 has a powder X-ray diffraction pattern represented by the diffraction angle 2θ as shown in Figure 4.

[0026] The present disclosure further provides a method for preparing the E-type crystal of the compound represented by Formula 1, the method comprising Method 1: dissolving the compound of Formula 1 in methanol and evaporating the solvent; and Method 2: adding the compound of Formula 1 to 10% water / methanol and stirring.

[0027] The F-type crystals of the compound represented by Formula 1 provided in this disclosure have characteristic peaks at 9.947, 15.672, 18.740, 20.712, 23.910, and 28.351 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0028] In some embodiments, the F-type crystals of the compound represented by formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 7.935, 9.947, 10.339, 15.672, 18.740, 19.933, 20.712, 23.910, 25.504, 26.139, and 28.351.

[0029] In some embodiments, the F-type crystals of the compound represented by formula 1 exhibit characteristic peaks at 7.935, 9.947, 10.339, 11.651, 11.990, 15.672, 16.642, 18.740, 19.933, 20.712, 21.471, 23.910, 25.504, 26.139, 27.660, 28.351, and 28.898 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0030] In some embodiments, the F-type crystal of the compound represented by Equation 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 5.

[0031] This disclosure further provides a method for preparing F-type crystals of a compound represented by Formula 1, the method being described above. Method 1, which involves adding the compound of formula 1 to purified water and stirring while performing a heating-cooling cycle between 50°C and 5°C, Method 2 includes dissolving the compound of formula 1 in 80% acetone / water, adding purified water, and stirring.

[0032] In this disclosure, raising and lowering the temperature from 50°C to 5°C involves repeatedly raising the temperature from 5°C to 50°C and then lowering it from 50°C to 5°C. In some embodiments, the temperature is lowered from 50°C to 5°C within one hour, and then raised from 5°C to 50°C within another hour.

[0033] The G-type crystals of the compound represented by Formula 1 provided in this disclosure have characteristic peaks at 10.701, 11.896, 12.669, 17.822, 25.246, and 27.288 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0034] In some embodiments, the G-type crystals of the compound represented by formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 7.457, 10.701, 11.896, 12.669, 17.822, 20.532, 21.378, 25.246, 27.288, and 32.704.

[0035] In some embodiments, the G-type crystals of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 7.457, 10.701, 11.896, 12.669, 17.822, 20.532, 21.015, 21.378, 22.429, 24.516, 25.246, 27.288, and 32.704.

[0036] In some embodiments, the G-type crystals of the compound represented by Equation 1 have powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, as shown in Figure 6.

[0037] This disclosure further provides a method for preparing G-type crystals of the compound represented by Formula 1, the method being described above. Method 1, which involves adding the compound of formula 1 to methanol and stirring while performing a heating-cooling cycle from 50°C to 5°C, Method 2 involves dissolving the compound of formula 1 in 80% acetone / water, adding methanol / water (V / V=4:3), and stirring. Method 3 comprises adding an E-type crystal of the compound of formula 1 to solvent IV and stirring, wherein solvent IV is selected from one or more of isopropyl ether, methyl tert-butyl ether, cyclohexane, isopropyl acetate, and water.

[0038] The H-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 7.961, 13.533, 15.180, 15.879, and 20.619 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0039] In some embodiments, the H-type crystals of the compound represented by Equation 1 exhibit characteristic peaks at 7.961, 13.533, 15.180, 15.879, 15.946, 20.619, 20.902, 22.595, and 25.444 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0040] In some embodiments, the H-type crystals of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 7.961, 13.533, 15.180, 15.879, 15.946, 20.619, 20.902, 22.595, 25.444, 29.305, and 30.671.

[0041] In some embodiments, the H-type crystals of the compound represented by Equation 1 have powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, as shown in Figure 7.

[0042] This disclosure further provides a method for preparing H-type crystals of a compound represented by formula 1, the method comprising the step of adding the compound of formula 1 to diethyl ether and forming a slurry.

[0043] In some embodiments, a method for preparing H-type crystals of the compound represented by Formula 1 of this disclosure further includes the step of adding E-type crystals of the compound of Formula 1 to diethyl ether and forming a slurry.

[0044] The type I crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 8.996, 12.286, 18.112, 19.719, and 24.005 in their powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ.

[0045] In some embodiments, type I crystals of the compound represented by formula 1 exhibit characteristic peaks at 8.996, 12.286, 15.616, 16.690, 18.112, 19.719, 22.812, and 24.005 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0046] In some embodiments, type I crystals of the compound represented by formula 1 exhibit characteristic peaks at 8.996, 12.286, 15.616, 16.690, 17.786, 18.112, 19.719, 22.812, 24.005, 26.757, and 27.698 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0047] In some embodiments, the type I crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 8.

[0048] This disclosure further provides a method for preparing type I crystals of a compound represented by formula 1, the method comprising the step of adding the compound of formula 1 to n-pentanol and forming a slurry.

[0049] The J-type crystals of the compound represented by Formula 1 provided in this disclosure have characteristic peaks at 8.928, 12.055, 17.726, 19.533, 22.991, and 23.657 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0050] In some embodiments, the J-type crystals of the compound represented by Equation 1 exhibit characteristic peaks at 8.928, 11.725, 12.055, 16.671, 17.726, 19.533, 22.991, 23.657, and 26.826 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0051] In some embodiments, J-type crystals of the compound represented by Equation 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 6.024, 8.928, 11.725, 12.055, 15.762, 16.671, 17.726, 19.533, 22.991, 23.657, 26.826, and 27.446.

[0052] In some embodiments, the J-type crystal of the compound represented by Equation 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 9.

[0053] This disclosure further provides a method for preparing J-type crystals of a compound represented by formula 1, the method comprising the step of adding the compound of formula 1 to isoamyl alcohol and forming a slurry.

[0054] The K-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 9.306, 12.132, 17.933, and 20.058 in their powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ.

[0055] In some embodiments, the K-type crystals of the compound represented by Equation 1 exhibit characteristic peaks at 6.121, 9.306, 12.132, 17.933, 20.058, 24.077, and 34.192 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0056] In some embodiments, the K-type crystal of the compound represented by Equation 1 has a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, as shown in Figure 10.

[0057] This disclosure further provides a method for preparing K-type crystals of the compound represented by Formula 1, the method being any one of the following, namely: Method 1, which involves adding the compound of formula 1 to 7% water / ethanol and stirring, Method 2, wherein the compound of formula 1 is dissolved in 1,4-dioxane or 10% water / acetone, and ethanol is added and stirred, Method 3 involves dissolving the compound of formula 1 in ethyl acetate / ethanol (v / v=1:1), and stirring while raising and lowering the temperature between 50°C and 5°C. Method 4 is selected from the following: dissolving the compound of formula 1 in acetonitrile, heating to 65°C to dissolve it, and then cooling.

[0058] The L-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 10.645, 16.725, 17.050, 19.513, and 19.780 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0059] In some embodiments, L-type crystals of the compound represented by Equation 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 6.580, 10.645, 14.011, 14.586, 16.725, 17.050, 19.513, 19.780, and 21.862.

[0060] In some embodiments, L-type crystals of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 6.580, 10.645, 14.011, 14.586, 16.725, 17.050, 19.513, 19.780, 21.862, 26.362, 26.952, and 27.932.

[0061] In some embodiments, the L-type crystals of the compound represented by Equation 1 have powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, as shown in Figure 11.

[0062] This disclosure further provides a method for preparing L-type crystals of a compound represented by Formula 1, the method comprising the step of adding F-type crystals of the compound of Formula 1 to water and stirring at 95°C.

[0063] The M-type crystals of the compound represented by Formula 1 provided in this disclosure have characteristic peaks at 8.313, 11.772, 15.173, 18.762, 20.945, and 25.849 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0064] In some embodiments, the M-type crystals of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 7.595, 8.313, 11.772, 12.680, 13.791, 15.173, 17.320, 18.762, 20.945, 25.849, and 26.857.

[0065] In some embodiments, the M-type crystals of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 7.595, 8.313, 11.772, 12.680, 13.359, 13.791, 15.173, 16.626, 17.320, 18.762, 19.506, 20.945, 25.849, 26.857, 29.605, and 30.545.

[0066] In some embodiments, the M-type crystal of the compound represented by Equation 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 12.

[0067] This disclosure further provides a method for preparing M-type crystals of the compound represented by Formula 1, the method being described above. Method 1, wherein the compound of formula 1 is added to isopropyl acetate and stirred, Method 2 includes dissolving the compound of formula 1 in isopropyl acetate, adding n-heptane, and stirring.

[0068] The N-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 6.324, 13.092, 13.626, 14.699, 19.483, 22.429, and 27.407 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0069] In some embodiments, the N-type crystals of the compound represented by Equation 1 exhibit characteristic peaks at 6.324, 13.092, 13.626, 14.699, 15.566, 19.483, 20.724, 22.429, 23.287, and 27.407 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0070] In some embodiments, the N-type crystals of the compound represented by Equation 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, at 6.324, 12.664, 13.092, 13.626, 14.699, 15.566, 19.483, 20.724, 22.429, 23.287, 25.042, 26.840, 27.407, and 30.152.

[0071] In some embodiments, the N-type crystal of the compound represented by Equation 1 has a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, as shown in Figure 13.

[0072] This disclosure further provides a method for preparing N-type crystals of a compound represented by Formula 1, the method being described above. Method 1 is a method in which the compound of formula 1 is added to solvent V, stirred and crystallized, and the solvent V is selected from water and methyl isobutyl ketone. Method 2 is a method in which the compound of formula 1 is dissolved in solvent VI, a seed crystal is added and crystallized, and the solvent VI is selected from one or more types of methyl isobutyl ketone and isopropyl acetate. Method 3 includes dissolving the compound of formula 1 in ethyl acetate, adding n-heptane, and stirring.

[0073] The O-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 7.224, 8.423, 11.843, 16.829, 19.735, and 20.425 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0074] In some embodiments, the O-type crystals of the compound represented by Equation 1 have powder X-ray diffraction patterns, represented by a diffraction angle of 2θ, as shown in Figure 14.

[0075] This disclosure further provides a method for preparing O-type crystals of a compound represented by formula 1, the method comprising dissolving the compound of formula 1 in 2-butanone, adding water, stirring for 2 hours, and then centrifuging.

[0076] The P-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 7.848, 16.342, 19.613, 21.305, and 24.786 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0077] In some embodiments, the P-type crystals of the compound represented by Equation 1 exhibit characteristic peaks at 7.848, 13.063, 16.342, 19.613, 21.305, 23.584, and 24.786 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0078] In some embodiments, the P-type crystals of the compound represented by Equation 1 have powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, as shown in Figure 15.

[0079] This disclosure further provides a method for preparing P-type crystals of a compound represented by Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in 2-butanone, adding water, stirring for 24 hours, and centrifuging.

[0080] The Q-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 7.921, 8.455, 15.468, 18.035, 22.224, and 26.015 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0081] In some embodiments, the Q-type crystals of the compound represented by Equation 1 have powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, as shown in Figure 16.

[0082] This disclosure further provides a method for preparing Q-type crystals of a compound represented by Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in 2-butanone, adding water, stirring for 2 hours, centrifuging, and drying.

[0083] The R-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 9.598, 11.283, 13.705, 15.045, 19.714, and 24.020 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0084] In some embodiments, the R-type crystals of the compound represented by Formula 1 exhibit characteristic peaks at 8.248, 9.598, 11.283, 12.828, 13.705, 15.045, 15.539, 19.714, 22.430, 24.020, and 26.248 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0085] In some embodiments, the R-type crystals of the compound represented by Formula 1 exhibit characteristic peaks at 8.248, 9.598, 9.884, 11.283, 11.748, 12.828, 13.705, 15.045, 15.539, 16.670, 17.686, 19.714, 20.791, 22.430, 24.020, 25.017, and 26.248 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0086] In some embodiments, the R-type crystal of the compound represented by Equation 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 17.

[0087] This disclosure further provides a method for preparing R-type crystals of a compound represented by Formula 1, the method being described above. Step 1 involves dissolving the compound of formula 1 in 2-butanone, adding water, and heating and stirring at 50°C to crystallize it. Step 2 includes adding the crystals from Step 1 to water and stirring at 60°C to cause crystallization.

[0088] The S-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 10.810, 13.597, 14.706, 19.971, and 22.751 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0089] In some embodiments, the S-type crystals of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 6.465, 10.810, 11.872, 13.597, 14.706, 15.563, 19.971, 22.751, 23.881, and 26.322.

[0090] In some embodiments, the S-type crystals of the compound represented by Formula 1 exhibit characteristic peaks at 6.465, 10.810, 11.872, 12.996, 13.597, 14.706, 15.563, 16.385, 19.971, 20.914, 22.751, 23.881, 25.414, 26.322, 29.235, and 32.963 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0091] In some embodiments, the S-type crystals of the compound represented by Equation 1 have powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, as shown in Figure 18.

[0092] This disclosure further provides a method for preparing S-type crystals of a compound represented by Formula 1, the method being described above. Step 1 involves adding the compound of formula 1 to methyl isobutyl ketone and stirring to crystallize it. Step 2 includes vacuum drying the crystals from Step 1 at 100°C.

[0093] The T-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 6.431, 19.884, 21.207, 21.993, 24.138, 24.924, and 25.111 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0094] In some embodiments, the T-type crystals of the compound represented by Equation 1 have powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, as shown in Figure 19.

[0095] This disclosure further provides a method for preparing T-type crystals of a compound represented by Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in isopropanol and evaporating the solvent.

[0096] The U-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 6.843, 7.185, 8.193, 13.870, 14.416, and 20.769 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0097] In some embodiments, U-type crystals of the compound represented by Equation 1 exhibit characteristic peaks at 6.843, 7.185, 8.193, 13.870, 14.416, 16.683, 18.102, 18.721, and 20.769 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0098] In some embodiments, the U-type crystals of the compound represented by Equation 1 have powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, as shown in Figure 20.

[0099] This disclosure further provides a method for preparing U-type crystals of a compound represented by Formula 1, the method comprising the step of adding the compound of Formula 1 to 90% methanol / water and forming a slurry.

[0100] The type B crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 8.587, 10.089, 11.875, 16.987, 21.717, and 23.436 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0101] In some embodiments, the type B crystals of the compound represented by formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 7.545, 8.587, 10.089, 11.117, 11.875, 16.601, 16.987, 17.056, 18.838, 19.285, 21.287, 21.717, and 23.436.

[0102] In some embodiments, the type B crystals of the compound represented by formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 7.545, 8.587, 10.089, 11.117, 11.875, 15.809, 16.601, 16.987, 17.056, 18.397, 18.515, 18.838, 19.285, 21.287, 21.717, 22.527, 22.881, 23.436, 26.541, 29.276, and 30.437.

[0103] In some embodiments, the type B crystal of the compound represented by Equation 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 22.

[0104] This disclosure further provides a method for preparing type B crystals of a compound represented by formula 1, the method comprising the step of adding type E crystals of the compound of formula 1 to ethyl acetate and stirring.

[0105] The α-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 6.622, 9.944, 11.103, 17.932, 22.143, and 25.120 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0106] In some embodiments, the α-type crystals of the compound represented by Equation 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 6.622, 9.944, 11.103, 15.927, 17.932, 20.112, 22.143, 23.602, 25.120, and 29.026.

[0107] In some embodiments, the α-type crystal of the compound represented by Equation 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 23.

[0108] This disclosure further provides a method for preparing α-type crystals of a compound represented by formula 1, the method comprising adding N-type crystals of the compound of formula 1 to solvent c and stirring, wherein solvent c is selected from one or more of methanol, 50% methanol / water, 7% water / ethanol, and 50% acetonitrile / methanol.

[0109] The β-type crystals of the compound represented by Formula 1 provided herein have characteristic peaks at 7.683, 12.400, 15.616, 19.040, 22.856, and 24.802 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0110] In some embodiments, the β-type crystals of the compound represented by Equation 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 7.683, 11.501, 12.400, 14.114, 15.616, 16.527, 19.040, 22.856, 24.200, 24.802, 26.963, and 29.420.

[0111] In some embodiments, the β-type crystals of the compound represented by Equation 1 have characteristic peaks in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, at 7.683, 11.501, 12.400, 14.114, 15.616, 16.527, 19.040, 19.592, 19.861, 21.815, 22.856, 24.200, 24.802, 26.963, 28.023, 29.420, 31.500, and 33.726.

[0112] In some embodiments, the β-type crystal of the compound represented by Equation 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 24.

[0113] This disclosure further provides a method for preparing β-type crystals of a compound represented by Formula 1, the method comprising the step of adding B-type crystals of the compound of Formula 1 to propylene glycol methyl ether and stirring.

[0114] This disclosure further provides a pharmaceutical composition comprising one or more crystal types from the above-mentioned A-type to U-type crystals, α-type crystals, or β-type crystals, and a medicinal additive selected optionally from pharmaceutically acceptable excipients.

[0115] This disclosure further provides pharmaceutical compositions prepared from one or more crystal types among the above-mentioned A-type to U-type crystals, α-type crystals, or β-type crystals, and optionally pharmaceutically acceptable excipients.

[0116] This disclosure further provides a method for preparing a pharmaceutical composition, comprising the step of mixing one or more crystal types from the above-mentioned A-type to U-type crystals, α-type crystals, or β-type crystals with a pharmaceutically acceptable excipient.

[0117] This disclosure further provides the use of any one or more of the above-mentioned A-type to U-type crystals, α-type crystals, or β-type crystals, or the above-mentioned compositions, in the preparation of agents for the prevention and / or treatment of tumors.

[0118] In the uses described herein, the tumors mentioned above include breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, bronchial cancer, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, fetal cancer, hemangioendothelioma, ependymoma, epithelial carcinoma, esophageal cancer, primary thrombocytosis, Ewing's sarcoma, testicular cancer, glioma, heavy chain disease, and hematologic cancer. The tumors are selected from ductus blastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal cancer, oral cancer, thyroid cancer, pineal glandoma, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminomas, skin cancer, squamous cell carcinoma, synoviomas, sweat gland carcinoma, Valdenström macroglobulinemia, and Wilms' tumor, and preferably the above tumors are selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, and lung cancer.

[0119] In this disclosure, “2θ or 2θ angle” refers to the diffraction angle, where θ is the Bragg angle, the unit is ° or degrees, and the error range of each characteristic peak 2θ is ±0.20 (including when numbers with more than one decimal place are rounded), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, - The values ​​are 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, and 0.20.

[0120] For example, the numerical values ​​in this disclosure regarding substance content are measured and calculated data, and some degree of error is unavoidable. Generally, ±10% is within a reasonable margin of error. Depending on the context in which it is used, there may be some variation in error, and such variation in error may not exceed ±10%, but may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0121] In the method for preparing crystalline forms according to this disclosure, the starting materials used may be compounds in any form, and specific forms include, but are not limited to, amorphous, any crystalline form, hydrates, solvates, etc.

[0122] The drying temperature described in this disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and may be dried under normal pressure or under reduced pressure.

[0123] The crystallization methods described herein include room temperature crystallization, cooling crystallization, crystallization by solvent evaporation, and induction of crystallization by adding seed crystals. The cooling temperature is less than 65°C, preferably selected from -10°C to 60°C, and stirring may be used during the crystallization process.

[0124] As described in this disclosure, “differential scanning calorimetry or DSC” refers to measuring the temperature difference and heat flow difference between a sample and a reference object in order to characterize all physical and chemical changes related to thermal effects during a heating or constant-temperature process of a sample and to obtain information on the phase transition of the sample.

[0125] Based on the description of hygroscopic characteristics and the definition of weight increase due to hygroscopicity in the "Guidelines for the Hygroscopicity of 9103 Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia, Deliquescence: The process of absorbing a sufficient amount of water to form a liquid. Highly hygroscopic: Weight increase due to moisture absorption is 15% or more. Hygroscopic: Weight increase due to moisture absorption is less than 15%, but 2% or more. Slightly hygroscopic: Weight increase due to moisture absorption is less than 2%, but more than 0.2%. No or almost no hygroscopicity: Weight increase due to moisture absorption is less than 0.2%.

[0126] The “excipients” described herein include, but are not limited to, any excipients, carriers, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, or emulsifiers that have already been approved by the U.S. Food and Drug Administration and are permitted for use in humans or livestock. [Brief explanation of the drawing]

[0127] [Figure 1] This is the XRPD pattern of the A-type crystal of compound 1. [Figure 2] This is the XRPD pattern of the C-type crystal of compound 1. [Figure 3] This is the XRPD pattern of the D-type crystal of compound 1. [Figure 4] This is the XRPD pattern of the E-type crystal of compound 1. [Figure 5] This is the XRPD pattern of the F-type crystal of compound 1. [Figure 6] This is the XRPD pattern of the G-type crystal of compound 1. [Figure 7] This is the XRPD pattern of the H-type crystal of compound 1. [Figure 8] This is the XRPD pattern of the type I crystal of compound 1. [Figure 9] This is the XRPD pattern of the J-type crystal of compound 1. [Figure 10] This is the XRPD pattern of the K-type crystal of compound 1. [Figure 11] This is the XRPD pattern of the L-type crystal of compound 1. [Figure 12] This is the XRPD pattern of the M-type crystal of compound 1. [Figure 13] This is the XRPD pattern of the N-type crystal of compound 1. [Figure 14] This is the XRPD pattern of the O-type crystal of compound 1. [Figure 15] This is the XRPD pattern of the P-type crystal of compound 1. [Figure 16] This is the XRPD pattern of the Q-type crystal of compound 1. [Figure 17] This is the XRPD pattern of the R-type crystal of compound 1. [Figure 18] This is the XRPD pattern of the S-type crystal of compound 1. [Figure 19] This is the XRPD pattern of the T-type crystal of compound 1. [Figure 20] This is the XRPD pattern of the U-type crystal of compound 1. [Figure 21] This is the amorphous XRPD pattern of compound 1. [Figure 22] This is the XRPD pattern of the B-type crystal of compound 1. [Figure 23] This is the XRPD pattern of the α-type crystal of compound 1. [Figure 24] This is the XRPD pattern of the β-type crystal of compound 1. [Modes for carrying out the invention]

[0128] The present disclosure will be described in more detail below in combination with examples or experimental examples, but the examples or experimental examples of the present disclosure are merely for illustrating the technical proposal of the present disclosure and do not limit the substance or scope of the present disclosure.

[0129] Test conditions for the equipment used in the experiment: The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6 The values ​​are expressed in units of ppm. A Bruker AVANCE NEO 500M nuclear magnetic resonance spectrometer was used for the NMR measurements, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0130] For MS measurements, the following liquid chromatograph mass spectrometers were used: Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (Manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive).

[0131] High-performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489.

[0132] For high-performance liquid preparative chromatography, the Waters 2767 preparative chromatograph, Waters 2767-SQ Detector2, Shimadzu LC-20AP, and Gilson-281 were used.

[0133] For chiral preparative chromatography, a Shimadzu LC-20AP preparative chromatograph was used.

[0134] For the CombiFlash high-speed preparative chromatograph, the CombiFlash Rf200 (TELEDYNE ISCO) was used.

[0135] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications of the silica gel plates used for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications for isolation and purification of products by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0136] For silica gel column chromatography, silica gel with a mesh size of 200-300, manufactured by Yantai Huanghai Silica Gel, was commonly used as the support material.

[0137] A NovoStar plate reader (BMG GmbH, Germany) was used to measure the mean kinase inhibition rate and IC50 value.

[0138] The known starting materials of this disclosure may be synthesized by or in accordance with methods known in the art, or may be purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., and Dalui Chemicals.

[0139] In the examples, unless otherwise specified, all reactions can be carried out in an argon gas atmosphere or a nitrogen gas atmosphere.

[0140] An argon or nitrogen gas atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1 liter.

[0141] A hydrogen gas atmosphere refers to a reaction flask connected to a hydrogen gas balloon with a volume of approximately 1 liter.

[0142] For the pressurized hydrogenation reaction, a Parr 3916EKX type hydrogenator and either a QL-500 type hydrogen gas generator or an HC2-SS type hydrogenator were used.

[0143] The hydrogenation reaction typically involves repeating the process of evacuating the system and filling it with hydrogen gas three times.

[0144] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0145] In the examples, unless otherwise specified, "solution" refers to an aqueous solution.

[0146] In the examples, unless otherwise specified, the reaction temperature is room temperature between 20°C and 30°C.

[0147] Thin-layer chromatography (TLC) was used to monitor the progress of the reaction in the examples. The developing solvent used in the reaction, the eluent system for column chromatography to purify the compound, and the developing solvent system for thin-layer chromatography included A: petroleum ether / ethyl acetate system and B: dichloromethane / methanol system. The volume ratio of the solvents was adjusted according to the polarity of the compound, and small amounts of basic or acidic reagents such as triethylamine and acetic acid may be added to adjust the ratio.

[0148] XRPD is a detection method using powder X-ray diffraction. A BRUKER D8 type X-ray diffractometer is used for the measurement, and the specific information collected is as follows: Cu anode (40kV, 40mA), radiation: monochromatic Cu-Ka radiation (λ=1.5418Å). Scanning method: θ / 2θ, scanning range (2θ range): 3°~45°.

[0149] DSC stands for Differential Scanning Calorimetry: Measurements are performed using a METTLER TOLEDO DSC 3+ differential scanning calorimetry instrument, with a heating rate of 10°C / min, the specific temperature range is determined by referring to the corresponding pattern (mainly 25-350°C), and the nitrogen gas purge rate is 50 mL / min.

[0150] TGA is a thermogravimetric analysis: detection is performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer, with a heating rate of 10°C / min, the specific temperature range is determined by referring to the corresponding pattern (mainly 25-350°C), and the nitrogen gas purge rate is 50 mL / min.

[0151] DVS is dynamic moisture adsorption: detection is performed using SMS DVS Advantage, with humidity changes of 50%-95%-0%-95%-50% at 25°C, with step sizes of 10% (the last step being 5%) (the specific humidity range is based on the corresponding pattern, and the usage described here is the most common method), and the criterion for judgment is that dm / dt is 0.002% or less.

[0152] Example 1: Preparation of compound 1 of formula 1 (S)-4-((S)-10-acryloyl-4-chloro-2-fluoro-14-oxo-8,8a,9,10,11,12-hexahydro-7H,14H-pyrazino[1',2':5,6][1,5]diazosino[3,2,1-hi]indazole-3-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitriel (Refer to the preparation method of Example 7-P2 in the application with application number PCT / CN2022 / 12665) [ka] Step 1 4-Bromo-5-fluoro-1H-indazole-7-formate methyl 1b Methyl 2-amino-4-bromo-5-fluoro-3-methylbenzoate 1a (2.7 g, 10.3 mmol, prepared by the method disclosed in step (iv) on page 103 of the specification in patent application "WO2016020836A1") is dissolved in chloroform (50 mL), acetic anhydride (3.16 g, 30.9 mmol) is added, and the temperature is set to 40°C. oThe reaction was carried out with stirring for 90 minutes while maintaining a temperature below 1°C. Potassium acetate (302 mg, 3.08 mmol) and tert-butyl nitrite (2.12 g, 20.6 mmol) were added, and the reaction was carried out under reflux for 14 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (50 mL), and washed sequentially with water (30 mL), saturated sodium carbonate solution (10 mL), and saturated sodium chloride solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 1b (2.8 g). This product was used directly in the next reaction without purification.

[0153] MS m / z (ESI): 272.9 [M+1].

[0154] Step 2 4-Bromo-5-fluoro-1H-indazole-7-carboxylic acid 1c Crude compound 1b (2.8g, 10.25 mmol) is dissolved in a mixed solvent of tetrahydrofuran (20 mL), methanol (10 mL), and water (10 mL), and lithium hydroxide (2.15 g, 51.26 mmol) is added, and 40 o The reaction was carried out in C for 1 hour with stirring. The reaction mixture was concentrated under reduced pressure to remove most of the solvent, water was added, and the mixture was extracted with ethyl acetate (150 mL x 6). The organic phases were combined and washed sequentially with dilute hydrochloric acid and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain crude compound 1c (1.4 g). The product was used directly in the next reaction without purification.

[0155] MS m / z (ESI): 259.0 [M+1].

[0156] Step 3 (S)-4-(4-bromo-5-fluoro-1H-indazole-7-carbonyl)-3-(2-hydroxyethyl)piperazine-1-formate tert-butyl1f Crude compound 1c (600 mg, 2.32 mmol) and (S)-3-(2-hydroxyethyl)piperazine-1-formate tert-butyl 1d (586 mg, 2.54 mmol, prepared by the method disclosed in preparation 65 on page 80 of the specification in patent application "WO2021118877A1") were dissolved in 30 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (898 mg, 6.95 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.05 g, 2.78 mmol) were added and the mixture was reacted with stirring for 1 hour under ice bath. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed sequentially with water, saturated sodium carbonate solution, and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using eluent system A by silica gel column chromatography to obtain the title compound 1f (600 mg, yield: 54.9%).

[0157] MS m / z (ESI): 415.2 [M-55].

[0158] Step 4 (S)-3-bromo-2-fluoro-14-oxo-7,8,8a,9,11,12-hexahydro-10H,14H-pyrazino[1',2':5,6][1,5]diazosino[3,2,1-hi]indazole-10-formate tert-butyl 1g Under a nitrogen atmosphere, compound 1f (600 mg, 1.27 mmol) was dissolved in 36 mL of tetrahydrofuran. Under an ice bath, triphenylphosphine (667 mg, 2.54 mmol) and diethyl azodicarboxylate (514 mg, 2.54 mmol) were added in sequence, and the mixture was reacted with stirring while maintaining the temperature for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (15 mL x 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using eluent system A by silica gel column chromatography to obtain 1 g (577 mg, yield: 99.9%) of the title compound.

[0159] MS m / z (ESI): 397.2 [M-55].

[0160] Step 5 (S)-3-bromo-4-chloro-2-fluoro-14-oxo-7,8,8a,9,11,12-hexahydro-10H,14H-pyrazino[1',2':5,6][1,5]diazosino[3,2,1-hi]indazole-10-formate tert-butyl1h 1 g (630 mg, 1.38 mmol) of the compound was dissolved in acetonitrile (6 mL), N-chlorosuccinimide (278 mg, 2.08 mmol) was added, and the mixture was heated to 60°C and reacted for 0.5 hours to precipitate a solid. N-chlorosuccinimide (100 mg, 0.75 mmol) was added, and the reaction was continued for 20 minutes. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified using eluent system A by silica gel column chromatography to obtain 1 h (380 mg, yield: 56%) of the title compound.

[0161] MS m / z (ESI): 487.1 [M+1].

[0162] Step 6 (8aS)-3-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-4-chloro-2-fluoro-14-oxo-7,8,8a,9,11,12-hexahydro-10H,14H-pyrazino[1',2':5,6][1,5]diazosino[3,2,1-hi]indazole-10-formate tert-butyl1j Compound 1h (150 mg, 0.31 mmol) and Compound 1i (186 mg, 0.46 mmol, prepared by the method disclosed in preparation 15 on page 50 of the specification in patent application "WO2021118877A1") were dissolved in 5 mL of toluene, dichloro[bis(diphenylphosphinofinophenyl) ether]palladium(II) (43 mg, 0.06 mmol) and cesium carbonate (300 mg, 0.92 mmol) were added, and the mixture was replaced with nitrogen gas and 105 o The reaction was carried out in C for 6 hours with stirring, the reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified with eluent system A by silica gel column chromatography to obtain the title compound 1j (40 mg, yield: 18.6%).

[0163] MS m / z (ESI): 699.2 [M+1].

[0164] Step 7 2-Amino-4-((S)-4-chloro-2-fluoro-14-oxo-8,8a,9,10,11,12-hexahydro-7H,14H-pyrazino[1',2':5,6][1,5]diazosino[3,2,1-hi]indazole-3-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile bis(2,2,2-trifluoroacetic acid) salt 1k Compound 1j (40 mg, 57.21 μmol) was dissolved in 1 mL of dichloromethane, 1 mL of trifluoroacetic acid was added at 0°C, and the reaction was carried out with stirring for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, title compound 1k (41 mg), which was used directly in the next reaction without purification.

[0165] MS m / z (ESI): 499.2 [M+1].

[0166] Step 8 (S)-4-((S)-10-acryloyl-4-chloro-2-fluoro-14-oxo-8,8a,9,10,11,12-hexahydro-7H,14H-pyrazino[1',2':5,6][1,5]diazosino[3,2,1-hi]indazole-3-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitriel Crude compound 1k (41 mg, 56.4 μmol) was suspended in 2 mL of ethyl acetate, 1 mL of tetrahydrofuran, and 2 mL of water. Anhydrous potassium carbonate (24 mg, 173.6 μmol) was added, and acryloyl chloride (5.4 mg, 59.6 μmol) was added under ice bath. After reacting for 5 minutes, the mixture was extracted with ethyl acetate (5 mL x 2), the organic phases were combined, and the mixture was concentrated under reduced pressure to obtain crude compound 1, i.e., 4-((S)-10-Acryloyl Chloride). Liloyl-4-chloro-2-fluoro-14-oxo-8,8a,9,10,11,12-hexahydro-7H,14H-pyrazino[1',2':5][1,5]diazosino[3,2,1-hi]indazole-3-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (39 mg) was obtained and purified by high-performance liquid preparative chromatography (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient mixing ratio: acetonitrile 30%~45%, flow rate: 30 mL / min) to obtain title compound 1 (5 mg, yield: 15.1%). The compound was detected by X-ray powder diffraction, and the product was amorphous, with the XRPD pattern shown in Figure 21.

[0167] Single-stereoconfiguration compound (relatively short retention time) 1 (5 mg, yield: 15.1%) MS m / z (ESI): 553.2 [M+1].

[0168] HPLC analysis: Retention time 2.21 minutes, purity: 99% (Column: ACQUITY UPLC® BEH, C18, 1.7 μm, 2.1 × 50 mm, Mobile phase: Water (10 mM ammonium bicarbonate), acetonitrile, Gradient ratio: acetonitrile 10%~95%).

[0169] 1 H NMR (500 MHz, CD3OD): δ 7.67 (d, 1H), 7.20 (t, 1H), 7.02 (dd, 1H), 6.87 (dd, 1H), 6.72-6.28 (m, 1H), 5.81 (t, 1H), 4.74-4.67 (m, 1H), 4.66-4.56 (m, 1H), 4.41 (d, 1H), 4.30 (d, -1H), 4.12-4.00 (m, 1H), 3.96 (d, 1H), 3.49 (d, 1H), 3.09 (dd, 2H), 2.26-2.16 (m, 1H), 1.94 (s, 1H).

[0170] Single-stereoconfiguration compound (relatively long retention time) 1-P1 (2 mg, yield: 6%) MS m / z (ESI): 553.2 [M+1].

[0171] HPLC analysis: Retention time 2.29 minutes, purity: 95% (Column: ACQUITY UPLC® BEH, C18, 1.7 μm, 2.1 × 50 mm, Mobile phase: Water (10 mM ammonium bicarbonate), acetonitrile, Gradient ratio: acetonitrile 10%~95%).

[0172] 1 H NMR (500 MHz, CD3OD): δ 7.65 (d, 1H), 7.20 (t, 1H), 7.00 (dd, 1H), 6.85 (dd, 1H), 6.70-6.26 (m, 1H), 5.81 (t, 1H), 4.73-4.65 (m, 1H), 4.66-4.56 (m, 1H), 4.39 (d, 1H), 4.30 (d, 1H), 4.10-4.00 (m, 1H), 3.92 (d, 1H), 3.49 (d, 1H), 3.12 (dd, 2H), 2.24-2.16 (m, 1H), 1.92 (s, 1H).

[0173] Test Example 1: H358 Cell Proliferation Test The following method is for measuring the inhibitory activity of the compounds relating to this disclosure on H358 cell proliferation, and the experimental method is briefly described below.

[0174] H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 medium (Hyclone, SH30809.01) (i.e., complete medium) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, H358 cells were seeded in 96-well plates at a density of 1200 cells / well using complete medium, and 100 μL of cell suspension was added to each well and incubated overnight in a cell incubator at 37°C and 5% CO2. The following day, 10 μL of the compound, prepared in complete medium and gradient diluted, was added to each well, with the final concentration of the compound being 10 μM, resulting in 9 concentration points obtained by a 5-fold gradient dilution. A blank control containing 0.5% DMSO was set up, and the well plates were incubated for 120 hours in a cell incubator at 37°C and 5% CO2. On day 7, the 96-well cell culture plate was removed, 50 μL of CellTiter-Glo® Luminescent Cell Viability Assay (Promega, G7573) was added to each well, and after standing at room temperature for 10 minutes, the luminescence signal values ​​were read using a multifunctional microplate reader (PerkinElmer, EnVision® 2105), and the IC of compound inhibitory activity was measured using Graphpad Prism software. 50 The value was calculated. [Table 1] Conclusion: The compounds described herein have an inhibitory effect on the proliferation of H358 cells.

[0175] Test Example 2: MIA PaCa-2 Cell Proliferation Test The following method is for measuring the inhibitory activity of the compounds relating to this disclosure on MIA PaCa-2 cell proliferation. The experimental method is briefly described below.

[0176] MIA PaCa-2 cells (ATCC, CRL-1420) were cultured in DMEM / HIGH GLUCOSE (GE, SH30243.01) medium (i.e., complete medium) containing 10% fetal bovine serum (Corning, 35-076-CV) and 2.5% equine serum (Biyuntian Biotechnology, C0262). On the first day of the experiment, MIA PaCa-2 cells were seeded at a density of 500 cells / well in a 96-well plate using complete medium, and 90 μL of cell suspension was placed in each well and cultured overnight in a cell incubator at 37°C and 5% CO2. The following day, 10 μL of the compound, prepared in complete medium and gradient-diluted, was added to each well, resulting in nine concentration points representing a 5-fold gradient dilution from 10 μM. A blank control containing 0.5% DMSO was placed, and the well plate was incubated in a cell incubator at 37°C and 5% CO2 for 72 hours. On day 5, the 96-well cell culture plate was removed, and 50 μL of luminescent cell viability assay (CellTiter-Glo® Luminescent Cell Viability Assay) (Promega, G7573) was added to each well. After standing at room temperature for 10 minutes, the luminescence signal values ​​were read using a multifunctional microplate reader (PerkinElmer, EnVision2015). IC50 of the inhibitory activity of the compound was measured using Graphpad Prism software. 50 The value was calculated. [Table 2]

[0177] Example 2: Preparation of Type A Crystals 5 mg of the compound shown in formula 1 was weighed, 0.5 mL of ethyl acetate / n-heptane (v / v=1:1) was added, and the mixture was stirred at room temperature for 2 days. After centrifugation, the solid was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product, which was defined as a type A crystal. The XRPD pattern is shown in Figure 1, and the positions of its characteristic peaks are shown in Table 3. The DSC pattern indicated that the peak temperatures of the endothermic peak were 156.75°C and 206.08°C. The TGA pattern showed a weight loss of 10.64% between 30°C and 140°C. [Table 3-1] [Table 3-2]

[0178] Example 3: Preparation of Type A Crystals 20 mg of the compound shown in Formula 1 was weighed, 0.5 mL of ethyl acetate was added, and the mixture was stirred for 1 day while raising and lowering the temperature between 50°C and 5°C (at a rate of ±0.75°C / min). After centrifugation, the solid was vacuum-dried to obtain the title product. Detection by powder X-ray diffraction revealed that the product was a type A crystal.

[0179] Example 4: Preparation of C-type crystals 10 mg of the compound shown in formula 1 was weighed, 1 mL of isopropanol was added, and the mixture was stirred at room temperature for 3 days. After centrifugation, it was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product, which was defined as a C-type crystal. The XRPD pattern is shown in Figure 2, and the positions of its characteristic peaks are shown in Table 4. The DSC pattern indicated that the peak temperature of the endothermic peak was 239.41 °C. The TGA pattern showed a weight loss of 0.50% from 30 °C to 159 °C and a weight loss of 5.50% from 159 °C to 269 °C. [Table 4-1] [Table 4-2]

[0180] Example 5: Preparation of C-type crystals 10 mg of the compound shown in Formula 1 was weighed, and a solvent was added (as shown in Table 5 below). Solvent precipitation occurred at room temperature, followed by continuous stirring for 3 days. After centrifugation, the solid was vacuum-dried to obtain the title product. Detection by powder X-ray diffraction revealed that the product was a C-type crystal. [Table 5]

[0181] Example 6: Preparation of C-type crystals 5 mg of the compound shown in Formula 1 was weighed, 0.05 mL of 1,4-dioxane was added, and the mixture was stirred at room temperature to dissolve it. 0.45 mL of solvent was added (the solvent is as shown in Table 6 below), and the mixture was stirred to crystallize. The mixture was then formed into a slurry at room temperature for 3 days, centrifuged, and the solid was vacuum-dried to obtain the title product. Powder X-ray diffraction detected the product as a C-type crystal. [Table 6]

[0182] Example 7 Preparation of C-type crystals 10 mg of the compound shown in Formula 1 was weighed, 0.2 mL of n-propanol was added, and the mixture was slurryed at 60°C for 1 day. After centrifugation, the solid was vacuum-dried to obtain the title product. Detection by powder X-ray diffraction revealed that the product was a C-type crystal.

[0183] Example 8: Preparation of D-type crystals 80 mg of the compound shown in Equation 1 was weighed, 1 mL of n-butanol was added, and the mixture was stirred for 2 days while heating and cooling between 50°C and 5°C (at a rate of ±0.75°C / min). After centrifugation, the solid was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product, which was defined as a D-type crystal. The XRPD pattern is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 7. The DSC pattern indicated that the peak temperature of the endothermic peak was 235.17°C. The TGA pattern showed a weight loss of 1.10% between 30°C and 119°C, and a weight loss of 5.62% between 120°C and 266°C. [Table 7-1] [Table 7-2]

[0184] Example 9: Preparation of D-type crystals 10 mg of the compound shown in Formula 1 was weighed, 0.2 mL of tert-butyl alcohol was added, and the mixture was slurryed at 60°C for 1 day. After centrifugation, the solid was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as a D-type crystal.

[0185] Example 10: Preparation of E-type crystals 10 mg of the compound shown in formula 1 was weighed, 1 mL of methanol was added, and the mixture was heated at 50°C to dissolve it. The mixture was then gradually evaporated to obtain a solid. Powder X-ray diffraction detected the product, which was defined as an E-type crystal. The XRPD pattern is shown in Figure 4, and the positions of its characteristic peaks are shown in Table 8. The DSC pattern indicated that the peak temperatures of the endothermic peaks were 229.16°C and 259.36°C. The TGA pattern showed a weight loss of 2.17% between 30°C and 177°C, and a weight loss of 5.94% between 177°C and 260°C. [Table 8-1] [Table 8-2]

[0186] Example 11: Preparation of E-type crystals 5 mg of the compound shown in Formula 1 was weighed, 0.2 mL of methanol was added, and the mixture was stirred for 1 day while raising and lowering the temperature between 50°C and 5°C (at a rate of ±0.75°C / min). After centrifugation, the solid was vacuum-dried to obtain the title product. Detection by powder X-ray diffraction revealed that the product was an E-type crystal.

[0187] Example 12: Preparation of E-type crystals 5 mg of the compound shown in Formula 1 was weighed, 0.125 mL of 10% water / methanol was added, and the mixture was stirred for 1 day while raising and lowering the temperature between 50°C and 5°C (at a rate of ±0.75°C / min). After centrifugation, the solid was vacuum-dried to obtain the title product. Detection by powder X-ray diffraction revealed that the product was an E-type crystal.

[0188] Example 13: Preparation of F-type crystals 1 g of the compound shown in Equation 1 was weighed, 13 mL of purified water was added, and the mixture was stirred for 4 days while raising and lowering the temperature between 50°C and 5°C (at a rate of ±0.75°C / min). After filtration under reduced pressure, the solid was vacuum-dried to obtain a solid. Powder X-ray diffraction detection revealed that the product was defined as an F-type crystal. The XRPD pattern is shown in Figure 5, and the positions of its characteristic peaks are shown in Table 9. The DSC pattern indicated that the peak temperatures of the endothermic peaks were 85.97°C, 150.99°C, and 222.57°C. The TGA pattern showed a weight loss of 6.03% between 30°C and 101°C. DVS detection revealed that under normal storage conditions (i.e., 25°C, 60% RH), the sample showed a weight increase of approximately 6.35% due to moisture absorption; under accelerated experimental conditions (i.e., 70% RH), the weight increase was approximately 6.44%; and under extreme conditions (90% RH), the weight increase was approximately 6.65%. During the RH humidity change process from 0% to 95%, the desorption and adsorption processes of the sample did not coincide, and re-measurement of the crystal type after DVS detection showed that the crystal type did not change. [Table 9-1] [Table 9-2]

[0189] Example 14: Preparation of F-type crystals 100 mg of the compound shown in Formula 1 was weighed, 1 mL of 80% acetone / water was added, and the mixture was stirred at room temperature to dissolve it. Then, 3.8 mL of purified water was added and the mixture was stirred to crystallize. The temperature was raised to 50°C and stirred continuously for 3 days. After centrifugation, the mixture was air-dried overnight at 40°C to obtain a solid. Powder X-ray diffraction detected the product as an F-type crystal.

[0190] Example 15: Preparation of G-type crystals 80 mg of the compound shown in Equation 1 was weighed, 1 mL of methanol was added, and the mixture was stirred for 2 days while heating and cooling between 50°C and 5°C (at a rate of ±0.75°C / min). After centrifugation, the solid was vacuum-dried at 80°C for 7.5 hours to obtain a solid. Powder X-ray diffraction detected the product, which was defined as a G-type crystal. The XRPD pattern is shown in Figure 6, and the positions of its characteristic peaks are shown in Table 10. The DSC pattern indicated that the peak temperature of the endothermic peak was 237.35°C. The TGA pattern showed a weight loss of 0.59% between 30°C and 100°C, and a weight loss of 0.43% between 100°C and 270°C. According to DVS detection, the sample showed a weight increase due to moisture absorption of approximately 1.04% under normal storage conditions (i.e., 25°C, 60% RH), approximately 1.21% under accelerated experimental conditions (i.e., 70% RH), and approximately 1.60% under extreme conditions (90% RH). During the RH humidity change process from 0% to 95%, the desorption and adsorption processes of the sample essentially overlapped, and re-measurement of the crystal form after DVS detection showed that the crystal form did not change. [Table 10-1] [Table 10-2]

[0191] Example 16: Preparation of G-type crystals 500 mg of the compound shown in Formula 1 was weighed, 2 mL of 80% acetone / water was added, and the mixture was stirred at room temperature to dissolve it. Then, 8 mL of methanol and 6 mL of purified water were added, and the mixture was stirred for 4 days. After filtration, the mixture was vacuum-dried overnight at 80°C to obtain a solid. Powder X-ray diffraction detected the product as a G-type crystal.

[0192] Example 17: Preparation of G-type crystals 10 mg of E-type crystals of the compound shown in formula 1 were weighed, and 0.2 mL of solvent was added. The solvent was as shown in Table 11 below. The mixture was stirred at 60°C for 1 day, centrifuged, and then vacuum-dried overnight at 80°C to obtain a solid. Powder X-ray diffraction detected the product as G-type crystals. [Table 11]

[0193] Example 18: Preparation of H-type crystals 25 mg of E-type crystals of the compound represented by formula 1 were weighed, 1 mL of diethyl ether was added, and the mixture was slurryed at room temperature or 50°C for 4 hours. After centrifugation, the mixture was vacuum-dried overnight at 80°C to obtain a solid. Powder X-ray diffraction detected the product as an H-type crystal. The XRPD pattern is shown in Figure 7, and the positions of its characteristic peaks are shown in Table 12. The DSC pattern indicated that the peak temperatures of the endothermic peaks were 46.77°C and 221.95°C. The TGA pattern showed a weight loss of 2.23% from 30°C to 100°C and a weight loss of 0.20% from 100°C to 220°C. [Table 12-1] [Table 12-2]

[0194] Example 19: Preparation of H-type crystals 25 mg of the compound shown in Formula 1 was weighed, 1 mL of diethyl ether was added, and the mixture was slurryed at room temperature for 5 days. After centrifugation, it was vacuum-dried overnight at 40°C to obtain a solid. Powder X-ray diffraction detected the product as an H-type crystal.

[0195] Example 20: Preparation of Type I Crystals 30 mg of the compound shown in Formula 1 was weighed, 0.6 mL of n-pentanol was added, and the mixture was slurryed at 60°C for 1 day. After centrifugation, the mixture was vacuum-dried overnight at 40°C to obtain the title product. Powder X-ray diffraction detected the product as a type I crystal. The XRPD pattern is shown in Figure 8, and the positions of its characteristic peaks are shown in Table 13. The DSC pattern indicated that the peak temperatures of the endothermic peaks were 66.03°C, 222.56°C, and 245.19°C. The TGA pattern showed a weight loss of 0.97% from 30°C to 100°C and a weight loss of 8.15% from 100°C to 240°C. [Table 13-1] [Table 13-2]

[0196] Example 21: Preparation of J-type crystals 30 mg of the compound shown in Formula 1 was weighed, 0.6 mL of isoamyl alcohol was added, and the mixture was slurryed at 60°C for 1 day. After centrifugation, it was vacuum-dried overnight at 40°C to obtain a solid. Powder X-ray diffraction detected the product, which was defined as a J-type crystal. The XRPD pattern is shown in Figure 9, and the positions of its characteristic peaks are shown in Table 14. The DSC pattern indicated that the peak temperatures of the endothermic peaks were 230.96°C and 242.37°C. The TGA pattern showed a weight loss of 0.46% from 31°C to 100°C and a weight loss of 7.85% from 171°C to 260°C. [Table 14-1] [Table 14-2]

[0197] Example 22: Preparation of K-type crystals 10 mg of the compound shown in formula 1 was weighed, 1 mL of 7% water / ethanol was added, and the mixture was stirred at room temperature for 3 days. After centrifugation, it was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product, which was defined as a K-type crystal. The XRPD pattern is shown in Figure 10, and the positions of its characteristic peaks are shown in Table 15. The DSC pattern indicated that the peak temperature of the endothermic peak was 240.73°C. The TGA pattern showed a weight loss of 1.42% from 30°C to 108°C and a weight loss of 3.32% from 108°C to 272°C. [Table 15]

[0198] Example 23: Preparation of K-type crystals 5 mg of the compound shown in Formula 1 was weighed, 0.050 mL of 1,4-dioxane was added, and the mixture was stirred at room temperature to dissolve it. 0.450 mL of ethanol was added and the mixture was stirred to crystallize. The mixture was then formed into a slurry at room temperature for 3 days, centrifuged, and vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as a K-type crystal.

[0199] Example 24: Preparation of K-type crystals 5 mg of the compound shown in Formula 1 was weighed, 0.075 mL of ethyl acetate / ethanol mixed solvent (v / v=1:1) was added, and the mixture was stirred at room temperature to dissolve it. The mixture was stirred for 1 day while raising and lowering the temperature between 50°C and 5°C (at a rate of ±0.75°C / min), then centrifuged and vacuum-dried to obtain a solid. Detection by powder X-ray diffraction revealed that the product was a K-type crystal.

[0200] Example 25: Preparation of L-type crystals 10 mg of F-type crystals of the compound shown in formula 1 were weighed, 0.5 mL of water was added, the mixture was stirred at 95°C for 2 hours, centrifuged, and then vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as an L-type crystal, and the XRPD pattern is shown in Figure 11, with the characteristic peak positions shown in Table 16. The DSC pattern indicated that the peak temperatures of the endothermic peak were 98.46°C and 237.45°C. The TGA pattern showed a weight loss of 2.6% between 30°C and 270°C. [Table 16-1] [Table 16-2]

[0201] Example 26: Preparation of M-type crystals 10 mg of the compound shown in Formula 1 was weighed, 0.1 mL of isopropyl acetate was added, and the mixture was stirred at room temperature for 2 days. After centrifugation, it was vacuum-dried to obtain a solid. Powder X-ray diffraction detection revealed that the product was defined as an M-type crystal. The XRPD pattern is shown in Figure 12, and the positions of its characteristic peaks are shown in Table 17. DSC pattern indicated that the peak temperature of the endothermic peak was 254.20°C. TGA pattern showed a weight loss of 0.23% between 27°C and 247°C. DVS detection showed that under normal storage conditions (i.e., 25°C, 60% RH), the weight increase due to moisture absorption was approximately 0.48%, under accelerated experimental conditions (i.e., 70% RH), it was approximately 0.55%, and under extreme conditions (90% RH), it was approximately 0.73%. During the RH humidity change from 0% to 95%, the desorption and adsorption processes of the sample essentially overlapped, and re-measurement of the crystal type after DVS detection showed that no crystal type change occurred. [Table 17-1] [Table 17-2]

[0202] Example 27: Preparation of M-Type Crystal Weighed 100 mg of the compound represented by Formula 1, added 2.5 mL of isopropyl acetate, stirred and dissolved at 60 °C, cooled to room temperature, then added 1 mL of n-heptane, and stirred overnight at room temperature. After centrifugation, it was dried under vacuum to obtain a solid. As detected by powder X-ray diffraction, the product was an M-type crystal.

[0203] Example 28: Preparation of N-Type Crystal Weighed 10 mg of the compound represented by Formula 1, added 0.1 mL of water, stirred at 95 °C for 3 days, centrifuged, and then dried under vacuum to obtain a solid. As detected by powder X-ray diffraction, the product was defined as an N-type crystal, the XRPD pattern was as shown in Figure 13, and the positions of its characteristic peaks were as shown in Table 18. According to the DSC pattern, the peak temperatures of the endothermic peaks were 59.31 °C and 268.68 °C. According to the TGA pattern, it showed a weight loss of 2.1% from 25 °C to 213 °C. According to DVS detection, for the sample, under normal storage conditions (i.e., 25 °C, 60% RH), the weight increase due to moisture absorption was about 3.00%, under accelerated experimental conditions (i.e., 70% RH), the weight increase due to moisture absorption was about 3.06%, and under extreme conditions (90% RH), the weight increase due to moisture absorption was about 3.18%. During the humidity change process from 0% to 95% RH, the desorption process and adsorption process of the sample basically overlapped, and as a result of re-measuring the crystal form after DVS detection, the crystal form was not converted. [Table 18-1] [Table 18-2]

[0204] Example 29: Preparation of N-Type Crystal 10 mg of the compound shown in Formula 1 was weighed, dissolved in 0.5 mL of ethyl acetate, and 1 mL of n-heptane was added. The mixture was stirred overnight at room temperature. After precipitating the solid, it was filtered, and the solid was collected, water was added, and the mixture was stirred overnight at 95°C. After centrifugation, the mixture was vacuum dried to obtain a solid. Detection by powder X-ray diffraction revealed that the product was an N-type crystal.

[0205] Example 30: Preparation of N-type crystals 100 mg of the compound shown in Formula 1 was weighed and dissolved in 1.0 mL of a mixed solution of methyl isobutyl ketone / isopropyl acetate (v / v=1:1). 5 mg of N-type crystal seed crystals were added, and the mixture was stirred overnight at room temperature. After centrifugation, the solid was vacuum-dried to obtain the title product.

[0206] Example 31: Preparation of N-type crystals 100 mg of the compound shown in Formula 1 was weighed, 1.0 mL of methyl isobutyl ketone was added, and the mixture was stirred overnight at room temperature. After centrifugation, the mixture was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as an N-type crystal.

[0207] Example 32: Preparation of O-type crystals 50 mg of the compound shown in Formula 1 was weighed, dissolved in 0.5 mL of 2-butanone, 3.5 mL of water was added, and the mixture was stirred at 50°C for 2 hours. The mixture was then centrifuged, and the supernatant was discarded to obtain a solid. Powder X-ray diffraction detected the product, which was defined as an O-type crystal. The XRPD pattern is shown in Figure 14, and the positions of its characteristic peaks are shown in Table 19. [Table 19]

[0208] Example 33: Preparation of P-type crystals 50 mg of the compound shown in Formula 1 was weighed, dissolved in 0.5 mL of 2-butanone, 3.5 mL of water was added, and the mixture was stirred at 50°C for 24 hours. The mixture was then centrifuged, and the supernatant was discarded to obtain a solid. Powder X-ray diffraction detected the product, which was defined as a free P-type crystal. The XRPD pattern is shown in Figure 15, and the positions of its characteristic peaks are shown in Table 20. [Table 20-1] [Table 20-2]

[0209] Example 34: Preparation of Q-type crystals 50 mg of the compound shown in Formula 1 was weighed, dissolved in 0.5 mL of 2-butanone, 3.5 mL of water was added, the mixture was stirred at 50°C for 2 hours, and the solid was collected by centrifugation and vacuum-dried to obtain the title product. Powder X-ray diffraction detected the product as a free Q-type crystal, and the XRPD pattern is shown in Figure 16, with the characteristic peak positions shown in Table 21. [Table 21]

[0210] Example 35: Preparation of R-type crystals 50 mg of the compound shown in Formula 1 was weighed, dissolved in 0.5 mL of 2-butanone, 3.5 mL of water was added, the mixture was stirred at 50°C for 2 hours, and the solid was obtained by centrifugation and vacuum drying. 1.0 mL of water was added, the mixture was stirred at 60°C for 12 hours, and the mixture was centrifuged and vacuum dried to obtain a solid. Powder X-ray diffraction detected the product, which was defined as an R-type crystal. The XRPD pattern is shown in Figure 17, and the positions of its characteristic peaks are shown in Table 22. [Table 22]

[0211] Example 36: Preparation of S-type crystals Weighed 50 mg of the compound represented by Formula 1, added 0.5 mL of methyl isobutyl ketone, and stirred overnight at room temperature. After centrifugation, it was dried under vacuum at 100 °C overnight to obtain a solid. As detected by powder X-ray diffraction, the product was defined as the free S-type crystal, and the XRPD pattern is shown in Figure 18, and the positions of its characteristic peaks are as shown in Table 23. According to the DSC pattern, the peak temperature of the endothermic peak was shown to be 280.11 °C. According to the TGA pattern, a weight loss of 0.52% was shown at 33 °C to 333 °C. [Table 23]

[0212] Example 37: Preparation of T-Type Crystal Weighed 10 mg of the compound represented by Formula 1, added it to 1 mL of isopropanol, stirred the solution system at room temperature until it became clear, filtered it through a 0.22 μm filter membrane, gradually evaporated the solution at room temperature for crystallization, and obtained a solid. As detected by powder X-ray diffraction, the product was defined as the T-type crystal, and the XRPD pattern is shown in Figure 19, and the positions of its characteristic peaks are as shown in Table 24. [Table 24]

[0213] Example 38: Preparation of U-Type Crystal Weighed 20 mg of the compound represented by Formula 1, stirred it in a mixed solution of 0.18 mL of methanol and 0.02 mL of water for 24 hours, filtered it, and then dried the product at 50 °C for 16 hours to obtain a solid. As detected by powder X-ray diffraction, the product was defined as the U-type crystal, and the XRPD pattern is shown in Figure 20, and the positions of its characteristic peaks are as shown in Table 25. [Table 25-1] [Table 25-2]

[0214] Example 39: Preparation of free-state B-type crystals 10 mg of E-type crystals of the compound shown in formula 1 were weighed, 0.5 mL of ethyl acetate was added, and the mixture was stirred at room temperature for 2 days. After centrifugation, the mixture was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as free B-type crystals. The XRPD pattern is shown in Figure 22, and the positions of its characteristic peaks are shown in Table 26. [Table 26-1] [Table 26-2]

[0215] Example 40: Preparation of α-type crystals 10 mg of N-type crystals of the compound represented by formula 1 were weighed, 0.2 mL of methanol was added, and the mixture was stirred at room temperature to crystallize. After centrifugation, the mixture was vacuum-dried to obtain a solid. Powder X-ray diffraction revealed that the product was defined as free α-type crystals. The XRPD pattern is shown in Figure 23, and the positions of its characteristic peaks are shown in Table 27. The DSC pattern indicated that the peak temperatures of the endothermic peaks were 42.51°C and 262.81°C. The TGA pattern showed a weight loss of 3.43% between 30°C and 316°C. [Table 27]

[0216] Example 41: Preparation of α-type crystals 10 mg of N-type crystals of the compound shown in formula 1 were weighed, and 0.2 mL of solvent was added. The solvent is as shown in Table 27 below. The mixture was stirred at room temperature to crystallize, then centrifuged and vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as free α-type crystals. [Table 28]

[0217] Example 42: Preparation of β-type crystals 10 mg of B-type crystals of the compound shown in formula 1 were weighed, 0.1 mL of propylene glycol methyl ether was added, and the mixture was stirred at room temperature to crystallize. After centrifugation, the mixture was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as free β-type crystals. The XRPD pattern is shown in Figure 24, and the positions of its characteristic peaks are shown in Table 29. The DSC pattern indicated that the peak temperatures of the endothermic peaks were 157.49°C and 221.33°C. The TGA pattern showed a weight loss of 7.16% between 30°C and 187°C. [Table 29-1] [Table 29-2]

[0218] Example 43: Stability study of factors influencing crystal type Free C-type, F-type, G-type, H-type, L-type, M-type, and N-type crystals were placed flat in an open state, and their stability was examined under various conditions: light irradiation (4500 Lux), high temperature (40°C, 60°C), and high humidity (75% RH, 92.5% RH). The sampling and analysis period was 30 days. [Table 30-1] [Table 30-2] [Table 31] [Table 32] [Table 33-1] [Table 33-2] [Table 34-1] [Table 34-2] [Table 35-1] [Table 35-2] [Table 36-1] [Table 36-2]

[0219] Conclusion: Experiments on influencing factors show that C-type, F-type, G-type, H-type, L-type, M-type, and N-type crystals all exhibit good physicochemical stability under conditions of light irradiation, high temperature (40°C, 60°C), and high humidity (75% RH, 92.5% RH) for 30 days.

[0220] Example 44: Long-term accelerated stability study of free-state crystalline form The stability of C-type, F-type, G-type, H-type, L-type, M-type, and N-type crystals was investigated under conditions of 25°C / 60% RH and 40°C / 75% RH. [Table 37] [Table 38-1] [Table 38-2] [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] Conclusion: Long-term accelerated experiments show that the physicochemical stability of C-type, F-type, G-type, H-type, L-type, M-type, and N-type crystals is good under conditions of 25°C / 60% RH and 40°C / 75% RH for 6 months.

Claims

1. A C-type crystal of the compound represented by formula 1, wherein the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 9.150, 12.034, 17.860, 19.920, 23.604, and 23.997, preferably at 9.150, 11.840, 12.034, 17.860, 19.920, 23.604, 23.997, 25.803, 27.536, and 28.038, and more preferably at 9.150, 11.840, 12.034, 17.860, 19.920, 23.604, 23.997, 25.803, 27.536, 28.038, 30.743, and 31.

353. C-type crystal. 【Chemistry 1】

2. The powder X-ray diffraction pattern, represented by the diffraction angle 2θ, is as shown in Figure 2. The C-type crystal according to claim 1.

3. A method for preparing a C-type crystal according to claim 1 or 2, wherein the method is: Method 1 is a method in which the compound of formula 1 is added to solvent I, stirred and crystallized, and the solvent I is selected from one or more of isopropanol, ethanol, and n-propanol. Method 2 is a method in which the compound of formula 1 is dissolved in 1,4-dioxane, solvent II is added and stirred to crystallize, wherein solvent II is selected from one or more of isopropanol, methyl tert-butyl ether, n-heptane, isopropyl acetate, dichloromethane, and cyclohexane. Method 3 comprises dissolving the compound of formula 1 in solvent III, stirring to crystallize, wherein solvent III is selected from one or more of acetone, tetrahydrofuran, 1,4-dioxane, isopropyl acetate, dichloromethane, and tetrahydrofuran / ethanol (v / v = 2:1), method.

4. The F-type crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern expressed at a diffraction angle of 2θ, with characteristic peaks at 9.947, 15.672, 18.740, 20.712, 23.910 and 28.351, preferably at 7.935, 9.947, 10.339, 15.672, 18.740, 19.933, 20.712, 23.910, 25.504, and 26. The molecule has characteristic peaks at 139 and 28.351, and more preferably, characteristic peaks at 7.935, 9.947, 10.339, 11.651, 11.990, 15.672, 16.642, 18.740, 19.933, 20.712, 21.471, 23.910, 25.504, 26.139, 27.660, 28.351 and 28.

898. F type crystal.

5. The powder X-ray diffraction pattern, represented by the diffraction angle 2θ, is as shown in Figure 5. The F-type crystal according to claim 4.

6. A method for preparing an F-type crystal according to claim 4 or 5, wherein the method is: Method 1, which involves adding the compound of formula 1 to purified water and stirring while performing a heating and cooling cycle between 50°C and 5°C, Method 2 includes dissolving the compound of formula 1 in 80% acetone / water, adding purified water and stirring, method.

7. A G-type crystal of the compound represented by formula 1, wherein the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 10.701, 11.896, 12.669, 17.822, 25.246, and 27.288, preferably at 7.457, 10.701, 11.896, 12.669, 17.822, 20.532, 21.378, 25.246, 27.288, and 32.704, and more preferably at 7.457, 10.701, 11.896, 12.669, 17.822, 20.532, 21.015, 21.378, 22.429, 24.516, 25.246, 27.288, and 32.

704. G-type crystal.

8. The powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, is as shown in Figure 6. The G-type crystal according to claim 7.

9. A method for preparing G-type crystals according to claim 7 or 8, wherein the method is: Method 1, which involves adding the compound of formula 1 to methanol and stirring while performing a heating-cooling cycle between 50°C and 5°C, Method 2 involves dissolving the compound of formula 1 in 80% acetone / water, adding methanol / water (V / V = 4:3), and stirring. Method 3 comprises adding an E-type crystal of the compound of formula 1 to solvent IV and stirring, wherein solvent IV is selected from one or more of isopropyl ether, methyl tert-butyl ether, cyclohexane, isopropyl acetate, and water. method.

10. An H-type crystal of the compound represented by formula 1, wherein the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 7.961, 13.533, 15.180, 15.879 and 20.619, preferably characteristic peaks at 7.961, 13.533, 15.180, 15.879, 15.946, 20.619, 20.902, 22.595 and 25.444, and more preferably characteristic peaks at 7.961, 13.533, 15.180, 15.879, 15.946, 20.619, 20.902, 22.595, 25.444, 29.305 and 30.

671. H type crystal.

11. The powder X-ray diffraction pattern, represented by the diffraction angle 2θ, is as shown in Figure 7. The H-type crystal according to claim 10.

12. A method for preparing H-type crystals according to claim 10 or 11, the method comprising the step of adding a compound of formula 1 to diethyl ether and stirring, method.

13. An L-type crystal of the compound represented by formula 1, wherein the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 10.645, 16.725, 17.050, 19.513, and 19.780, preferably at 6.580, 10.645, 14.011, 14.586, 16.725, 17.050, 19.513, 19.780, and 21.862, and more preferably at 6.580, 10.645, 14.011, 14.586, 16.725, 17.050, 19.513, 19.780, 21.862, 23.529, 26.952, and 27.

932. L-type crystal.

14. The powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, is as shown in Figure 11. The L-type crystal according to claim 13.

15. A method for preparing L-type crystals according to claim 13 or 14, the method comprising the step of adding F-type crystals of the compound of formula 1 to water and stirring at 95°C, method.

16. The M-type crystal of the compound represented by formula 1, whose powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 8.313, 11.772, 15.173, 18.762, 20.945 and 25.849, preferably at 7.595, 8.313, 11.772, 12.680, 13.791, 15.173, 17.320, 18.762, and 20.945, The molecule has characteristic peaks at 25.849 and 26.857, and more preferably, characteristic peaks at 7.595, 8.313, 11.772, 12.680, 13.359, 13.791, 15.173, 16.626, 17.320, 18.762, 19.506, 20.945, 25.849, 26.857, 29.605 and 30.

545. M type crystal.

17. The powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, is as shown in Figure 12. The M-type crystal according to claim 16.

18. A method for preparing M-type crystals according to claim 16 or 17, wherein the method is: Method 1, wherein the compound of formula 1 is added to isopropyl acetate and stirred, Method 2 includes dissolving the compound of formula 1 in isopropyl acetate and adding n-heptane and stirring, method.

19. An N-type crystal of the compound represented by formula 1, the powder X-ray diffraction pattern expressed at a diffraction angle of 2θ has characteristic peaks at 6.324, 13.092, 13.626, 14.699, 19.483, 22.429 and 27.407, preferably at 6.324, 13.092, 13.626, 14.699, 15.566, 19.483, 20.724, Characteristic peaks are present at 22.429, 23.287, and 27.407, and more preferably at 6.324, 12.664, 13.092, 13.626, 14.699, 15.566, 19.483, 20.724, 22.429, 23.287, 25.042, 26.840, 27.407, and 30.

152. N-type crystal.

20. The powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, is as shown in Figure 13. The N-type crystal according to claim 19.

21. A method for preparing an N-type crystal according to claim 19 or 20, wherein the method is: Method 1 is a method in which the compound of formula 1 is added to solvent V, stirred and crystallized, and the solvent V is selected from water and methyl isobutyl ketone. Method 2 is a method in which the compound of formula 1 is dissolved in solvent VI, a seed crystal is added and crystallized, and the solvent VI is selected from one or more types of methyl isobutyl ketone and isopropyl acetate. Method 3 includes dissolving the compound of formula 1 in ethyl acetate, adding n-heptane, and stirring. method.

22. An R-type crystal of the compound represented by formula 1, the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 9.598, 11.283, 13.705, 15.045, 19.714 and 24.020, preferably at 8.248, 9.598, 11.283, 12.828, 13.705, 15.045, 15.539, 19.714, 22.430, and 24. It is characterized by having characteristic peaks at 020 and 26.248, and more preferably by having characteristic peaks at 8.248, 9.598, 9.884, 11.283, 11.748, 12.828, 13.705, 15.045, 15.539, 16.670, 17.686, 19.714, 20.791, 22.430, 24.020, 25.017 and 26.

248. R-type crystal.

23. The powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, is as shown in Figure 17. The R-type crystal according to claim 22.

24. A method for preparing R-type crystals according to claim 22 or 23, wherein the method is: Step 1 involves dissolving the compound of formula 1 in 2-butanone, adding water, and stirring to crystallize it. Step 2 includes adding the crystals from Step 1 to water and stirring at 60°C to crystallize them. method.

25. An S-type crystal of the compound represented by formula 1, in which the powder X-ray diffraction pattern expressed at a diffraction angle of 2θ, has characteristic peaks at 10.810, 13.597, 14.706, 19.971 and 22.751, preferably at 6.465, 10.810, 11.872, 13.597, 14.706, 15.563, 19.971, 22.751 and 23.

881. The molecule has characteristic peaks at 26.322, and more preferably, it has characteristic peaks at 6.465, 10.810, 11.872, 12.996, 13.597, 14.706, 15.563, 16.385, 19.971, 20.914, 22.751, 23.881, 25.414, 26.322, 29.235 and 32.

963. S type crystal.

26. The powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, is as shown in Figure 18. The S-type crystal according to claim 25.

27. A method for preparing S-type crystals according to claim 25 or 26, wherein the method is: Step 1 involves adding the compound of formula 1 to methyl isobutyl ketone and stirring to crystallize it. Step 2 includes vacuum drying the crystal from Step 1 at 100°C. method.

28. The error range for the aforementioned 2θ angle is ±0.

20. The crystal form according to any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 22-23, or 25-26.

29. A pharmaceutical composition comprising a crystalline form described in any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 22-23, 25-26 and optionally pharmaceutically acceptable excipients. Pharmaceutical composition.

30. A method for preparing a pharmaceutical composition, comprising the step of mixing a crystalline form and a pharmaceutically acceptable excipient as described in any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 22-23, 25-26. Preparation method.

31. Use of the crystalline form according to any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 22-23, 25-26, or the pharmaceutical composition according to claim 26, in the preparation of an agent for treating and / or preventing tumors. use.

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