Crystalline form of methionine adenosyltransferase 2A heterocyclic inhibitor, method for producing the same, and use

Abstract

This invention discloses the crystalline form of a methionine adenosyltransferase 2A heterocyclic inhibitor, its manufacturing method, and its use, and more specifically, the crystalline form of the compound shown in the following formula I, its manufacturing method, and its use. The above crystalline form has high purity and stable chemical properties, is suitable for industrial production, and is of great importance in the development of drugs with good biological activity. JPEG2026521556000067.jpg4052

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority to Chinese patent application 202310705912.8, filed on 14 June 2023, and incorporates the entire text of the aforementioned Chinese patent application.

[0002] [Technical field] This invention belongs to the field of biopharmaceuticals and specifically relates to the crystalline form of a methionine adenosyltransferase 2A heterocyclic inhibitor, its manufacturing method, and its use. [Background technology]

[0003] Methionine adenosyltransferase (MAT) (also known as S-adenosylmethionine synthase) is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP, and is considered the rate-limiting step in the methionine cycle. SAM is a propylamino group donor in polyamine biosynthesis, as well as a major methyl group donor for DNA methylation, and is involved in gene transcription, cell proliferation, and the production of secondary metabolites. The three human isozymes of MAT are MAT1, MAT2, and MAT3. Of these, MAT1 and MAT3 are expressed in liver tissue, while methionine adenosyltransferase 2A (MAT2A) is a subtype of MAT2, is universally expressed in human cell types, is the main form of human cancer, and plays an important role in SAM production.

[0004] MTAP (methylthioadenosine phosphorylase) is an enzyme widely 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. When purine synthesis is inhibited, for example by an antimetabolite, MTA can serve as an alternative purine source.

[0005] The gene encoding MTAP is located in a single region on chromosome 9 and is frequently deleted in cells of the central nervous system, pancreas, esophagus, bladder, and lungs in cancer patients. When MTAP is deleted, MTA accumulates, and MTAP-deficient cells become more dependent on SAM production, and consequently on MAT2A activity, compared to cells that express MTAP. In a screening of approximately 400 cancer cell lines, the inactivation rate of MTAP-deficient cells by MAT2A knockdown was higher compared to cells that normally express MTAP. Furthermore, inducible knockdown of the MAT2A protein suppresses tumor growth in vivo. These results suggest that MAT2A inhibitors may offer a novel therapeutic option for patients with MTAP-deficient tumors.

[0006] PCT / CN2022 / 140380 provides a novel heterocyclic methionine adenosyltransferase 2A inhibitor. The crystalline structure of a pharmaceutical active ingredient always affects the chemical stability of the drug. The crystalline structure of a compound can change depending on the crystal form, manufacturing method, and storage conditions, and in some cases, this may lead to the formation of other crystalline forms. Therefore, in-depth research into the crystalline polymorphism of a compound and obtaining a crystalline form with high purity and stable chemical properties is of great importance in the development of drugs that are suitable for industrial production and have good biological activity. [Overview of the project]

[0007] All provisions relating to patent PCT / CN2022 / 140380 are incorporated herein by reference.

[0008] The present invention provides a crystalline form of the compound shown in the following formula I, [ka] Here, X is CR 3 Alternatively, selected from N, and Y is CR 4 Or selected from N, and Z is CR 5 Alternatively, selected from N, and W is CR 6 Or selected from N, Here, R 3 , R4 、R 5 and R 6 are each independently selected from hydrogen, a cyano group, a C2-C6 alkynyl group, a halogen, a hydroxy group, -NH2, (C1-C6 alkyl)-NR 7 -, (C1-C6 alkyl)-O-, (C1-C6 alkyl)-S-, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 6- to 10-member aryl group, a C2-C6 alkenyl group or a C3-C6 cycloalkenyl group, and the C1-C6 alkyl group, C2-C6 alkenyl group, C3-C6 cycloalkyl group or C3-C6 cycloalkenyl group is optionally substituted, as itself or as part of another group, with a halogen, a cyano group, a hydroxy group, -NR 7 R 8 , a C1-C3 alkyl group, a C1-C3 alkoxy group, a C2-C6 alkenyl group or a C2-C6 alkynyl group, and the 6- to 10-member aryl group is optionally substituted with a halogen, a hydroxy group, a cyano group, -NR 7 R 8 , -NO2, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C2-C6 alkenyl group or a C2-C6 alkynyl group, and the C1-C3 alkyl group, C1-C3 alkoxy group, C2-C6 alkenyl group or C2-C6 alkynyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, -NR 7 R 8 or -NO2, R 1 and R 2 are each independently selected from a 6- to 10-member aryl group or a 9- to 18-member benzoheterocyclyl group, and the 6- to 10-member aryl group or 9- to 18-member benzoheterocyclyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, -NR 7 R 8 , -NO2, -NR 9 C(O)R 10 , a C1-C6 alkyl group, (C1-C6 alkyl)-O-, -C(O)NR 9 R 10Alternatively, it may be substituted with a 5-7 membered heteroaryl group, either as part of the C1-C6 alkyl group itself or as part of another group, or the 5-7 membered heteroaryl group may optionally be a halogen, cyano group, hydroxyl group, C1-C3 alkyl group, (C1-C3 alkyl)-O- or -NR 7 R 8 Replaced by, R 7 , R 8 , R 9 and R 10 Each is independently selected from H or C1-C6 alkyl groups. The condition is that at least two of W, X, Y, and Z are simultaneously N.

[0009] The present invention further provides a crystalline form of the compound represented by formula I, wherein the compound of formula I has the structure represented by formula II. [ka] Here, R 1 , R 2 , R 3 , R 4 and R 5 The definition is as defined for the compound of formula I.

[0010] In one embodiment of the present invention, R 3 , R 4 , R 5 and R 6 These are, independently, hydrogen, halogen, hydroxyl group, -NH2, and (C1-C6 alkyl)-NR. 7 -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl, or 6-10 membered aryl group, where the C1-C6 alkyl itself or as part of another group, or the C3-C6 cycloalkyl, is optionally a halogen, cyano group, hydroxyl group, or -NR. 7 R 8 The above 6-10 membered aryl group is substituted with a halogen-substituted C1-C3 alkoxy group, Preferably, R 3 , R 4, R 5 and R 6 These are, independently, hydrogen, halogen, hydroxyl group, -NH2, and (C1-C6 alkyl)-NR. 7 -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl, or 6-10 membered aryl group, where the C1-C6 alkyl itself or as part of another group, or the C3-C6 cycloalkyl group, is optionally substituted with a halogen, and the 6-10 membered aryl group is optionally substituted with a halogen-substituted C1-C3 alkoxy group. Comfortable, R 3 , R 4 , R 5 and R 6 These are, independently, hydrogen, halogen, hydroxyl group, -NH2, and (C1-C6 alkyl)-NR. 7 -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl, or 6-10 membered aryl group are selected, where the C1-C6 alkyl itself or as part of another group, or the C3-C6 cycloalkyl group, is optionally substituted with fluorine, and the 6-10 membered aryl group is optionally substituted with a fluorine-substituted C1-C3 alkoxy group.

[0011] In one embodiment of the present invention, R 3 R is selected from hydrogen, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group, preferably R 3 is selected from hydrogen or a C1-C6 alkyl group, more preferably R 3 is selected from hydrogen, a methyl group, or a cyclopropyl group, and more preferably R 3 is selected from hydrogen or a methyl group, most preferably R 3 It is selected from hydrogen.

[0012] In one embodiment of the present invention, R 4 is selected from hydrogen or a C1-C6 alkyl group, preferably R 4 is selected from hydrogen or a methyl group, more preferably R 4 It is selected from hydrogen.

[0013] In one embodiment of the present invention, R 5 This includes hydrogen, halogen, hydroxyl group, and (C1-C6 alkyl)-NR 7 -, (C1-C6 alkyl)-O-, C3-C6 cycloalkyl group or 6-10 membered aryl group, where the C1-C6 alkyl group itself or as part of another group, or the C3-C6 cycloalkyl group, is optionally substituted with fluorine, and the 6-10 membered aryl group is optionally substituted with a fluorine-substituted C1-C3 alkoxy group, preferably R 5 is selected from hydrogen, chlorine, hydroxyl group, cyclopropyl group, CF3CH2O-, CHF2O-, CF3CH2NH-, 4-difluoromethoxyphenyl group or CH3CH2O-, and more preferably R 5 The group is selected from cyclopropyl group, CF3CH2O-, CF3CH2NH-, or CH3CH2O-, and more preferably R 5 is selected from a cyclopropyl group, CF3CH2O- or CF3CH2NH-, and most preferably R 5 It is selected from cyclopropyl groups.

[0014] In one embodiment of the present invention, R 1 and R 2 Each of them independently contains a phenyl group, [ka] or [ka] Selected from, where the above group is optionally a halogen, a hydroxyl group, a cyano group, or -NR 7 R 8 -NO2, -NR 9 C(O)R 10 , C1-C6 alkyl, (C1-C6 alkyl)-O-, -C(O)NR 9 R 10Alternatively, it may be substituted with a 5-7 membered heteroaryl group, either as part of the C1-C6 alkyl group itself or as part of another group, or the 5-7 membered heteroaryl group may optionally be a halogen, cyano group, hydroxyl group, C1-C3 alkyl group, (C1-C3 alkyl)-O- or -NR 7 R 8 Replaced with, preferably, R 1 and R 2 These are, independently, a phenyl group and the following groups [ka] Selected from, where the above group is optionally substituted with a C1-C6 alkyl group or (C1-C6 alkyl)-O-, and optionally substituted with a halogen, either as the C1-C6 alkyl group itself or as part of another group, preferably R 7 , R 8 , R 9 and R 10 Each is independently selected from H.

[0015] In another embodiment of the present invention, R 1 is a phenyl group, [ka] or [ka] Selected from, where the above group is optionally substituted with a C1-C6 alkyl group or (C1-C6 alkyl)-O-, and optionally substituted with a halogen, either as the C1-C6 alkyl group itself or as part of another group, preferably R 1 The following is based [ka] Selected from, more comfortably, R 1 teeth, [ka] They are selected from among them.

[0016] In one embodiment of the present invention, R 2 is a phenyl group or [ka] Selected from, where the above group is optionally substituted with (C1-C6 alkyl)-O-, and the above C1-C6 alkyl group is optionally substituted with a halogen, preferably R 2 teeth, [ka] or [ka] Selected from, more comfortably, R 2 teeth, [ka] They are selected from among them.

[0017] The present invention further provides the following crystalline forms of compounds. [ka]

[0018] In one embodiment of the present invention, a crystalline form of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one having the following structure is provided. [ka]

[0019] In one embodiment of the present invention, A-type to Q-type crystals of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one are provided.

[0020] In one embodiment of the present invention, a type A crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ.

[0021] Preferably, the above-mentioned type A crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0022] More preferably, the above-mentioned type A crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0023] More preferably, the above-mentioned type A crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0024] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the A-type crystal is shown in detail in the table below.

[0025] [Table 1]

[0026] In one embodiment, the A-type crystal exhibits an endothermic peak in a thermal analysis chart measured by differential scanning calorimetry (DSC) at a starting temperature of 257°C to 267°C.

[0027] In one embodiment, the above-mentioned type A crystal has an endothermic peak at a starting temperature of 260°C to 264°C in a thermal analysis chart measured by differential scanning calorimetry (DSC).

[0028] In one embodiment, the A-type crystal exhibits an endothermic peak at a starting temperature of 262°C in a thermal analysis chart measured by differential scanning calorimetry (DSC).

[0029] In one embodiment, the A-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 5.

[0030] In one embodiment, the A-type crystal has the TGA pattern shown in Figure 6.

[0031] In one embodiment, the A-type crystal has the DSC pattern shown in Figure 7.

[0032] In one embodiment of the present invention, a type B crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ.

[0033] Preferably, the above-mentioned type B crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0034] More preferably, the above-mentioned type B crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0035] More preferably, the B-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0036] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the B-type crystal is shown in detail in the table below.

[0037] [Table 2]

[0038] In one embodiment, the B-type crystal exhibits endothermic peaks at starting temperatures of 215°C to 225°C and 260°C to 270°C in a thermal analysis chart measured by differential scanning calorimetry (DSC).

[0039] In one embodiment, the B-type crystal exhibits endothermic peaks at starting temperatures of 217°C to 222°C and 264°C to 268°C in a thermal analysis chart measured by differential scanning calorimetry (DSC).

[0040] In one embodiment, the B-type crystal exhibits endothermic peaks at starting temperatures of 220°C and 266°C in a thermal analysis chart measured by differential scanning calorimetry (DSC).

[0041] In one embodiment, the B-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 8.

[0042] In one embodiment, the B-type crystal has the TGA pattern shown in Figure 9.

[0043] In one embodiment, the B-type crystal has the DSC pattern shown in Figure 10.

[0044] In one embodiment of the present invention, a C-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ.

[0045] Preferably, the C-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0046] More preferably, the C-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0047] More preferably, the C-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0048] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the C-type crystal is shown in detail in the table below.

[0049] [Table 3]

[0050] In one embodiment, the C-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 11.

[0051] In one embodiment, the C-type crystal has the TGA pattern shown in Figure 12.

[0052] In one embodiment, the C-type crystal has the DSC pattern shown in Figure 13.

[0053] In one embodiment of the present invention, a D-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ.

[0054] Preferably, the D-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0055] More preferably, the D-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0056] More preferably, the D-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0057] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the D-type crystal is shown in detail in the table below.

[0058] [Table 4]

[0059] In one embodiment, the D-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 14.

[0060] In one embodiment, the D-type crystal has the TGA pattern shown in Figure 15.

[0061] In one embodiment, the D-type crystal has the DSC pattern shown in Figure 16.

[0062] In one embodiment, the D-type crystal has the single-crystal structure shown in Figure 17.

[0063] In one embodiment of the present invention, an E-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 5.8°±0.2°, 6.3°±0.2°, 7.0°±0.2°, and 10.8°±0.2° of 2θ.

[0064] Preferably, the E-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0065] More preferably, the E-type crystal has an X-ray powder diffraction pattern with diffraction peaks at 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° of 2θ.

[0066] More preferably, the E-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0067] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the E-type crystal is shown in detail in the table below.

[0068] [Table 5]

[0069] In one embodiment, the E-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 18.

[0070] In one embodiment, the E-type crystal has the TGA pattern shown in Figure 19.

[0071] In one embodiment of the present invention, an F-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ.

[0072] Preferably, the F-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0073] More preferably, the F-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0074] More preferably, the F-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0075] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the F-type crystal is shown in detail in the table below.

[0076] [Table 6]

[0077] In one embodiment, the F-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 20.

[0078] In one embodiment, the F-type crystal has the TGA pattern shown in Figure 21.

[0079] In one embodiment, the F-type crystal has the DSC pattern shown in Figure 22.

[0080] In one embodiment, the F-type crystal is shown in Figure 23. 1 The 1H NMR spectrum is evaluated.

[0081] In one embodiment of the present invention, a G-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 6.3°±0.2°, 6.8°±0.2°, 13.9°±0.2°, and 15.3°±0.2° of 2θ.

[0082] Preferably, the G-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0083] More preferably, the G-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0084] More preferably, the G-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0085] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the G-type crystal is shown in detail in the table below.

[0086] [Table 7]

[0087] In one embodiment, the G-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 24.

[0088] In one embodiment, the G-type crystal has the TGA pattern shown in Figure 25.

[0089] In one embodiment, the G-type crystal has the DSC pattern shown in Figure 26.

[0090] In one embodiment of the present invention, an H-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ.

[0091] Preferably, the H-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0092] More preferably, the H-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0093] More preferably, the H-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0094] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the H-type crystal is shown in detail in the table below.

[0095] [Table 8]

[0096] In one embodiment, the H-type crystal exhibits endothermic peaks at starting temperatures of 220°C to 230°C and 260°C to 270°C in a thermal analysis chart measured by differential scanning calorimetry (DSC).

[0097] In one embodiment, the H-type crystal exhibits endothermic peaks at starting temperatures of 222°C to 226°C and 263°C to 268°C in a thermal analysis chart measured by differential scanning calorimetry (DSC).

[0098] In one embodiment, the H-type crystal exhibits endothermic peaks at starting temperatures of 224°C and 265°C in a thermal analysis chart measured by differential scanning calorimetry (DSC).

[0099] In one embodiment, the H-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 27.

[0100] In one embodiment, the H-type crystal has the TGA pattern shown in Figure 28.

[0101] In one embodiment, the H-type crystal has the DSC pattern shown in Figure 29.

[0102] In one embodiment of the present invention, a type I crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 6.8°±0.2°, 8.9°±0.2°, 20.7°±0.2°, and 30.1°±0.2° of 2θ.

[0103] Preferably, the type I crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0104] More preferably, the above-mentioned type I crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0105] More preferably, the type I crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0106] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the above-mentioned type I crystal is shown in detail in the table below.

[0107] [Table 9]

[0108] In one embodiment, the type I crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 30.

[0109] In one embodiment, the type I crystal has the TGA pattern shown in Figure 31.

[0110] In one embodiment, the type I crystal has the DSC pattern shown in Figure 32.

[0111] In one embodiment of the present invention, a J-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 6.7°±0.2°, 25.0°±0.2°, and 25.6°±0.2° of 2θ.

[0112] Preferably, the J-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 6.7°±0.2°, 8.7°±0.2°, 25.0°±0.2°, and 25.6°±0.2° of 2θ.

[0113] More preferably, the J-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0114] More preferably, the J-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0115] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the J-type crystal is shown in detail in the table below.

[0116] [Table 10]

[0117] In one embodiment, the J-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 33.

[0118] In one embodiment, the J-type crystal has the TGA pattern shown in Figure 34.

[0119] In one embodiment, the J-type crystal has the DSC pattern shown in Figure 35.

[0120] In one embodiment of the present invention, a K-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 6.2°±0.2°, 17.7°±0.2°, and 18.9°±0.2° of 2θ.

[0121] Preferably, the K-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 6.2°±0.2°, 16.8°±0.2°, 17.7°±0.2°, and 18.9°±0.2° of 2θ.

[0122] More preferably, the K-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0123] More preferably, the K-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0124] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the K-type crystal is shown in detail in the table below.

[0125] [Table 11]

[0126] In one embodiment, the K-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 36.

[0127] In one embodiment of the present invention, an L-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ.

[0128] Preferably, the L-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0129] More preferably, the L-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0130] More preferably, the L-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0131] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the L-type crystal is shown in detail in the table below.

[0132] [Table 12-1] [Table 12-2]

[0133] In one embodiment, the L-type crystal exhibits endothermic peaks at starting temperatures of 223°C to 233°C and 260°C to 270°C in a thermal analysis chart measured by differential scanning calorimetry (DSC).

[0134] In one embodiment, the L-type crystal exhibits endothermic peaks at starting temperatures of 225°C to 230°C and 263°C to 268°C in a thermal analysis chart measured by differential scanning calorimetry (DSC).

[0135] In one embodiment, the L-type crystal exhibits endothermic peaks at starting temperatures of 228°C and 265°C in a thermal analysis chart measured by differential scanning calorimetry (DSC).

[0136] In one embodiment, the L-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 37.

[0137] In one embodiment, the L-type crystal has the TGA pattern shown in Figure 38.

[0138] In one embodiment, the L-type crystal has the DSC pattern shown in Figure 39.

[0139] In one embodiment of the present invention, an M-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ.

[0140] Preferably, the M-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0141] More preferably, the M-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0142] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the M-type crystal is shown in detail in the table below.

[0143] [Table 13]

[0144] In one embodiment, the M-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 40.

[0145] In one embodiment, the M-type crystal has the TGA pattern shown in Figure 41.

[0146] In one embodiment, the M-type crystal has the DSC pattern shown in Figure 42.

[0147] In one embodiment of the present invention, an N-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 6.5°±0.2°, 7.0°±0.2°, 8.6°±0.2°, and 18.1°±0.2° of 2θ.

[0148] Preferably, the N-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0149] More preferably, the N-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0150] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the N-type crystal is shown in detail in the table below.

[0151] [Table 14]

[0152] In one embodiment, the N-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 43.

[0153] In one embodiment, the N-type crystal has the TGA pattern shown in Figure 44.

[0154] In one embodiment, the N-type crystal has the DSC pattern shown in Figure 45.

[0155] In one embodiment of the present invention, an O-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 7.3°±0.2° and 18.5°±0.2° of 2θ.

[0156] Preferably, the O-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 3.7°±0.2°, 7.3°±0.2°, 18.5°±0.2°, and 26.0°±0.2° of 2θ.

[0157] More preferably, the O-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0158] More preferably, the O-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0159] In one embodiment, the 2θ of the X-ray powder diffraction pattern of the O-type crystal is shown in detail in the table below.

[0160] [Table 15]

[0161] In one embodiment, the O-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 46.

[0162] In one embodiment, the O-type crystal has the TGA pattern shown in Figure 47.

[0163] In one embodiment, the O-type crystal has the DSC pattern shown in Figure 48.

[0164] In one embodiment of the present invention, a P-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, the X-ray powder diffraction pattern of which has diffraction peaks at 6.9°±0.2° and 18.2°±0.2° of 2θ.

[0165] Preferably, the P-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 6.2°±0.2°, 6.9°±0.2°, 13.9°±0.2°, and 18.2°±0.2° of 2θ.

[0166] More preferably, the P-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0167] More preferably, the P-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0168] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the P-type crystal is shown in detail in the table below.

[0169] [Table 16]

[0170] In one embodiment, the P-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 49.

[0171] In one embodiment, the P-type crystal has the TGA pattern shown in Figure 50.

[0172] In one embodiment, the P-type crystal has the DSC pattern shown in Figure 51.

[0173] In one embodiment of the present invention, a Q-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is provided, and its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ.

[0174] Preferably, the Q-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0175] More preferably, the Q-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0176] More preferably, the Q-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 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° of 2θ.

[0177] In one embodiment of the present invention, the 2θ of the X-ray powder diffraction pattern of the Q-type crystal is shown in detail in the table below.

[0178] [Table 17]

[0179] In one embodiment, the Q-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle, as shown in Figure 52.

[0180] In one embodiment, the Q-type crystal has the TGA pattern shown in Figure 53.

[0181] In one embodiment, the Q-type crystal has the DSC pattern shown in Figure 54.

[0182] In preferred embodiments of the present invention, the crystalline form of the compound is solvent-containing or solvent-free, where the solvent is one or more selected from water, methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, isobutanol, acetone, 2-butanone, 3-pentanone, dichloromethane, trichloromethane, ethyl formate, ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 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.

[0183] In a preferred embodiment of the present invention, the crystalline form of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is a solvent-containing or solvent-free crystalline form, where the solvent is one or more selected from water, ethanol, acetone, n-heptane, dichloromethane, trichloromethane, 2-butanone, tetrahydrofuran, and N,N-dimethylformamide.

[0184] In a preferred embodiment of the present invention, the crystal 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 one or more selected from water, ethanol, acetone, n-heptane, dichloromethane, trichloromethane, and tetrahydrofuran.

[0185] In a further preferred embodiment of the present invention, the crystal 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 crystal form.

[0186] In another aspect, the present invention further provides a method for producing a crystal form of a compound represented by formula I, including, but not limited to, an anti-solvent addition method, an inverse-anti-solvent addition method, a solvent evaporation method, a gas-solid diffusion method, a suspension stirring method, and a cooling crystallization method.

[0187] In one embodiment of the present invention, the method for producing a crystal form of a compound represented by formula I includes weighing an appropriate amount of the free base of the compound, adding and dissolving the corresponding positive solvent, filtering, and adding the corresponding anti-solvent while stirring the filtrate until a solid precipitates.

[0188] In one embodiment of the present invention, the method for producing a crystal form of a compound represented by formula I includes weighing an appropriate amount of the free base of the compound, adding and dissolving the corresponding positive solvent, filtering, and cooling the supernatant until a solid precipitates.

[0189] In one embodiment of the present invention, the method for producing a crystal form of a compound represented by formula I includes weighing an appropriate amount of the free base of the compound, adding and dissolving the corresponding positive solvent, and sealing until a solid precipitates.

[0190] In one embodiment of the present invention, the method for producing the crystalline form of the compound represented by Formula I includes the steps of weighing an appropriate amount of the free base of the compound, adding and dissolving the corresponding positive solvent, slurrying, drying, and collecting the solid.

[0191] In the present invention, the above positive solvent includes one or more of water, methanol, ethanol, acetone, 2-butanone, ethyl acetate, tetrahydrofuran, acetonitrile, n-hexane, n-heptane, dichloromethane, trichloromethane, 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, and preferably one or more of water, methanol, ethanol, acetonitrile, n-hexane, n-heptane, dichloromethane, trichloromethane, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, acetone, 2-butanone, ethyl acetate, 1,4-dioxane, isopropanol, isopropyl acetate, and methyl isobutyl ketone.

[0192] In the present invention, the above antisolvent 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, and preferably one or more of methyl tert-butyl ether, n-heptane, isopropyl acetate, acetonitrile, isopropyl ether, n-hexane, water, tert-butanol, cyclohexane, and toluene.

[0193] In another aspect, the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of the compound represented by Formula I above.

[0194] In another embodiment, the present invention further 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.

[0195] The pharmaceutical compositions described in the present invention may be administered by any suitable route or method, for example, orally or parenterally (e.g., intravenously). The therapeutically effective dose of the crystalline form of the above compound is approximately 1 mg to 1 g / kg body weight / day.

[0196] For oral administration, the pharmaceutical compositions of the present invention are usually provided in the form of tablets, capsules, or solutions. Tablets may contain the crystalline form of the compound of the present invention and a pharmaceutically acceptable carrier. The carrier may include, but is not limited to, diluents, disintegrants, binders, and lubricants.

[0197] For parenteral administration, the pharmaceutical composition of the present invention may be administered by intravenous injection, intramuscular injection, or subcutaneous injection. Generally, it is provided as a sterile aqueous solution or suspension, or as a lyophilized powder, and is adjusted to an appropriate pH and isotonicity.

[0198] In another embodiment, the present invention further provides the use of the crystalline form of the compound or a pharmaceutical composition thereof in the manufacture of a drug for preventing and / or treating a MAT2A-mediated disease or disease condition.

[0199] In another embodiment, the present invention further provides a method for preventing and / or treating a MAT2A-mediated disease or disease condition, comprising administering an effective amount of the crystalline form of the compound or a pharmaceutical composition thereof to an individual in need.

[0200] In another embodiment, the present invention further provides crystalline forms of the above-mentioned compounds or pharmaceutical compositions of the present invention for preventing and / or treating MAT2A-mediated diseases or disease conditions. Examples of the above-mentioned MAT2A-mediated diseases or disease conditions include colorectal cancer.

[0201] In some specific embodiments, the MAT2A-mediated disease is a MAT2A overexpression-mediated disease.

[0202] Related definitions Unless otherwise specified, the following terms used in the specification and claims have the meanings set forth below.

[0203] The terms “optional” or “optionally” refer to whether or not the event or situation described thereafter may or may not occur, and such description includes both cases in which the event or situation occurs and cases in which it does not occur.

[0204] In this specification, the range of numbers refers to each integer within a given range. For example, "C1-C6" means that the group may have one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms. "C3-C6" means that the group may have three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms.

[0205] The term "member" refers to the number of skeletal atoms or atomic groups that make up a ring. For example, "5-7 member" means that the number of skeletal atoms or atomic groups that make up the ring is 5, 6, or 7. Therefore, for example, pyridine, piperidine, piperazine, and benzene are 6-membered rings, while thiophene and pyrrole are 5-membered rings.

[0206] The term "substituted" means that one or more hydrogen atoms in a particular group are replaced by a substituent, provided that the valence of that group remains normal and the resulting compound is stable. For example, "halogen-substituted" means that one or more hydrogen atoms in a particular group are replaced by a halogen, provided that the valence of that group remains normal and the resulting compound is stable.

[0207] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group containing a straight-chain or branched-chain saturated hydrocarbon group, and the above hydrocarbon group has the indicated number of carbon atoms. For example, the term "C1-C6 alkyl group" includes a C1 alkyl group, a C2 alkyl group, a C3 alkyl group, a C4 alkyl group, a C5 alkyl group or a C6 alkyl group, and examples thereof include, but are not limited to, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, a 2-pentyl group, a 3-pentyl group, an n-hexyl group, a 2-hexyl group or a 3-hexyl group.

[0208] The term "cycloalkyl group" refers to a monocyclic saturated hydrocarbon system without heteroatoms and without double bonds. Examples of the "3- to 6-member cycloalkyl group" include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

[0209] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0210] The term "aryl group" refers to a fully carbon monocyclic or fused bicyclic aromatic ring group having a conjugated π electron system, which is obtained by removing one hydrogen atom from a single carbon atom of the parent aromatic ring system. It includes bicyclic groups fused to a saturated ring, a partially unsaturated ring or an aromatic carbon ring, and examples thereof include, but are not limited to, a phenyl group, a naphthyl group, an anthryl group, indene, indane, 1,2-dihydronaphthalene or 1,2,3,4-tetrahydronaphthalene.

[0211] The term "heteroaryl group" refers to a monovalent aryl group containing at least one heteroatom independently selected from nitrogen, oxygen and sulfur. For example, examples of the "5- to 7-member heteroaryl group" include, but are not limited to, a pyridyl group, a thienyl group, an imidazolyl group, a pyrimidinyl group, a pyridyl group, a furanyl group, a pyrazinyl group or a thiazolyl group.

[0212] The term "9-18 membered benzoheterocyclyl group" refers to a ring system having 9-18 ring atoms or ring groups formed by the condensation of a benzene ring and a heterocycle, where the benzene ring and heterocycle share a pair of adjacent ring atoms, and the linkage site to the parent nucleus structure is located in the benzene ring portion. Here, the heterocycle portion is a 5-12 membered saturated, partially unsaturated, or fully unsaturated ring system having a ring carbon atom and 1-4 ring heteroatoms or heterogroups, where the heteroatoms or heterogroups are independently nitrogen, sulfur, oxygen, sulfoxide, sulfone, or the following groups [ka] Selected from: The heterocycle may be a monocycle, dicycle, or tricycle, where two or more rings exist in the form of a connecting ring, a spirocycle, or a bridging ring. Examples are: [ka] or [ka] This includes, but is not limited to, the following:

[0213] [ka] in [ka] This refers to the linking site of a chemical bond. It can be bicyclic or polycyclic. [ka] If a nucleotide appears and its linkage position is unknown, then, as long as the valence is acceptable, the linkage site is [ka] This indicates that it is limited to any atom in the monoring where it is located. For example, [ka] This indicates that the linking site must be located only on any carbon atom in the bicyclic benzene ring and satisfy the requirements for a valence bond.

[0214] The "X-ray powder diffraction pattern" in this invention was measured using Cu-Kα rays. It should be noted that in X-ray powder diffraction patterns (XRD), the diffraction pattern obtained from a crystalline compound is often characteristic of a particular crystal, and the relative intensity of the bands (especially at low angles) may change due to preferential orientation effects caused by differences in crystal conditions, grain size, and other measurement conditions. Therefore, the relative intensity of the diffraction peaks is not characteristic of the target crystal. When determining whether it is the same as a known crystal, more attention should be paid to the relative position of the peaks rather than their relative intensity. Also, for any given crystal type, there may be slight errors in the position of the peaks, which is well known in the field of crystallography. For example, the position of the peaks can shift due to changes in temperature during sample analysis, sample movement, or instrument calibration, and the measurement error of the 2θ value may be approximately ±0.5° or approximately ±0.2°. Therefore, when determining each crystal structure, this error must be taken into consideration. If the deviation of the shift 2θ of the important characteristic peaks is around ±0.5°, and especially around ±0.2°, then they can all be identified as the same crystal type.

[0215] Differential scanning calorimetry (DSC) measures the transition temperature at which a crystal absorbs or releases heat due to a change in its crystal structure or melting. For the same crystalline form of the same compound, the error in thermal transition temperature and melting point in a series of analyses is typically within approximately 5°C, and usually within approximately 3°C. When a compound is described as having a particular DSC peak or melting point, this refers to ±5°C of that DSC peak or melting point. DSC provides an auxiliary method for identifying different crystalline forms. Different crystalline forms can be distinguished by their different transition temperature characteristics. For mixtures, it should be noted that their DSC peaks or melting points may vary over a wider range. Furthermore, since substances decompose during the melting process, the melting temperature is related to the heating rate.

[0216] Thermogravimetric analysis (TGA) refers to a thermal analysis technique that measures the relationship between the mass and temperature change of a sample awaiting measurement at a program-controlled temperature. When the substance being measured sublimes or vaporizes during heating, its mass changes as it decomposes into gas or loses water of crystallization. In this case, the thermogravimetric curve is not a straight line but shows a downward trend. By analyzing the thermogravimetric curve, it is possible not only to know at what temperature the substance being measured changes, but also to calculate the amount of substance lost based on the weight loss.

[0217] For example, when referring to XRD patterns, DSC patterns, or TGA patterns, the term "shown in..." includes patterns that are within the limits of experimental error, although this is not necessarily the same as that described herein.

[0218] The term "effective dose" or "therapeutic dose" refers to a sufficient amount of a drug or medication that is non-toxic but capable of achieving the desired effect.

[0219] The term "pharmaceutically acceptable carrier" refers to a carrier that does not have any apparent irritant effect on living organisms and does not impair the biological activity and performance of the active compound. This includes, but is not limited to, any diluent, disintegrant, binder, flow enhancer, or wetting agent approved by the China National Food and Drug Administration for use in humans or animals.

[0220] The meanings of the abbreviations used in the claims and specification are as follows:

[0221] M: mol / L, mM: mmol / L, μM: μmol / L, nM: nmol / L, LCMS: Liquid Chromatography-Mass Spectrometry Brij35: Lauryl polyoxyethylene ether, BSA: Bovine serum albumin, DMSO: Dimethyl sulfoxide, rpm: revolutions per minute, Tris-HCl: Tris(hydroxymethyl)aminomethane hydrochloride, OD 620 Absorbance value at a wavelength of 620 nm, SAM: S-adenosylmethionine or S-adenosylmethionine, MeOH: methanol, 1,4-Dioxane: 1,4-dioxane, EtOH: Ethanol, MIBK: Methyl isobutyl ketone, IPA: Isopropanol, acetate: ethyl acetate, IPAc: Isopropyl acetate, ACN: Acetonitrile, DMF: N,N-dimethylformamide, DCM: Dichloromethane, DMAc: N,N-dimethylacetamide, CHCl3: Trichloromethane, Acetone: Acetone, MEK:2-butanone, MTBE: Methyl tert-butyl ether, THF: Tetrahydrofuran. [Brief explanation of the drawing]

[0222] [Figure 1] This is the tumor inhibition curve of the HCT116 MTAP- / - transplanted tumor model in Test Example 3. [Figure 2] This shows the results of intratumoral SAM inhibition in the HCT116 MTAP- / - transplanted tumor model in Test Example 3. [Figure 3] This is the tumor inhibition curve of the KP-4 transplanted tumor model in Test Example 4. [Figure 4] This shows the results of intratumoral SAM inhibition in a KP-4 transplanted tumor model in Test Example 4. [Figure 5] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one type A crystal. [Figure 6] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one type A crystal. [Figure 7] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one type A crystal. [Figure 8] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one type B crystal. [Figure 9]This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one type B crystal. [Figure 10] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one type B crystal. [Figure 11] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one C-type crystal. [Figure 12] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one C-type crystal. [Figure 13] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one C-type crystal. [Figure 14] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one D-type crystal. [Figure 15] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one D-type crystal. [Figure 16] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one D-type crystal. [Figure 17] This is a schematic diagram (along the a-axis) of the molecular deposition structure in the single crystal structure of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one D-type crystal. [Figure 18] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one E-type crystal. [Figure 19] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one E-type crystal. [Figure 20] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one F-type crystal. [Figure 21] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one F-type crystal. [Figure 22] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one F-type crystal. [Figure 23] This is the 1H NMR spectrum of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one F-type crystal. [Figure 24]This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one G-type crystal. [Figure 25] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one G-type crystal. [Figure 26] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one G-type crystal. [Figure 27] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one H-type crystal. [Figure 28] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one H-type crystal. [Figure 29] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one H-type crystal. [Figure 30] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one type I crystal. [Figure 31] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one type I crystal. [Figure 32] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one type I crystal. [Figure 33] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one J-type crystal. [Figure 34] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one J-type crystal. [Figure 35] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one J-type crystal. [Figure 36] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one K-type crystal. [Figure 37] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one L-type crystal. [Figure 38] This is the TGA pattern of the L-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one. [Figure 39]This is the DSC pattern of the L-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one. [Figure 40] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one M-type crystal. [Figure 41] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one M-type crystal. [Figure 42] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one M-type crystal. [Figure 43] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one N-type crystal. [Figure 44] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one N-type crystal. [Figure 45] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one N-type crystal. [Figure 46] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one O-type crystal. [Figure 47] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one O-type crystal. [Figure 48] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one O-type crystal. [Figure 49] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one P-type crystal. [Figure 50] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one P-type crystal. [Figure 51] This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one P-type crystal. [Figure 52] This is the X-ray powder diffraction pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one Q-type crystal. [Figure 53] This is the TGA pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one Q-type crystal. [Figure 54]This is the DSC pattern of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one Q-type crystal. [Modes for carrying out the invention]

[0223] The following describes in more detail the methods for producing the compounds of the present invention, but these specific production methods do not limit the scope of the present invention. Furthermore, the reaction conditions, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, and reaction time, are not limited to the examples below.

[0224] The compounds of the present invention can also be conveniently produced by selectively combining various synthetic methods described herein or known in the art, such combinations can be readily performed by those skilled in the art.

[0225] Example 1: 2-Cyclopropyl-7,9-bis[4-(difluoromethoxy)phenyl]-8H-pyrimido[1,2-b]pyridazine-8-one [ka] a) Preparation of N-(5-methoxypyridazine-3-yl)acetamide 3-chloro-5-methoxypyridazine (1 g), acetamide (0.61 g), tridibenzylideneacetone dipalladium (0.32 g), 4,5-bisdiphenylphosphine-9,9-dimethyloxazine (0.40 g), and cesium carbonate (6.76 g) were added in order to a reaction flask, and 1,4-dioxane (100 mL) was added. The mixture was stirred at 100°C for 3 hours under nitrogen gas protection, concentrated under reduced pressure, and a dry residue was obtained. This residue was extracted with ethyl acetate (3 × 50 mL), the combined organic phase was washed with saturated saline solution (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The compound was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 10 / 1 (V / V)) to obtain 780 mg of the title compound. LCMS m / z = 168.05[M+1]+

[0226] b) Preparation of 6-aminopyridazine-4(1H)-one N-(5-methoxypyridazin-3-yl)acetamide (500 mg) and hydrochloric acid aqueous solution (15 mL) were added to a microwave tube, and the mixture was stirred at 140°C for 5 hours under microwave irradiation. The mixture was then concentrated under reduced pressure to obtain 360 mg of the title compound. LCMS m / z = 111.95[M+1]+

[0227] c) Preparation of 6-amino-3,5-dibromopyridazine-4(1H)-one 6-aminopyridazine-4(1H)-one (360 mg) and N-bromosuccinimide (1.73 g) were added to a reaction flask, and the mixture was stirred in N,N-dimethylformamide (4 mL) at room temperature for 2 hours. The mixture was then concentrated under reduced pressure and evaporated to obtain the residue, which was washed with acetonitrile (3 × 5 mL) to obtain 360 mg of the title compound.

[0228] d) Preparation of 6-amino-3,5-dibromo-1-[(1E)-3-cyclopropyl-3-oxoprop-1-en-1-yl]pyridazine-4(1H)-one 6-amino-3,5-dibromopyridazine-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 to a reaction flask. The mixture was stirred overnight at 25°C in N,N-dimethylformamide (43 mL) and 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 × 10 mL) to obtain 335 mg of the title compound.

[0229] e) Preparation of 7,9-dibromo-2-cyclopropyl-8H-pyrimido[1,2-b]pyridazine-8one 6-amino-3,5-dibromo-1-[(1E)-3-cyclopropyl-3-oxoprop-1-en-1-yl]pyridazine-4(1H)-one (355 mg) was added to a reaction flask, and a 2 mol / L solution of 1,4-dioxane (10 mL) in hydrogen chloride was further added. The mixture was stirred at 25°C for 1 hour, concentrated under reduced pressure, and a dry residue was obtained. The residue was washed with an aqueous solution of sodium bicarbonate (1 × 10 mL), filtered, and the filter cake was collected. The mixture was then washed with water (3 × 5 mL) to obtain 320 mg of the title compound.

[0230] f) Preparation of 2-cyclopropyl-7,9-bis[4-(difluoromethoxy)phenyl]-8H-pyrimido[1,2-b]pyridazine-8one 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) were added to a reaction flask, stirred at 80 °C for 1 hour under nitrogen gas protection, concentrated under reduced pressure to obtain a dried residue, and 37 mg of the title compound was obtained by preparative separation. The preparative separation conditions were as follows: column: XBridge Prep OBD 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: elute with 45% B - 85% B from 0 to 10 min and with 85% B after 10 min; detection wavelength: UV 220 nm; retention time (min): 7.32.

[0231] 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 7.2 Hz, 1H), 8.27 - 8.21 (m, 2H), 7.64 - 7.58 (m, 2H), 7.56 - 7.26 (m, 3H), 7.21 - 7.11 (m, 3H), 7.07 (d, J = 7.2 Hz, 1H), 2.20 (tt, J = 8.1, 4.5 Hz, 1H), 1.18 - 1.10 (m, 2H), 1.01 (p, J = 3.8 Hz, 2H). LCMS m / z = 472 [M+H]+

[0232] Example 2: 7,9-Bis(benzo[d][1,3]dioxol-5-yl)-2-cyclopropyl-8H-pyrimido[1,2-b]pyridazin-8-one

Chemical formula

[0233] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 7.2 Hz, 1H), 7.88 (dd, J = 8.3, 1.7 Hz, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.09 - 6.99 (m, 4H), 6.93 (d, J = 8.0 Hz, 1H), 6.11 (s, 2H), 6.04 (s, 2H), 2.18 (td, J = 8.0, 4.1 Hz, 1H), 1.12 (dt, J = 6.7, 3.4 Hz, 2H), 1.01 (t, J = 3.8 Hz, 2H). LCMS m / z = 428 [M+1]+

[0234] Example 3: 2-Cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one [ka] a) Preparation of 9-bromo-2-cyclopropyl-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8-one 7,9-Dibromo-2-cyclopropyl-8H-pyrimido[1,2-b]pyridazin-8-one (50 mg), 2-methylindazole-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) were added sequentially to a reaction flask. The mixture was stirred at 60°C for 1 hour under nitrogen gas protection, and the reaction product was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 4 / 1 (V / V)) to obtain 40 mg of the title compound.

[0235] 1 H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.81 (d, J = 7.1 Hz, 1H), 8.54 (s, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.14 (d, J = 7.1 Hz, 1H), 4.20 (s, 3H), 2.34 (s, 1H), 1.46 - 1.10 (m, 4H). LCMS m / z = 396[M+1]+

[0236] b) Preparation of 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-8one 9-bromo-2-cyclopropyl-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazine-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) were added sequentially to a reaction flask. The mixture was stirred at 80°C for 1 hour under nitrogen gas protection, and the reaction product was concentrated under reduced pressure. The title compound was obtained by preparative separation to yield 14.4 mg. The preparative separation conditions were as follows: Column: XBridge PrepOBD C18 column, 30 × 150 mm, 5 μm; Column temperature: 25°C; Mobile phase A: Water (10 mmol / LNH4HCO3), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: Elution occurs at 25%B to 70%B at 0 to 10 mins, and at 85%B after 10 mins; Detection wavelength: UV 220 nm; Retention time (min): 6.8.

[0237] 1 H NMR (400 MHz, DMSO-d6) 8.97 (s, 1H), 8.76 (d, J = 7.2 Hz, 1H), 8.52 (s, 1H), 7.97 (dd, J = 9.2, 1.6 Hz, 1H), 7.68 - 7.59 (m, 3H), 7.31 (t, J = 74.4 Hz, 1H), 7.22 - 7.16 (m, 2H), 7.06 (d, J = 7.2 Hz, 1H), 4.20 (s, 3H), 2.19 (dq, J = 8.1, 4.6, 4.0 Hz, 1H), 1.13 (dd, J = 7.8, 3.5 Hz, 2H), 1.02 (t, J (= 3.8 Hz, 2H). LCMS m / z = 460[M+1]+

[0238] Test Example 1: Biological Activity Test 1. MAT2A Enzymatic Test Method 1. Experimental Procedure a) First, a 5×MAT2A test buffer (250 mM Tris-HCl, pH 8.0, 250 mM KCl, 75 mM MgCl2, 0.025% BSA, 0.05% Brij35, 1.5 mM EDTA) was prepared, and a portion was diluted to 1× for use.

[0239] 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) using 1× MAT2A test buffer. Using a BioTek (MultiFlo FX) automated separatory system, 15 μL of the 1.67× MAT2A enzyme solution was added to the compound test well and the negative control well, respectively, while simultaneously adding 15 μL of 1× MAT2A test buffer to the blank control well.

[0240] c) Preparation and addition of compounds: The compounds awaiting measurement were diluted with DMSO from a 10 mM stock solution to 100 μM. The positive reagent AGI-24512 was diluted under similar conditions and automatically injected into each well according to a preset concentration gradient using a Tecan compound titrator (D300e). The injection volume was very small and negligible. The concentration gradient started at 1 μM, and was diluted by 1 / 2 log, creating a total of 8 gradients. The mixtures were centrifuged at 2500 rpm for 30 seconds and incubated at 25°C for 30 minutes.

[0241] d) Preparation of ATP: 10 mM ATP (Sigma, A7699) was diluted to 700 μM using 1 × MAT2A test buffer to prepare for use.

[0242] e) Preparation and addition of substrate-ATP mixture: 3 μL / well of 5×MAT2A test buffer, 2.5 μL / well of 750 μM L-methionine (Adamas, 01100469), 2.5 μL / well of 700 μM ATP, and 2 μL / well of double-distilled water. Prepare the required total volume of mixture according to the number of detection wells, add 10 μL to each well using a BioTek (MultiFlo FX) automatic separatory, centrifuge at 2500 rpm for 30 seconds, and react at 25°C for 150 minutes.

[0243] 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) automatic pipettor, centrifuged at 2500 rpm for 30 s, and incubated at 25 °C for 20 min.

[0244] g) After the reaction, the OD 620 value was read using a Perkin Elmer (Envision 2105) multifunctional plate reader.

[0245] 2. Data analysis The calculation formula for the inhibition rate is as follows:

Equation

[0246] Furthermore, a dose - effect curve was fitted using GraphPad Prism 5 software log(inhibitor) vs. response - Variable slope to obtain the inhibition IC 50 value of the compound against the MAT2A enzyme.

[0247] II. Cell test method 1. Experimental procedure HCT116 MTAP- / - cells (purchased from Horizon Discovery): Human colorectal cancer cell lines lacking the MTAP gene were cultured in RPMI 1640 + 10% FBS (fetal bovine serum). On day 0 of the experiment, the viable cell density of the above cells in the logarithmic growth phase was adjusted to 5000 cells / mL, and these cells were inoculated into 96-well plates at a rate of 100 μL / well. Blank cells were placed in parallel, and the inoculated cell plates were cultured overnight in an incubator at 37°C with 5% CO2.

[0248] On the first day of the experiment, the cell plates, cultured overnight, were removed, the supernatant was discarded, and 80 μL of serum-free RPMI 1640 medium was added to each well. The cells were then cultured in a starved state in an incubator for 4 hours. The compounds awaiting measurement were dissolved in DMSO (Dimethyl sulfoxide) to prepare a 10 mM compound liquor. After ending the starved state, the cell plates were removed, and 80 μL of RPMI 1640 + 20% FBS medium was added to each well. The cell plates were placed in an automated liquid dispenser D300e (Tecan), and the drug dosing program was set so that the maximum concentration of the compound test was 30 μM, and a 3-fold gradient dilution with DMSO was performed, resulting in a total of 10 concentrations. Two parallel wells were set for each concentration, and the final DMSO concentration in each well of the 96-well plate was set to 0.3%, v / v. The pre-prepared 10 mM compound liquor awaiting measurement was taken out and administered using the above drug dosing program. After the completion of medication, the cell plates were placed in an incubator and cultured for 120 hours.

[0249] On the sixth day of the experiment, the cell plate was removed, 50 μL of CellTiter-Glo® (purchased from Promega) was added to each well, and the fluorescence signal was measured using Envision (PerkinElmer) according to the operating flow in the instruction manual.

[0250] 2. Data Analysis Using GraphPad Prism 5 software, log(inhibitor)vs.response-Variable slope, we fitted dose-effect curves and evaluated the IC of compounds inhibiting cell proliferation. 50 The value was obtained. Formula for calculating the inhibition rate:

number

[0251] III. Experimental results: Inhibition IC on MAT2A by AGI-24512 as measured by the experimental method described above 50 The value was 26.79 nM.

[0252] AGI-24512 structure: [ka] The experimental results for the compounds of the present invention are shown in Table 18 below.

[0253] [Table 18]

[0254] Study Example 2: In vivo pharmacokinetic study of ICR mice 1. Experimental Procedure Male ICR mice (6-10 weeks old, Weitong Lihua Experimental Animal Technology Co., Ltd.) were reared in an SPF animal rearing room at a temperature of 20-25°C, relative humidity of 40-70%, and under 12 hours of light and dark lighting each day. The animals were given free access to water and food. After at least 5 days of normal rearing, mice with good physical condition were registered for this experiment based on veterinary examination. Each mouse was numbered on its tail.

[0255] The day before the experiment, the mice were fasted overnight, given free access to water, and fed 4 hours after administration. The compound was prepared as a 20 mg / mL stock solution with DMSO, an appropriate volume of the 20 mg / mL stock solution was accurately drawn into a glass bottle, an appropriate volume of PEG400 was added, and after homogeneous mixing, propylene glycol (PG) was added. The solvent ratio in the final formulation was DMSO:PEG400:PG(v / v / v)=5:65:30, and administration reagents of each compound awaiting measurement at a concentration of 1 mg / mL were obtained.

[0256] After weighing the mice, the theoretical dose volume for each mouse was calculated according to the following formula. The actual dose and blood sample collection time for each mouse must be recorded in detail in the corresponding table.

number

[0257] On the day of the experiment, mice in each group were administered intragastricly at a dose of 10 mg / kg of the reagent for each compound awaiting measurement. After administration, approximately 40 μL of blood was collected from the orbit of each mouse at each time point and placed in an EDTA-K2 anticoagulation tube. The whole blood samples were centrifuged at 1500-1600 g for 10 minutes, and the resulting plasma was stored in a refrigerator at -40 to -20°C and used for biological sample analysis.

[0258] 2. Data Analysis The concentrations of compounds in biological samples obtained from experiments were measured using LC-MS / MS analysis. Pharmacokinetic parameters were calculated using a non-compartmental model in Pharsight Phoenix 7.0.

[0259] 3. Experimental Results The calculation results for pharmacokinetic parameters are shown in Table 19 below.

[0260] [Table 19]

[0261] Test Example 3: HCT116 MTAP - / - In vivo drug efficacy experiments of subcutaneous xenograft tumors in nude mice 1. Experimental Procedure Female Nu / Nu nude mice (6-8 weeks old, Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.) were housed in an SPF animal rearing room at a temperature of 20-25°C, relative humidity of 40-70%, and 12 hours each of light and dark lighting. The animals were given free access to water and food. Adaptive feeding was administered to the animals before the experiment.

[0262] HCT116 MTAP - / - Cells (Horizon) were cultured and amplified in vitro, and cells in the logarithmic growth phase were collected and resuspended in serum-free RPMI-1640 medium to a cell concentration of 6.0 × 10⁶. 7 The cell suspension was adjusted to a cell / mL concentration and injected subcutaneously into the anterior right axilla of nude mice using a 1 mL syringe. 100 μL was injected into each animal, and the animals' condition was regularly observed to monitor the growth of the transplanted tumors.

[0263] Tumor volume is 100-300 mm 3 Upon reaching a certain stage, animals with excessively large or small tumor volumes, or those with unclear tumor formation, were excluded. Tumor mice in good health with similar tumor volumes were selected and randomized into groups. The treatment group received daily intragastric administration (AG-270: 50 mg / kg, structure shown below; compound awaiting measurement: 5 mg / kg), while the control group received the same volume of blank solvent intragastricly daily. Tumor diameter was measured twice a week during the administration period, and tumor volume was calculated. Simultaneously, the body weight of the animals was weighed and recorded.

[0264] Detection of SAM in transplanted tumors: At the end of the experiment, the animals were euthanized with CO2, the tumor tissue was removed, thoroughly washed with cold PBS, weighed, rapidly frozen with liquid nitrogen, and then stored at low temperature (-80°C) for use. The frozen tumor tissue was removed, thawed in an ice bath, and then an 80% methanol aqueous solution (containing 1M formic acid) was added. The ratio of tumor tissue to methanol aqueous solution (containing 1M formic acid) was 1:10 (w / v), and the tissue was homogenized. After homogenization, the homogenized solution was collected, and SAM (S-adenosylmethionine) was detected using LC-MS / MS after processing.

[0265] AG-270 structure: [ka]

[0266] 2. Data Analysis The formula for calculating tumor volume (TV) is TV = 1 / 2 × a × b 2 Here, a represents the longest diameter of the tumor, and b represents the shortest diameter of the tumor.

[0267] The formula for calculating relative tumor volume (RTV) is RTV = TV t / TV initial And here, TV initial This is the tumor volume measured at the time of group administration, TV t This represents the tumor volume at each measurement during the administration period.

[0268] The formula for calculating the relative tumor growth rate (T / C(%)) is T / C% = (RTV T / RTV C ) × 100%, and here, RTV T This shows the relative tumor volume in the treatment group, RTV C This shows the relative tumor volume of the solvent control group.

[0269] The formula for calculating tumor growth inhibition rate (TGI (%)) is: TGI = [1 - (TV t(T)-TV initial(T) ) / (TV t(C) -TV initial(C) ) × 100%, and here, TV t(T) The numbers indicate the tumor volume for each measurement in the treatment group, and TV initial(T) This shows the tumor volume of the treatment group at the time of group administration, TV t(C) The graph shows the tumor volume for each measurement in the solvent control group, and TV initial(C) The graph shows the tumor volume in the solvent control group during group administration.

[0270] The formula for calculating the percentage of weight loss in an animal is: Percentage of weight loss in an animal = 100% × (BW initial -BW t ) / BW initial And here, BW t The numbers indicate the animal body weight at each measurement during the administration period, BW initial The numbers indicate the animal body weight at the time of group administration.

[0271] The formula for calculating the tumor weight inhibition rate (IR) is IR = 100% × (W C -W T ) / W C And here, W C The graph shows the tumor weight of the control group, W T This indicates the tumor weight in the treatment group.

[0272] The test data were calculated and statistically processed using Microsoft Office Excel 2007 software. Unless otherwise specified, the data are expressed as mean ± standard error (Mean ± SE), and t-tests were used for comparisons between two groups.

[0273] 3. Experimental Results HCT116 MTAP - / - The tumor inhibition curves and intratumor SAM inhibition results for the transplanted tumor model are shown in Figures 1 and 2, respectively.

[0274] Test Example 4: In vivo efficacy experiment of subcutaneous xenograft tumors in KP-4 mice 1. Experimental Procedure Female NOD SCID mice (6-8 weeks old, Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.) were housed in an SPF animal rearing room at a temperature of 20-25°C, relative humidity of 40-70%, and under 12 hours of light and dark lighting each day. The animals were given free access to water and food. The animals were given adaptive feeding before the experiment.

[0275] KP-4 cells (Nanjing Kebai Biotechnology Co., Ltd.) were cultured and amplified in vitro, and cells in the logarithmic growth phase were collected and resuspended in serum-free RPMI-1640 medium, with a cell concentration of 1.0 × 10⁶. 8 The cell suspension was adjusted to a cell / mL concentration and injected subcutaneously into the anterior right axilla of nude mice using a 1 mL syringe. 100 μL was injected into each animal, and the animals' condition was regularly observed to monitor the growth of the transplanted tumors.

[0276] Tumor volume is 80-100 mm 3 Upon reaching a certain stage, animals with excessively large or small tumor volumes, or those with unclear tumor formation, were excluded. Tumor mice in good health with similar tumor volumes were selected and randomized into groups. The treatment group received daily intragastric administration (AG-270: 100 mg / kg, compound awaiting measurement: 2.5 mg / kg), while the control group received the same volume of blank solvent intragastricly daily. Tumor diameter was measured twice a week during the administration period, and tumor volume was calculated. Simultaneously, the body weight of the animals was weighed and recorded.

[0277] Detection of SAM in transplanted tumors: At the end of the experiment, the animals were euthanized with CO2, the tumor tissue was removed, thoroughly washed with cold PBS, weighed, rapidly frozen with liquid nitrogen, and then stored at low temperature (-80°C) for use. The frozen tumor tissue was removed, thawed in an ice bath, and then an 80% methanol aqueous solution (containing 1M formic acid) was added. The ratio of tumor tissue to methanol aqueous solution (containing 1M formic acid) was 1:10 (w / v), and the tissue was homogenized. After homogenization, the homogenized solution was collected, and SAM (S-adenosylmethionine) was detected using LC-MS / MS after processing.

[0278] 2. Data Analysis The formula for calculating tumor volume (TV) is TV = 1 / 2 × a × b 2 Here, a represents the longest diameter of the tumor, and b represents the shortest diameter of the tumor.

[0279] The formula for calculating relative tumor volume (RTV) is RTV = TV t / TV initial And here, TV initial This is the tumor volume measured at the time of group administration, TV t This represents the tumor volume at each measurement during the administration period.

[0280] The formula for calculating the relative tumor growth rate (T / C(%)) is T / C% = (RTV T / RTV C ) × 100%, and here, RTV T This shows the relative tumor volume in the treatment group, RTV C This shows the relative tumor volume of the solvent control group.

[0281] The formula for calculating tumor growth inhibition rate (TGI (%)) is: TGI = [1 - (TV t(T) -TV initial(T) ) / (TV t(C) -TV initial(C) ) × 100%, and here, TV t(T) The numbers indicate the tumor volume for each measurement in the treatment group, and TV initial(T) This shows the tumor volume of the treatment group at the time of group administration, TV t(C) The graph shows the tumor volume for each measurement in the solvent control group, and TV initial(C) The graph shows the tumor volume in the solvent control group during group administration.

[0282] The formula for calculating the percentage of weight loss in an animal is: Percentage of weight loss in an animal = 100% × (BW initial -BW t ) / BW initial And here, BW t The numbers indicate the animal body weight at each measurement during the administration period, BW initial The numbers indicate the animal body weight at the time of group administration.

[0283] The formula for calculating the tumor weight inhibition rate (IR) is IR = 100% × (W C -W T ) / W C And here, W C The graph shows the tumor weight of the control group, W T This indicates the tumor weight in the treatment group.

[0284] The test data were calculated and statistically processed using Microsoft Office Excel 2007 software. Unless otherwise specified, the data are expressed as mean ± standard error (Mean ± SE), and t-tests were used for comparisons between two groups.

[0285] 3. Experimental Results The tumor inhibition curves and intratumor SAM inhibition results for the KP-4 transplanted tumor model are shown in Figures 3 and 4, respectively.

[0286] Experiment Example 5: Study of Crystalline Polymorphism The following specific descriptions of the production and characterization of crystal types do not limit the scope of the claims of the present invention, and those skilled in the art can obtain more crystals of the compounds of the present invention based on the present invention, all of which are protected by the present invention. Specifically, these are as follows:

[0287] 1. Equipment Test Information [Table 20]

[0288] [Table 21]

[0289] [Table 22]

[0290] 2. Preparation of buffer solution 2.1. Hydrochloric acid solution with pH 1.0: 9.00 mL of hydrochloric acid was taken, diluted with water to 1000 mL, and uniformly shaken to obtain the solution.

[0291] 2.2. Phosphate buffer: 0.2 mol / L potassium dihydrogen phosphate solution: 27.22 g of potassium dihydrogen phosphate was taken, dissolved in water, and diluted to 1000 mL.

[0292] 0.2 mol / L sodium hydroxide solution: 8.00 g of sodium hydroxide was taken, dissolved in water, and diluted to 1000 mL.

[0293] 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution was taken, mixed with the specified amount of 0.2 mol / L sodium hydroxide solution shown in the table below, then diluted with water to 1000 mL, and uniformly shaken to obtain the solution.

[0294] [Table 23]

[0295] 3. Manufacturing of crystal forms A-type to Q-type crystals of 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one were prepared.

[0296] 3.1. Manufacturing of Type A Crystals In the reaction flask, add 9-bromo-2-cyclopropyl-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one (3.8g), 4-(difluoromethoxy)phenylboronic acid (3.6g), potassium carbonate (3.98g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.78g), and 1,4-dioxane ( 40 mL of [compound name], 8 mL of water, and nitrogen gas protection were used to stir and react at 80°C for 2 hours. The reactant was concentrated under reduced pressure and purified by column chromatography (DCM: EA = 0%~100%) to obtain a crude product (1.5 g). The crude product was slurryed with DMF / MeCN (5 mL: 5 mL), filtered, and the filtered cake was washed twice with MeCN (1 mL). The mixture was then vacuum-dried at 70°C to obtain type A crystals (535.1 mg). Detection analysis showed that the XRD results are shown in Figure 5, the TGA results in Figure 6, and there was no significant weight loss when the sample was heated to 120°C. The DSC results are shown in Figure 7, and the sample had a sharp endothermic peak at 262.42°C (starting temperature). In summary, the type A crystals were anhydrous crystalline form.

[0297] 3.2. Manufacturing of Type B Crystals A 20 mg sample of G-type crystals was slurryed in 0.6 mL of methanol (or ethyl acetate) at room temperature for 3 days, vacuum-dried at 50°C for 4 hours, and the product was collected to obtain B-type crystals. Detection analysis showed that the XRD results are shown in Figure 8, the TGA results are shown in Figure 9, there was no significant weight loss when heated to 150°C, and the DSC results are shown in Figure 10, showing two endothermic peaks at 219.76°C and 266.19°C (start temperature). In summary, the B-type crystals were anhydrous crystalline form.

[0298] 3.3. Manufacturing of C-type crystals Using 10 mg of type A crystals as a starting material, the mixture was slurryed in 0.5 mL of acetone / water (3:1, v:v) at room temperature for 3 days, vacuum-dried at 50°C for 4 hours, and the product was collected to obtain type C crystals. Detection analysis showed that the XRD results are shown in Figure 11, the TGA results are shown in Figure 12, there was no significant weight loss when heated to 150°C, and the DSC results are shown in Figure 13, showing an endothermic peak at 265.61°C (starting temperature). In summary, the type C crystals were anhydrous crystalline form.

[0299] 3.4. Manufacturing of D-type crystals A 3.1 mg sample of G-type crystals was dissolved in 2.0 mL of acetone / n-heptane (4:1, v:v), filtered, and the filtrate was sealed with a sealing film, with a small hole made. The mixture was then slowly evaporated at room temperature for two days to obtain sheet-like crystals, thus obtaining D-type crystals. Detection analysis revealed that the XRD results are shown in Figure 14, the TGA results in Figure 15, showed a 1.99% weight loss upon heating to 180°C, and the DSC results in Figure 16 showed three endothermic peaks at 108.57°C (start temperature), 255.80°C (peak temperature), and 264.94°C (start temperature). The depositional plot of the single crystal structure is shown in Figure 17. Based on the solid-state characterization results and the depositional plot of the single crystal structure, the D-type crystals were found to be pipeline solvates.

[0300] 3.5. Manufacturing of Type E Crystals Using 10 mg of C-type crystals as a starting material, the mixture was slurryed overnight at room temperature in 0.5 mL of ethanol (or a solvent such as 2-butanone / chloroform) with 2.0 equivalents of sulfuric acid (2.42 μL of concentrated sulfuric acid). The mixture was then vacuum-dried at room temperature for 4 hours, and the product was collected to obtain E-type crystals. Detection analysis showed that the XRD results are shown in Figure 18 and the TGA results are shown in Figure 19, with a weight loss of 10.77% upon heating to 100°C.

[0301] 3.6. Manufacturing of F-type crystals Using 20 mg of free base type B crystals as a starting material, the mixture was slurryed in 0.5 mL of chloroform at room temperature for 3 days, vacuum-dried at 40°C for 3.5 hours, and the product was collected to obtain type F crystals. Detection analysis showed that the XRD results are shown in Figure 20, the TGA results are shown in Figure 21, and there was a 1.16% weight loss when heated to 150°C. The DSC results are shown in Figure 22 and showed an endothermic peak at 264.29°C (starting temperature). 1 The 1H NMR results are shown in Figure 23, and the molar ratio of the residual solvent (trichloromethane) to the compound was 0.04:1. In summary, the F-type crystals were anhydrous crystalline form.

[0302] 3.7. Manufacturing of G-type crystals Add 9-bromo-2-cyclopropyl-7-(2-methyl-2H-indazole-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) to a reaction flask. Stir under nitrogen gas protection at 72°C for 2 hours to allow the reaction to proceed. Concentrate the reaction product under reduced pressure at 50°C to obtain a black solid, and then add 400 mL of the mixture. Water was added and the mixture was stirred for 40 minutes, then filtered to obtain a black filter cake. The filter cake was mixed with 400 mL of anhydrous ethanol, heated to 72°C, filtered while hot to obtain another filter cake, mixed with 450 mL of DMSO and stirred for 40 minutes, filtered, and the filtrate was collected. 300 mL of water was added to the filtrate, filtered, and the filter cake was collected. The filter cake was mixed with 150 mL of DMSO, heated to 82°C, kept warm and stirred for 50 minutes, cooled to room temperature, filtered, and the filter cake was collected. The filter cake was mixed with 300 mL of anhydrous ethanol, stirred at room temperature for 1 hour, filtered, and the product was collected. Detection analysis showed that the XRD results are shown in Figure 24, the TGA results are shown in Figure 25, and there was a 0.71% weight loss when heated to 150°C. The DSC results are shown in Figure 26. In summary, the G-type crystals were anhydrous crystalline form.

[0303] 3.8. Manufacturing of H-type crystals 20 mg of free base G-type crystals were used as a starting material, dissolved in 0.6 mL of DMSO, filtered, and 4.0 mL of tert-butanol was added dropwise while stirring the filtrate. A solid precipitate formed, and after stirring at room temperature for approximately 2 hours, the mixture was filtered, vacuum-dried at 50°C for 3.5 hours, and the product was collected to obtain H-type crystals. Detection analysis showed that the XRD results are shown in Figure 27, the TGA results are shown in Figure 28, and there was no significant weight loss when heated to 150°C. The DSC results are shown in Figure 29, and there were two endothermic peaks at 224.39°C and 265.40°C (starting temperature). In summary, the H-type crystals were anhydrous crystalline form.

[0304] 3.9. Manufacturing of Type I Crystals 20 mg of free base G-type crystals were used as a starting material, dissolved in 1.4 mL of tetrahydrofuran, filtered, and 4.0 mL of acetonitrile was added dropwise while stirring the filtrate. A solid precipitated, and after stirring at room temperature for approximately 1 hour, the product was filtered to obtain type I crystals. Detection analysis showed that the XRD results are shown in Figure 30, the TGA results are shown in Figure 31, and there was a weight loss of 11.83% when heated to 120°C. The DSC results are shown in Figure 32, and there were three endothermic peaks at 77.29°C, 115.04°C, and 264.34°C (starting temperature). In summary, the type I crystals were solvates.

[0305] 3.10. Manufacturing of J-type crystals 20 mg of free base G-type crystals were mixed with 2.0 mL of acetone and stirred at 50°C for approximately 2 hours to dissolve. After thermal filtration, the supernatant was cooled from 50°C to 5°C at a rate of 0.1°C / min to precipitate the solid, yielding J-type crystals. Detection analysis showed that the XRD results are shown in Figure 33, the TGA results in Figure 34, and there was a 7.70% weight loss when heated to 120°C. The DSC results in Figure 35 showed three endothermic peaks at 95.17°C, 252.10°C, and 261.16°C (starting temperature). In summary, the J-type crystals were solvates.

[0306] 3.11. Manufacturing of K-type crystals 20 mg of free base G-type crystals were used as a starting material, dissolved in 0.4 mL of DMF, filtered, and 1.0 mL of purified water was added dropwise while stirring the filtrate until a solid precipitate formed. After stirring continued at room temperature for approximately 2 hours, K-type crystals were obtained. Detection analysis was performed, and the XRD results are shown in Figure 36.

[0307] 3.12. Manufacturing of L-type crystals 20 mg of free base G-type crystals were mixed with 2.0 mL of methanol and stirred at 50°C for approximately 2 hours to dissolve. After thermal filtration, the supernatant was cooled from 50°C to 5°C at a rate of 0.1°C / min to precipitate the solid and obtain L-type crystals. Detection analysis showed that the XRD results are shown in Figure 37, the TGA results are shown in Figure 38, there was no significant weight loss when heated to 150°C, and the DSC results are shown in Figure 39, showing two endothermic peaks at 227.72°C and 264.84°C (starting temperature). In summary, the L-type crystals were anhydrous crystalline form.

[0308] 3.13. Manufacturing of M-type crystals 20 mg of free base G-type crystals were used as a starting material. They were slurryed in 0.6 mL of ethanol (or acetone, methanol / dichloromethane (1:1, v:v)) at room temperature for 5 days, filtered, and vacuum-dried at 50°C for 3.5 hours. The product was collected to obtain M-type crystals. Detection analysis showed that the XRD results are shown in Figure 40, the TGA results are shown in Figure 41, and there was a 1.28% weight loss when heated to 120°C. The DSC results are shown in Figure 42, and there was a heat dissipation peak at 101.54°C (starting temperature) and an endothermic peak at 264.24°C (starting temperature). In summary, the M-type crystals were anhydrous crystalline form.

[0309] 3.14. Manufacturing of N-type crystals 20 mg of free base G-type crystals were used as a starting material. They were slurryed 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. The product was collected to obtain N-type crystals. Detection analysis showed that the XRD results are shown in Figure 43, the TGA results in Figure 44, a weight loss of 1.73% was observed when heated to 50°C at room temperature, and a weight loss of 6.43% was observed when heated to 150°C at 50°C. The DSC results are shown in Figure 45, showing three endothermic peaks at 79.53°C (peak temperature), 250.32°C (start temperature), and 264.02°C (start temperature). In summary, the N-type crystals were solvates.

[0310] 3.15. Manufacturing of O-type crystals Free base type I crystals were vacuum-dried at 50°C for 3.5 hours to obtain type O crystals. Detection analysis showed that the XRD results are shown in Figure 46, the TGA results in Figure 47, there was no significant weight loss when heated to 150°C, and the DSC results in Figure 48 showed two endothermic peaks at 109.30°C (peak temperature) and 265.73°C (start temperature), and a heat dissipation signal at 131.64°C (peak temperature). In summary, the type O crystals were anhydrous crystalline form.

[0311] 3.16. Manufacturing of P-type crystals Free base J-type crystals were vacuum-dried at 50°C for 3.5 hours to obtain P-type crystals. Detection analysis revealed XRD results (shown in Figure 49) and TGA results (shown in Figure 50), showing a 4.90% weight loss upon heating to 150°C. DSC results (shown in Figure 51) showed three endothermic peaks at 90.45°C, 250.99°C, and 263.51°C (starting temperature). In summary, the P-type crystals were solvates.

[0312] 3.17. Manufacturing of Q-type crystals 20 mg of G-type crystals were dissolved in 1.0 mL of chloroform, filtered, and 1.0 mL of methyl tert-ether (or n-heptane) was added dropwise to the filtrate while stirring. A solid precipitated, and after stirring at room temperature for approximately 2 hours, the product was collected to obtain Q-type crystals. Detection analysis showed that the XRD results are shown in Figure 52, the TGA results in Figure 53, and there was a weight loss of 16.11% when heated to 150°C. The DSC results are shown in Figure 54, and there were two endothermic peaks at 86.24°C and 263.46°C (starting temperature). Summarizing the solid-state characterization data, the free base Q-type crystals were trichloromethane solvate (theoretical weight loss 20.62%).

[0313] 4. Stability experiment 4.1. Stability in the Solid State Samples of type B, type H, and type L crystals were left for 17 days under conditions of 25°C / 60%RH and 40°C / 75%RH, respectively. The physical and chemical stability of the samples was then detected by XRD and HPLC. The test data are shown in Table 24 below.

[0314] [Table 24]

[0315] The results showed that after leaving B-type and L-type crystals for 17 days under conditions of 25°C / 60%RH and 40°C / 75%RH, neither the crystal type nor the purity changed. After leaving H-type crystals for 17 days under conditions of 25°C / 60%RH, the purity did not change, but the degree of crystallinity of the sample decreased. After leaving them for 17 days under conditions of 40°C / 75%RH, neither the crystal type nor the purity changed.

[0316] 4.2. Research on Interconversion Relationships 4.2.1. Suspension Competition The interconversion relationships between various anhydrous crystalline forms were investigated using a suspension stirring competition method at different temperatures and solvent systems.

[0317] 1) Equivalent mass (3-4 mg) of each anhydrous crystalline form (A / B / C / G / H / L / M type crystals) was weighed into HPLC vials, and 1.0 mL of the corresponding solvent presaturated with the G crystalline form at the corresponding temperature was added. The resulting suspensions were magnetically stirred (1000 rpm) at room temperature or 50°C. Samples were taken for 10 minutes, 3 days, and 7 days, and the solids were collected by centrifugation and subjected to XRD testing. The results are summarized in Table 25.

[0318] [Table 25]

[0319] 2) Equivalent mass (~5 mg) of each anhydrous crystalline form (B / H / L type crystal) was weighed into HPLC vials, and 1.0 mL of solvent presaturated with G type crystals at the corresponding temperature was added. The resulting suspensions were magnetically stirred (1000 rpm) at room temperature or 50°C. Samples were taken at 10 minutes, 6 hours, 1 day, 4 days, and 7 days, and the solids were collected by centrifugation and subjected to XRD testing. The results are summarized in Table 26.

[0320] [Table 26]

[0321] 4.2.2. Heating Experiment Based on the DSC characterization results for each free base crystal type, for crystal types that showed clear endothermic / exothermic signals before the melting point, the excess endothermic / exothermic peak temperatures were heated using DSC, and the samples after heating were collected and XRD measurements were taken. The results are summarized in Table 27.

[0322] [Table 27]

[0323] The interconversion relationships between each crystal form were studied through suspension stirring competition and heating tests. The results of the suspension stirring competition showed that, under different solvent and temperature conditions (room temperature / 50°C), the free base L-type crystal was the stable crystal form, and all crystal forms tended to convert to free base A-type crystals after heating (>100°C), indicating that the free base A-type crystal is the high-temperature stable crystal form.

[0324] 4.3. Study on Long-Term Stability L-type crystalline samples were stored at 40°C ± 2°C / 75% RH ± 5% RH, and the physical and chemical stability of the samples was detected by XRD and HPLC. The test data are shown in Table 28 below.

[0325] [Table 28]

[0326] 5. Solubility Experiment 5.1. Room temperature solubility The solubility of G-type crystals was measured at room temperature using 20 different solvents. Approximately 2 mg of the sample was weighed into a 3 mL vial, and each of the solvents listed in Table 29 below was added. 100 μL was added each time until the solid dissolved. If the solid was still not clear after adding 2 mL of solvent, the addition was stopped. The solubility range in the corresponding solvent was calculated based on the sample mass and the volume of solvent.

[0327] [Table 29]

[0328] 5.2.Dynamic solubility The solubility of the sample at 1 hour, 4 hours, and 24 hours was measured in four solvent systems—pH 1.0, pH 4.5, pH 6.8 buffer solutions, and water—at a dose concentration of 10 mg / mL under shaking conditions (400 rpm) at 37°C. Sampling was performed at each time point, centrifuged (10000 rpm, 2 min), filtered (through a 0.22 μm PTFE filter membrane, discarding the pre-filter solution), and the HPLC concentration of the filtrate was measured. The XRD of the remaining solid was then measured. The results of the solubility tests are summarized in Table 30.

[0329] [Table 30]

Claims

1. The crystalline form of the compound, The specific structure of the aforementioned compound is: 【Chemistry 1】 A crystal type characterized by the following:

2. The compound is 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its specific structural formula is: 【Chemistry 2】 The crystal form according to claim 1, characterized in that it is the same as the one described in claim 1.

3. The aforementioned crystalline form is a type A crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction patterns are 6.0°±0.2°, 8.2°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.4°±0.2°, and Preferably, the A-type crystal has diffraction peaks at 25.4°±0.2°, and its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ, and more preferably, the A-type crystal has diffraction peaks at 2θ, The pattern has diffraction peaks at 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° of 2θ, and more preferably, the A-type crystal has its X-ray powder diffraction pattern at 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° of 2θ. The diffraction peaks are located at °±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°, and preferably, the A-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle as shown in Figure 5. Preferably, the type A crystal has an endothermic peak in a thermal analysis chart measured by differential scanning calorimetry (DSC) at a starting temperature of 257°C to 267°C, more preferably, the type A crystal has an endothermic peak in a thermal analysis chart measured by differential scanning calorimetry at a starting temperature of 260°C to 264°C, even more preferably, the type A crystal has an endothermic peak at a starting temperature of 262°C in a thermal analysis chart measured by differential scanning calorimetry, and most preferably, the type A crystal has the DSC pattern shown in Figure 7. Preferably, the A-type crystal has the TGA pattern shown in Figure 6. Alternatively, the crystalline form is a B-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction patterns are 7.5°±0.2°, 14.8°±0.2°, 17.6°±0.2°, 22.4°±0.2°, and 24.6°±0.2° at 2θ. and has a diffraction peak at 26.3°±0.2°, preferably the type B crystal has diffraction peaks at 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° of 2θ, more preferably the type B crystal has diffraction peaks at 2θ The pattern has diffraction peaks at 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° of 2θ, and more preferably, the B-type crystal has its X-ray powder diffraction pattern at 7.5°±0.2°, 13.6° The B-type crystal has diffraction peaks at 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°, and most preferably the B-type crystal has the pattern shown in Figure 8 when X-ray powder diffraction is expressed at a 2θ angle. Preferably, the B-type crystal has endothermic peaks at starting temperatures of 215°C to 225°C and 260°C to 270°C in a thermal analysis chart measured by differential scanning calorimetry, more preferably, the B-type crystal has endothermic peaks at starting temperatures of 217°C to 222°C and 264°C to 268°C in a thermal analysis chart measured by differential scanning calorimetry, even more preferably, the B-type crystal has endothermic peaks at starting temperatures of 220°C and 266°C in a thermal analysis chart measured by differential scanning calorimetry, preferably, the B-type crystal has the DSC pattern shown in Figure 10, and preferably, the B-type crystal has the TGA pattern shown in Figure 9. Alternatively, the crystalline form is a C-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern is 9.2°±0.2°, 17.6°±0.2°, 19.7°±0.2°, 21.8°±0.2°, and 22.7°±0.2° at 2θ. And having diffraction peaks at 24.6°±0.2°, preferably the C-type crystal has diffraction peaks at 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° of 2θ in its X-ray powder diffraction pattern, more preferably the C-type crystal has diffraction peaks at 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° in its X-ray powder diffraction pattern, The pattern has diffraction peaks at 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° of 2θ, and more preferably, the C-type crystal has its X-ray powder diffraction pattern at 9.2°±0.2°, 10.6° The C-type crystal has diffraction peaks at 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°, and most preferably the C-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle as shown in Figure 11. Preferably, the C-type crystal has the TGA pattern shown in Figure 12. Preferably, the C-type crystal has the DSC pattern shown in Figure 13, Alternatively, the crystalline form is a D-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction patterns are 6.8°±0.2°, 8.8°±0.2°, 13.0°±0.2°, 18.1°±0.2°, and 21.6°±0.2° at 2θ. and has a diffraction peak at 22.8°±0.2°, preferably the D-type crystal has an X-ray powder diffraction pattern with diffraction peaks at 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° of 2θ, more preferably the D-type crystal has an X-ray powder diffraction pattern with diffraction peaks at 2θ. The pattern has diffraction peaks at 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° of 2θ, and more preferably, the D-type crystal has its X-ray powder diffraction pattern at 6.8°±0.2° and 8.8° of 2θ. The D-type crystal has diffraction peaks at ±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°, and most preferably the D-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle as shown in Figure 14. Preferably, the D-type crystal has the TGA pattern shown in Figure 15. Preferably, the D-type crystal has the DSC pattern shown in Figure 16. Preferably, the D-type crystal is characterized by having the single-crystal structure shown in Figure 17. The crystal type according to claim 2.

4. The crystalline form is an E-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 5.8°±0.2°, 6.3°±0.2°, 7.0°±0.2° and 10.8°±0.2° of 2θ, preferably the E-type crystal has diffraction peaks at 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° of 2θ, and more preferably the E-type crystal has diffraction peaks at 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° of 2θ, The turns have diffraction peaks at 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° of 2θ, and more preferably, the E-type crystal has its X-ray powder diffraction pattern at 5.8°±0.2°, 6.3°± The E-type crystal has diffraction peaks at 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°, and most preferably the E-type crystal has the pattern shown in Figure 18 when the X-ray powder diffraction is represented by a 2θ angle. Preferably, the E-type crystal has the TGA pattern shown in Figure 19, Alternatively, the crystalline form is an F-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern is 8.9°±0.2°, 13.4°±0.2°, 16.8°±0.2°, 19.9°±0.2°, and 20.4°±0.2° at 2θ. and has diffraction peaks at 22.5°±0.2°, preferably the F-type crystal has diffraction peaks at 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° of 2θ in its X-ray powder diffraction pattern, more preferably the F-type crystal has diffraction peaks at 2θ in its X-ray powder diffraction pattern. The pattern has diffraction peaks at 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° of 2θ, and more preferably, the F-type crystal has its X-ray powder diffraction pattern at 8.9°±0.2°, 10.0° The F-type crystal has diffraction peaks at 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°, and most preferably the F-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle as shown in Figure 20. Preferably, the F-type crystal has the TGA pattern shown in Figure 21, Preferably, the F-type crystal has the DSC pattern shown in Figure 22, Preferably, the F-type crystal is as shown in Figure 23. １ It has an H NMR spectrum, Alternatively, the crystal type is a G-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 6.3°±0.2°, 6.8°±0.2°, 13.9°±0.2° and 15.3°±0.2° of 2θ, preferably the G-type crystal has diffraction peaks at 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° of 2θ, and more preferably the G-type crystal has diffraction peaks at 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° of 2θ, The folding pattern has diffraction peaks at 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° of 2θ, and more preferably, the G-type crystal has its X-ray powder diffraction pattern at 6.3°±0.2°, 6.8°±0.2° of 2θ. The G-type crystal has diffraction peaks at 0.2°±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°, and most preferably the G-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle as shown in Figure 24. Preferably, the G-type crystal has the TGA pattern shown in Figure 25. Preferably, the G-type crystal has the DSC pattern shown in Figure 26, Alternatively, the crystalline form is an H-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern is 5.8°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 17.7°±0.2°, and 19.8°±0.2° at 2θ. The H-type crystal has diffraction peaks at 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° of 2θ, and more preferably the H-type crystal has diffraction peaks at 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° of 2θ. The pattern has diffraction peaks at 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° of 2θ, and more preferably, the H-type crystal has X-ray powder diffraction patterns at 5.8°±0.2° and 9.8° of 2θ. The H-type crystal has diffraction peaks at ±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°, and most preferably the H-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle as shown in Figure 27. Preferably, the H-type crystal has endothermic peaks at starting temperatures of 220°C to 230°C and 260°C to 270°C in a thermal analysis chart measured by differential scanning calorimetry, more preferably, the H-type crystal has endothermic peaks at starting temperatures of 222°C to 226°C and 263°C to 268°C in a thermal analysis chart measured by differential scanning calorimetry, and even more preferably, the H-type crystal has endothermic peaks at starting temperatures of 224°C and 265°C in a thermal analysis chart measured by differential scanning calorimetry. Preferably, the H-type crystal has the TGA pattern shown in Figure 28. Preferably, the H-type crystal is characterized by having the DSC pattern shown in Figure 29. The crystal type according to claim 2.

5. The crystalline form is a type I crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 6.8°±0.2°, 8.9°±0.2°, 20.7°±0.2° and 30.1°±0.2° of 2θ, preferably the type I crystal has diffraction peaks at 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° of 2θ, and more preferably the type I crystal has diffraction peaks at 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° of 2θ The plane has diffraction peaks at 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° of 2θ, and more preferably the type I crystal has X-ray powder diffraction patterns at 6.8°±0.2°, 8.9°± The diffraction peaks are located at 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°, and most preferably, the type I crystal has an X-ray powder diffraction pattern represented by a 2θ angle as shown in Figure 30. Preferably, the type I crystal has the TGA pattern shown in Figure 31, Preferably, the type I crystal has the DSC pattern shown in Figure 32, Alternatively, the crystal type is a J-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 6.7°±0.2°, 25.0°±0.2° and 25.6°±0.2° of 2θ, preferably the J-type crystal has diffraction peaks at 6.7°±0.2°, 8.7°±0.2°, 25.0°±0.2° and 25.6°±0.2° of 2θ, and more preferably the J-type crystal is The X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ, and more preferably, the J-type crystal has diffraction peaks at 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° of 2θ, and most preferably, the J-type crystal has an X-ray powder diffraction pattern represented by the 2θ angle shown in Figure 33. Preferably, the J-type crystal has the TGA pattern shown in Figure 34. Preferably, the J-type crystal has the DSC pattern shown in Figure 35, Alternatively, the crystal type is a K-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 6.2°±0.2°, 17.7°±0.2° and 18.9°±0.2° of 2θ, preferably the K-type crystal has diffraction peaks at 6.2°±0.2°, 16.8°±0.2°, 17.7°±0.2° and 18.9°±0.2° of 2θ, and more preferably the K-type crystal is The X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ, and more preferably, the K-type crystal has diffraction peaks at 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° of 2θ, and most preferably, the K-type crystal has an X-ray powder diffraction pattern represented by the 2θ angle shown in Figure 36. Alternatively, the crystalline form is an L-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern is 14.9°±0.2°, 18.6°±0.2°, 21.4°±0.2°, 22.8°±0.2°, and 23.5°±0.2° at 2θ. The L-type crystal has diffraction peaks at 2θ and 26.0°±0.2°, preferably the X-ray powder diffraction pattern of the L-type crystal has diffraction peaks at 2θ at 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°, and more preferably the L-type crystal has diffraction peaks at 2θ at 2θ The folding pattern has diffraction peaks at 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° of 2θ, and more preferably, the L-type crystal has its X-ray powder diffraction pattern at 8.3°±0.2°, 8.9°±0.2° of 2θ. The L-type crystal has diffraction peaks at 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°, and most preferably, the L-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle as shown in Figure 37. Preferably, the L-type crystal has endothermic peaks at starting temperatures of 223°C to 233°C and 260°C to 270°C in a thermal analysis chart measured by differential scanning calorimetry, more preferably, the L-type crystal has endothermic peaks at starting temperatures of 225°C to 230°C and 263°C to 268°C in a thermal analysis chart measured by differential scanning calorimetry, and even more preferably, the L-type crystal has endothermic peaks at starting temperatures of 228°C and 265°C in a thermal analysis chart measured by differential scanning calorimetry. Preferably, the L-type crystal has the TGA pattern shown in Figure 38. Preferably, the L-type crystal is characterized by having the DSC pattern shown in Figure 39. The crystal type according to claim 2.

6. The aforementioned crystalline form is an M-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ, preferably the M-type crystal has X-ray powder diffraction patterns at 7.1°±0.2°, 11.4°±0.2°, 13.5°±0.2° and 17.4° The M-type crystal has diffraction peaks at 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° of 2θ, and more preferably, the M-type crystal has diffraction peaks in its X-ray powder diffraction pattern at 2θ at 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°, and even more preferably, the M-type crystal has an X-ray powder diffraction pattern represented by the 2θ angle shown in Figure 40. Preferably, the M-type crystal has the TGA pattern shown in Figure 41. Preferably, the M-type crystal has the DSC pattern shown in Figure 42, Alternatively, the crystalline form is an N-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 6.5°±0.2°, 7.0°±0.2°, 8.6°±0.2° and 18.1°±0.2° of 2θ, preferably the N-type crystal has X-ray powder diffraction patterns at 6.5°±0.2°, 7.0°±0.2°, 8.6°±0.2° and 18.1°±0.2° of 2θ. The N-type crystal has diffraction peaks at 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° in its X-ray powder diffraction pattern. More preferably, the N-type crystal has X-ray powder diffraction, expressed at a 2θ angle, the pattern shown in Figure 43. Preferably, the N-type crystal has the TGA pattern shown in Figure 44, Preferably, the N-type crystal has the DSC pattern shown in Figure 45, Alternatively, the crystal type is an O-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 7.3°±0.2° and 18.5°±0.2° of 2θ, preferably the O-type crystal has diffraction peaks at 3.7°±0.2°, 7.3°±0.2°, 18.5°±0.2° and 26.0°±0.2° of 2θ, and more preferably the O-type crystal has diffraction peaks at 3.7°±0.2°, 7.3°±0.2°, 18.5°±0.2° and 26.0°±0.2° of 2θ. The pattern has diffraction peaks at 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° of 2θ, more preferably the O-type crystal has diffraction peaks at 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° of 2θ, most preferably the O-type crystal has an X-ray powder diffraction pattern represented by the 2θ angle shown in Figure 46. Preferably, the O-type crystal has the TGA pattern shown in Figure 47. Preferably, the O-type crystal has the DSC pattern shown in Figure 48, Alternatively, the crystalline form is a P-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern has diffraction peaks at 6.9°±0.2° and 18.2°±0.2° of 2θ, preferably the P-type crystal has diffraction peaks at 6.2°±0.2°, 6.9°±0.2°, 13.9°±0.2° and 18.2°±0.2° of 2θ, and more preferably the P-type crystal has diffraction peaks at 6.2°±0.2°, 6.9°±0.2°, 13.9°±0.2° and 18.2°±0.2° of 2θ. The pattern has diffraction peaks at 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° of 2θ, more preferably the P-type crystal has diffraction peaks at 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° of 2θ, most preferably the P-type crystal has an X-ray powder diffraction pattern represented by the 2θ angle shown in Figure 49. Preferably, the P-type crystal has the TGA pattern shown in Figure 50, and its DSC has the pattern shown in Figure 51. Alternatively, the crystalline form is a Q-type crystal of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, and its X-ray powder diffraction pattern is 12.2±0.2°, 16.1°±0.2°, 19.8°±0.2°, 21.5°±0.2°, and 23.2°±0.2° at 2θ. The Q-type crystal has diffraction peaks at 28.7°±0.2°, and preferably its X-ray powder diffraction pattern has diffraction peaks at 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° of 2θ, and more preferably the Q-type crystal has diffraction peaks at 2θ The pattern has diffraction peaks at 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° of 2θ, and more preferably, the Q-type crystal has its X-ray powder diffraction pattern at 12.2±0.2°, 14.9°±0.2° of 2θ. The Q-type crystal has diffraction peaks at 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°, and most preferably the Q-type crystal has an X-ray powder diffraction pattern represented by a 2θ angle as shown in Figure 52. Preferably, the Q-type crystal has the TGA pattern shown in Figure 53. Preferably, the Q-type crystal is characterized by having the DSC pattern shown in Figure 54. The crystal type according to claim 2.

7. The crystalline form of the compound is solvent-containing or solvent-free, and the solvent is one or more selected from water, methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, isobutanol, acetone, 2-butanone, 3-pentanone, dichloromethane, trichloromethane, ethyl formate, ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 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 one or more selected from water, ethanol, acetone, n-heptane, dichloromethane, trichloromethane, 2-butanone, tetrahydrofuran, and N,N-dimethylformamide. More preferably, the crystalline form of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one is a solvate, and the solvent is one or more selected from water, ethanol, acetone, n-heptane, dichloromethane, trichloromethane, and tetrahydrofuran. More preferably, the crystalline form of compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazole-5-yl)-8H-pyrimido[1,2-b]pyridazin-8one is anhydrous crystalline form. The crystal type according to claim 2.

8. A method for producing the crystal form according to any one of claims 1 to 7, This includes reverse solvent addition, reverse-reverse solvent addition, solvent volatilization, gas-solid diffusion, suspension stirring, and cooling crystallization methods. Preferably, the manufacturing method involves weighing an appropriate amount of the free base of the compound, dissolving it in the corresponding forward solvent, filtering it, and adding the corresponding reverse solvent while stirring the filtrate until a solid precipitates. Alternatively, the process involves weighing an appropriate amount of the free base of the compound, dissolving it in the corresponding correct solvent, filtering it, and then cooling the supernatant until a solid precipitate forms. Alternatively, weigh an appropriate amount of the free base of the compound, dissolve it in the corresponding correct solvent, and seal the container until a solid precipitates. Alternatively, the process may include weighing an appropriate amount of the free base of the compound, dissolving it in the corresponding positive solvent, forming a slurry, drying it, and collecting the solid. Preferably, the positive solvent comprises one or more of the following: water, methanol, ethanol, acetone, 2-butanone, ethyl acetate, tetrahydrofuran, acetonitrile, n-hexane, n-heptane, dichloromethane, trichloromethane, 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, the positive solvent comprises one or more of the following: water, methanol, ethanol, acetonitrile, n-hexane, n-heptane, dichloromethane, trichloromethane, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, acetone, 2-butanone, ethyl acetate, 1,4-dioxane, isopropanol, isopropyl acetate, and methyl isobutyl ketone. The reverse solvent comprises 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, and is preferably one or more of methyl tert-butyl ether, n-heptane, isopropyl acetate, acetonitrile, isopropyl ether, n-hexane, water, tert-butanol, cyclohexane, and toluene. Manufacturing method.

9. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form described in 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 manufacture of a drug for preventing and / or treating a MAT2A-mediated disease or disease state.

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