Crystal form of nitrogen-containing tetracyclic compound and preparation method thereof

Abstract

The present disclosure relates to a crystalline form of a nitrogen-containing tetracyclic compound and a method of preparing the same. Specifically, the invention provides a crystal form C, a crystal form F, a crystal form G, a crystal form H, a crystal form L, a crystal form M, a crystal form N, a crystal form R and a crystal form S 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] diazacyclo [3, 2, 1-hi] indazole-3-yl)-2-amino-7-fluorobenzo [b] thiophene-3-formonitrile (formula 1), and the crystal form C, the crystal form F, the crystal form G, the crystal form H, the crystal form L, the crystal form M, the crystal form N and the medicine can be better used for clinical treatment.

Description

A crystalline form of a nitrogen-containing tetracyclic compound and a preparation method thereof Technical Field

[0001] The present disclosure belongs to the field of medical technology and relates to a crystalline form of a nitrogen-containing tetracyclic compound and a preparation method thereof. Background Art

[0002] The RAS (Rat Sarcoma Viral Oncogene Homolog) family belongs to the small GTPase superfamily and is widely expressed in various eukaryotic organisms. There are three RAS genes in humans (HRAS, KRAS, and NARS), which can express four highly related RAS small GTPases (HRAS, KRAS4A, KARS4B, and NRAS). They function as binary switches regulated by GDP-GTP. Normally, they exist in two forms: an inactive state bound to GDP (guanosine diphosphate) and an active state bound to GTP (guanosine triphosphate). By switching between these two active states, RAS proteins regulate multiple downstream pathways, including RAF-MEK-ERK, PI3K / Akt / mTOR, thereby affecting cell growth, proliferation, and differentiation (Nat Rev Cancer, 2007, 7, 295-308). RAS genes have a high mutation rate in various tumors, including pancreatic cancer, colorectal cancer, and non-small cell lung cancer. Activated mutant RAS proteins promote abnormal signal transduction, leading to cancer development and progression, as well as resistance to targeted drugs. KRAS mutations are the most frequently mutated human oncogenes, accounting for 20-30% of all tumors.

[0003] KRAS G12C has attracted many well-known new drug research and development companies at home and abroad to participate. Although Amgen's fastest-progressing small molecule KRAS G12C inhibitor Sotorasib (AMG510) was approved for marketing by the FDA on May 28, 2021, for use in patients with non-small cell lung cancer who have received at least one systemic treatment and carry KRAS G12C mutations, Eli Lilly's new generation of KRAS G12C inhibitor LY3537982 has attracted more attention. Eli Lilly reported the preclinical data of LY3537982 at the American Association for Cancer Research (AACR) Annual Meeting in April 2021. The data showed that LY3537982 inhibited cell activity more than 10 times that of Sotorasib, and it entered Phase I clinical trials in July 2021. It can be seen that highly selective, safe and effective KRAS G12C inhibitors are still needed clinically.

[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]diazaoctino[3,2,1-hi]indazol-3-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile, having the structure shown in Formula 1.

[0005] The crystal form of a pharmaceutically active ingredient often affects the chemical stability of the drug. Differences in crystallization and storage conditions can lead to variations in the compound's crystal structure, sometimes resulting in the formation of alternative crystal forms. Generally speaking, amorphous drug products lack a regular crystal structure and often exhibit other drawbacks, such as poor product stability, fine crystallization, difficulty in filtration, susceptibility to agglomeration, and poor flowability. Polymorphic drug forms impose varying requirements on product storage, production, and scale-up. Therefore, in-depth research into the crystal forms of these compounds is essential to improve their various properties.

[0006] Summary of the Invention

[0007] The present disclosure provides a new crystal form of the compound represented by Formula 1, which has good stability and can be better applied in clinical practice.

[0008] The crystalline form A of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.406, 10.960, 11.530, 18.216 and 22.849.

[0009] In some embodiments, the crystalline form A of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.419, 8.406, 10.960, 11.530, 18.216, 21.298, 22.849 and 28.948.

[0010] In some embodiments, Form A of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.419, 8.406, 10.960, 11.530, 18.216, 21.298, 22.433, 22.849, 28.948 and 30.452.

[0011] In some embodiments, the X-ray powder diffraction pattern of Form A of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG1 .

[0012] The present disclosure also provides a method for preparing a crystalline form A of the compound represented by Formula 1, the method comprising adding the compound represented by Formula 1 to a solvent a, stirring and crystallizing; the solvent a is selected from one or more of ethyl acetate and n-heptane.

[0013] The crystalline form C of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 9.150, 12.034, 17.860, 19.920, 23.604 and 23.997.

[0014] In some embodiments, Form C of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 9.150, 11.840, 12.034, 17.860, 19.920, 23.604, 23.997, 25.803, 27.536 and 28.038.

[0015] In some embodiments, Form C of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks 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.

[0016] In some embodiments, the X-ray powder diffraction pattern of Form C of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG2 .

[0017] The present disclosure also provides a method for preparing Form C of the compound represented by Formula 1, the method comprising:

[0018] Method 1: Add the compound of formula 1 to solvent I, stir and crystallize, wherein the solvent I is selected from one or more of isopropanol, ethanol, and n-propanol;

[0019] Method 2: dissolving the compound of formula 1 in 1,4-dioxane, adding solvent II, stirring and crystallizing, wherein the solvent II is selected from one or more of isopropyl alcohol, methyl tert-butyl ether, n-heptane, isopropyl acetate, dichloromethane, and cyclohexane;

[0020] Method 3: dissolving the compound of formula 1 in solvent III, stirring and crystallizing, wherein the solvent III is selected from one or more of acetone, tetrahydrofuran, 1,4-dioxane, isopropyl acetate, dichloromethane, and tetrahydrofuran / ethanol (v / v=2:1).

[0021] The crystalline form D of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 9.096, 11.735, 12.094, 17.928 and 23.968.

[0022] In some embodiments, the crystalline form D of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 9.096, 11.735, 12.094, 14.894, 16.002, 17.928, 19.870, 23.397 and 23.968.

[0023] In some embodiments, Form D of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 9.096, 11.735, 12.094, 14.894, 16.002, 17.928, 19.870, 23.397, 23.968, 24.917 and 29.556.

[0024] In some embodiments, the X-ray powder diffraction pattern of Form D of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG3 .

[0025] The present disclosure also provides a method for preparing a crystalline form D of a compound represented by Formula 1, comprising adding the compound of Formula 1 to a solvent b, stirring and crystallizing; the solvent b is selected from one or more of n-butanol and tert-butanol.

[0026] The crystalline form E of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.296, 10.626, 17.905, 23.131 and 25.377.

[0027] In some embodiments, the crystalline form E of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.296, 10.626, 11.393, 12.647, 17.905, 20.706, 23.131 and 25.377.

[0028] In some embodiments, Form E of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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.

[0029] In some embodiments, the X-ray powder diffraction pattern of Form E of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG4 .

[0030] The present disclosure also provides a method for preparing the crystalline form E of the compound represented by Formula 1, the method comprising:

[0031] Method 1: dissolve the compound of formula 1 in methanol and evaporate the solvent;

[0032] Method 2: Add the compound of formula 1 into 10% water / methanol and stir.

[0033] The crystalline form F of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 9.947, 15.672, 18.740, 20.712, 23.910 and 28.351.

[0034] In some embodiments, Form F of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.935, 9.947, 10.339, 15.672, 18.740, 19.933, 20.712, 23.910, 25.504, 26.139 and 28.351.

[0035] In some embodiments, Form F of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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.

[0036] In some embodiments, the X-ray powder diffraction pattern of Form F of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG5 .

[0037] The present disclosure also provides a method for preparing Form F of the compound represented by Formula 1, the method comprising:

[0038] Method 1: Add the compound of formula 1 into purified water and heat and cool it in a cycle from 50°C to 5°C with stirring;

[0039] Method 2: Dissolve the compound of formula 1 in 80% acetone / water, add purified water and stir.

[0040] In the present disclosure, the temperature rise and fall of 50°C to 5°C is repeated from 5°C to 50°C and then from 50°C to 5°C. In some embodiments, the temperature is reduced from 50°C to 5°C within 1 hour and then raised from 5°C to 50°C within 1 hour.

[0041] The crystalline form G of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 10.701, 11.896, 12.669, 17.822, 25.246 and 27.288.

[0042] In some embodiments, the crystalline form G of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.457, 10.701, 11.896, 12.669, 17.822, 20.532, 21.378, 25.246, 27.288 and 32.704.

[0043] In some embodiments, the crystalline form G of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks 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.

[0044] In some embodiments, the X-ray powder diffraction pattern of Form G of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG6 .

[0045] The present disclosure also provides a method for preparing the crystalline form G of the compound represented by Formula 1, the method comprising:

[0046] Method 1: Add the compound of formula 1 to methanol and heat and cool cyclically from 50°C to 5°C with stirring;

[0047] Method 2: Dissolve the compound of formula 1 in 80% acetone / water, add methanol / water (V / V = 4:3), and stir;

[0048] Method 3: Add the crystalline form E of the compound of formula 1 into solvent IV and stir, wherein the solvent IV is selected from one or more of isopropyl ether, methyl tert-butyl ether, cyclohexane, isopropyl acetate, and water.

[0049] The crystalline form H of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.961, 13.533, 15.180, 15.879 and 20.619.

[0050] In some embodiments, the crystalline form H of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.961, 13.533, 15.180, 15.879, 15.946, 20.619, 20.902, 22.595 and 25.444.

[0051] In some embodiments, the crystalline form H of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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.

[0052] In some embodiments, the X-ray powder diffraction pattern of Form H of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG7 .

[0053] The present disclosure also provides a method for preparing the crystalline form H of the compound represented by Formula 1, comprising the steps of adding the compound represented by Formula 1 to diethyl ether and slurrying.

[0054] In some embodiments, the method of preparing the crystalline form H of the compound of Formula 1 disclosed herein further comprises the step of adding the crystalline form E of the compound of Formula 1 into diethyl ether and slurrying.

[0055] The crystalline form I of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.996, 12.286, 18.112, 19.719 and 24.005.

[0056] In some embodiments, the crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.996, 12.286, 15.616, 16.690, 18.112, 19.719, 22.812 and 24.005.

[0057] In some embodiments, the crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with 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.

[0058] In some embodiments, the X-ray powder diffraction pattern of Form I of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG8 .

[0059] The present disclosure also provides a method for preparing the crystalline form I of the compound represented by Formula 1, comprising the steps of adding the compound represented by Formula 1 to n-pentanol and slurrying.

[0060] The crystalline form J of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.928, 12.055, 17.726, 19.533, 22.991 and 23.657.

[0061] In some embodiments, Form J of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.928, 11.725, 12.055, 16.671, 17.726, 19.533, 22.991, 23.657 and 26.826.

[0062] In some embodiments, Form J of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks 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.

[0063] In some embodiments, the X-ray powder diffraction pattern of Form J of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG9 .

[0064] The present disclosure also provides a method for preparing the crystalline form J of the compound represented by Formula 1, comprising the steps of adding the compound represented by Formula 1 to isoamyl alcohol and slurrying.

[0065] The crystalline form K of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 9.306, 12.132, 17.933 and 20.058.

[0066] In some embodiments, the crystalline form K of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.121, 9.306, 12.132, 17.933, 20.058, 24.077 and 34.192.

[0067] In some embodiments, the X-ray powder diffraction pattern of Form K of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG10 .

[0068] The present disclosure also provides a method for preparing the crystalline form K of the compound represented by Formula 1, wherein the method is selected from any one of the following methods:

[0069] Method 1: Add the compound of formula 1 to 7% water / ethanol and stir;

[0070] Method 2: Dissolve the compound of formula 1 in 1,4-dioxane or 10% water / acetone, add ethanol and stir;

[0071] Method 3: Dissolve the compound of formula 1 in ethyl acetate / ethanol (v / v = 1:1), and heat from 50°C to 5°C with stirring;

[0072] Method 4: Dissolve the compound of formula 1 in acetonitrile, heat to 65°C to dissolve, and cool down;

[0073] The crystalline form L of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 10.645, 16.725, 17.050, 19.513 and 19.780.

[0074] In some embodiments, the crystalline form L of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.580, 10.645, 14.011, 14.586, 16.725, 17.050, 19.513, 19.780 and 21.862.

[0075] In some embodiments, the crystalline form L of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks 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.

[0076] In some embodiments, the X-ray powder diffraction pattern of Form L of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG11 .

[0077] The present disclosure also provides a method for preparing the crystalline form L of the compound represented by Formula 1, comprising the steps of adding the crystalline form F of the compound represented by Formula 1 into water and stirring at 95°C.

[0078] The crystalline form M of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.313, 11.772, 15.173, 18.762, 20.945 and 25.849.

[0079] In some embodiments, the crystalline form M of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.595, 8.313, 11.772, 12.680, 13.791, 15.173, 17.320, 18.762, 20.945, 25.849 and 26.857.

[0080] In some embodiments, the crystalline form M of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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.

[0081] In some embodiments, the X-ray powder diffraction pattern of Form M of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG12 .

[0082] The present disclosure also provides a method for preparing the crystalline form M of the compound represented by Formula 1, the method comprising:

[0083] Method 1: Add the compound of formula 1 to isopropyl acetate and stir;

[0084] Method 2: Dissolve the compound of formula 1 in isopropyl acetate, add n-heptane and stir.

[0085] The crystalline form N of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.324, 13.092, 13.626, 14.699, 19.483, 22.429 and 27.407.

[0086] In some embodiments, the crystalline form N of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.324, 13.092, 13.626, 14.699, 15.566, 19.483, 20.724, 22.429, 23.287 and 27.407.

[0087] In some embodiments, the crystalline form N of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks 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.

[0088] In some embodiments, the X-ray powder diffraction pattern of Form N of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG13 .

[0089] The present disclosure also provides a method for preparing the crystalline form N of the compound represented by Formula 1, the method comprising:

[0090] Method 1: Add the compound of formula 1 to solvent V, stir and crystallize, wherein the solvent V is selected from water and methyl isobutyl ketone;

[0091] Method 2: dissolving the compound of formula 1 in solvent VI, adding seed crystals for crystallization, wherein the solvent VI is selected from one or more of methyl isobutyl ketone and isopropyl acetate;

[0092] Method 3: Dissolve the compound of formula 1 in ethyl acetate, add n-heptane and stir.

[0093] The crystalline form O of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.224, 8.423, 11.843, 16.829, 19.735 and 20.425.

[0094] In some embodiments, the X-ray powder diffraction pattern of Form O of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG14 .

[0095] The present disclosure also provides a method for preparing the crystalline form O of the compound represented by Formula 1, the method comprising: dissolving the compound represented by Formula 1 in 2-butanone, adding water, stirring for 2 hours, and centrifuging.

[0096] The crystalline form P of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.848, 16.342, 19.613, 21.305 and 24.786.

[0097] In some embodiments, the crystalline form P of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.848, 13.063, 16.342, 19.613, 21.305, 23.584 and 24.786.

[0098] In some embodiments, the X-ray powder diffraction pattern of the crystalline form P of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG15 .

[0099] The present disclosure also provides a method for preparing a crystalline form P of a compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in 2-butanone, adding water, stirring for 24 hours, and centrifuging.

[0100] The crystalline form Q of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.921, 8.455, 15.468, 18.035, 22.224 and 26.015.

[0101] In some embodiments, the X-ray powder diffraction pattern of Form Q of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG16 .

[0102] The present disclosure also provides a method for preparing the crystalline form Q of the compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in 2-butanone, adding water, stirring for 2 hours, centrifuging, and drying.

[0103] The crystalline form R of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 9.598, 11.283, 13.705, 15.045, 19.714 and 24.020.

[0104] In some embodiments, the crystalline form R of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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.

[0105] In some embodiments, the crystalline form R of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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.

[0106] In some embodiments, the X-ray powder diffraction pattern of Form R of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG17 .

[0107] The present disclosure also provides a method for preparing the crystalline form R of the compound represented by Formula 1, the method comprising:

[0108] Step 1: Dissolve the compound of formula 1 in 2-butanone, add water, and heat at 50°C with stirring to crystallize.

[0109] Step 2: Add the crystals obtained in step 1 into water and stir at 60°C for crystallization.

[0110] The crystalline form S of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 10.810, 13.597, 14.706, 19.971 and 22.751.

[0111] In some embodiments, the crystalline form S of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.465, 10.810, 11.872, 13.597, 14.706, 15.563, 19.971, 22.751, 23.881 and 26.322.

[0112] In some embodiments, the crystalline form S of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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.

[0113] In some embodiments, the X-ray powder diffraction pattern of Form S of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG18 .

[0114] The present disclosure also provides a method for preparing the crystalline form S of the compound represented by Formula 1, the method comprising:

[0115] Step 1: adding the compound of formula 1 to methyl isobutyl ketone, stirring and crystallizing;

[0116] Step 2: Dry the crystals in step 1 at 100°C in vacuum.

[0117] The crystalline form T of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.431, 19.884, 21.207, 21.993, 24.138, 24.924 and 25.111.

[0118] In some embodiments, the X-ray powder diffraction pattern of Form T of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG19 .

[0119] The present disclosure also provides a method for preparing a crystalline form T of a compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in isopropanol and evaporating the solvent.

[0120] The crystalline form U of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.843, 7.185, 8.193, 13.870, 14.416 and 20.769.

[0121] In some embodiments, the crystalline form U of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.843, 7.185, 8.193, 13.870, 14.416, 16.683, 18.102, 18.721 and 20.769.

[0122] In some embodiments, the X-ray powder diffraction pattern of Form U of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG20 .

[0123] The present disclosure also provides a method for preparing the crystalline form U of the compound represented by Formula 1, comprising the steps of adding the compound represented by Formula 1 to 90% methanol / water and slurrying.

[0124] The crystalline form B of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.587, 10.089, 11.875, 16.987, 21.717, and 23.436.

[0125] In some embodiments, Form B of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks 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.

[0126] In some embodiments, the crystalline form B of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, and has characteristic peaks 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.

[0127] In some embodiments, the X-ray powder diffraction pattern of Form B of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG. 22 .

[0128] The present disclosure also provides a method for preparing Form B of the compound of Formula 1, comprising the steps of adding Form E of the compound of Formula 1 to ethyl acetate and stirring.

[0129] The crystalline form α of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.622, 9.944, 11.103, 17.932, 22.143, and 25.120.

[0130] In some embodiments, the crystalline form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.622, 9.944, 11.103, 15.927, 17.932, 20.112, 22.143, 23.602, 25.120, and 29.026.

[0131] In some embodiments, the X-ray powder diffraction pattern of Form α of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG23 .

[0132] The present disclosure also provides a method for preparing the crystalline form α of the compound represented by Formula 1, the method comprising adding the crystalline form N of the compound represented by Formula 1 to a solvent c and stirring; the solvent c is selected from one or more of methanol, 50% methanol / water, 7% water / ethanol, and 50% acetonitrile / methanol.

[0133] The crystalline form β of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.683, 12.400, 15.616, 19.040, 22.856, and 24.802.

[0134] In some embodiments, the crystalline form β of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.683, 11.501, 12.400, 14.114, 15.616, 16.527, 19.040, 22.856, 24.200, 24.802, 26.963, and 29.420.

[0135] In some embodiments, the crystalline form β of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks 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.

[0136] In some embodiments, the X-ray powder diffraction pattern of the crystalline form β of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG. 24 .

[0137] The present disclosure also provides a method for preparing the crystalline form β of the compound represented by Formula 1, comprising the steps of adding the crystalline form B of the compound represented by Formula 1 to propylene glycol methyl ether and stirring.

[0138] The present disclosure also provides a pharmaceutical composition comprising any one or more of the aforementioned crystalline forms A to U, crystalline form α, or crystalline form β, and a pharmaceutical excipient selected from pharmaceutically acceptable excipients.

[0139] The present disclosure also provides a pharmaceutical composition, which is prepared from any one or more of the aforementioned crystalline forms A to U, crystalline form α or crystalline form β, and optional pharmaceutically acceptable excipients.

[0140] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing any one or more of the aforementioned crystalline forms A to U, crystalline form α, or crystalline form β with a pharmaceutically acceptable excipient.

[0141] The present disclosure also provides use of any one or more of the aforementioned crystalline forms A to U, crystalline form α, or crystalline form β, or the aforementioned composition in the preparation of a drug for preventing and / or treating tumors.

[0142] The use disclosed herein, wherein the tumor is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, bronchial cancer, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial cancer, esophageal cancer, essential thrombocythemia, Ewing's tumor, testicular cancer, glioma, heavy chain disease, Hemangioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal cancer, oral cancer, thyroid cancer, pinealoma, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, Waldenstrom's macroglobulinemia and Wilms' tumor; preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer and lung cancer.

[0143] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0144] Numerical values ​​in this disclosure, such as those related to substance content, are derived from measurements and calculations, and therefore inevitably have a certain degree of error. Generally speaking, ±10% is considered within a reasonable error range. While there may be some degree of error depending on the context in which they are used, this error may not exceed ±10% and may include ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0145] The starting material used in the crystal form preparation method of the present invention can be a compound in any form, including but not limited to: amorphous, any crystal form, hydrate, solvate, etc.

[0146] The drying temperature in the present disclosure is generally 25°C-100°C, preferably 40°C-70°C, and can be dried under normal pressure or reduced pressure.

[0147] The crystallization methods described in the present disclosure include room temperature crystallization, cooling crystallization, volatile solvent crystallization, adding seed crystals to induce crystallization, etc. The cooling temperature is selected from below 65°C, preferably -10°C to 60°C, and stirring can also be performed during the crystallization process.

[0148] The "differential scanning calorimetry or DSC" described in this disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0149] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "9103 Guiding Principles for Hygroscopicity of Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia,

[0150] Deliquescent: Absorbs sufficient water to form a liquid;

[0151] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0152] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0153] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0154] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0155] The "excipients" described in this disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier that has been approved by the U.S. Food and Drug Administration for use by humans or livestock animals. BRIEF DESCRIPTION OF THE DRAWINGS

[0156] Figure 1 is the XRPD spectrum of Compound 1 Form A.

[0157] Figure 2 is the XRPD spectrum of Compound 1 Form C.

[0158] Figure 3 is the XRPD spectrum of Compound 1 Form D.

[0159] Figure 4 is the XRPD spectrum of Compound 1 Form E.

[0160] Figure 5 is the XRPD spectrum of Compound 1 Form F.

[0161] Figure 6 is the XRPD spectrum of Compound 1 Form G.

[0162] Figure 7 is the XRPD spectrum of Compound 1 Form H.

[0163] Figure 8 is the XRPD spectrum of Compound 1 Form I.

[0164] Figure 9 is the XRPD spectrum of Compound 1 Form J.

[0165] Figure 10 is the XRPD spectrum of Compound 1 Form K.

[0166] Figure 11 is the XRPD spectrum of Compound 1 Form L.

[0167] Figure 12 is the XRPD spectrum of Compound 1 Form M.

[0168] Figure 13 is the XRPD spectrum of Compound 1 Form N.

[0169] Figure 14 is the XRPD spectrum of Compound 1 Form O.

[0170] Figure 15 is the XRPD spectrum of Compound 1 Form P.

[0171] Figure 16 is the XRPD spectrum of Compound 1 Form Q.

[0172] Figure 17 is the XRPD spectrum of Compound 1 Form R.

[0173] Figure 18 is the XRPD spectrum of Compound 1 Form S.

[0174] Figure 19 is the XRPD spectrum of Compound 1 Form T.

[0175] Figure 20 is the XRPD spectrum of Compound 1 Form U.

[0176] Figure 21 is the XRPD spectrum of the amorphous form of Compound 1.

[0177] Figure 22 is the XRPD spectrum of Compound 1 Form B.

[0178] Figure 23 is the XRPD spectrum of Compound 1 Form α.

[0179] Figure 24 is the XRPD spectrum of Compound 1 Form β. DETAILED DESCRIPTION

[0180] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure, and are not intended to limit the essence and scope of the present disclosure.

[0181] Test conditions of the instruments used in the experiment:

[0182] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0183] MS was measured using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid spectrometer / mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO QExactive).

[0184] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0185] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0186] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0187] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0188] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0189] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0190] The average kinase inhibition rate and IC50 value were determined using a NovoStar microplate reader (BMG, Germany).

[0191] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0192] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0193] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0194] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0195] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0196] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0197] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0198] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0199] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0200] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: petroleum ether / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0201] XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), radiation: monochromatic Cu-Ka radiation Scanning mode: θ / 2θ, scanning range (2θ range): 3°~45°.

[0202] DSC is differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C / min. The specific temperature range was referred to the corresponding spectrum (mostly 25-350°C), and a nitrogen purge rate of 50 mL / min.

[0203] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C / min. The specific temperature range refers to the corresponding spectrum (mostly 25-350°C) and a nitrogen purge rate of 50 mL / min.

[0204] DVS stands for dynamic moisture sorption: the test uses SMSDVS Advantage. At 25°C, the humidity changes from 50% to 95% to 0% to 95% to 50%, with a step of 10% (the last step is 5%) (the specific humidity range is based on the corresponding spectrum, and the method listed here is mostly used). The judgment standard is dm / dt no more than 0.002%.

[0205] Example 1 Preparation of the compound of formula 1

[0206] (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]diazacinno[3,2,1-hi]indazol-3-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 1

[0207] (Refer to the preparation method of Example 7-P2 in application number PCT / CN2022 / 126650)

[0208] first step

[0209] Methyl 4-bromo-5-fluoro-1H-indazole-7-carboxylate 1b

[0210] Methyl 2-amino-4-bromo-5-fluoro-3-methylbenzoate 1a (2.7 g, 10.3 mmol, prepared using the method disclosed in step (iv) on page 103 of the specification of patent application "WO2016020836A1") was dissolved in chloroform (50 mL), and acetic anhydride (3.16 g, 30.9 mmol) was added. The temperature was maintained below 40°C, and the reaction was stirred for 90 minutes. Potassium acetate (302 mg, 3.08 mmol) and tert-butyl nitrite (2.12 g, 20.6 mmol) were added and refluxed for 14 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (50 mL), and washed with water (30 mL), saturated sodium carbonate solution (10 mL), and saturated sodium chloride solution (10 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1b (2.8 g). The product was used directly in the next step without purification.

[0211] MS m / z (ESI): 272.9 [M+1].

[0212] Step 2

[0213] 4-Bromo-5-fluoro-1H-indazole-7-carboxylic acid 1c

[0214] Crude compound 1b (2.8 g, 10.25 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 mL), methanol (10 mL), and water (10 mL). Lithium hydroxide (2.15 g, 51.26 mmol) was added, and the mixture was stirred at 40°C for 1 hour. The reaction solution was concentrated under reduced pressure to remove most of the solvent, and water was added. The mixture was extracted with ethyl acetate (150 mL x 6). The organic phases were combined, washed sequentially with dilute hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure to obtain crude compound 1c (1.4 g), which was used directly in the next step without purification.

[0215] MS m / z (ESI): 259.0 [M+1].

[0216] Step 3

[0217] (S)-tert-Butyl 4-(4-bromo-5-fluoro-1H-indazole-7-carbonyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate 1f

[0218] The crude compound 1c (600 mg, 2.32 mmol) and tert-butyl (S)-3-(2-hydroxyethyl)piperazine-1-carboxylate 1d (586 mg, 2.54 mmol, prepared by the method disclosed in prep-aration 65 on page 80 of the specification of patent application "WO2021118877A1") were dissolved in 30 mL of N,N-dimethylformamide, and 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 under ice bath, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate, followed by washing with water, saturated sodium carbonate solution, and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 1f (600 mg, yield: 54.9%).

[0219] MS m / z(ESI):415.2[M-55].

[0220] Step 4

[0221] (S)-tert-Butyl 3-bromo-2-fluoro-14-oxo-7,8,8a,9,11,12-hexahydro-10H,14H-pyrazino[1',2':5,6][1,5]diazaoctino[3,2,1-hi]indazole-10-carboxylate 1g

[0222] Under a nitrogen atmosphere, compound 1f (600 mg, 1.27 mmol) was dissolved in 36 mL of tetrahydrofuran, and triphenylphosphine (667 mg, 2.54 mmol) and diethyl azodicarboxylate (514 mg, 2.54 mmol) were added sequentially under ice bath. The temperature was maintained and stirred for 30 minutes. The reaction solution was quenched by adding saturated ammonium chloride solution and extracted with ethyl acetate (15 mL×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 by silica gel column chromatography with eluent System A to give the title compound 1g (577 mg, yield: 99.9%).

[0223] MS m / z (ESI): 397.2 [M-55].

[0224] Step 5

[0225] (S)-tert-Butyl 3-bromo-4-chloro-2-fluoro-14-oxo-7,8,8a,9,11,12-hexahydro-10H,14H-pyrazino[1',2':5,6][1,5]diazaoctino[3,2,1-hi]indazole-10-carboxylate

[0226] Compound 1g (630 mg, 1.38 mmol) was dissolved in acetonitrile (6 mL), and N-chlorosuccinimide (278 mg, 2.08 mmol) was added. The mixture was heated to 60°C and reacted for 0.5 hour. Solid precipitated, and additional N-chlorosuccinimide (100 mg, 0.75 mmol) was added. The reaction was continued for 20 minutes. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and the desiccant was filtered to remove the desiccant. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 1h (380 mg, yield: 56%).

[0227] MS m / z(ESI):487.1[M+1].

[0228] Step 6

[0229] (8aS)-tert-Butyl 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]diazacinno[3,2,1-hi]indazole-10-carboxylate 1j

[0230] 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 of patent application "WO2021118877A1") were dissolved in 5 mL of toluene, and bis(diphenylphosphinophenyl ether)palladium (II) dichloride (43 mg, 0.06 mmol) and cesium carbonate (300 mg, 0.92 mmol) were added. The mixture was replaced with nitrogen and stirred at 105°C for 6 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1j (40 mg, yield: 18.6%).

[0231] MS m / z(ESI):699.2[M+1].

[0232] Step 7

[0233] 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]diazacinno[3,2,1-hi]indazol-3-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile bis(2,2,2-trifluoroacetic acid) salt 1k

[0234] Compound 1j (40 mg, 57.21 μmol) was dissolved in 1 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added at 0°C. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1k (41 mg), which was used directly in the next step without purification.

[0235] MS m / z(ESI):499.2[M+1].

[0236] Step 8

[0237] (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]diazacinno[3,2,1-hi]indazol-3-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 1

[0238] The 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, and anhydrous potassium carbonate (24 mg, 173.6 μmol) was added. 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×2). The organic phases were combined and concentrated under reduced pressure to obtain the crude compound 1, i.e., 4-((S)-10-acryloyl-4-chloro-2-fluoro-14-oxo-8,8a,9,10,11,12-hexahydro-7H,14H-pyrazino[1',2':5][1,5]diazolyl The title compound 1 (5 mg, yield: 15.1%) was obtained by preparative HPLC (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min). X-ray powder diffraction analysis showed that the product was amorphous. The XRPD spectrum is shown in FIG21 .

[0239] Single configuration compound (shorter retention time) 1 (5 mg, yield: 15.1%)

[0240] MS m / z(ESI):553.2[M+1].

[0241] HPLC analysis: retention time 2.21 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0242] 1 H NMR (500MHz, CD3OD): δ7.67(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).

[0243] Single configuration compound (longer retention time) 1-P1 (2 mg, yield: 6%)

[0244] MS m / z(ESI):553.2[M+1].

[0245] HPLC analysis: retention time 2.29 minutes, purity: 95% (chromatographic column: ACQUITY BEH, C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0246] 1 H NMR (500MHz, CD3OD): δ7.65(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),4.6 6-4.56(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).

[0247] Test Example 1 H358 cell proliferation test

[0248] The following method was used to determine the inhibitory activity of the disclosed compounds on H358 cell proliferation. The experimental method is briefly described as follows:

[0249] 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 a 96-well plate at a density of 1200 cells / well using complete medium, with 100 μL of cell suspension per well, and cultured overnight in a 37°C, 5% CO2 cell culture incubator. On the second day, 10 μL of a gradient dilution of the test compound prepared in complete medium was added to each well. The final concentration of the compound was 9 concentration points of a 5-fold gradient dilution starting from 10 μM. A blank control containing 0.5% DMSO was set up, and the well plate was placed in a 37°C, 5% CO2 cell culture incubator for 120 hours. On the seventh day, the 96-well cell culture plate was removed, and 50 μL of CellTiter- Luminescent Cell Viability Assay (Promega, G7573) was placed at room temperature for 10 minutes and then analyzed using a multi-function microplate reader (PerkinElmer, En 2105) read the luminescence signal value and calculate the IC of the compound inhibitory activity using Graphpad Prism software 50 value.

[0250] Table 1 Inhibitory activity of the disclosed compounds on H358 cell proliferation

[0251] Conclusion: The disclosed compounds have an inhibitory effect on the proliferation of H358 cells.

[0252] Test Example 2 MIA PaCa-2 cell proliferation assay

[0253] The following method was used to determine the inhibitory activity of the disclosed compounds on MIAPaCa-2 cell proliferation. The experimental method is briefly described as follows:

[0254] MIA PaCa-2 cells (ATCC, CRL-1420) were cultured in DMEM / HIGH GLUCOSE (GE, SH30243.01) medium (i.e., complete medium) supplemented with 10% fetal bovine serum (Corning, 35-076-CV) and 2.5% horse serum (Beyotime Biotech, C0262). On the first day of the experiment, MIA PaCa-2 cells were seeded in a 96-well plate at a density of 500 cells / well using complete medium. 90 μL of cell suspension was added to each well and incubated overnight at 37°C, 5% CO2 in a cell culture incubator. On the second day, 10 μL of a serial dilution of the test compound prepared in complete medium was added to each well. The final concentration of the compound was 9 concentration points, starting from 10 μM and diluted 5-fold. A blank control containing 0.5% DMSO was also added. The plates were incubated in a cell culture incubator at 37°C, 5% CO2 for 72 hours. On the fifth day, the 96-well cell culture plate was taken out and 50 μL of luminescent cell activity detection reagent (CellTiter- Luminescent Cell Viability Assay (Promega, G7573) was used. After standing at room temperature for 10 minutes, the luminescent signal value was read using a multifunctional microplate reader (PerkinElmer, EnVision 2015). The IC value of the inhibitory activity of the compound was calculated using Graphpad Prism software. 50 value.

[0255] Table 2 Inhibitory activity of the disclosed compounds on MIA PaCa-2 cell proliferation

[0256] Example 2 Preparation of Form A

[0257] 5 mg of the compound represented by Formula 1 was weighed and added to 0.5 ml of ethyl acetate / n-heptane (v / v = 1:1). The mixture was stirred at room temperature for 2 days. After centrifugation, the solid was vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as Form A. The XRPD spectrum is shown in Figure 1, and the positions of its characteristic peaks are shown in Table 3. The DSC spectrum showed endothermic peak temperatures of 156.75°C and 206.08°C. The TGA spectrum showed a weight loss of 10.64% between 30°C and 140°C.

[0258] Table 3

[0259] Example 3 Preparation of Form A

[0260] Weigh 20 mg of the compound of Formula 1, add 0.5 mL of ethyl acetate, and heat and cool from 50°C to 5°C (at a rate of ±0.75°C / min) with stirring for 1 day. After centrifugation, the solid was vacuum-dried to obtain the title product. X-ray powder diffraction analysis confirmed that the product was Form A.

[0261] Example 4 Preparation of Form C

[0262] Weigh 10 mg of the compound represented by Formula 1, add 1 mL of isopropanol, stir at room temperature for 3 days, centrifuge, and vacuum dry to obtain a solid. X-ray powder diffraction analysis identified the product as Form C. The XRPD spectrum is shown in Figure 2, and the positions of its characteristic peaks are shown in Table 4. The DSC spectrum shows an endothermic peak temperature of 239.41°C. The TGA spectrum shows a weight loss of 0.50% between 30°C and 159°C, and a weight loss of 5.50% between 159°C and 269°C.

[0263] Table 4

[0264] Example 5 Preparation of Form C

[0265] 10 mg of the compound of Formula 1 was weighed and added to a solvent as shown in Table 5 below. The mixture was dissolved at room temperature and stirred for 3 days. After centrifugation, the solid was vacuum dried to obtain the title product. X-ray powder diffraction analysis confirmed that the product was Form C.

[0266] Table 5

[0267] Example 6 Preparation of Form C

[0268] Weigh 5 mg of the compound represented by Formula 1, add 0.05 mL of 1,4-dioxane and dissolve with stirring at room temperature. Add 0.45 mL of the solvent listed in Table 6 below, stir to crystallize, and blend at room temperature for 3 days. After centrifugation, the solid was vacuum-dried to obtain the title product. X-ray powder diffraction analysis confirmed that the product was Form C.

[0269] Table 6

[0270] Example 7 Preparation of Form C

[0271] 10 mg of the compound of Formula 1 was weighed, 0.2 mL of n-propanol was added, and the mixture was slurried at 60°C for 1 day. After centrifugation, the solid was vacuum dried to obtain the title product. X-ray powder diffraction analysis showed that the product was Form C.

[0272] Example 8 Preparation of Form D

[0273] 80 mg of the compound represented by Formula 1 was weighed, 1 mL of n-butanol was added, and the mixture was stirred at a temperature ramp of 50°C to 5°C (at a rate of ±0.75°C / min) for 2 days. After centrifugation, the solid was vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as Form D. The XRPD spectrum is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 7. The DSC spectrum showed an endothermic peak temperature of 235.17°C. The TGA spectrum 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.

[0274] Table 7

[0275] Example 9: Preparation of Form D

[0276] 10 mg of the compound of Formula 1 was weighed, 0.2 mL of tert-butanol was added, and the mixture was slurried at 60°C for 1 day. After centrifugation, the solid was vacuum dried to obtain a solid. X-ray powder diffraction analysis showed that the product was Form D.

[0277] Example 10: Preparation of Form E

[0278] Weigh 10 mg of the compound represented by Formula 1, add 1 mL of methanol, heat at 50°C to dissolve, and slowly evaporate to obtain a solid. X-ray powder diffraction analysis identified the product as Form E. The XRPD spectrum is shown in Figure 4, and the positions of its characteristic peaks are shown in Table 8. The DSC spectrum shows endothermic peaks at 229.16°C and 259.36°C. The TGA spectrum shows 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.

[0279] Table 8

[0280] Example 11: Preparation of Form E

[0281] Weigh 5 mg of the compound of Formula 1, add 0.2 mL of methanol, and heat and cool from 50°C to 5°C (at a rate of ±0.75°C / min) with stirring for 1 day. After centrifugation, the solid was vacuum-dried to obtain the title product. X-ray powder diffraction analysis confirmed the product to be Form E.

[0282] Example 12: Preparation of Form E

[0283] Weigh 5 mg of the compound of Formula 1, add 0.125 mL of 10% water / methanol, and stir at a temperature of 50°C to 5°C (at a rate of ±0.75°C / min) for 1 day. After centrifugation, the solid was vacuum-dried to obtain the title product. X-ray powder diffraction analysis confirmed the product to be Form E.

[0284] Example 13: Preparation of Form F

[0285] 1 g of the compound represented by Formula 1 was weighed, and 13 mL of purified water was added. The mixture was stirred at a temperature ramp of 50°C to 5°C (at a rate of ±0.75°C / min) for 4 days. The solid was filtered under reduced pressure and vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as Form F. The XRPD spectrum is shown in Figure 5, and the positions of its characteristic peaks are shown in Table 9. The DSC spectrum showed endothermic peaks at 85.97°C, 150.99°C, and 222.57°C. The TGA spectrum showed a weight loss of 6.03% between 30°C and 101°C. DVS analysis showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample experienced a moisture gain of approximately 6.35%; under accelerated storage conditions (i.e., 70% RH), the moisture gain was approximately 6.44%; and under extreme conditions (90% RH), the moisture gain was approximately 6.65%. During the humidity change from 0% to 95% RH, the desorption process of the sample did not overlap with the adsorption process. After DVS detection and retesting of the crystal form, the crystal form did not change.

[0286] Table 9

[0287] Example 14: Preparation of Form F

[0288] Weigh 100 mg of the compound of Formula 1, add 1 mL of 80% acetone / water, and dissolve with stirring at room temperature. Add 3.8 mL of purified water and stir to crystallize. Heat to 50°C and continue stirring for 3 days. After centrifugation, air dry at 40°C overnight to obtain a solid. X-ray powder diffraction analysis confirmed the product to be Form F.

[0289] Example 15: Preparation of Form G

[0290] 80 mg of the compound represented by Formula 1 was weighed, 1 mL of methanol was added, and the mixture was stirred at a temperature ramp of 50°C to 5°C (at a rate of ±0.75°C / min) for 2 days. After centrifugation, the solid was dried in vacuo at 80°C for 7.5 hours to obtain a solid. X-ray powder diffraction analysis identified the product as Form G. The XRPD spectrum is shown in Figure 6, and the positions of its characteristic peaks are shown in Table 10. The DSC spectrum showed an endothermic peak at 237.35°C. The TGA spectrum 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. DVS analysis revealed that under normal storage conditions (i.e., 25°C, 60% RH), the sample experienced a moisture gain of approximately 1.04%; under accelerated storage conditions (i.e., 70% RH), the moisture gain was approximately 1.21%; and under extreme conditions (90% RH), the moisture gain was approximately 1.60%. During the humidity change from 0% to 95% RH, the desorption process of the sample basically coincided with the adsorption process, and the crystal form was re-tested after DVS detection, and the crystal form did not change.

[0291] Table 10

[0292] Example 16: Preparation of Form G

[0293] Weigh 500 mg of the compound of Formula 1, add 2 mL of 80% acetone / water, and stir at room temperature to dissolve. Then, add 8 mL of methanol and 6 mL of purified water. Stirring is continued for 4 days. After filtration, vacuum dry at 80°C overnight to obtain a solid. X-ray powder diffraction analysis confirmed the product to be Form G.

[0294] Example 17: Preparation of Form G

[0295] Weigh 10 mg of the crystalline Form E compound of Formula 1, add 0.2 mL of the solvent listed in Table 11 below, stir at 60°C for 1 day, centrifuge, and vacuum dry at 80°C overnight to obtain a solid. X-ray powder diffraction analysis confirmed that the product was Form G.

[0296] Table 11

[0297] Example 18: Preparation of Form H

[0298] Weigh 25 mg of Form E of the compound represented by Formula 1, add 1 mL of ether, and slurry at room temperature or 50°C for 4 hours. After centrifugation, vacuum dry at 80°C overnight to obtain a solid. X-ray powder diffraction analysis identified this product as Form H. The XRPD spectrum is shown in Figure 7, and the positions of its characteristic peaks are shown in Table 12. The DSC spectrum shows endothermic peaks at 46.77°C and 221.95°C. The TGA spectrum shows 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.

[0299] Table 12

[0300] Example 19: Preparation of Form H

[0301] 25 mg of the compound of Formula 1 was weighed, 1 mL of ether was added, and the mixture was slurried at room temperature for 5 days. After centrifugation, the mixture was vacuum-dried at 40°C overnight to obtain a solid. X-ray powder diffraction analysis showed that the product was Form H.

[0302] Example 20: Preparation of Form I

[0303] 30 mg of the compound represented by Formula 1 was weighed, 0.6 mL of n-pentanol was added, and the mixture was slurried at 60°C for 1 day. After centrifugation, the mixture was vacuum-dried at 40°C overnight to obtain the title product. X-ray powder diffraction analysis identified the product as Form I. The XRPD spectrum is shown in Figure 8, and the positions of its characteristic peaks are shown in Table 13. The DSC spectrum showed endothermic peak temperatures at 66.03°C, 222.56°C, and 245.19°C. The TGA spectrum showed a weight loss of 0.97% from 30°C to 100°C and an 8.15% weight loss from 100°C to 240°C.

[0304] Table 13

[0305] Example 21: Preparation of Form J

[0306] 30 mg of the compound represented by Formula 1 was weighed, 0.6 mL of isoamyl alcohol was added, and the mixture was slurried at 60°C for 1 day. After centrifugation, the mixture was vacuum-dried at 40°C overnight to obtain a solid. X-ray powder diffraction analysis identified the product as Form J. The XRPD spectrum is shown in Figure 9, and the positions of its characteristic peaks are shown in Table 14. The DSC spectrum showed endothermic peak temperatures at 230.96°C and 242.37°C. The TGA spectrum showed a weight loss of 0.46% between 31°C and 100°C, and a weight loss of 7.85% between 171°C and 260°C.

[0307] Table 14

[0308] Example 22: Preparation of Form K

[0309] 10 mg of the compound represented by Formula 1 was weighed and added to 1 mL of 7% water / ethanol. The mixture was stirred at room temperature for 3 days, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as Form K. The XRPD spectrum is shown in Figure 10 , and the positions of its characteristic peaks are shown in Table 15 . The DSC spectrum showed an endothermic peak temperature of 240.73°C. The TGA spectrum showed a weight loss of 1.42% between 30°C and 108°C, and a weight loss of 3.32% between 108°C and 272°C.

[0310] Table 15

[0311] Example 23: Preparation of Form K

[0312] Weigh 5 mg of the compound of Formula 1, add 0.050 mL of 1,4-dioxane and stir at room temperature to dissolve. Add 0.450 mL of ethanol and stir to crystallize. Pulp the solution at room temperature for 3 days, centrifuge, and vacuum dry to obtain a solid. X-ray powder diffraction analysis confirmed the product to be Form K.

[0313] Example 24: Preparation of Form K

[0314] Weigh 5 mg of the compound represented by Formula 1 and add 0.075 mL of a 1:1 ethyl acetate / ethanol mixture to dissolve the mixture at room temperature with stirring. The mixture was then heated and cooled from 50°C to 5°C (at a rate of ±0.75°C / min) for 1 day. The mixture was centrifuged and then vacuum-dried to obtain a solid. X-ray powder diffraction analysis confirmed the product to be Form K.

[0315] Example 25: Preparation of Form L

[0316] Weigh 10 mg of Form F of the compound represented by Formula 1, add 0.5 ml of water, stir at 95°C for 2 hours, centrifuge, and vacuum dry to obtain a solid. X-ray powder diffraction analysis identified this product as Form L. The XRPD spectrum is shown in Figure 11, and the positions of its characteristic peaks are shown in Table 16. The DSC spectrum shows endothermic peak temperatures at 98.46°C and 237.45°C. The TGA spectrum shows a 2.6% weight loss between 30°C and 270°C.

[0317] Table 16

[0318] Example 26: Preparation of Form M

[0319] 10 mg of the compound represented by Formula 1 was weighed, 0.1 ml of isopropyl acetate was added, and the mixture was stirred at room temperature for 2 days. The mixture was centrifuged and vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as Form M. The XRPD spectrum is shown in Figure 12, and the positions of its characteristic peaks are shown in Table 17. The DSC spectrum showed an endothermic peak temperature of 254.20°C. The TGA spectrum showed a weight loss of 0.23% from 27°C to 247°C. DVS analysis showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample gained approximately 0.48% by moisture absorption; under accelerated test conditions (i.e., 70% RH), the weight gain was approximately 0.55%; and under extreme conditions (90% RH), the weight gain was approximately 0.73%. During the humidity fluctuation from 0% to 95% RH, the desorption process of the sample essentially overlapped with the adsorption process. After DVS analysis, the crystal form was retested and no change in form was observed.

[0320] Table 17

[0321] Example 27: Preparation of Form M

[0322] Weigh 100 mg of the compound of Formula 1, add 2.5 mL of isopropyl acetate, and dissolve with stirring at 60°C. After cooling to room temperature, add 1 mL of n-heptane and stir at room temperature overnight. Centrifuge and vacuum dry to obtain a solid. X-ray powder diffraction analysis confirmed the product to be Form M.

[0323] Example 28: Preparation of Form N

[0324] 10 mg of the compound represented by Formula 1 was weighed, 0.1 ml of water was added, and the mixture was stirred at 95°C for 3 days. The mixture was centrifuged and vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as Form N. The XRPD spectrum is shown in Figure 13, and the positions of its characteristic peaks are shown in Table 18. The DSC spectrum showed endothermic peaks at 59.31°C and 268.68°C. The TGA spectrum showed a 2.1% weight loss from 25°C to 213°C. DVS analysis showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample gained approximately 3.00% by moisture absorption; under accelerated storage conditions (i.e., 70% RH), the sample gained approximately 3.06% by moisture absorption; and under extreme conditions (90% RH), the sample gained approximately 3.18% by moisture absorption. During the humidity cycle from 0% to 95% RH, the desorption process of the sample essentially overlapped with the adsorption process. DVS analysis and subsequent crystal form testing revealed no change in form.

[0325] Table 18

[0326] Example 29: Preparation of Form N

[0327] Weigh 10 mg of the compound represented by Formula 1 and dissolve it in 0.5 mL of ethyl acetate. Add 1 mL of n-heptane and stir at room temperature overnight. Filter the precipitated solid, add water, and stir overnight at 95°C. Centrifuge and vacuum dry to obtain a solid. X-ray powder diffraction analysis confirmed the product to be Form N.

[0328] Example 30: Preparation of Form N

[0329] Weigh 100 mg of the compound of Formula 1 and dissolve it in 1.0 ml of a mixture of methyl isobutyl ketone and isopropyl acetate (v / v = 1:1). Add 5 mg of Form N seed crystals and stir overnight at room temperature. After centrifugation, the solid was vacuum dried to obtain the title product.

[0330] Example 31: Preparation of Form N

[0331] Weigh 100 mg of the compound of Formula 1, add 1.0 ml of methyl isobutyl ketone, and stir overnight at room temperature. Centrifuge and vacuum dry to obtain a solid. X-ray powder diffraction analysis confirmed the product to be Form N.

[0332] Example 32: Preparation of Form O

[0333] Weigh 50 mg of the compound represented by Formula 1 and dissolve it in 0.5 mL of 2-butanone. Add 3.5 mL of water, stir at 50°C for 2 hours, and centrifuge to remove the supernatant to obtain a solid. X-ray powder diffraction analysis identified this product as Form O. The XRPD spectrum is shown in Figure 14 , and the positions of its characteristic peaks are shown in Table 19.

[0334] Table 19

[0335] Example 33: Preparation of Form P

[0336] Weigh 50 mg of the compound represented by Formula 1 and dissolve it in 0.5 mL of 2-butanone. Add 3.5 mL of water, stir at 50°C for 24 hours, and centrifuge to remove the supernatant to obtain a solid. X-ray powder diffraction analysis identified the product as the free-state Form P. The XRPD spectrum is shown in Figure 15 , and the positions of its characteristic peaks are shown in Table 20.

[0337] Table 20

[0338] Example 34: Preparation of Form Q

[0339] Weigh 50 mg of the compound represented by Formula 1 and dissolve it in 0.5 mL of 2-butanone. Add 3.5 mL of water and stir at 50°C for 2 hours. Centrifuge the solid and dry it in vacuo to obtain the title product. X-ray powder diffraction analysis identified this product as the free form Q. The XRPD spectrum is shown in Figure 16, and the positions of its characteristic peaks are shown in Table 21.

[0340] Table 21

[0341] Example 35: Preparation of Form R

[0342] 50 mg of the compound represented by Formula 1 was weighed and 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 solid was centrifuged and dried under vacuum. 1.0 mL of water was added, and the mixture was stirred at 60°C for 12 hours. The solid was then centrifuged and dried under vacuum to obtain a solid. X-ray powder diffraction analysis identified the product as Form R. The XRPD spectrum is shown in Figure 17, and the positions of its characteristic peaks are shown in Table 22.

[0343] Table 22

[0344] Example 36: Preparation of Form S

[0345] Weigh 50 mg of the compound represented by Formula 1, add 0.5 ml of methyl isobutyl ketone, and stir at room temperature overnight. After centrifugation, vacuum dry at 100°C overnight to obtain a solid. X-ray powder diffraction analysis identified the product as the free S crystalline form. The XRPD spectrum is shown in Figure 18, and the positions of its characteristic peaks are shown in Table 23. The DSC spectrum shows an endothermic peak temperature of 280.11°C. The TGA spectrum shows a weight loss of 0.52% between 33°C and 333°C.

[0346] Table 23

[0347] Example 37: Preparation of Form T

[0348] Weigh 10 mg of the compound represented by Formula 1 and add it to 1 ml of isopropanol. Stir the solution at room temperature until it becomes clear, filter it through a 0.22 μm filter, and slowly evaporate the solution at room temperature to obtain a solid. X-ray powder diffraction analysis identified this product as Form T. The XRPD spectrum is shown in Figure 19, and the positions of its characteristic peaks are shown in Table 24.

[0349] Table 24

[0350] Example 38: Preparation of Form U

[0351] Weigh 20 mg of the compound represented by Formula 1 in a mixture of 0.18 ml of methanol and 0.02 ml of water and stir for 24 hours. After filtration, the product was oven-dried at 50°C for 16 hours to obtain a solid. X-ray powder diffraction analysis identified the product as Form U. The XRPD spectrum is shown in Figure 20, and the positions of its characteristic peaks are shown in Table 25.

[0352] Table 25

[0353] Example 39: Preparation of Free Form B

[0354] Weigh 10 mg of Form E of the compound represented by Formula 1, add 0.5 ml of ethyl acetate, stir at room temperature for 2 days, centrifuge, and vacuum dry to obtain a solid. X-ray powder diffraction analysis identified this product as Form B. The XRPD spectrum is shown in Figure 22, and the positions of its characteristic peaks are shown in Table 26.

[0355] Table 26

[0356] Example 40: Preparation of Form α

[0357] Weigh 10 mg of Form N of the compound represented by Formula 1, add 0.2 ml of methanol, and stir at room temperature to crystallize. Centrifuge and vacuum dry to obtain a solid. X-ray powder diffraction analysis identified the product as free Form α. The XRPD spectrum is shown in Figure 23, and the positions of its characteristic peaks are shown in Table 27. The DSC spectrum shows endothermic peaks at 42.51°C and 262.81°C. The TGA spectrum shows a weight loss of 3.43% between 30°C and 316°C.

[0358] Table 27

[0359] Example 41: Preparation of Form α

[0360] Weigh 10 mg of Form N of the compound represented by Formula 1, add 0.2 ml of a solvent as shown in Table 27 below, stir at room temperature to crystallize, centrifuge, and vacuum dry to obtain a solid. X-ray powder diffraction analysis confirmed that the product was Form α in the free state.

[0361] Table 28

[0362] Example 42: Preparation of Form β

[0363] 10 mg of Form B of the compound represented by Formula 1 was weighed, and 0.1 mL of propylene glycol methyl ether was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and then vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as free Form β. The XRPD spectrum is shown in Figure 24, and the positions of its characteristic peaks are shown in Table 29. The DSC spectrum showed endothermic peak temperatures of 157.49°C and 221.33°C. The TGA spectrum showed a weight loss of 7.16% between 30°C and 187°C.

[0364] Table 29

[0365] Example 43: Study on factors affecting the stability of crystal form

[0366] The free-state crystalline forms C, F, G, H, L, M, and N were laid out in the open air, and the stability of the samples was investigated under light (4500 Lux), high temperature (40°C, 60°C), and high humidity (75% RH, 92.5% RH) conditions, respectively. The sampling period was 30 days.

[0367] Table 30 Stability study of factors affecting Form C

[0368] Table 31 Stability study of factors affecting Form F

[0369] Table 32 Stability study of factors affecting Form G

[0370] Table 33 Stability study of factors affecting Form H

[0371] Table 34 Stability study of factors affecting crystal form L

[0372] Table 35 Stability study of factors affecting crystal form M

[0373] Table 36 Stability study of factors affecting crystal form N

[0374] Conclusion: The influencing factor experiment showed that under the conditions of light, high temperature (40℃, 60℃), and high humidity (75% RH, 92.5% RH) for 30 days, the physical and chemical stability of Form C, Form F, Form G, Form H, Form L, Form M, and Form N were all good.

[0375] Example 44: Long-term accelerated stability study of free crystal form

[0376] The stability of Form C, Form F, Form G, Form H, Form L, Form M, and Form N was investigated under conditions of 25°C / 60% RH and 40°C / 75% RH.

[0377] Table 37 Long-term accelerated stability study of Form C

[0378] Table 38 Long-term accelerated stability study of Form F

[0379] Table 39 Long-term accelerated stability study of Form G

[0380] Table 40 Long-term accelerated stability study of Form H

[0381] Table 41 Long-term accelerated stability study of Form L

[0382] Table 42 Long-term accelerated stability study of Form M

[0383] Table 43 Long-term accelerated stability study of Form N

[0384] Conclusion: Long-term accelerated experiments show that at 25°C / 60RH and 40°C / 75RH for 6 months, the physicochemical stability of Form C, Form F, Form G, Form H, Form L, Form M, and Form N are all good.

Claims

1. A crystalline form C of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 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, 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.

2. The crystal form C according to claim 1, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG2 .

3. A method for preparing the crystalline form C according to claim 1 or 2, the method comprising: Method 1: adding the compound of formula 1 into solvent I, stirring and crystallizing, wherein the solvent I is selected from one or more of isopropanol, ethanol, and n-propanol; Method 2: dissolving the compound of formula 1 in 1,4-dioxane, adding solvent II, stirring and crystallizing, wherein the solvent II is selected from one or more of isopropanol, methyl tert-butyl ether, n-heptane, isopropyl acetate, dichloromethane and cyclohexane; Method three: dissolving the compound of formula 1 in solvent III, stirring and crystallizing, wherein the solvent III is selected from one or more of acetone, tetrahydrofuran, 1,4-dioxane, isopropyl acetate, dichloromethane, tetrahydrofuran / ethanol (v / v=2:1).

4. A crystalline form F of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has 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, 26.139 and 28.351, and more preferably have 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.

5. The crystal form F according to claim 4, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG5 .

6. A method for preparing the crystalline form F according to claim 4 or 5, the method comprising: Method 1: Add the compound of formula 1 into purified water, and heat and cool cyclically from 50°C to 5°C with stirring; Method 2: Dissolve the compound of formula 1 in 80% acetone / water, add purified water and stir.

7. A crystalline form G of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern, represented by a diffraction angle 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, 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.

8. The crystal form G according to claim 7, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG6 .

9. A method for preparing the crystalline form G according to claim 7 or 8, comprising: Method 1: Add the compound of formula 1 into methanol, and heat and cool cyclically from 50°C to 5°C with stirring; Method 2: Dissolve the compound of formula 1 in 80% acetone / water, add methanol / water (V / V=4:3), and stir; Method three: adding the crystalline form E of the compound of formula 1 into solvent IV and stirring, wherein the solvent IV is selected from one or more of isopropyl ether, methyl tert-butyl ether, cyclohexane, isopropyl acetate and water.

10. A crystalline form H of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.961, 13.533, 15.180, 15.879 and 20.619, preferably has characteristic peaks at 7.961, 13.533, 15.180, 15.879, 15.946, 20.619, 20.902, 22.595 and 25.444, more preferably has 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.

11. The crystal form H according to claim 10, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG. 7 .

12. A method for preparing the crystalline form H according to claim 10 or 11, comprising the step of adding the compound of formula 1 into diethyl ether and stirring.

13. A crystalline form L of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern, represented by a diffraction angle 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, 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.

14. The crystal form L according to claim 13, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG11 .

15. A method for preparing the crystal form L as claimed in claim 13 or 14, comprising the step of adding the crystal form F of the compound of formula 1 into water and stirring at 95°C.

16. A crystalline form M of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 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, 20.945, 25.

849. The invention discloses a novel nanostructured carbonyl carbonyl compound having characteristic peaks at 849 and 26.857, and more preferably 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.

17. The crystal form M according to claim 16, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG12 .

18. A method for preparing the crystalline form M according to claim 16 or 17, the method comprising: Method 1: Add the compound of formula 1 into isopropyl acetate and stir; Method 2: Dissolve the compound of formula 1 in isopropyl acetate, add n-heptane and stir.

19. A crystalline form N of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 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, 22. The invention discloses a novel nanostructured carbonyl compound having a nanostructured carbonyl group and a nanostructured carbonyl group. The nanostructured carbonyl group has characteristic peaks at 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.

20. The crystal form N according to claim 19, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG13 .

21. A method for preparing the crystalline form N according to claim 19 or 20, the method comprising: Method 1: Add the compound of formula 1 into solvent V, stir and crystallize, wherein the solvent V is selected from water and methyl isobutyl ketone; Method 2: Dissolve the compound of formula 1 in solvent VI, add seed crystals for crystallization, and the solvent VI is selected from One or more of isobutyl ketone and isopropyl acetate; Method 3: Dissolve the compound of formula 1 in ethyl acetate, add n-heptane and stir.

22. A crystalline form R of a compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed as a diffraction angle 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, 24.02 0 and 26.248, more preferably 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 23. The crystal form R according to claim 22, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG. 17 .

24. A method for preparing the crystalline form R according to claim 22 or 23, the method comprising: Step 1: dissolve the compound of formula 1 in 2-butanone, add water, and stir to crystallize. Step 2: Add the crystals obtained in step 1 into water and stir at 60°C for crystallization.

25. A crystalline form S of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed as a diffraction angle 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, 23.881 and 26 .322, more preferably 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 26. The crystal form S according to claim 25, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG18 .

27. A method for preparing the crystalline form S according to claim 25 or 26, the method comprising: Step 1: adding the compound of formula 1 into methyl isobutyl ketone, stirring and crystallizing; Step 2: Dry the crystals in step 1 at 100°C in vacuum.

28. According to any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 22-23, and 25-26, the 2θ angle error range is ±0.

20.

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

30. A method for preparing a pharmaceutical composition, comprising the step of mixing the crystal 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 a pharmaceutically acceptable excipient.

31. Use of the crystal 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, or the pharmaceutical composition described in claim 26 in the preparation of a drug for treating and / or preventing tumors.

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