Crystal form of methionine adenosyltransferase 2a heterocyclic inhibitor, preparation method therefor, and use thereof

Abstract

The present invention relates to a crystal form of a methionine adenosyltransferase 2A heterocyclic inhibitor, a preparation method therefor, and a use thereof, and in particular to a crystal form of a compound as represented by the following formula I, a preparation method therefor, and a use thereof. The crystal form has high purity and stable chemical properties, and has important significance for developing drugs which are suitable for industrial production and have good biological activity.

Description

Crystal form of methionine adenosyltransferase 2A heterocyclic inhibitor, preparation method and use thereof

[0001] This application claims priority to Chinese patent application No. 202310705912.8, filed on June 14, 2023, and cites the full text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of biomedicine, and specifically relates to a crystal form of a methionine adenosyltransferase 2A heterocyclic inhibitor, a preparation method thereof, and uses thereof. Background Art

[0003] Methionine adenosyltransferase (MAT) (also known as S-adenosylmethionine synthetase) is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP and is considered to be the rate-limiting step of the methionine cycle. SAM is the propylamino donor in polyamine biosynthesis and the major methyl donor for DNA methylation, and is involved in gene transcription and cell proliferation, as well as the production of secondary metabolites. The three human isoenzymes of MAT include MAT1, MAT2, and MAT3, of which MAT1 and MAT3 are expressed in liver tissue. Methionine adenosyltransferase 2A (MAT2A) is a subtype of MAT2 that is ubiquitously expressed in human cell types and is the predominant form in human cancers, and it also plays a key role in the production of SAM.

[0004] MTAP (methylthioadenosine phosphorylase) is an enzyme ubiquitously expressed in normal tissues that catalyzes the conversion of methylthioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate, adenine to adenosine monophosphate, and 5-methylthioribose-1-phosphate to methionine and formate. MTA can be used as an alternative purine source when purine synthesis is blocked, for example by antimetabolites.

[0005] The gene encoding MTAP is located in a region on chromosome 9 and is frequently deleted in cancer patients from cells of the central nervous system, pancreas, esophagus, bladder, and lung. Loss of MTAP leads to the accumulation of MTA, making MTAP-deficient cells more dependent on SAM production and, therefore, MAT2A activity, compared to cells expressing MTAP. In a screen of approximately 400 cancer cell lines, MAT2A knockdown resulted in a greater percentage of MTAP-deficient cells losing viability than cells normally expressing MTAP. Furthermore, inducible knockdown of the MAT2A protein reduced tumor growth in vivo. These results suggest that MAT2A inhibitors may provide a novel therapeutic approach for patients with tumors that lack MTAP.

[0006] PCT / CN2022 / 140380 provides a novel heterocyclic methionine adenosyltransferase 2A inhibitor. The crystalline structure of a pharmaceutically active ingredient often affects the chemical stability of the drug. Differences in crystal form, preparation method, and storage conditions can lead to variations in the compound's crystalline structure, sometimes accompanied by the formation of other morphologies. Therefore, in-depth research on the polymorphic forms of compounds and obtaining highly pure and chemically stable crystalline forms are of great significance for the development of drugs suitable for industrial production and with good biological activity.

[0007] Summary of the Invention

[0008] All contents involved in patent PCT / CN2022 / 140380 are added to the present invention by reference.

[0009] The present invention provides a crystalline form of the compound represented by the following formula I:

[0010] Where X is selected from CR 3 or N; Y is selected from CR 4 or N; Z is selected from CR 5 or N; W is selected from CR 6 or N;

[0011] where R 3 、R 4 、R 5 and R 6 are each independently selected from hydrogen, cyano, C2-C6 alkynyl, halogen, hydroxyl, NH2, (C1-C6 alkyl)-NR 7 -, (C1-C6 alkyl)-O-, (C1-C6 alkyl)-S-, C1-C6 alkyl, C3-C6 cycloalkyl, 6-10 membered aryl, C2-C6 alkenyl or C3-C6 cycloalkenyl, said C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl or C3-C6 cycloalkenyl itself or as part of another group is optionally substituted by halogen, cyano, hydroxyl, -NR 7 R 8 , C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl, the 6-10 membered aryl is optionally substituted by halogen, hydroxyl, cyano, -NR 7 R 8 , NO2, C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl substituted, wherein the C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with halogen, hydroxy, cyano, -NR 7 R 8 or NO2 replacement;

[0012] R 1and R 2 Each is independently selected from 6-10 membered aryl or 9-18 membered benzoheterocyclyl, wherein the 6-10 membered aryl or 9-18 membered benzoheterocyclyl is optionally substituted by halogen, hydroxyl, cyano, -NR 7 R 8 、NO2、-NR 9 C(O)R 10 , C1-C6 alkyl, (C1-C6 alkyl)-O-, -C(O)NR 9 R 10 or 5-7 membered heteroaryl, wherein the C1-C6 alkyl itself or as part of another group or the 5-7 membered heteroaryl is optionally substituted with halogen, cyano, hydroxy, C1-C3 alkyl, (C1-C3 alkyl)-O- or -NR 7 R 8 replace;

[0013] R 7 、R 8 、R 9 and R 10 Each independently selected from H or C1-C6 alkyl;

[0014] The condition is: at most 2 of W, X, Y and Z are N at the same time.

[0015] The present invention also provides a crystalline form of a compound of formula I, wherein the compound of formula I has a structure as shown in formula II,

[0016] Among them, R 1 、R 2 、R 3 、R 4 and R 5 The definition of is as defined in the compound of formula I.

[0017] In one embodiment of the present invention, R 3 、R 4 、R 5 and R 6 Each is independently selected from hydrogen, halogen, hydroxy, NH2, (C1-C6 alkyl)-NR 7 -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl or 6-10 membered aryl, wherein the C1-C6 alkyl itself or as part of another group or C3-C6 cycloalkyl is optionally substituted by halogen, cyano, hydroxy or -NR 7 R 8 Substituted, the 6-10 membered aryl group is optionally substituted by a halogen-substituted C1-C3 alkoxy group;

[0018] Preferably, R 3 、R 4、R 5 and R 6 Each is independently selected from hydrogen, halogen, hydroxy, NH2, (C1-C6 alkyl)-NR 7 -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl or 6-10 membered aryl, wherein the C1-C6 alkyl itself or as part of another group or C3-C6 cycloalkyl is optionally substituted with halogen, and the 6-10 membered aryl is optionally substituted with halogen-substituted C1-C3 alkoxy;

[0019] More preferably, R 3 、R 4 、R 5 and R 6 Each is independently selected from hydrogen, halogen, hydroxy, NH2, (C1-C6 alkyl)-NR 7 -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl or 6-10 membered aryl, wherein the C1-C6 alkyl itself or as part of another group or the C3-C6 cycloalkyl is optionally substituted with fluorine, and the 6-10 membered aryl is optionally substituted with a fluorine-substituted C1-C3 alkoxy group.

[0020] In one embodiment of the present invention, R 3 is selected from hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; preferably, R 3 is selected from hydrogen or C1-C6 alkyl; more preferably, R 3 is selected from hydrogen, methyl or cyclopropyl; further preferably, R 3 is selected from hydrogen or methyl; most preferably, R 3 Selected from hydrogen.

[0021] In one embodiment of the present invention, R 4 is selected from hydrogen or C1-C6 alkyl; preferably, R 4 is selected from hydrogen or methyl; more preferably, R 4 Selected from hydrogen.

[0022] In one embodiment of the present invention, R 5 Selected from hydrogen, halogen, hydroxy, (C1-C6 alkyl)-NR 7 -, (C1-C6 alkyl) -O-, C3-C6 cycloalkyl or 6-10 membered aryl, wherein the C1-C6 alkyl itself or as part of another group or C3-C6 cycloalkyl is optionally substituted with fluorine, and the 6-10 membered aryl is optionally substituted with fluorine-substituted C1-C3 alkoxy; preferably, R 5 is selected from hydrogen, chlorine, hydroxy, cyclopropyl, CF3CH2O-, CHF2O-, CF3CH2NH-, 4-difluoromethoxyphenyl or CH3CH2O-; more preferably, R5 is selected from cyclopropyl, CF3CH2O-, CF3CH2NH- or CH3CH2O-; further preferably, R 5 is selected from cyclopropyl, CF3CH2O- or CF3CH2NH-; most preferably, R 5 Selected from cyclopropyl.

[0023] In one embodiment of the present invention, R 1 and R 2 Each independently selected from phenyl, wherein the groups are optionally substituted by halogen, hydroxy, cyano, -NR 7 R 8 、NO2、-NR 9 C(O)R 10 , C1-C6 alkyl, (C1-C6 alkyl)-O-, -C(O)NR 9 R 10 or 5-7 membered heteroaryl, wherein the C1-C6 alkyl itself or as part of another group or the 5-7 membered heteroaryl is optionally substituted with halogen, cyano, hydroxy, C1-C3 alkyl, (C1-C3 alkyl)-O- or -NR 7 R 8 substituted; preferably, R 1 and R 2 Each independently selected from phenyl, wherein the group is optionally substituted by C1-C6 alkyl or (C1-C6 alkyl)-O-, wherein the C1-C6 alkyl itself or as part of another group is optionally substituted by halogen; preferably, R 7 、R 8 、R 9 and R 10 are each independently selected from H.

[0024] In another embodiment of the present invention, R1 is selected from phenyl, wherein the group is optionally substituted by C1-C6 alkyl or (C1-C6 alkyl)-O-, wherein the C1-C6 alkyl itself or as part of another group is optionally substituted by halogen; preferably, R 1 Selected from More preferably, R 1 Selected from

[0025] In one embodiment of the present invention, R2 is selected from phenyl or wherein the group is optionally substituted by (C1-C6 alkyl)-O-, and the C1-C6 alkyl is optionally substituted by halogen; preferably, R 2 Selected from More preferably, R 2 Selected from

[0026] The present invention also provides the following crystalline forms of the compound:

[0027] In one embodiment of the present invention, a crystalline form of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and the structure of the compound is as follows:

[0028] In one embodiment of the present invention, crystalline forms A to Q of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one are provided.

[0029] In one embodiment of the present invention, a crystalline form A of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.0°±0.2°, 8.2°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.4°±0.2° and 25.4°±0.2°.

[0030] Preferably, the crystalline form A has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.0°±0.2°, 6.3°±0.2°, 8.2°±0.2°, 12.1°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.4°±0.2° and 25.4°±0.2°.

[0031] More preferably, the crystalline form A has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.0°±0.2°, 6.3°±0.2°, 8.2°±0.2°, 12.1°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.4°±0.2°, 18.2°±0.2°, 23.7°±0.2° and 25.4°±0.2°.

[0032] Further preferably, the crystalline form A has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.0°±0.2°, 6.3°±0.2°, 8.2°±0.2°, 12.1°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.4°±0.2°, 18.2°±0.2°, 21.1°±0.2°, 23.7°±0.2°, 24.8°±0.2° and 25.4°±0.2°.

[0033] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the crystalline form A is shown in the following table:

[0034] Table 1: X-ray powder diffraction data of Form A

[0035] In one embodiment, the crystalline form A has an endothermic peak at an onset temperature of 257° C. to 267° C. in a thermal analysis diagram measured by differential scanning calorimetry (DSC).

[0036] In one embodiment, the crystalline form A has an endothermic peak at an onset temperature of 260° C. to 264° C. in a thermal analysis diagram measured by differential scanning calorimetry (DSC).

[0037] In one embodiment, the crystalline form A has an endothermic peak at an onset temperature of 262° C. in a thermogram measured by differential scanning calorimetry (DSC).

[0038] In one embodiment, the X-ray powder diffraction pattern of the crystalline form A expressed in 2θ angles has the pattern shown in FIG5 .

[0039] In one embodiment, the crystalline form A has a TGA spectrum as shown in FIG6 .

[0040] In one embodiment, the crystalline form A has a DSC spectrum as shown in FIG7 .

[0041] In one embodiment of the present invention, a crystalline form B of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 7.5°±0.2°, 14.8°±0.2°, 17.6°±0.2°, 22.4°±0.2°, 24.6°±0.2° and 26.3°±0.2°.

[0042] Preferably, the crystalline form B has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 7.5°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 17.6°±0.2°, 22.4°±0.2°, 24.6°±0.2°, 26.3°±0.2° and 27.5°±0.2°.

[0043] More preferably, the crystalline form B has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 7.5°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 15.6°±0.2°, 17.6°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 24.6°±0.2°, 26.3°±0.2° and 27.5°±0.2°.

[0044] Further preferably, the crystalline form B has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 7.5°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 15.6°±0.2°, 17.1°±0.2°, 17.6°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 24.6°±0.2°, 25.2°±0.2°, 26.3°±0.2° and 27.5°±0.2°.

[0045] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the crystalline form B is shown in the following table:

[0046] Table 2: X-ray powder diffraction data of Form B

[0047] In one embodiment, the crystalline form B has endothermic peaks at onset temperatures of 215°C to 225°C and 260°C to 270°C in a thermogram measured by differential scanning calorimetry (DSC).

[0048] In one embodiment, the crystalline form B has endothermic peaks at onset temperatures of 217°C to 222°C and 264°C to 268°C in a thermal analysis diagram measured by differential scanning calorimetry (DSC).

[0049] In one embodiment, the crystalline form B has endothermic peaks at onset temperatures of 220° C. and 266° C. in a thermogram measured by differential scanning calorimetry (DSC).

[0050] In one embodiment, the X-ray powder diffraction pattern of the crystalline form B expressed in 2θ angles has a pattern as shown in FIG8 .

[0051] In one embodiment, the crystalline Form B has a TGA spectrum as shown in FIG9 .

[0052] In one embodiment, the crystalline Form B has a DSC spectrum as shown in FIG10 .

[0053] In one embodiment of the present invention, a crystalline form C of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 9.2°±0.2°, 17.6°±0.2°, 19.7°±0.2°, 21.8°±0.2°, 22.7°±0.2° and 24.6°±0.2°.

[0054] Preferably, the crystalline form C has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 9.2°±0.2°, 10.6°±0.2°, 13.0°±0.2°, 17.6°±0.2°, 19.7°±0.2°, 21.8°±0.2°, 22.7°±0.2° and 24.6°±0.2°.

[0055] More preferably, the crystalline form C has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 9.2°±0.2°, 10.6°±0.2°, 13.0°±0.2°, 15.2°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 21.8°±0.2°, 22.7°±0.2° and 24.6°±0.2°.

[0056] Further preferably, the crystalline form C has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 9.2°±0.2°, 10.6°±0.2°, 13.0°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 21.8°±0.2°, 22.7°±0.2°, 23.1°±0.2° and 24.6°±0.2°.

[0057] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the crystalline form C is shown in the following table:

[0058] Table 3: X-ray powder diffraction data of Form C

[0059] In one embodiment, the X-ray powder diffraction pattern of the crystalline form C expressed in 2θ angles has a pattern as shown in FIG11 .

[0060] In one embodiment, the crystalline Form C has a TGA spectrum as shown in FIG12 .

[0061] In one embodiment, the crystalline Form C has a DSC spectrum as shown in FIG13 .

[0062] In one embodiment of the present invention, a crystalline form D of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.8°±0.2°, 8.8°±0.2°, 13.0°±0.2°, 18.1°±0.2°, 21.6°±0.2° and 22.8°±0.2°.

[0063] Preferably, the crystalline form D has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.8°±0.2°, 8.8°±0.2°, 13.0°±0.2°, 18.1°±0.2°, 21.6°±0.2°, 22.8°±0.2°, 23.4°±0.2° and 26.1°±0.2°.

[0064] More preferably, the crystalline form D has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.8°±0.2°, 8.8°±0.2°, 13.0°±0.2°, 18.1°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 22.8°±0.2°, 23.4°±0.2°, 25.0°±0.2° and 26.1°±0.2°.

[0065] Further preferably, the crystalline form D has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.8°±0.2°, 8.8°±0.2°, 13.0°±0.2°, 18.1°±0.2°, 20.6°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 22.8°±0.2°, 23.4°±0.2°, 25.0°±0.2°, 26.1°±0.2° and 30.2°±0.2°.

[0066] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the crystalline form D is shown in the following table:

[0067] Table 4: X-ray powder diffraction data of Form D

[0068] In one embodiment, the X-ray powder diffraction pattern of the crystalline form D expressed in 2θ angles has a pattern as shown in FIG14 .

[0069] In one embodiment, the crystalline form D has a TGA spectrum as shown in FIG15 .

[0070] In one embodiment, the crystalline form D has a DSC spectrum as shown in FIG16 .

[0071] In one embodiment, the crystalline form D has a single crystal structure as shown in FIG17 .

[0072] In one embodiment of the present invention, a crystalline form E of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 5.8°±0.2°, 6.3°±0.2°, 7.0°±0.2° and 10.8°±0.2°.

[0073] Preferably, the crystalline form E has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 5.8°±0.2°, 6.3°±0.2°, 7.0°±0.2°, 10.8°±0.2°, 15.6°±0.2° and 20.1°±0.2°.

[0074] More preferably, the crystalline form E has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 5.8°±0.2°, 6.3°±0.2°, 7.0°±0.2°, 8.5°±0.2°, 10.8°±0.2°, 15.6°±0.2°, 20.1°±0.2° and 21.7°±0.2°.

[0075] Further preferably, the crystalline form E has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 5.8°±0.2°, 6.3°±0.2°, 7.0°±0.2°, 8.5°±0.2°, 10.8°±0.2°, 15.6°±0.2°, 19.4°±0.2°, 20.1°±0.2°, 21.5°±0.2° and 21.7°±0.2°.

[0076] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the crystalline form E is shown in the following table:

[0077] Table 5: X-ray powder diffraction data of Form E

[0078] In one embodiment, the X-ray powder diffraction pattern of the crystalline form E expressed in 2θ angles has a pattern as shown in FIG18 .

[0079] In one embodiment, the crystalline Form E has a TGA spectrum as shown in FIG19 .

[0080] In one embodiment of the present invention, a crystalline form F of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 8.9°±0.2°, 13.4°±0.2°, 16.8°±0.2°, 19.9°±0.2°, 20.4°±0.2° and 22.5°±0.2°.

[0081] Preferably, the crystalline form F has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 8.9°±0.2°, 12.2°±0.2°, 13.4°±0.2°, 16.8°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 22.5°±0.2° and 25.5°±0.2°.

[0082] More preferably, the crystalline form F has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 8.9°±0.2°, 10.0°±0.2°, 12.2°±0.2°, 13.4°±0.2°, 16.8°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 22.5°±0.2°, 25.5°±0.2° and 26.0°±0.2°.

[0083] Further preferably, the crystalline form F has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 8.9°±0.2°, 10.0°±0.2°, 12.2°±0.2°, 13.4°±0.2°, 16.1°±0.2°, 16.8°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 22.5°±0.2°, 23.3°±0.2°, 25.5°±0.2° and 26.0°±0.2°.

[0084] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the crystal form F is shown in the following table:

[0085] Table 6: X-ray powder diffraction pattern data of Form F

[0086] In one embodiment, the X-ray powder diffraction pattern of the crystalline form F expressed in 2θ angles has a pattern as shown in FIG20 .

[0087] In one embodiment, the crystalline Form F has a TGA spectrum as shown in FIG21 .

[0088] In one embodiment, the crystalline Form F has a DSC spectrum as shown in FIG22 .

[0089] In one embodiment, the crystalline form F has the 1 H NMR spectrum.

[0090] In one embodiment of the present invention, a crystalline form G of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.3°±0.2°, 6.8°±0.2°, 13.9°±0.2° and 15.3°±0.2°.

[0091] Preferably, the crystalline form G has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.3°±0.2°, 6.8°±0.2°, 8.2°±0.2°, 12.7°±0.2°, 13.9°±0.2° and 15.3°±0.2°.

[0092] More preferably, the crystalline form G has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.3°±0.2°, 6.8°±0.2°, 8.2°±0.2°, 12.7°±0.2°, 13.9°±0.2°, 15.3°±0.2°, 19.9°±0.2° and 25.7°±0.2°.

[0093] Further preferably, the crystalline form G has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.3°±0.2°, 6.8°±0.2°, 8.2°±0.2°, 8.8°±0.2°, 12.7°±0.2°, 13.9°±0.2°, 15.3°±0.2°, 17.7°±0.2°, 19.9°±0.2° and 25.7°±0.2°.

[0094] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the crystalline form G is shown in the following table:

[0095] Table 7: X-ray powder diffraction pattern data of Form G

[0096] In one embodiment, the X-ray powder diffraction of the crystalline form G expressed in 2θ angle has a pattern as shown in FIG. 24 .

[0097] In one embodiment, the crystalline Form G has a TGA spectrum as shown in FIG25 .

[0098] In one embodiment, the crystalline Form G has a DSC spectrum as shown in FIG26 .

[0099] In one embodiment of the present invention, a crystalline form H of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 5.8°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 19.8°±0.2° and 20.7°±0.2°.

[0100] Preferably, the crystalline form H has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 5.8°±0.2°, 9.8°±0.2°, 11.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 19.8°±0.2° and 20.7°±0.2°.

[0101] More preferably, the crystalline form H has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 5.8°±0.2°, 9.8°±0.2°, 11.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 23.8°±0.2° and 27.1°±0.2°.

[0102] Further preferably, the crystalline form H has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 5.8°±0.2°, 9.8°±0.2°, 11.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 23.8°±0.2°, 25.4°±0.2°, 25..7°±0.2° and 27.1°±0.2°.

[0103] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the crystalline form H is shown in the following table:

[0104] Table 8: X-ray powder diffraction data of Form H

[0105] In one embodiment, the crystalline form H has endothermic peaks at starting temperatures of 220°C to 230°C and 260°C to 270°C in a thermal analysis diagram measured by differential scanning calorimetry (DSC).

[0106] In one embodiment, the crystalline form H has endothermic peaks at onset temperatures of 222°C to 226°C and 263°C to 268°C in a thermogram measured by differential scanning calorimetry (DSC).

[0107] In one embodiment, the crystalline form H has endothermic peaks at onset temperatures of 224° C. and 265° C. in a thermogram measured by differential scanning calorimetry (DSC).

[0108] In one embodiment, the X-ray powder diffraction of the crystalline form H expressed in 2θ angle has a pattern as shown in FIG27 .

[0109] In one embodiment, the crystalline Form H has a TGA spectrum as shown in FIG28 .

[0110] In one embodiment, the crystalline Form H has a DSC spectrum as shown in FIG29 .

[0111] In one embodiment of the present invention, a crystalline form I of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.8°±0.2°, 8.9°±0.2°, 20.7°±0.2° and 30.1°±0.2°.

[0112] Preferably, the crystalline form I has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.8°±0.2°, 8.9°±0.2°, 20.7°±0.2°, 21.8°±0.2°, 23.7°±0.2° and 30.1°±0.2°.

[0113] More preferably, the crystalline form I has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.8°±0.2°, 8.9°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 23.7°±0.2°, 27.7°±0.2° and 30.1°±0.2°.

[0114] Further preferably, the crystalline form I has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.8°±0.2°, 8.9°±0.2°, 13.8°±0.2°, 15.1°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 23.7°±0.2°, 27.7°±0.2° and 30.1°±0.2°.

[0115] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the crystalline form I is shown in the following table:

[0116] Table 9: X-ray powder diffraction pattern data of Form I

[0117] In one embodiment, the X-ray powder diffraction of the crystalline form I expressed in 2θ angle has a pattern as shown in Figure 30.

[0118] In one embodiment, the crystalline Form I has a TGA spectrum as shown in FIG31 .

[0119] In one embodiment, the crystalline Form I has a DSC spectrum as shown in FIG32 .

[0120] In one embodiment of the present invention, a crystalline form J of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.7°±0.2°, 25.0°±0.2° and 25.6°±0.2°.

[0121] Preferably, the crystalline form J has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.7°±0.2°, 8.7°±0.2°, 25.0°±0.2° and 25.6°±0.2°.

[0122] More preferably, the crystalline form J has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.7°±0.2°, 8.7°±0.2°, 20.5°±0.2°, 25.0°±0.2°, 25.6°±0.2° and 27.4°±0.2°.

[0123] Further preferably, the crystalline form J has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.7°±0.2°, 8.7°±0.2°, 13.6°±0.2°, 20.5°±0.2°, 23.4°±0.2°, 25.0°±0.2°, 25.6°±0.2° and 27.4°±0.2°.

[0124] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the crystal form J is shown in the following table:

[0125] Table 10: X-ray powder diffraction data of Form J

[0126] In one embodiment, the X-ray powder diffraction pattern of the crystalline form J expressed in 2θ angles has the pattern shown in FIG33 .

[0127] In one embodiment, the crystalline Form J has a TGA pattern as shown in FIG34 .

[0128] In one embodiment, the crystalline Form J has a DSC spectrum as shown in FIG35 .

[0129] In one embodiment of the present invention, a crystalline form K of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.2°±0.2°, 17.7°±0.2° and 18.9°±0.2°.

[0130] Preferably, the crystal form K has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 6.2°±0.2°, 16.8°±0.2°, 17.7°±0.2° and 18.9°±0.2°.

[0131] More preferably, the X-ray powder diffraction pattern of the crystalline form K has diffraction peaks at 2θ of 6.2°±0.2°, 11.4°±0.2°, 16.8°±0.2°, 17.7°±0.2°, 18.9°±0.2° and 27.6°±0.2°.

[0132] Further preferably, the X-ray powder diffraction pattern of the crystalline form K has diffraction peaks at 2θ of 6.2°±0.2°, 11.4°±0.2°, 16.8°±0.2°, 17.7°±0.2°, 18.9°±0.2°, 24.4°±0.2°, 25.3°±0.2°, and 27.6°±0.2°.

[0133] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the crystal form K is shown in the following table:

[0134] Table 11: X-ray powder diffraction data of Form K

[0135] In one embodiment, the X-ray powder diffraction pattern of the crystalline form K expressed in 2θ angles has the pattern shown in FIG36 .

[0136] In one embodiment of the present invention, a crystalline form L of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 14.9°±0.2°, 18.6°±0.2°, 21.4°±0.2°, 22.8°±0.2°, 23.5°±0.2° and 26.0°±0.2°.

[0137] Preferably, the crystalline form L has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 14.9°±0.2°, 18.6°±0.2°, 21.4°±0.2°, 22.8°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 26.0°±0.2° and 27.3°±0.2°.

[0138] More preferably, the crystalline form L has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 8.3°±0.2°, 14.9°±0.2°, 18.6°±0.2°, 21.4°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 26.0°±0.2° and 27.3°±0.2°.

[0139] Further preferably, the crystalline form L has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 8.3°±0.2°, 8.9°±0.2°, 14.9°±0.2°, 18.6°±0.2°, 19.5°±0.2°, 21.4°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 26.0°±0.2° and 27.3°±0.2°.

[0140] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the crystalline form L is shown in the following table:

[0141] Table 12: X-ray powder diffraction pattern data of Form L

[0142] In one embodiment, the crystalline form L has endothermic peaks at starting temperatures of 223°C to 233°C and 260°C to 270°C in a thermal analysis diagram measured by differential scanning calorimetry (DSC).

[0143] In one embodiment, the crystalline form L has endothermic peaks at onset temperatures of 225°C to 230°C and 263°C to 268°C in a thermal analysis diagram measured by differential scanning calorimetry (DSC).

[0144] In one embodiment, the crystalline form L has endothermic peaks at onset temperatures of 228°C and 265°C in a thermogram measured by differential scanning calorimetry (DSC).

[0145] In one embodiment, the X-ray powder diffraction of the crystalline form L expressed in 2θ angle has a pattern as shown in Figure 37.

[0146] In one embodiment, the crystalline Form L has a TGA pattern as shown in FIG38 .

[0147] In one embodiment, the crystalline form L has a DSC spectrum as shown in FIG39 .

[0148] In one embodiment of the present invention, a crystalline form M of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 7.1°±0.2°, 13.5°±0.2°, 17.4°±0.2°, 18.7°±0.2°, 23.7°±0.2° and 27.1°±0.2°.

[0149] Preferably, the crystalline form M has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 7.1°±0.2°, 11.4°±0.2°, 13.5°±0.2°, 17.4°±0.2°, 18.7°±0.2°, 21.5°±0.2°, 23.7°±0.2° and 27.1°±0.2°.

[0150] More preferably, the crystalline form M has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 7.1°±0.2°, 9.2°±0.2°, 11.4°±0.2°, 13.5°±0.2°, 17.4°±0.2°, 18.7°±0.2°, 20.5°±0.2°, 21.5°±0.2°, 23.7°±0.2° and 27.1°±0.2°.

[0151] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the crystal form M is shown in the following table:

[0152] Table 13: X-ray powder diffraction pattern data of Form M

[0153] In one embodiment, the X-ray powder diffraction of the crystalline form M expressed in 2θ angle has a pattern as shown in Figure 40.

[0154] In one embodiment, the crystalline form M has a TGA spectrum as shown in FIG41 .

[0155] In one embodiment, the crystalline Form M has a DSC spectrum as shown in FIG42 .

[0156] In one embodiment of the present invention, a crystalline form N of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.5°±0.2°, 7.0°±0.2°, 8.6°±0.2° and 18.1°±0.2°.

[0157] Preferably, the crystalline form N has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.5°±0.2°, 7.0°±0.2°, 8.6°±0.2°, 13.0°±0.2°, 18.1°±0.2° and 21.4°±0.2°.

[0158] More preferably, the crystalline form N has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.5°±0.2°, 7.0°±0.2°, 8.6°±0.2°, 13.0°±0.2°, 18.1°±0.2°, 21.4°±0.2°, 22.5°±0.2° and 24.1°±0.2°.

[0159] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the crystal form N is shown in the following table:

[0160] Table 14: X-ray powder diffraction pattern data of Form N

[0161] In one embodiment, the X-ray powder diffraction of the crystalline form N expressed in 2θ angle has a pattern as shown in Figure 43.

[0162] In one embodiment, the crystalline Form N has a TGA spectrum as shown in FIG44 .

[0163] In one embodiment, the crystalline Form N has a DSC spectrum as shown in FIG45 .

[0164] In one embodiment of the present invention, a crystalline form O of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 7.3°±0.2° and 18.5°±0.2°.

[0165] Preferably, the crystalline form O has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 3.7°±0.2°, 7.3°±0.2°, 18.5°±0.2° and 26.0°±0.2°.

[0166] More preferably, the crystalline form O has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 3.7°±0.2°, 7.3°±0.2°, 16.2°±0.2°, 18.5°±0.2°, 26.0°±0.2° and 26.3°±0.2°.

[0167] Further preferably, the crystalline form O has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 3.7°±0.2°, 7.3°±0.2°, 16.2°±0.2°, 18.5°±0.2°, 22.6°±0.2°, 25.6°±0.2°, 26.0°±0.2° and 26.3°±0.2°.

[0168] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the crystalline form O is shown in the following table:

[0169] Table 15: O-ray powder diffraction data of Form L

[0170] In one embodiment, the X-ray powder diffraction of the crystalline form O expressed in 2θ angle has a pattern as shown in Figure 46.

[0171] In one embodiment, the crystalline Form O has a TGA spectrum as shown in FIG47 .

[0172] In one embodiment, the crystalline Form O has a DSC spectrum as shown in FIG48 .

[0173] In one embodiment of the present invention, a crystalline form P of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.9°±0.2° and 18.2°±0.2°.

[0174] Preferably, the crystalline form P has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.2°±0.2°, 6.9°±0.2°, 13.9°±0.2° and 18.2°±0.2°.

[0175] More preferably, the crystalline form P has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.2°±0.2°, 6.9°±0.2°, 13.1°±0.2°, 13.9°±0.2°, 18.2°±0.2° and 26.1°±0.2°.

[0176] Further preferably, the crystalline form P has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 6.2°±0.2°, 6.9°±0.2°, 11.8°±0.2°, 13.1°±0.2°, 13.9°±0.2°, 18.2°±0.2°, 25.4°±0.2° and 26.1°±0.2°.

[0177] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the crystal form P is shown in the following table:

[0178] Table 16: X-ray powder diffraction data of Form P

[0179] In one embodiment, the X-ray powder diffraction of the crystalline form P expressed in 2θ angle has a pattern as shown in Figure 49.

[0180] In one embodiment, the crystalline form P has a TGA spectrum as shown in Figure 50.

[0181] In one embodiment, the crystalline form P has a DSC spectrum as shown in Figure 51.

[0182] In one embodiment of the present invention, a crystalline form Q of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 12.2±0.2°, 16.1°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 23.2°±0.2° and 28.7°±0.2°.

[0183] Preferably, the crystalline form Q has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 12.2±0.2°, 16.1°±0.2°, 18.1°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 23.2°±0.2° and 28.7°±0.2°.

[0184] More preferably, the crystalline form Q has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 12.2±0.2°, 14.9°±0.2°, 15.4°±0.2°, 16.1°±0.2°, 18.1°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 23.2°±0.2° and 28.7°±0.2°.

[0185] Further preferably, the crystalline form Q has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 12.2±0.2°, 14.9°±0.2°, 15.4°±0.2°, 16.1°±0.2°, 18.1°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 23.2°±0.2°, 25.1°±0.2°, 28.7°±0.2° and 31.5°±0.2°.

[0186] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the crystal form Q is shown in the following table:

[0187] Table 17: X-ray powder diffraction pattern data of Form Q

[0188] In one embodiment, the X-ray powder diffraction of the crystalline form Q expressed in 2θ angle has a pattern as shown in Figure 52.

[0189] In one embodiment, the crystalline Form Q has a TGA spectrum as shown in Figure 53.

[0190] In one embodiment, the crystalline Form Q has a DSC spectrum as shown in FIG54 .

[0191] In a preferred embodiment of the present invention, the crystalline form of the compound is a solvent-containing or solvent-free crystalline form, wherein the solvent is selected from one or more of water, methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, isobutanol, acetone, 2-butanone, 3-pentanone, dichloromethane, chloroform, ethyl formate, ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, n-heptane, heptane, isopropyl acetate, cyclohexane, methyl tert-butyl ether and isopropyl ether.

[0192] In a preferred embodiment of the present invention, the crystalline form of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is a solvent-containing or solvent-free crystalline form, and the solvent is selected from one or more of water, ethanol, acetone, n-heptane, dichloromethane, chloroform, 2-butanone, tetrahydrofuran and N,N-dimethylformamide.

[0193] In a preferred embodiment of the present invention, the crystalline form of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is a solvate, and the solvent is selected from one or more of water, ethanol, acetone, n-heptane, dichloromethane, chloroform and tetrahydrofuran.

[0194] In a further preferred embodiment of the present invention, the crystalline form of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is an anhydrous crystalline form.

[0195] On the other hand, the present invention also provides a method for preparing a crystalline form of the compound represented by Formula I, including but not limited to an antisolvent addition method, an anti-antisolvent addition method, a solvent volatilization method, a gas-solid diffusion method, a suspension stirring method, and a cooling crystallization method.

[0196] In one embodiment of the present invention, the method for preparing the crystalline form of the compound represented by Formula I comprises the following steps: weighing an appropriate amount of the free base of the compound, adding a corresponding positive solvent to dissolve it, filtering it, and adding a corresponding anti-solvent to the filtrate while stirring until a solid precipitates.

[0197] In one embodiment of the present invention, the method for preparing the crystalline form of the compound represented by Formula I comprises the following steps: weighing an appropriate amount of the free base of the compound, adding a corresponding positive solvent to dissolve it, filtering it, and cooling the supernatant until solid precipitates.

[0198] In one embodiment of the present invention, the method for preparing the crystalline form of the compound represented by Formula I comprises the following steps: weighing an appropriate amount of the free base of the compound, adding a corresponding positive solvent to dissolve it, and sealing until solid precipitates.

[0199] In one embodiment of the present invention, the method for preparing the crystalline form of the compound represented by Formula I comprises the following steps: weighing an appropriate amount of the free base of the compound, adding a corresponding positive solvent to dissolve, beating, drying, and collecting the solid.

[0200] In the present invention, the positive solvent includes one or more of water, methanol, ethanol, acetone, 2-butanone, ethyl acetate, tetrahydrofuran, acetonitrile, n-hexane, n-heptane, dichloromethane, chloroform, 1,4-dioxane, benzene, toluene, chlorobenzene, isopropyl alcohol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, ethyl formate, isopropyl acetate, tert-butanol, methyl isobutyl ketone and 3-pentanone; preferably one or more of water, methanol, ethanol, acetonitrile, n-hexane, n-heptane, dichloromethane, chloroform, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, acetone, 2-butanone, ethyl acetate, 1,4-dioxane, isopropyl alcohol, isopropyl acetate and methyl isobutyl ketone.

[0201] In the present invention, the anti-solvent includes one or more of methanol, ethanol, acetonitrile, ethyl acetate, acetone, isopropanol, tert-butanol, n-heptane, water, isopropyl acetate, n-hexane, cyclohexane, toluene, methyl tert-butyl ether and isopropyl ether; preferably one or more of methyl tert-butyl ether, n-heptane, isopropyl acetate, acetonitrile, isopropyl ether, n-hexane, water, tert-butanol, cyclohexane and toluene.

[0202] On the other hand, the present invention also provides a pharmaceutical composition containing a therapeutically effective amount of the crystalline form of the compound represented by Formula I.

[0203] On the other hand, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of the compound represented by Formula I and a pharmaceutically acceptable carrier.

[0204] The pharmaceutical composition of the present invention can be administered by any suitable route or method, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the aforementioned crystalline compound is from about 1 mg to 1 g / kg body weight / day.

[0205] For oral administration, the pharmaceutical compositions of the present invention are typically provided in the form of tablets, capsules, or solutions. Tablets may comprise a crystalline form of the compound of the present invention and a pharmaceutically acceptable carrier. The carrier includes, but is not limited to, a diluent, a disintegrant, a binder, and a lubricant.

[0206] For parenteral administration, the pharmaceutical composition of the present invention can be administered by intravenous injection, intramuscular injection or subcutaneous injection. It is usually provided in a sterile aqueous solution or suspension or lyophilized powder, and the appropriate pH and isotonicity are adjusted.

[0207] On the other hand, the present invention also provides the use of a crystalline form of the aforementioned compound or a pharmaceutical composition thereof in the preparation of a medicament for preventing and / or treating a disease or disease state mediated by MAT2A.

[0208] On the other hand, the present invention also provides a method for preventing and / or treating a disease or disease state mediated by MAT2A, comprising administering an effective amount of a crystalline form of the aforementioned compound or a pharmaceutical composition thereof to an individual in need thereof.

[0209] In another aspect, the present invention further provides a crystalline form of the aforementioned compound of the present invention or a pharmaceutical composition of the present invention for use in preventing and / or treating a disease or condition mediated by MAT2A. Examples of the MAT2A-mediated disease or condition include colorectal cancer, etc.

[0210] In some embodiments, the MAT2A-mediated disease is a disease mediated by MAT2A overexpression.

[0211] Related definitions

[0212] Unless otherwise specified, the following terms used in the specification and claims have the following meanings:

[0213] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring.

[0214] As used herein, numerical ranges refer to the individual integers within the given range. For example, "C1-C6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; "C3-C6" means that the group can have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0215] The term "membered" refers to the number of skeletal atoms or groups of atoms that make up the ring. For example, "5-7 membered" means that the number of skeletal atoms or groups of atoms that make up the ring is 5, 6, or 7. Thus, for example, pyridine, piperidine, piperazine, and benzene are six-membered rings, while thiophene and pyrrole are five-membered rings.

[0216] The term "substituted" means that any one or more hydrogen atoms on a specified group are replaced by a substituent, as long as the valence state of the specified group is normal and the compound after the substitution is stable. For example, "substituted with halogen" means that any one or more hydrogen atoms on a specified group are replaced by a halogen, as long as the valence state of the specified group is normal and the compound after the substitution is stable.

[0217] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched saturated hydrocarbon groups, having the indicated number of carbon atoms. For example, the term "C1-C6 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, or 3-hexyl.

[0218] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system with no heteroatoms and no double bonds. Examples of the term "3-6 membered cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0219] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0220] The term "aryl" refers to an all-carbon monocyclic or fused bicyclic aromatic ring group having a conjugated π-electron system, derived by removing a single hydrogen atom from a single carbon atom of a parent aromatic ring system. This includes bicyclic groups fused to saturated, partially unsaturated, or aromatic carbocyclic rings; examples include, but are not limited to, phenyl, naphthyl, anthracenyl, indene, indane, 1,2-dihydronaphthalene, or 1,2,3,4-tetrahydronaphthalene.

[0221] The term "heteroaryl" refers to a monovalent aromatic group containing at least one heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of "5-7 membered heteroaryl" include, but are not limited to, pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furyl, pyrazinyl or thiazolyl.

[0222] The term "9-18 membered benzoheterocyclyl" refers to a ring system having 9-18 ring atoms or ring atom groups formed by the fusion of a benzene ring and a heterocycle, wherein the benzene ring and the heterocycle share a pair of adjacent ring atoms, and the connection site with the parent core structure is located in the benzene ring portion. The heterocycle portion is a 5-12 membered saturated, partially unsaturated or fully unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms or heteroatoms, and the heteroatoms or heteroatoms are independently selected from nitrogen, sulfur, oxygen, sulfoxide, sulfone, Heterocycles can be monocyclic, bicyclic, or tricyclic ring systems, in which two or more rings are present in fused, spiro, or bridged forms. Examples include, but are not limited to,

[0223] in Refers to the chemical bond connection. When it appears in a bicyclic or polycyclic ring When the connection position is uncertain, it means that the connection site is limited to Any atom on the monocyclic ring where the valence permits. For example, It means that the connection sites are located only on any carbon atom of the benzene ring in the bicyclic ring and must meet the requirements of atomic valence bonds.

[0224] The "X-ray powder diffraction pattern" in the present invention is obtained by measuring using Cu-Kα radiation. It should be noted that in the X-ray powder diffraction spectrum (XRD), the diffraction spectrum obtained from the crystalline compound is often characteristic for a specific crystal, wherein the relative intensity of the bands (especially at low angles) may vary due to the dominant orientation effect caused by differences in crystallization conditions, particle size and other measurement conditions. Therefore, the relative intensity of the diffraction peak is not characteristic for the crystal targeted. When judging whether it is the same as a known crystal, more attention should be paid to the relative position of the peak rather than their relative intensity. In addition, for any given crystal, there may be slight errors in the position of the peak, which is also well known in the field of crystallography. For example, due to changes in temperature during sample analysis, sample movement, or instrument calibration, the position of the peak can move, and the measurement error of the 2θ value is sometimes about ±0.5 and sometimes about ±0.2°. Therefore, this error should be taken into account when determining each crystal structure. When the 2θ deviation of the key characteristic peak shift is around ±0.5, especially around ±0.2, they can all be identified as the same crystal form.

[0225] Differential Scanning Calorimetry (DSC) measures the transition temperatures of a crystal when heat is absorbed or released due to changes in its crystal structure or melting. For the same crystalline form of the same compound, the thermal transition temperatures and melting points typically agree within about 5°C, usually about 3°C, in consecutive analyses. When a compound is described as having a given DSC peak or melting point, this refers to the DSC peak or melting point ±5°C. DSC provides an auxiliary method for distinguishing between different crystalline forms. Different crystalline forms can be identified by their distinct transition temperature signatures. It should be noted that for mixtures, the DSC peak or melting point may fluctuate over a wider range. Furthermore, because decomposition occurs during melting, the melting temperature is related to the heating rate.

[0226] Thermogravimetric analysis (TGA) is a thermal analysis technique that measures the relationship between the mass of a sample and temperature changes under a controlled temperature. When the substance being tested sublimes or vaporizes during heating, releasing gases or losing water of crystallization, the mass of the substance changes. In this case, the thermogravimetric curve is not a straight line but rather shows a downward trend. By analyzing the thermogravimetric curve, we can determine the temperature at which the change occurs and, based on the weight loss, calculate the amount of mass lost.

[0227] The term "as shown" when referring to, for example, an XRD pattern, a DSC pattern, or a TGA pattern includes patterns that are not necessarily identical to those depicted herein, but that fall within the limits of experimental error when considered by one skilled in the art.

[0228] The term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or pharmaceutical agent to achieve the desired effect.

[0229] The term "pharmaceutically acceptable carrier" refers to any carrier that is non-irritating to the body and does not impair the biological activity and properties of the active compound. This includes, but is not limited to, any diluent, disintegrant, binder, glidant, or wetting agent approved by the State Food and Drug Administration for use in humans or animals.

[0230] The abbreviations used in the claims and description have the following meanings:

[0231] M:mol / L;

[0232] mM: mmol / L;

[0233] μM: μmol / L;

[0234] nM: nmol / L;

[0235] LCMS: liquid chromatography-mass spectrometry;

[0236] Brij35: lauryl polyoxyethylene ether;

[0237] BSA: bovine serum albumin;

[0238] DMSO: dimethyl sulfoxide;

[0239] rpm: revolutions per minute;

[0240] Tris-HCl: tris(hydroxymethyl)aminomethane hydrochloride;

[0241] OD 620 : Absorbance at 620nm wavelength;

[0242] SAM: S-adenosylmethionine or S-adenosylmethionine;

[0243] MeOH: methanol;

[0244] 1,4-Dioxane:1,4-dioxane;

[0245] EtOH: ethanol;

[0246] MIBK: methyl isobutyl ketone;

[0247] IPA: isopropyl alcohol;

[0248] EtOAc: ethyl acetate;

[0249] IPAc: isopropyl acetate;

[0250] ACN: acetonitrile;

[0251] DMF: N,N-dimethylformamide;

[0252] DCM: dichloromethane;

[0253] DMAc: N,N-dimethylacetamide;

[0254] CHCl3: chloroform;

[0255] Acetone: acetone;

[0256] MEK: 2-butanone;

[0257] MTBE: methyl tert-butyl ether;

[0258] THF: tetrahydrofuran. BRIEF DESCRIPTION OF THE DRAWINGS

[0259] Figure 1 shows the HCT116MTAP in test case 3. - / - Tumor inhibition curve of transplanted tumor model.

[0260] Figure 2 shows the HCT116MTAP in test case 3. - / - Results of intratumoral SAM inhibition in the transplanted tumor model.

[0261] FIG3 is the tumor inhibition curve of the KP-4 transplanted tumor model in Test Example 4.

[0262] FIG4 shows the results of intratumoral SAM inhibition in the KP-4 transplanted tumor model in Test Example 4.

[0263] Figure 5 is an X-ray powder diffraction pattern of Form A of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0264] Figure 6 is a TGA spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form A.

[0265] Figure 7 is the DSC spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form A.

[0266] Figure 8 is an X-ray powder diffraction pattern of Form B of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0267] Figure 9 is a TGA spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form B.

[0268] Figure 10 is the DSC spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form B.

[0269] Figure 11 is an X-ray powder diffraction pattern of Form C of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0270] Figure 12 is a TGA spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one crystal form C.

[0271] Figure 13 is the DSC spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form C.

[0272] Figure 14 is an X-ray powder diffraction pattern of Form D of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0273] Figure 15 is a TGA spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one crystal form D.

[0274] Figure 16 is a DSC spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one crystal form D.

[0275] Figure 17 is a schematic diagram of the molecular stacking structure (along the a-axis direction) in the single crystal structure of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form D.

[0276] Figure 18 is an X-ray powder diffraction pattern of Form E of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0277] Figure 19 is a TGA spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one crystal form E.

[0278] Figure 20 is an X-ray powder diffraction pattern of Form F of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0279] Figure 21 is a TGA spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form F.

[0280] Figure 22 is the DSC spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form F.

[0281] Figure 23 shows the crystal form F of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one 1 H NMR spectrum.

[0282] Figure 24 is an X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form G.

[0283] Figure 25 is a TGA spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form G.

[0284] Figure 26 is a DSC spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form G.

[0285] Figure 27 is an X-ray powder diffraction pattern of Form H of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0286] Figure 28 is a TGA spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form H.

[0287] Figure 29 is a DSC spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form H.

[0288] Figure 30 is an X-ray powder diffraction pattern of Form I of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0289] Figure 31 is the TGA spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form I.

[0290] Figure 32 is the DSC spectrum of Form I of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0291] Figure 33 is an X-ray powder diffraction pattern of Form J of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0292] Figure 34 is a TGA spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form J.

[0293] Figure 35 is a DSC spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form J.

[0294] Figure 36 is an X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form K.

[0295] Figure 37 is an X-ray powder diffraction pattern of Form L of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0296] Figure 38 is a TGA spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form L.

[0297] Figure 39 is a DSC spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form L.

[0298] Figure 40 is an X-ray powder diffraction pattern of Form M of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0299] Figure 41 is a TGA spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form M.

[0300] Figure 42 is the DSC spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form M.

[0301] Figure 43 is an X-ray powder diffraction pattern of Form N of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0302] Figure 44 is a TGA spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form N.

[0303] Figure 45 is a DSC spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form N.

[0304] Figure 46 is an X-ray powder diffraction pattern of Form O of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0305] Figure 47 is a TGA spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form O.

[0306] Figure 48 is the DSC spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form O.

[0307] Figure 49 is an X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form P.

[0308] Figure 50 is a TGA spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one crystal form P.

[0309] Figure 51 is the DSC spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one crystal form P.

[0310] Figure 52 is an X-ray powder diffraction pattern of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form Q.

[0311] Figure 53 is the TGA spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form Q.

[0312] Figure 54 is the DSC spectrum of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one Form Q. DETAILED DESCRIPTION

[0313] The preparation method of compound of the present invention is described in more detail below, but these specific preparation methods do not constitute any restriction to the scope of the present invention.In addition, reaction conditions such as the amount of reactant, solvent, alkali, compound used, reaction temperature, reaction times etc. are not limited to the following example.

[0314] The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such a combination can be easily performed by those skilled in the art.

[0315] Example 1: 2-cyclopropyl-7,9-bis[4-(difluoromethoxy)phenyl]-8H-pyrimido[1,2-b]pyridazin-8-one

[0316] a) Preparation of N-(5-methoxypyridazin-3-yl)acetamide

[0317] To the reaction flask were added 3-chloro-5-methoxypyridazine (1 g), acetamide (0.61 g), trisdibenzylideneacetone dipalladium (0.32 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.40 g), and cesium carbonate (6.76 g) in sequence, followed by 1,4-dioxane (100 mL). The mixture was stirred at 100° C. for 3 hours under nitrogen protection and concentrated under reduced pressure to obtain the residue, which was evaporated to dryness. The residue was extracted with ethyl acetate (3×50 mL), and the combined organic phases were washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound (780 mg) was obtained.

[0318] LCMS m / z=168.05[M+1] +

[0319] b) Preparation of 6-aminopyridazin-4(1H)-one

[0320] N-(5-methoxypyridazin-3-yl)acetamide (500 mg) and aqueous hydrogen bromide solution (15 mL) were added to a microwave tube, stirred at 140°C for 5 hours under microwave irradiation, and concentrated under reduced pressure to obtain 360 mg of the title compound.

[0321] LCMS m / z=111.95[M+1] +

[0322] c) Preparation of 6-amino-3,5-dibromopyridazin-4(1H)-one

[0323] To the reaction flask, 6-aminopyridazin-4(1H)-one (360 mg) and N-bromosuccinimide (1.73 g) were added, and the mixture was stirred at room temperature for 2 hours in N,N-dimethylformamide (4 mL). The residue was concentrated and evaporated to dryness under reduced pressure, and washed with acetonitrile (3 x 5 mL) to obtain 360 mg of the title compound.

[0324] d) Preparation of 6-amino-3,5-dibromo-1-[(1E)-3-cyclopropyl-3-oxoprop-1-en-1-yl]pyridazin-4(1H)-one

[0325] To a reaction flask, 6-amino-3,5-dibromopyridazin-4(1H)-one (430 mg), (2E)-3-chloro-1-cyclopropylprop-2-en-1-one (167.0 mg) and potassium carbonate (663.0 mg) were added and stirred at 25°C overnight in N,N-dimethylformamide (43 mL). The mixture was concentrated under reduced pressure to obtain a mixture. The pH of the mixture was adjusted to 2-3 with 1 M hydrochloric acid, and the mixture was washed with water (3 x 10 mL) to obtain 335 mg of the title compound.

[0326] e) Preparation of 7,9-dibromo-2-cyclopropyl-8H-pyrimido[1,2-b]pyridazin-8-one

[0327] To the reaction flask was added 6-amino-3,5-dibromo-1-[(1E)-3-cyclopropyl-3-oxoprop-1-en-1-yl]pyridazin-4(1H)-one (355 mg) and a 2 mol / L solution of hydrogen chloride in 1,4-dioxane (10 mL). The mixture was stirred at 25°C for 1 h. The resulting residue was concentrated under reduced pressure and evaporated to dryness. The residue was washed with aqueous sodium bicarbonate solution (1 x 10 mL). The filter cake was collected by filtration and washed with water (3 x 5 mL) to give 320 mg of the title compound.

[0328] f) Preparation of 2-cyclopropyl-7,9-bis[4-(difluoromethoxy)phenyl]-8H-pyrimido[1,2-b]pyridazin-8-one

[0329] To the reaction flask were added 7,9-dibromo-2-cyclopropyl-8H-pyrimido[1,2-b]pyridazin-8-one (60 mg), 4-(difluoromethoxy)phenylboronic acid (98.1 mg), water (0.4 mL), 1,4-dioxane (2 mL), potassium phosphate (184.6 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (14.17 mg). Under nitrogen protection, the mixture was stirred at 80°C for 1 hour, and the mixture was concentrated under reduced pressure to dryness. The title compound (37 mg) was obtained by preparative separation. Preparation and separation conditions: Chromatographic column: XBridge PrepOBD C18 column, 30*150 mm, 5 μm; column temperature: 25°C; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 45% B to 85% B from 0 to 10 min, and elution at 85% B after 10 min; detection wavelength: UV 220 nm; retention time (min): 7.32.

[0330] 1 H NMR(400MHz, DMSO-d6)δ8.72(d,J=7.2Hz,1H),8.27-8.21(m,2H),7.64-7.58(m,2H),7.56-7.26(m,3H),7.2 1-7.11(m,3H),7.07(d,J=7.2Hz,1H),2.20(tt,J=8.1,4.5Hz,1H),1.18-1.10(m,2H),1.01(p,J=3.8Hz,2H).

[0331] LCMS m / z=472[M+H] +

[0332] Example 2: 7,9-bis(benzo[d][1,3]dioxol-5-yl)-2-cyclopropyl-8H-pyrimido[1,2-b]pyridazin-8-one

[0333] Prepared by referring to the preparation method of Example 1, replacing 4-(difluoromethoxy)phenylboronic acid in step f) with benzo[d][1,3]dioxol-5-ylboronic acid ( ) can be used.

[0334] 1H NMR (400MHz, DMSO-d6) δ8.69(d,J=7.2Hz,1H),7.88(dd,J=8.3,1.7Hz,1H),7.76(d,J=1.7Hz,1H),7.09-6.99(m,4H),6.93( d,J=8.0Hz,1H),6.11(s,2H),6.04(s,2H),2.18(td,J=8.0,4.1Hz,1H),1.12(dt,J=6.7,3.4Hz,2H),1.01(t,J=3.8Hz,2H).

[0335] LCMS m / z=428[M+1] +

[0336] Example 3: 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one

[0337] a) Preparation of 9-bromo-2-cyclopropyl-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one

[0338] To the reaction flask were added 7,9-dibromo-2-cyclopropyl-8H-pyrimido[1,2-b]pyridazin-8-one (50 mg), 2-methylindazol-5-ylboronic acid (28.06 mg), potassium carbonate (60.09 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (11.81 mg), 1,4-dioxane (0.5 mL), and water (0.1 mL) in sequence. Under nitrogen protection, the mixture was stirred at 60°C for 1 h. The reactants were concentrated under reduced pressure and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 4 / 1 (V / V)) to give 40 mg of the title compound.

[0339] 1 H NMR (400MHz, DMSO) δ8.98(s,1H),8.81(d,J=7.1Hz,1H),8.54(s,1H),7.95(d,J=8.9Hz,1H) ,7.66(d,J=9.1Hz,1H),7.14(d,J=7.1Hz,1H),4.20(s,3H),2.34(s,1H),1.46-1.10(m,4H).

[0340] LCMS m / z=396[M+1] +

[0341] b) Preparation of 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one

[0342] To the reaction flask were added 9-bromo-2-cyclopropyl-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one (35 mg), 4-(difluoromethoxy)phenylboronic acid (24.90 mg), potassium carbonate (36.62 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (7.20 mg), 1,4-dioxane (1 mL), and water (0.2 mL) in sequence. Under nitrogen protection, the mixture was stirred at 80°C for 1 h. The reactants were concentrated under reduced pressure to obtain 14.4 mg of the title compound. Preparation and separation conditions: Chromatographic column: XBridge PrepOBD C18 column, 30*150 mm, 5 μm; column temperature: 25°C; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 25% B to 70% B at 0 to 10 min, and 85% B after 10 min; detection wavelength: UV 220 nm; retention time (min): 6.8.

[0343] 1 H NMR (400MHz, DMSO-d6)8.97(s,1H),8.76(d,J=7.2Hz,1H),8.52(s,1H),7.97(dd,J=9.2,1.6Hz,1H),7.68-7.59(m,3H),7.31(t,J=74.4Hz,1H ),7.22-7.16(m,2H),7.06(d,J=7.2Hz,1H),4.20(s,3H),2.19(dq,J=8.1,4.6,4.0Hz,1H),1.13(dd,J=7.8,3.5Hz,2H),1.02(t,J=3.8Hz,2H).

[0344] LCMS m / z=460[M+1] +

[0345] Test Example 1: Biological Activity Test

[0346] 1. MAT2A Enzyme Test Method

[0347] 1. Experimental Procedure

[0348] a) First, prepare 5× MAT2A assay buffer (250 mM Tris-HCl, pH 8.0; 250 mM KCl; 75 mM MgCl2; 0.025% BSA; 0.05% Brij35; 1.5 mM EDTA) and partially dilute to 1× for later use;

[0349] b) Preparation and addition of MAT2A enzyme (BPS, 71401): MAT2A enzyme was prepared to 3.674 ng / μL (1.67×, final concentration 2.20 ng / μL) in 1× MAT2A assay buffer. Using a BioTek (MultiFlo FX) automated dispenser, 15 μL of 1.67× MAT2A enzyme solution was added to each of the compound test wells and negative control wells. Simultaneously, 15 μL of 1× MAT2A assay buffer was added to the blank control well.

[0350] c) Compound Preparation and Addition: Dilute the test compound from a 10 mM stock solution to 100 μM using DMSO. Dilute the positive drug AGI-24512 under the same conditions. Use a Tecan compound titrator (D300e) to automatically dispense the compound into each well according to a pre-set concentration gradient. Negligible amounts of the injected volume should be considered. The concentration gradient starts at 1 μM and is divided into 1 / 2 log dilutions, with a total of eight steps. Centrifuge at 2500 rpm for 30 seconds and incubate at 25°C for 30 minutes.

[0351] d) ATP preparation: dilute 10 mM ATP (Sigma, A7699) to 700 μM using 1× MAT2A assay buffer;

[0352] e) Preparation and addition of substrate and ATP mixture: 5× MAT2A assay buffer, 3 μL / well; 750 μM L-methionine (Adamas, 01100469), 2.5 μL / well; 700 μM ATP, 2.5 μL / well; double-distilled water, 2 μL / well. Prepare the required total volume of mixture based on the number of wells tested. Add 10 μL to each well using a BioTek (MultiFlo FX) automated dispenser. Centrifuge at 2500 rpm for 30 seconds and incubate at 25°C for 150 minutes.

[0353] f) Addition of Biomol Green detection reagent: 50 μL of Biomol Green (Enzo, BML-AK111) was added to each well using a BioTek (MultiFlo FX) automated dispenser. The cells were centrifuged at 2500 rpm for 30 seconds and incubated at 25°C for 20 minutes.

[0354] g) After the reaction, the OD was read using a Perkin Elmer (Envision 2105) multi-function plate reader. 620 value.

[0355] 2. Data Analysis

[0356] The inhibition rate calculation formula is as follows:

[0357] in,

[0358] OD sample: OD of the sample well 620 value;

[0359] ODmin: represents the OD of the blank control well without enzyme or test compound 620 mean;

[0360] ODmax: represents the OD of the negative control well with enzyme and no compound 620 Mean.

[0361] GraphPad Prism 5 software was then used to fit the dose-effect curve using log(inhibitor) vs. response-Variable slope to obtain the IC of the compound for MAT2A enzyme inhibition. 50 value.

[0362] 2. Cell Testing Methods

[0363] 1. Experimental Procedure

[0364] HCT116MTAP- / - cells (purchased from Horizon Discovery): A human colorectal cancer cell line lacking the MTAP gene, cultured in RPMI 1640 medium supplemented with 10% FBS (fetal bovine serum). On day 0, cells in logarithmic growth phase were plated at a viable cell density of 5,000 cells / ml and seeded into 96-well plates at 100 μl / well. A blank control was also established. The plate was incubated overnight at 37°C in a 5% CO2 incubator.

[0365] On day 1 of the experiment, the cell plates were removed from the overnight cultures, the supernatant discarded, and 80 μl of serum-free RPMI 1640 medium was added to each well. The cells were then starved for 4 hours in an incubator. The test compound was dissolved in DMSO (dimethyl sulfoxide) to prepare a 10 mM stock solution. After the starvation period, the cell plates were removed and 80 μl of RPMI 1640 + 20% FBS medium was added to each well. The cell plates were then placed in a D300e automated dosing system (Tecan). The dosing program was set as follows: the highest test compound concentration was 30 μM, and a three-fold serial dilution was performed with DMSO for a total of 10 concentrations, with two replicates per well. The final DMSO concentration in each well of the 96-well plate was 0.3% (v / v). The pre-prepared 10 mM stock solution of the test compound was removed and the dosing protocol described above was repeated. After the dosing period, the cell plates were incubated in an incubator for 120 hours.

[0366] On the 6th day of the experiment, the cell plates were removed and 50 μl CellTiter- (purchased from Promega), and the fluorescence signal was measured on Envision (PerkinElmer) according to the operating procedures of the instruction manual.

[0367] 2. Data Analysis

[0368] GraphPad Prism 5 software was used to fit the dose-effect curve: log (inhibitor) vs. response-Variable slope to obtain the IC value of the compound for cell proliferation inhibition. 50 The inhibition rate calculation formula is:

[0369] in:

[0370] Test substance signal value: mean fluorescence signal of cell+medium+compound group;

[0371] Blank group signal value: mean fluorescence signal of culture medium group;

[0372] Signal value of negative control group: mean fluorescence signal of cells+medium group.

[0373] 3. Experimental results:

[0374] According to the above experimental method, the IC50 of AGI-24512 in inhibiting MAT2A was 26.79 nM.

[0375] AGI-24512 structure:

[0376] The experimental results of the compounds of the present invention are shown in Table 18 below:

[0377] Table 18

[0378] Test Example 2: In vivo pharmacokinetic study in ICR mice

[0379] 1. Experimental Procedure

[0380] Male ICR mice (6-10 weeks old, Weitong Lihua Laboratory Animal Technology Co., Ltd.) were housed in a SPF animal room at a temperature of 20-25°C, a relative humidity of 40%-70%, and a 12-hour light and dark cycle. The animals had free access to water and food. After at least 5 days of normal feeding and good physical condition after veterinary examination, mice were enrolled in this experiment. Each mouse was numbered at the tail.

[0381] The day before the experiment, mice were fasted overnight with free access to water. Four hours after dosing, the compounds were prepared into 20 mg / ml stock solutions in DMSO. An appropriate volume of the 20 mg / ml stock solution was accurately pipetted into a glass vial. An appropriate volume of PEG400 was added, mixed, and then propylene glycol (PG) was added. The final formulation had a solvent ratio of DMSO:PEG400:PG (v / v / v) of 5:65:30, resulting in a dosing solution of each test compound at a concentration of 1 mg / ml.

[0382] After weighing the mice, calculate the theoretical dosing volume for each mouse using the following formula. The actual dosing volume for each mouse and the time of blood sample collection should be recorded in detail in the corresponding table.

[0383] On the day of the experiment, mice in each group were gavage-administered with a 10 mg / kg dose of the test compound. At various time points after dosing, approximately 40 μL of blood was collected from the mice via orbital orbital examination and placed in EDTA-K2 anticoagulant tubes. Whole blood samples were centrifuged at 1500–1600 g for 10 minutes, and the resulting plasma was stored at -40–-20°C for biological sample analysis.

[0384] 2. Data Analysis

[0385] The concentrations of the compounds in the biological samples were determined by LC-MS / MS analysis, and the pharmacokinetic parameters were calculated using a non-compartmental model in Pharsight Phoenix 7.0.

[0386] 3. Experimental Results

[0387] The pharmacokinetic parameter calculation results are shown in Table 19 below.

[0388] Table 19

[0389] Test Example 3: HCT116 MTAP - / - In vivo drug efficacy experiment on subcutaneous xenograft tumors in nude mice

[0390] 1. Experimental Procedure

[0391] Female Nu / Nu nude mice (6-8 weeks old, Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.) were housed in an SPF animal room at a temperature of 20-25°C, a relative humidity of 40%-70%, and a 12-h light and dark cycle. The animals had free access to water and food. Animals were acclimated to the environment before the experiment.

[0392] HCT116MTAP - / - Cells (Horizon) were cultured and expanded in vitro. Cells in the logarithmic growth phase were collected and resuspended in serum-free RPMI-1640 medium. The cell concentration was adjusted to 6.0×10 7 cells / mL; use a 1mL syringe to inject the cell suspension into the subcutaneous tissue of the right axilla of nude mice, inject 100μL into each animal, and observe the animal status and monitor the growth of the transplanted tumor regularly.

[0393] When the tumor volume reaches 100-300 mm 3 Animals with tumors that were excessively large, too small, or uncertain in size were eliminated. Tumor-bearing mice in good health with tumors of similar size were selected and grouped using a randomized block method. The treatment group received daily oral administration (AG-270: 50 mg / kg, structure shown below; test compound: 5 mg / kg), while the control group received the same volume of blank vehicle daily. Tumor diameters were measured twice weekly during the treatment period, and tumor volumes were calculated. Animal weights were also recorded.

[0394] SAM detection in transplanted tumors: At the end of the experiment, animals were euthanized using CO2. Tumor tissue was removed, washed with cold PBS, weighed, snap-frozen in liquid nitrogen, and stored at -80°C until use. The frozen tumor tissue was removed, thawed in an ice bath, and then homogenized with 80% methanol-water solution (containing 1 M formic acid) at a ratio of 1:10 (w / v). The homogenate was collected and processed for SAM (S-adenosylmethionine) analysis using LC-MS / MS.

[0395] AG-270 structure:

[0396] 2. Data Analysis

[0397] The calculation formula for tumor volume (TV) is: TV = 1 / 2 × a × b 2 ; Where a represents the long diameter of the tumor and b represents the short diameter of the tumor.

[0398] The formula for calculating relative tumor volume (RTV) is: RTV = TV t / TV initial Among them, TV initial is the tumor volume measured when the group was administered, TV t The tumor volume was measured at each time during the drug administration period.

[0399] The calculation formula of relative tumor proliferation rate (T / C (%)) is: T / C% = (RTV T / RTV C )×100%; among which, RTV T Relative tumor volume of the treatment group, RTV C Relative tumor volume to that of the vehicle control group is shown.

[0400] The calculation formula of tumor growth inhibition (TGI (%)) is: TGI = [1-(TV t(T) -TV initial(T) ) / (TV t(C) -TV initial(C) )]×100%; among them, TV t(T) Indicates the tumor volume of each treatment group, TV initial(T) Indicates the tumor volume of the treatment group at the time of drug administration, TV t(C) represents the tumor volume of the solvent control group at each measurement, TV initial(C) It represents the tumor volume of the solvent control group at the time of group administration.

[0401] The formula for calculating the animal weight loss rate is: Animal weight loss rate = 100% × (BW initial -BW t ) / BW initial Among them, BW t Indicates the animal body weight measured each time during the dosing period, BW initial Indicates the body weight of animals at the time of grouping and dosing.

[0402] The calculation formula of tumor weight inhibition rate IR (%) is: IR = 100% × (W C -W T ) / W C Among them, W C represents the tumor weight of the control group, W T Indicates tumor weight in treatment group.

[0403] The experimental data were calculated and statistically processed using Microsoft Office Excel 2007. Unless otherwise specified, the data were expressed as mean ± standard error (mean ± SE), and the t-test was used for comparison between the two groups.

[0404] 3. Experimental Results

[0405] HCT116 MTAP - / - The tumor inhibition curve of the transplanted tumor model and the results of intratumoral SAM inhibition are shown in Figures 1 and 2, respectively.

[0406] Test Example 4: In vivo efficacy experiment on KP-4 subcutaneous xenograft tumors in mice

[0407] 1. Experimental Procedure

[0408] Female NOD SCID mice (6-8 weeks old, Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.) were housed in a SPF animal room at a temperature of 20-25°C, a relative humidity of 40%-70%, and a 12-hour light and dark cycle. The animals had free access to water and food. Animals were acclimated to the feeding regimen before the experiment.

[0409] KP-4 cells (Nanjing Kebai Biotechnology Co., Ltd.) were cultured and expanded in vitro. Cells in the logarithmic growth phase were collected and resuspended in serum-free RPMI-1640 medium. The cell concentration was adjusted to 1.0 × 10 8 cells / mL; use a 1mL syringe to inject the cell suspension into the subcutaneous tissue of the right axilla of nude mice, inject 100μL into each animal, and observe the animal status and monitor the growth of the transplanted tumor regularly.

[0410] When the tumor volume reaches 80-100 mm 3 Animals with tumors that were excessively large, small, or of uncertain size were eliminated. Tumor-bearing mice in good health with tumors of similar size were selected and grouped using a randomized block method. The treatment group received daily oral administration (AG-270: 100 mg / kg, test compound: 2.5 mg / kg), while the control group received the same volume of blank vehicle daily. Tumor diameters were measured twice weekly during the treatment period, and tumor volumes were calculated. Animal weights were also recorded.

[0411] SAM detection in transplanted tumors: At the end of the experiment, animals were euthanized using CO2. Tumor tissue was removed, washed with cold PBS, weighed, snap-frozen in liquid nitrogen, and stored at -80°C until use. The frozen tumor tissue was removed, thawed in an ice bath, and then homogenized with 80% methanol-water solution (containing 1 M formic acid) at a ratio of 1:10 (w / v). The homogenate was collected and processed for SAM (S-adenosylmethionine) analysis using LC-MS / MS.

[0412] 2. Data Analysis

[0413] The calculation formula for tumor volume (TV) is: TV = 1 / 2 × a × b 2 ; Where a represents the long diameter of the tumor and b represents the short diameter of the tumor.

[0414] The formula for calculating relative tumor volume (RTV) is: RTV = TV t / TV initial ; Among them, TV initial is the tumor volume measured when the group was administered, TV t The tumor volume was measured at each time during the drug administration period.

[0415] The calculation formula of relative tumor proliferation rate (T / C (%)) is: T / C% = (RTV T / RTV C )×100%; among which, RTV T Relative tumor volume of the treatment group, RTV C Relative tumor volume to that of the vehicle control group is shown.

[0416] The calculation formula of tumor growth inhibition (TGI (%)) is: TGI = [1-(TV t(T) -TV initial(T) ) / (TV t(C) -TV initial(C) )]×100%; among them, TV t(T) Indicates the tumor volume of each treatment group, TV initial(T) Indicates the tumor volume of the treatment group at the time of drug administration, TV t(C) represents the tumor volume of the solvent control group at each measurement, TV initial(C) It represents the tumor volume of the solvent control group at the time of group administration.

[0417] The formula for calculating the animal weight loss rate is: Animal weight loss rate = 100% × (BWinitial -BW t ) / BW initial Among them, BW t Indicates the animal body weight measured each time during the dosing period, BW initial Indicates the body weight of animals at the time of grouping and dosing.

[0418] The calculation formula of tumor weight inhibition rate IR (%) is: IR = 100% × (W C -W T ) / W C Among them, W C represents the tumor weight of the control group, W T Indicates tumor weight in treatment group.

[0419] The experimental data were calculated and statistically processed using Microsoft Office Excel 2007. Unless otherwise specified, the data were expressed as mean ± standard error (mean ± SE), and the t-test was used for comparison between the two groups.

[0420] 3. Experimental Results

[0421] The tumor inhibition curve of the KP-4 transplanted tumor model and the intratumoral SAM inhibition results are shown in Figures 3 and 4, respectively.

[0422] Test Example 5: Polymorph Study

[0423] The preparation and characterization of the following specific crystal forms do not limit the scope of protection of the present invention. A person skilled in the art can obtain more crystals of the compound of the present invention based on the present invention, and these crystals are all solutions protected by the present invention. The details are as follows:

[0424] 1. Instrument test information

[0425] Table 20: X-ray powder diffractometer parameters

[0426] Table 21: TGA and DSC instrument test parameters

[0427] Table 22: DVS instrument test parameters

[0428] 2. Preparation of Buffer

[0429] 2.1 pH 1.0 hydrochloric acid solution: Take 9.00mL of the specified amount of hydrochloric acid, dilute it to 1000mL with water, and shake well.

[0430] 2.2 Phosphate buffer:

[0431] 0.2 mol / L potassium dihydrogen phosphate solution: Take 27.22 g of potassium dihydrogen phosphate, dissolve it in water and dilute to 1000 mL.

[0432] 0.2 mol / L sodium hydroxide solution: Take 8.00 g of sodium hydroxide, dissolve it in water and dilute to 1000 mL.

[0433] Take 250mL of 0.2mol / L potassium dihydrogen phosphate solution and mix it with the amount of 0.2mol / L sodium hydroxide solution specified in the table below, then add water to dilute to 1000mL and shake well to obtain the product.

[0434] Table 23: Phosphate Buffer

[0435] 3. Preparation of Crystalline Forms

[0436] Preparation of crystalline forms A to Q of 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one.

[0437] 3.1 Preparation of Form A

[0438] To the reaction flask were added 9-bromo-2-cyclopropyl-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one (3.8 g), 4-(difluoromethoxy)phenylboronic acid (3.6 g), potassium carbonate (3.98 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.78 g), 1,4-dioxane (40 mL), and water (8 mL). Under nitrogen protection, the reaction was stirred at 80°C for 2 hours. The reactants were concentrated under reduced pressure and purified by column chromatography (DCM:EA=0% to 100%) to give a crude product (1.5 g). The crude product was slurried with DMF / MeCN (5 mL:5 mL) and filtered. The filter cake was washed twice with MeCN (1 mL) and dried in vacuo at 70°C to give Form A (535.1 mg). After testing and analysis, the XRD results are shown in Figure 5; the TGA results are shown in Figure 6, showing no significant weight loss when the sample was heated to 120°C; and the DSC results are shown in Figure 7, showing a sharp endothermic peak at 262.42°C (onset temperature). Comprehensive characterization results indicate that Form A is an anhydrous crystalline form.

[0439] 3.2 Preparation of Form B

[0440] A 20 mg sample of Form G was slurried in 0.6 mL of methanol (or ethyl acetate) at room temperature for 3 days, dried under vacuum at 50°C for 4 hours, and collected to yield Form B. Analysis and testing revealed XRD results, as shown in Figure 8; TGA results, as shown in Figure 9, showed no significant weight loss upon heating to 150°C; and DSC results, as shown in Figure 10, revealed two endothermic peaks at 219.76°C and 266.19°C (onset temperature). Comprehensive characterization results indicated that Form B was an anhydrous crystalline form.

[0441] 3.3 Preparation of Form C

[0442] 10 mg of Form A was slurried in 0.5 mL of acetone / water (3:1, v:v) at room temperature for 3 days, dried under vacuum at 50°C for 4 hours, and collected to yield Form C. Analysis and testing revealed XRD results, as shown in Figure 11; TGA results, as shown in Figure 12, showed no significant weight loss upon heating to 150°C; and DSC results, as shown in Figure 13, revealed an endothermic peak at 265.61°C (onset temperature). Comprehensive characterization results indicated that Form C was an anhydrous crystalline form.

[0443] 3.4 Preparation of Form D

[0444] 3.1 mg of Form G sample was dissolved in 2.0 mL of acetone / n-heptane (4:1, v:v), filtered, and the filtrate sealed with parafilm and punctured with a few holes. The filtrate was slowly evaporated at room temperature for two days to obtain flaky crystals, Form D. Analysis and testing revealed XRD results (Figure 14) and TGA results (Figure 15), which showed a 1.99% weight loss upon heating to 180°C. DSC results (Figure 16) revealed three endothermic peaks at 108.57°C (onset temperature), 255.80°C (peak temperature), and 264.94°C (onset temperature). The single crystal structure stacking diagram is shown in Figure 17. Based on the solid-state characterization results and the single crystal structure stacking diagram, Form D is a pipe solvate.

[0445] 3.5 Preparation of Form E

[0446] 10 mg of Form C was used as the starting material, and 2.0 equivalents of sulfuric acid (2.42 μL of concentrated sulfuric acid) were slurried in 0.5 mL of ethanol (or a solvent such as 2-butanone / chloroform) at room temperature overnight. The mixture was then vacuum dried at room temperature for 4 hours, and the product was collected to obtain Form E. The XRD results are shown in Figure 18, and the TGA results are shown in Figure 19. Upon heating to 100°C, the product showed a weight loss of 10.77%.

[0447] 3.6 Preparation of Form F

[0448] 20 mg of the free base Form B was slurried in 0.5 mL of chloroform at room temperature for 3 days, dried under vacuum at 40°C for 3.5 hours, and collected to obtain Form F. Analysis and testing revealed XRD results, as shown in Figure 20 , and TGA results, as shown in Figure 21 , showing a 1.16% weight loss upon heating to 150°C. DSC results, as shown in Figure 22 , revealed an endothermic peak at 264.29°C (onset temperature). 1 The H NMR results are shown in Figure 23. The molar ratio of the residual solvent (chloroform) to the compound was 0.04:1. Comprehensive characterization results showed that Form F was an anhydrous crystalline form.

[0449] 3.7 Preparation of Form G

[0450] 9-Bromo-2-cyclopropyl-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one (24 g), 4-(difluoromethoxy)phenylboronic acid (19.17 g), potassium carbonate (24.96 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (4.32 g), 1,4-dioxane (480 mL), and water (96 mL) were added to the reaction flask. Under nitrogen protection, the reaction was stirred at 72°C for 2 hours. The reactants were concentrated under reduced pressure at 50°C to obtain a black solid. 400 mL of water was added and stirred for 40 minutes. The mixture was filtered to obtain a black filter cake. The filter cake was mixed with 400 mL of anhydrous ethanol, heated to 72°C, and filtered while hot to obtain a filter cake. The filter cake was mixed with 450 mL of ethanol. The mixture was stirred with DMSO for 40 minutes, filtered, and the filtrate collected. 300 mL of water was added to the filtrate, filtered, and the filter cake collected. The filter cake was mixed with 150 mL of DMSO, heated to 82°C, stirred at this temperature for 50 minutes, cooled to room temperature, filtered, and the filter cake collected. The filter cake was mixed with 300 mL of anhydrous ethanol, stirred at room temperature for 1 hour, and filtered to collect the product. Analysis and testing revealed XRD results as shown in Figure 24; TGA results as shown in Figure 25, showing a weight loss of 0.71% upon heating to 150°C; and DSC results as shown in Figure 26. Comprehensive characterization results indicated that Form G was an anhydrous crystalline form.

[0451] 3.8 Preparation of Form H

[0452] 20 mg of the free base Form G was dissolved in 0.6 mL of DMSO and filtered. 4.0 mL of tert-butanol was added dropwise to the filtrate with stirring, causing solid precipitation. Stirring was continued at room temperature for approximately 2 hours, followed by filtration and vacuum drying at 50°C for 3.5 hours. The product was collected to obtain Form H. Analysis and testing revealed XRD results, as shown in Figure 27. TGA results, as shown in Figure 28, showed no significant weight loss upon heating to 150°C. DSC results, as shown in Figure 29, revealed two endothermic peaks at 224.39°C and 265.40°C (onset temperature). Comprehensive characterization results indicated that Form H was an anhydrous crystalline form.

[0453] 3.9 Preparation of Form I

[0454] 20 mg of the free base Form G was dissolved in 1.4 mL of tetrahydrofuran and filtered. 4.0 mL of acetonitrile was added dropwise to the filtrate with stirring, causing solid precipitation. Stirring was continued at room temperature for approximately 1 hour, followed by filtration to obtain the product, Form I. Analysis and testing revealed XRD results, as shown in Figure 30; TGA results, as shown in Figure 31, showed an 11.83% weight loss upon heating to 120°C; and DSC results, as shown in Figure 32, revealed three endothermic peaks at 77.29°C, 115.04°C, and 264.34°C (onset temperature). Comprehensive characterization results indicated that Form I was a solvate.

[0455] 3.10 Preparation of Form J

[0456] 20 mg of free base Form G was dissolved in 2.0 mL of acetone at 50°C with stirring for approximately 2 hours, followed by hot filtration. The supernatant was cooled from 50°C to 5°C at a rate of 0.1°C / min to precipitate a solid, yielding Form J. Analysis and testing revealed XRD results, as shown in Figure 33, and TGA results, as shown in Figure 34, showing a 7.70% weight loss upon heating to 120°C. DSC results, as shown in Figure 35, revealed three endothermic peaks at 95.17°C, 252.10°C, and 261.16°C (onset temperature). Comprehensive characterization results indicated that Form J is a solvate.

[0457] 3.11 Preparation of Form K

[0458] 20 mg of the free base Form G was dissolved in 0.4 mL of DMF and filtered. 1.0 mL of purified water was added dropwise to the filtrate while stirring, causing solid precipitation. Stirring was continued at room temperature for approximately 2 hours to obtain Form K. XRD analysis results are shown in Figure 36.

[0459] 3.12 Preparation of Form L

[0460] 20 mg of free base Form G was dissolved in 2.0 mL of methanol at 50°C with stirring for approximately 2 hours, followed by hot filtration. The supernatant was cooled from 50°C to 5°C at a rate of 0.1°C / min to precipitate a solid, yielding Form L. Analysis and testing revealed that the XRD results are shown in Figure 37, and the TGA results, shown in Figure 38, showed no significant weight loss upon heating to 150°C. The DSC results, shown in Figure 39, showed two endothermic peaks at 227.72°C and 264.84°C (onset temperature). Comprehensive characterization results indicated that Form L was an anhydrous crystalline form.

[0461] 3.13 Preparation of Form M

[0462] 20 mg of free base Form G was slurried in 0.6 mL of ethanol (or acetone, methanol / dichloromethane (1:1, v:v)) at room temperature for 5 days, filtered, and dried under vacuum at 50°C for 3.5 hours to obtain Form M. Analysis and testing revealed that Form M exhibited an anhydrous crystalline form, as shown in Figure 40 and 1.28% weight loss upon heating to 120°C, respectively, as shown in Figure 41. Furthermore, DSC analysis revealed an exothermic peak at 101.54°C (onset temperature) and an endothermic peak at 264.24°C (onset temperature), respectively, as shown in Figure 42. Comprehensive characterization confirmed that Form M is an anhydrous crystalline form.

[0463] 3.14 Preparation of Form N

[0464] 20 mg of the free base Form G was slurried in 0.6 mL of acetonitrile (or dichloromethane) at room temperature for 5 days, filtered, and vacuum-dried at 50°C for 3.5 hours to obtain Form N. Analysis and testing revealed that Form N exhibited a 1.73% weight loss upon heating from room temperature to 50°C and a 6.43% weight loss upon heating from 50°C to 150°C, as shown in Figure 44. Furthermore, DSC results, as shown in Figure 45, revealed three endothermic peaks at 79.53°C (peak temperature), 250.32°C (onset temperature), and 264.02°C (onset temperature). Comprehensive characterization results indicated that Form N is a solvate.

[0465] 3.15 Preparation of Form O

[0466] The free base Form I was vacuum dried at 50°C for 3.5 hours to obtain Form O. Analysis and testing revealed no significant weight loss upon heating to 150°C, as shown in Figure 46 and the TGA results in Figure 47. DSC results in Figure 48 revealed two endothermic peaks at 109.30°C (peak temperature) and 265.73°C (onset temperature), and an exothermic signal at 131.64°C (peak temperature). Comprehensive characterization results indicated that Form O is an anhydrous crystalline form.

[0467] 3.16 Preparation of Form P

[0468] The free base Form J was vacuum dried at 50°C for 3.5 hours to obtain Form P. Analysis and testing revealed that Form P is a solvate. XRD results are shown in Figure 49 , TGA results are shown in Figure 50 , and a weight loss of 4.90% was observed upon heating to 150°C. DSC results, shown in Figure 51 , revealed three endothermic peaks at 90.45°C, 250.99°C, and 263.51°C (onset temperature). Comprehensive characterization results indicate that Form P is a solvate.

[0469] 3.17 Preparation of Form Q

[0470] 20 mg of Form G was dissolved in 1.0 mL of chloroform and filtered. 1.0 mL of tertiary methyl ether (or n-heptane) was added dropwise to the filtrate with stirring, causing solid precipitation. Stirring was continued at room temperature for approximately 2 hours, and the product was collected to obtain Form Q. Analysis and testing revealed that the free base Form Q is a chloroform solvate (theoretical weight loss: 20.62%). XRD results are shown in Figure 52 , and TGA results, shown in Figure 53 , show a 16.11% weight loss upon heating to 150°C. DSC results, shown in Figure 54 , show two endothermic peaks at 86.24°C and 263.46°C (onset temperature). Combined with solid-state characterization data, the free base Form Q is a chloroform solvate (theoretical weight loss: 20.62%).

[0471] 4. Stability test

[0472] 4.1 Solid-state stability

[0473] After samples of Forms B, H, and L were placed at 25°C / 60% RH and 40°C / 75% RH for 17 days, the physicochemical stability of the samples was tested using XRD and HPLC. The test data are listed in Table 24 below.

[0474] Table 24: Summary of Crystalline Form Solid State Stability Assessment

[0475] The results showed that the crystal form and purity of Form B and Form L did not change after being placed under 25°C / 60% RH and 40°C / 75% RH conditions for 17 days; the purity of Form H did not change after being placed under 25°C / 60% RH conditions for 17 days, but the crystallinity of the sample decreased, and the crystal form and purity did not change after being placed under 40°C / 75% RH conditions for 17 days.

[0476] 4.2 Study on mutual transformation relationship

[0477] 4.2.1 Competition in Suspension Market

[0478] The mutual transformation relationship between the various anhydrous crystalline forms was investigated by the method of suspension stirring competition at different temperatures and in different solvent systems.

[0479] 1) Equal masses (3-4 mg) of each anhydrous crystalline form (Form A / B / C / G / H / L / M) were weighed into HPLC vials. 1.0 mL of the corresponding solvent, presaturated with Form G at the corresponding temperature, was added. The resulting suspensions were magnetically stirred (1000 rpm) at room temperature or 50°C. Samples were collected after 10 minutes, 3 days, and 7 days, and the solids were collected by centrifugation and subjected to XRD analysis. The results are summarized in Table 25.

[0480] Table 25: Summary of the results of the suspension stirring competition test between various anhydrous crystalline forms

[0481] 2) Equal masses (~5 mg) of each anhydrous crystalline form (Form B / H / L) were weighed into HPLC vials. 1.0 mL of solvent presaturated with Form G at the corresponding temperature was added. The resulting suspensions were placed at room temperature or 50°C with magnetic stirring (1000 rpm). Samples were collected at 10 minutes, 6 hours, 1 day, 4 days, and 7 days. The solids were collected by centrifugation and subjected to XRD analysis. The results are summarized in Table 26.

[0482] Table 26: Summary of the results of the suspension stirring competition test between various anhydrous crystalline forms

[0483] 4.2.2 Heating experiment

[0484] Based on the DSC characterization results for each free base crystalline form, those with significant endothermic / exothermic signals before the melting point were heated by DSC above the endothermic / exothermic peak temperature. Samples were collected after heating and then subjected to XRD analysis. The results are summarized in Table 27.

[0485] Table 27: Summary of heating test results for each crystal form

[0486] The interconversion relationships between the various crystalline forms were studied through suspension stirring competition and heating tests. The suspension stirring competition results showed that the free base crystalline form L was the stable crystalline form under different solvent and temperature conditions (room temperature / 50°C). After heating (>100°C), each crystalline form tended to transform into the free base crystalline form A, which was the high-temperature stable crystalline form.

[0487] 4.3 Long-term stability study

[0488] The Form L sample was stored at 40°C ± 2°C / 75% RH ± 5% RH, and the physicochemical stability of the sample was tested using XRD and HPLC. The test data are listed in Table 28 below.

[0489] Table 28

[0490] 5. Solubility Experiment

[0491] 5.1 Solubility at room temperature

[0492] The solubility of Form G in 20 solvents at room temperature was determined. Approximately 2 mg of sample was weighed into a 3-mL vial. 100 μL of each solvent listed in Table 29 below was added at a time until the solid dissolved. If the solid did not dissolve after adding 2 mL of solvent, the addition was discontinued. The solubility range in the corresponding solvent was calculated based on the sample mass and solvent volume.

[0493] Table 29: Solubility range of Form G at room temperature

[0494] 5.2 Dynamic solubility

[0495] The solubility of the sample was measured at a feed concentration of 10 mg / mL at 37°C in four solvent systems: pH 1.0, pH 4.5, and pH 6.8 buffers, and water, for 1, 4, and 24 hours using a shaking system (400 rpm). Samples were centrifuged (10,000 rpm, 2 min) and filtered (through a 0.22 μm PTFE filter, discarding the pre-liquid). The filtrate concentration was determined by HPLC, and the remaining solid was analyzed by XRD. The solubility test results are summarized in Table 30.

[0496] Table 30: Summary of the results of the dynamic solubility test of Form G

Claims

1. The crystal form of the compound, It is characterized in that The specific structure of the compound is as follows:

2. The crystal form according to claim 1, It is characterized in that The compound is 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its specific structural formula is as follows:

3. The crystal form according to claim 2, It is characterized in that The crystalline form is the crystalline form A of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has 2θ of 6.0°±0.2°, 8.2°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.4°±0.2° and 25.4°±0.2° Preferably, the crystalline form A has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 6.0°±0.2°, 6.3°±0.2°, 8.2°±0.2°, 12.1°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.4°±0.2° and 25.4°±0.2°; More preferably, the crystalline form A has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 6.0°±0. 2θ is 6.0°±0.2°, 6.3°±0.2°, 8.2°±0.2°, 12.1°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.4°±0.2°, 18.2°±0.2°, 23.7°±0.2° and 25.4°±0.2°; further preferably, the crystalline form A has an X-ray powder diffraction pattern at 2θ of 6.0°±0.2°, 6.3°±0.2°, 8.2°±0.2°, 12.1°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.4°±0.2°, 18.2°±0.2°, 23.7°±0.2° and 25.4°±0.2°. , 8.2°±0.2°, 12.1°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.4°±0.2°, 18.2°±0.2°, 21.1°±0.2°, 23.7°±0.2°, 24.8°±0.2° and 25.4°±0.2° have diffraction peaks; preferably, the X-ray powder diffraction of the crystalline form A expressed in 2θ angles has a spectrum as shown in Figure 5; Preferably, the crystalline form A has an endothermic peak at a starting temperature of 257°C to 267°C in a thermal analysis diagram measured by differential scanning calorimetry (DSC); more preferably, the crystalline form A has an endothermic peak at a starting temperature of 260°C to 264°C in a thermal analysis diagram measured by differential scanning calorimetry; further preferably, the crystalline form A has an endothermic peak at a starting temperature of 262°C in a thermal analysis diagram measured by differential scanning calorimetry; further preferably, the crystalline form A has a DSC spectrum as shown in Figure 7; Preferably, the crystalline form A has a TGA spectrum as shown in Figure 6; Or the crystalline form is the crystalline form B of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has 2θ of 7.5°±0.2°, 14.8°±0.2°, 17.6°±0.2°, 22.4°±0.2°, 24.6°±0.2° and 26.3°±0.2° Preferably, the crystalline form B has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 7.5°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 17.6°±0.2°, 22.4°±0.2°, 24.6°±0.2°, 26.3°±0.2° and 27.5°±0.2°; More preferably, the crystalline form B has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 7.5°±0.2°. , 13.6°±0.2°, 14.8°±0.2°, 15.6°±0.2°, 17.6°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 24.6°±0.2°, 26.3°±0.2° and 27.5°±0.2°; further preferably, the crystalline form B has an X-ray powder diffraction pattern at 2θ of 7.5°±0.2°, 13.6°±0.2°, 1 4.8°±0.2°, 15.6°±0.2°, 17.1°±0.2°, 17.6°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 24.6°±0.2°, 25.2°±0.2°, 26.3°±0.2° and 27.5°±0.2° have diffraction peaks; further preferably, the X-ray powder diffraction of the crystalline form B expressed in 2θ angles has a spectrum as shown in Figure 8; Preferably, the crystalline form B has endothermic peaks at starting temperatures of 215°C to 225°C and 260°C to 270°C in the thermal analysis diagram measured by differential scanning calorimetry; more preferably, the crystalline form B has endothermic peaks at starting temperatures of 217°C to 222°C and 264°C to 268°C in the thermal analysis diagram measured by differential scanning calorimetry; further preferably, the crystalline form B has endothermic peaks at starting temperatures of 220°C and 266°C in the thermal analysis diagram measured by differential scanning calorimetry; preferably, the crystalline form B has a DSC spectrum as shown in FIG. 10; preferably, the crystalline form B has a TGA spectrum as shown in FIG. 9; Or the crystalline form is the crystalline form C of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has 2θ of 9.2°±0.2°, 17.6°±0.2°, 19.7°±0.2°, 21.8°±0.2°, 22.7°±0.2° and 24.6°±0.2° diffraction peak; preferably, the crystalline form C has an X-ray powder diffraction pattern at 2θ of 9.2°±0.2°, 10.6°±0.2°, 13.0°±0.2°, 17.6°±0.2°, 19.7°±0.2°, 21.8°±0.2°, 22.7°±0.2° and 24.6°±0.2° having diffraction peaks; more preferably, the crystalline form C has an X-ray powder diffraction pattern at 2θ of 9.2°±0.2°, The crystalline form C has diffraction peaks at 2θ of 9.2°±0.2°, 10.6°±0.2°, 13.0°±0.2°, 15.2°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 21.8°±0.2°, 22.7°±0.2° and 24.6°±0.2°; further preferably, the crystalline form C has an X-ray powder diffraction pattern at 2θ of 9.2°±0.2°, 10.6°±0.2°, 13.0°±0.2°, 15.2°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 21.8°±0.2°, 22.7°±0.2° and 24.6°±0.2°. .0°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 21.8°±0.2°, 22.7°±0.2°, 23.1°±0.2° and 24.6°±0.2° have diffraction peaks; further preferably, the X-ray powder diffraction of the crystalline form C expressed in 2θ angles has a spectrum as shown in Figure 11; Preferably, the crystalline form C has a TGA spectrum as shown in FIG12 ; Preferably, the crystalline form C has a DSC spectrum as shown in FIG13 ; Or the crystalline form is the crystalline form D of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has 2θ of 6.8°±0.2°, 8.8°±0.2°, 13.0°±0.2°, 18.1°±0.2°, 21.6°±0.2° and 22.8°±0.2° diffraction peak; preferably, the crystalline form D has an X-ray powder diffraction pattern at 2θ of 6.8°±0.2°, 8.8°±0.2°, 13.0°±0.2°, 18.1°±0.2°, 21.6°±0.2°, 22.8°±0.2°, 23.4°±0.2° and 26.1°±0.2° having diffraction peaks; more preferably, the crystalline form D has an X-ray powder diffraction pattern at 2θ of 6.8°±0.2°, 8.8°±0.2°, 13.0°±0.2°, 18.1°±0.2°, 21.6°±0.2°, 22.8°±0.2°, 23.4°±0.2° and 26.1°±0.2° having diffraction peaks. 8.8°±0.2°, 13.0°±0.2°, 18.1°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 22.8°±0.2°, 23.4°±0.2°, 25.0°±0.2° and 26.1°±0.2°; further preferably, the crystalline form D has an X-ray powder diffraction pattern at 2θ of 6.8°±0.2°, 8.8°±0.2°, 13. 0°±0.2°, 18.1°±0.2°, 20.6°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 22.8°±0.2°, 23.4°±0.2°, 25.0°±0.2°, 26.1°±0.2° and 30.2°±0.2° have diffraction peaks; further preferably, the X-ray powder diffraction of the crystalline form D expressed in 2θ angles has a spectrum as shown in Figure 14; Preferably, the crystalline form D has a TGA spectrum as shown in FIG15 ; Preferably, the crystalline form D has a DSC spectrum as shown in FIG16 ; Preferably, the crystal form D has a single crystal structure as shown in FIG17 .

4. The crystal form according to claim 2, It is characterized in that The crystalline form is the crystalline form E of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 5.8°±0.2°, 6.3°±0.2°, 7.0°±0.2° and 10.8°±0.2°; preferably, the crystalline form E has an X-ray powder diffraction pattern at 2θ of 5.8°±0.2°, 6.3°±0.2°, 7.0°±0.2°, 10.8°±0.2°, 15.6°±0.2° and 20.1°±0.2°; more preferably, the crystalline form E has an X-ray powder diffraction pattern at 2θ of 5.8°±0.2°. , 6.3°±0.2°, 7.0°±0.2°, 8.5°±0.2°, 10.8°±0.2°, 15.6°±0.2°, 20.1°±0.2° and 21.7°±0.2° have diffraction peaks; further preferably, the crystalline form E has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 5.8°±0.2°, 6.3°±0.2°, 7.0°±0.2°, 8.5°±0.2°, 10.8°±0.2°, 15.6°±0.2°, 19.4°±0.2°, 20.1°±0.2°, 21.5°±0.2° and 21.7°±0.2°; further preferably, the X-ray powder diffraction of the crystalline form E expressed in 2θ angles has a spectrum as shown in Figure 18; Preferably, the crystalline form E has a TGA spectrum as shown in FIG19 ; Or the crystalline form is the crystalline form F of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has 2θ of 8.9°±0.2°, 13.4°±0.2°, 16.8°±0.2°, 19.9°±0.2°, 20.4°±0.2° and 22.5°±0.2° diffraction peak; preferably, the crystalline form F has an X-ray powder diffraction pattern at 2θ of 8.9°±0.2°, 12.2°±0.2°, 13.4°±0.2°, 16.8°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 22.5°±0.2° and 25.5°±0.2° having diffraction peaks; more preferably, the crystalline form F has an X-ray powder diffraction pattern at 2θ of 8.9°±0.2°, The crystal form F has diffraction peaks at 10.0°±0.2°, 12.2°±0.2°, 13.4°±0.2°, 16.8°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 22.5°±0.2°, 25.5°±0.2° and 26.0°±0.2°; further preferably, the crystal form F has an X-ray powder diffraction pattern at 2θ of 8.9°±0.2°, 10.0°±0.2°, 12.2°±0.2°, 13.4°±0.2°, 16.8°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 22.5°±0.2°, 25.5°±0.2° and 26.0°±0.2°. .2°±0.2°, 13.4°±0.2°, 16.1°±0.2°, 16.8°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 22.5°±0.2°, 23.3°±0.2°, 25.5°±0.2° and 26.0°±0.2° have diffraction peaks; further preferably, the X-ray powder diffraction of the crystalline form F expressed in 2θ angles has a spectrum as shown in Figure 20; Preferably, the crystalline form F has a TGA spectrum as shown in FIG21 ; Preferably, the crystalline form F has a DSC spectrum as shown in FIG22 ; Preferably, the crystal form F spectrum has the following 1 H NMR spectrum; Or the crystalline form is crystalline form G of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.3°±0.2°, 6.8°±0.2°, 13.9°±0.2° and 15.3°±0.2°; preferably, the crystalline form G has an X-ray powder diffraction pattern at 2θ of 6.3°±0.2°, 6.8°±0.2°, 8.2°±0.2°, 12.7°±0.2°, 13.9°±0.2° and 15.3°±0.2°; more preferably, the crystalline form G has an X-ray powder diffraction pattern at 2θ of 6.3°±0.2°. , 6.8°±0.2°, 8.2°±0.2°, 12.7°±0.2°, 13.9°±0.2°, 15.3°±0.2°, 19.9°±0.2° and 25.7°±0.2° have diffraction peaks; further preferably, the crystalline form G has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 6.3°±0.2°, 6.8°±0.2°, 8.2°±0.2°, 8.8°±0.2°, 12.7°±0.2°, 13.9°±0.2°, 15.3°±0.2°, 17.7°±0.2°, 19.9°±0.2° and 25.7°±0.2°; further preferably, the X-ray powder diffraction of the crystalline form G expressed in 2θ angles has a spectrum as shown in Figure 24; Preferably, the crystalline form G has a TGA spectrum as shown in Figure 25; Preferably, the crystalline form G has a DSC spectrum as shown in FIG26 ; Or the crystalline form is crystalline form H of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 5.8°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 19.8°±0.2° and 20.7°±0.2°; preferably, the crystalline form H has an X-ray powder diffraction pattern at 2θ of 5.8°±0.2°, 9.8°±0.2°, 11.3°±0.2°, More preferably, the crystalline form H has diffraction peaks at 2θ of 5.8°±0.2°, 9.8°±0.2°, 11.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 19.8°±0.2°, and 20.7°±0.2°; more preferably, the crystalline form H has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 5.8°±0.2°, 9.8°±0.2°, 11.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 23.8°±0.2°, and 27.1°±0.2°; further Preferably, the X-ray powder diffraction pattern of the crystalline form H has diffraction peaks at 2θ of 5.8°±0.2°, 9.8°±0.2°, 11.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 23.8°±0.2°, 25.4°±0.2°, 25.7°±0.2° and 27.1°±0.2°; further preferably, the X-ray powder diffraction of the crystalline form H expressed in 2θ angles has a spectrum as shown in Figure 27; Preferably, the crystalline form H has endothermic peaks at starting temperatures of 220°C to 230°C and 260°C to 270°C in a thermal analysis diagram measured by differential scanning calorimetry; more preferably, the crystalline form H has endothermic peaks at starting temperatures of 222°C to 226°C and 263°C to 268°C in a thermal analysis diagram measured by differential scanning calorimetry; further preferably, the crystalline form H has endothermic peaks at starting temperatures of 224°C and 265°C in a thermal analysis diagram measured by differential scanning calorimetry; Preferably, the crystalline form H has a TGA spectrum as shown in FIG. 28 ; Preferably, the crystalline form H has a DSC spectrum as shown in Figure 29.

5. The crystal form according to claim 2, It is characterized in that The crystalline form is the crystalline form I of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.8°±0.2°, 8.9°±0.2°, 20.7°±0.2° and 30.1°±0.2°; preferably, the crystalline form I, its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.8°±0.2°, 8.9°±0.2°, 20.7°±0.2°, 21.8°±0.2°, 23.7°±0.2° and 30.1°±0.2°; more preferably, the crystalline form I, its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.8°±0.2°, 8.9°±0.2°, 20.7°±0.2°, 21.8°±0.2°, 23.7°±0.2° and 30.1°±0.2°. 8.9°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 23.7°±0.2°, 27.7°±0.2° and 30.1°±0.2° have diffraction peaks; further preferably, the crystalline form I has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 6.8°±0.2°, 8.9°±0.2°, 13.8°±0.2°, 15.1°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 23.7°±0.2°, 27.7°±0.2° and 30.1°±0.2°; further preferably, the X-ray powder diffraction of the crystalline form I expressed in 2θ angles has a spectrum as shown in Figure 30; Preferably, the crystalline form I has a TGA spectrum as shown in Figure 31; Preferably, the crystalline form I has a DSC spectrum as shown in FIG32 ; Or the crystalline form is the crystalline form J of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.7°±0.2°, 25.0°±0.2° and 25.6°±0.2°; preferably, the crystalline form J has an X-ray powder diffraction pattern at 2θ of 6.7°±0.2°, 8.7°±0.2°, 25.0°±0.2° and 25.6°±0.2°; more preferably, the crystalline form J has an X-ray powder diffraction pattern at 2θ of 6.7°±0.2°, 8.7°±0.2°, 25.0°±0.2° and 25.6°±0.2°. ±0.2°, 8.7°±0.2°, 20.5°±0.2°, 25.0°±0.2°, 25.6°±0.2° and 27.4°±0.2°; further preferably, the crystalline form J has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 6.7°±0.2°, 8.7°±0.2°, 13.6°±0.2°, 20.5°±0.2°, 23.4°±0.2°, 25.0°±0.2°, 25.6°±0.2° and 27.4°±0.2°; further preferably, the X-ray powder diffraction of the crystalline form J expressed in 2θ angles has a spectrum as shown in Figure 33; Preferably, the crystal form J has a TGA spectrum as shown in Figure 34; Preferably, the crystal form J has a DSC spectrum as shown in FIG35 ; Or the crystalline form is the crystalline form K of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, whose X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.2°±0.2°, 17.7°±0.2° and 18.9°±0.2°; preferably, the crystalline form K, its X X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.2°±0.2°, 16.8°±0.2°, 17.7°±0.2° and 18.9°±0.2°; More preferably, the crystalline form K has an X-ray powder diffraction pattern at 2θ of 6.2°±0.2°, 11.4°±0.2°, 16.8°±0.2°, 17.7°±0.2°, 18.9°±0.2° and 27.6°±0.2°; further preferably, the X-ray powder diffraction pattern of the crystalline form K has diffraction peaks at 2θ of 6.2°±0.2°, 11.4°±0.2°, 16.8°±0.2°, 17.7°±0.2°, 18.9°±0.2°, 24.4°±0.2°, 25.3°±0.2°, and 27.6°±0.2°; further preferably, the X-ray powder diffraction of the crystalline form K expressed in 2θ angles has a spectrum as shown in Figure 36; Or the crystalline form is the crystalline form L of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has 2θ of 14.9°±0.2°, 18.6°±0.2°, 21.4°±0.2°, 22.8°±0.2°, 23.5°±0.2° and 26.0°±0.2° Preferably, the crystalline form L has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 14.9°±0.2°, 18.6°±0.2°, 21.4°±0.2°, 22.8°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 26.0°±0.2° and 27.3°±0.2°; More preferably, the crystalline form L has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 8.3°±0.2 The crystalline form L has diffraction peaks at 2θ of 8.3°±0.2°, 8.9°±0.2°, 10.6°±0.2°, 11.7°±0.2°, 12.9°±0.2°, 13.5°±0.2°, 14.1°±0.2°, 18.6°±0.2°, 21.4°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 26.0°±0.2° and 27.3°±0.2°; further preferably, the crystalline form L has an X-ray powder diffraction pattern at 2θ of 8.3°±0.2°, 8.9°±0.2°, 1 4.9°±0.2°, 18.6°±0.2°, 19.5°±0.2°, 21.4°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 26.0°±0.2° and 27.3°±0.2° have diffraction peaks; further preferably, the X-ray powder diffraction of the crystalline form L expressed in 2θ angles has a spectrum as shown in Figure 37; Preferably, the crystalline form L has endothermic peaks at starting temperatures of 223°C to 233°C and 260°C to 270°C in a thermal analysis diagram measured by differential scanning calorimetry; more preferably, the crystalline form L has endothermic peaks at starting temperatures of 225°C to 230°C and 263°C to 268°C in a thermal analysis diagram measured by differential scanning calorimetry; further preferably, the crystalline form L has endothermic peaks at starting temperatures of 228°C and 265°C in a thermal analysis diagram measured by differential scanning calorimetry; Preferably, the crystalline form L has a TGA spectrum as shown in Figure 38; Preferably, the crystalline form L has a DSC spectrum as shown in Figure 39.

6. The crystal form according to claim 2, It is characterized in that The crystalline form is the crystalline form M of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 7.1°±0.2°, 13.5°±0.2°, 17.4°±0.2°, 18.7°±0.2°, 23.7°±0.2° and 27.1°±0.2°; preferably, the crystalline form M has an X-ray powder diffraction pattern at 2θ of 7.1°±0.2°, 11.4°±0.2°, 13.5°±0.2°, 17.4°±0.2°, 18.7°±0.2°, 23.7°±0.2° and 27.1°±0.2°. .7°±0.2°, 21.5°±0.2°, 23.7°±0.2° and 27.1°±0.2°; more preferably, the crystalline form M has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 7.1°±0.2°, 9.2°±0.2°, 11.4°±0.2°, 13.5°±0.2°, 17.4°±0.2°, 18.7°±0.2°, 20.5°±0.2°, 21.5°±0.2°, 23.7°±0.2° and 27.1°±0.2°; further preferably, the X-ray powder diffraction of the crystalline form M expressed in 2θ angles has a spectrum as shown in Figure 40; Preferably, the crystalline form M has a TGA spectrum as shown in FIG41 ; Preferably, the crystalline form M has a DSC spectrum as shown in FIG42 ; Or the crystalline form is the crystalline form N of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, whose X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.5°±0.2°, 7.0°±0.2°, 8.6°±0.2° and 18.1°±0.2°; preferably, the crystalline form N, whose X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.5°±0.2°, 7.0°±0.2°, 8.6°±0.2°, 13. 0°±0.2°, 18.1°±0.2° and 21.4°±0.2° have diffraction peaks; more preferably, the crystalline form N has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 6.5°±0.2°, 7.0°±0.2°, 8.6°±0.2°, 13.0°±0.2°, 18.1°±0.2°, 21.4°±0.2°, 22.5°±0.2° and 24.1°±0.2°; further preferably, the X-ray powder diffraction of the crystalline form N expressed in 2θ angles has a spectrum as shown in Figure 43; Preferably, the crystal form N has a TGA spectrum as shown in Figure 44; Preferably, the crystal form N has a DSC spectrum as shown in Figure 45; Or the crystalline form is the crystalline form O of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 7.3°±0.2° and 18.5°±0.2°; preferably, the crystalline form O has an X-ray powder diffraction pattern at 2θ of 3.7°±0.2°, 7.3°±0.2°, 18.5°±0.2° and 26.0°±0.2°; more preferably, the crystalline form O has an X-ray powder diffraction pattern at 2θ of 3.7°±0.2°. , 7.3°±0.2°, 16.2°±0.2°, 18.5°±0.2°, 26.0°±0.2° and 26.3°±0.2°; further preferably, the crystalline form O has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 3.7°±0.2°, 7.3°±0.2°, 16.2°±0.2°, 18.5°±0.2°, 22.6°±0.2°, 25.6°±0.2°, 26.0°±0.2° and 26.3°±0.2°; further preferably, the X-ray powder diffraction of the crystalline form O expressed in 2θ angles has a spectrum as shown in Figure 46; Preferably, the crystal form O has a TGA spectrum as shown in Figure 47; Preferably, the crystal form O has a DSC spectrum as shown in FIG48 ; Or the crystalline form is the crystalline form P of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.9°±0.2° and 18.2°±0.2°; preferably, the crystalline form P has an X-ray powder diffraction pattern at 2θ of 6.2°±0.2°, 6.9°±0.2°, 13.9°±0.2° and 18.2°±0.2°; more preferably, the crystalline form P has an X-ray powder diffraction pattern at 2θ of 6.2°±0.2°. , 6.9°±0.2°, 13.1°±0.2°, 13.9°±0.2°, 18.2°±0.2° and 26.1°±0.2°; further preferably, the crystalline form P has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 6.2°±0.2°, 6.9°±0.2°, 11.8°±0.2°, 13.1°±0.2°, 13.9°±0.2°, 18.2°±0.2°, 25.4°±0.2° and 26.1°±0.2°; further preferably, the X-ray powder diffraction of the crystalline form P expressed in 2θ angles has a spectrum as shown in Figure 49; Preferably, the crystal form P has a TGA spectrum as shown in FIG50 ; its DSC has a spectrum as shown in FIG51 ; Or the crystalline form Q is the crystalline form Q of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has 2θ of 12.2±0.2°, 16.1°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 23.2°±0.2° and 28.7°±0.2° Preferably, the crystalline form Q has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 12.2±0.2°, 16.1°±0.2°, 18.1°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 23.2°±0.2° and 28.7°±0.2°; More preferably, the crystalline form Q has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 12.2±0.2°. , 14.9°±0.2°, 15.4°±0.2°, 16.1°±0.2°, 18.1°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 23.2°±0.2° and 28.7°±0.2°; further preferably, the crystalline form Q has an X-ray powder diffraction pattern at 2θ of 12.2±0.2°, 14.9°±0.2°, 1 5.4°±0.2°, 16.1°±0.2°, 18.1°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 23.2°±0.2°, 25.1°±0.2°, 28.7°±0.2° and 31.5°±0.2° have diffraction peaks; further preferably, the X-ray powder diffraction of the crystalline form Q expressed in 2θ angles has a spectrum as shown in Figure 52; Preferably, the crystal form Q has a TGA spectrum as shown in Figure 53; Preferably, the crystal form Q has a DSC spectrum as shown in Figure 54.

7. The crystal form according to claim 2, It is characterized in that The crystalline form of the compound is a crystalline form containing a solvent or not containing a solvent; the solvent is selected from one or more of water, methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, isobutanol, acetone, 2-butanone, 3-pentanone, dichloromethane, chloroform, ethyl formate, ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, n-heptane, heptane, isopropyl acetate, cyclohexane, methyl tert-butyl ether and isopropyl ether; preferably, the solvent is selected from one or more of water, ethanol, acetone, n-heptane, dichloromethane, chloroform, 2-butanone, tetrahydrofuran and N,N-dimethylformamide; More preferably, the crystalline form of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is a solvate, and the solvent is selected from one or more of water, ethanol, acetone, n-heptane, dichloromethane, chloroform and tetrahydrofuran; More preferably, the crystalline form of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is an anhydrous crystalline form.

8. A method for preparing the crystal form according to any one of claims 1 to 7, It is characterized in that Including anti-solvent addition method, anti-anti-solvent addition method, solvent volatilization method, gas-solid diffusion method, suspension stirring method and cooling crystallization method; Preferably, the preparation method comprises the following steps: weighing an appropriate amount of the free base of the compound, adding a corresponding positive solvent to dissolve it, filtering it, and adding a corresponding anti-solvent to the filtrate while stirring until a solid precipitates; Alternatively, weigh an appropriate amount of the free base of the compound, add the corresponding positive solvent to dissolve it, filter it, and cool the supernatant until solid precipitates; Or weigh an appropriate amount of the free base of the compound, add the corresponding positive solvent to dissolve it, and seal it until solid precipitates; Alternatively, weigh an appropriate amount of the free base of the compound, add the corresponding positive solvent to dissolve, slurry, dry, and collect the solid; Preferably, the positive solvent includes one or more of water, methanol, ethanol, acetone, 2-butanone, ethyl acetate, tetrahydrofuran, acetonitrile, n-hexane, n-heptane, dichloromethane, chloroform, 1,4-dioxane, benzene, toluene, chlorobenzene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, ethyl formate, isopropyl acetate, tert-butanol, methyl isobutyl ketone and 3-pentanone; preferably one or more of water, methanol, ethanol, acetonitrile, n-hexane, n-heptane, dichloromethane, chloroform, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, acetone, 2-butanone, ethyl acetate, 1,4-dioxane, isopropanol, isopropyl acetate and methyl isobutyl ketone; The anti-solvent includes one or more of methanol, ethanol, acetonitrile, ethyl acetate, acetone, isopropanol, tert-butanol, n-heptane, water, isopropyl acetate, n-hexane, cyclohexane, toluene, methyl tert-butyl ether and isopropyl ether; preferably one or more of methyl tert-butyl ether, n-heptane, isopropyl acetate, acetonitrile, isopropyl ether, n-hexane, water, tert-butanol, cyclohexane and toluene.

9. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

10. Use of the crystalline form according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating a disease or disease state mediated by MAT2A.

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