Crystalline forms of quinoline derivative inhibitors, and their preparation methods and uses

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically relates to a crystalline form of a methanesulfonate salt of a TAM family kinase and / or CSF1R kinase and / or NTRK inhibitor represented by formula (I), as well as a preparation method and pharmaceutical use thereof. [C1] TIFF2025527820000027.tif41156

Description

[Technical Field]

[0001] <Reference to Related Applications> The present invention claims priority to an invention patent application filed in China on August 30, 2022, entitled "Crystalline Form of Quinoline Derivative Inhibitor, and Its Preparation Method and Use" and bearing application number 202211052009.8, the entirety of which is incorporated herein by reference.

[0002] <Technical field> The present invention belongs to the field of pharmaceutical technology, and specifically relates to a crystalline form of a TAM family kinase / CSF1R kinase inhibitor, as well as a preparation method and pharmaceutical use thereof. The crystalline form of the present invention can selectively inhibit the tyrosine kinase TAM family and / or CSF1R kinase and is used for the treatment and / or prevention of diseases mediated by the abnormal expression of TAM family kinase and / or CSF1R kinase receptors and / or their ligands. Furthermore, the crystalline form of the present invention can also be used for the treatment and / or prevention of related diseases caused by NTRK, more specifically, for the treatment and / or prevention of drug-resistant related diseases caused by NTRK mutations. [Background technology]

[0003] The TAM family includes three members: Axl, Mer, and Tyro-3, which contain an extracellular domain, a transmembrane domain, and a conservative intracellular kinase domain. Among them, Axl (also known as UFO, Ark, Tyro-7, and JTK1), Mer (also known as c-Mer, Mertk, Eyk, Nyk, and Tyro-12), Tyro-3 (also known as Sky, Byk, Rse, and Dtk), galectin-3, Gas6, and ProS are abnormally expressed in multiple solid tumors, including lung cancer, gastric cancer, and hepatoma, as well as multiple hematological tumors, including AML, ALL, and CML, and are strongly correlated with poor prognosis, disease progression, tumor metastasis, and tumor drug resistance (Douglas K, Nature reviews, 2014). In particular, Axl, a tyrosine kinase, has already been proven to be one of the causes of drug resistance to EGFR inhibitors in NSCLC, and is closely related to the metastasis of several types of solid tumors.

[0004] Colony-stimulating factor 1 receptor (CSF1R), also known as c-FMS, FMS, FIM2, MCSF, and CD115, is a 972-amino acid single-chain transmembrane glycoprotein that belongs to the type III receptor tyrosine kinase (RTK) family along with FLT-3, PDGFR, and KIT. In the CSF1 / CSF1R pathway, CSF1 and CSF1R form a signaling axis that promotes macrophage growth in the body and regulates the normal development and internal homeostasis of tissues and organs. However, disruption of homeostasis can lead to various diseases, such as inflammation, immune system disorders, and tumors.

[0005] NTRK genes include NTRK1, NTRK2, and NTRK3, which are responsible for the synthesis of tropomyosin-related kinase (TRK) family proteins TRKA, TRKB, and TRKC, respectively. NTRK gene fusions can occur anywhere in the body and are also found in a variety of adult and pediatric solid tumors, including mammary gland analog secretory carcinoma (MASC), colon cancer, lung cancer, pancreatic cancer, thyroid cancer, and various sarcomas. While NTRK fusions occur very rarely in common cancer types, such as colon cancer and lung cancer, with incidence rates of less than 5% in each, they are highly prevalent in some rare cancer types, such as congenital kidney tumors, infantile sarcoma, salivary gland cancer, and breast secretory carcinoma, with incidence rates exceeding 90% in individual cancer types ( Journal of Clinical Drugs, Vol. 15, Issue 12, 2017). Therefore, the development of NTRK inhibitors is of great clinical value.

[0006] In the process of drug research and development, the study of crystalline forms is very important, as the crystalline forms of compounds differ greatly from other forms in terms of stability, solubility, etc. WO2020038460A1 discloses compounds as TAM family kinase and / or CSF1R kinase and / or NTRK inhibitors, which are used for the treatment and / or prevention of diseases mediated by the abnormal expression of TAM family kinase and / or CSF1R kinase receptors and / or their ligands, including tumors, tumor immunity, ectopic endometriosis, vascular diseases / damage, psoriasis, visual disorders / lesions (due to causes such as macular degeneration, diabetes, and premature birth), kidney diseases, rheumatoid arthritis, osteoporosis, and other related diseases; and further for use in the preparation of drugs for the treatment and / or prevention of related diseases caused by NTRK, particularly drug-resistant related diseases produced by NTRK mutations, which include, but are not limited to, non-small cell lung cancer, colorectal cancer, mammary analog secretory carcinoma, sarcoma, astrocytoma, glioblastoma, Spitz-like melanoma, cholangiocarcinoma, papillary thyroid carcinoma, mammary secretory carcinoma, and breast carcinoma - pathological type unknown. The present inventors have conducted studies on compound 15 in order to obtain a crystalline form that is pharmaceutically useful. Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a crystalline form of the methanesulfonic acid of the compound of formula (I) and a process for its preparation. [Means for solving the problem]

[0008] The present invention provides crystalline Form I of the methanesulfonic acid salt of compound of formula (I), The crystalline form of the methanesulfonate salt of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide, a compound represented by formula (I), i.e., crystalline form I, is characterized in that powder X-ray diffraction using Cu-Kα radiation at 2θ angles has characteristic peaks at 8.13±0.2°, 14.78±0.2°, 21.82±0.2°, 22.24±0.2°, 23.91±0.2°, 24.24±0.2°, 25.19±0.2°, and 26.94±0.2°. [ka]

[0009] In one embodiment of the present invention, crystalline Form I of the methanesulfonate salt of Formula (I) exhibits characteristic peaks at 11.11±0.2°, 17.37±0.2°, and 20.27±0.2° in addition to the characteristic peaks described above, in powder X-ray diffraction at 2θ angles using Cu-Kα radiation.

[0010] In one embodiment of the present invention, crystalline Form I of the methanesulfonate salt of Formula (I) exhibits characteristic peaks at 12.52±0.2°, 13.75±0.2°, and 19.13±0.2° in powder X-ray diffraction at 2θ angles using Cu-Kα radiation in addition to the characteristic peaks described above.

[0011] In one embodiment of the present invention, crystalline form I of the methanesulfonate salt of formula (I) exhibits a powder X-ray diffraction pattern essentially as shown in FIG. 1 when Cu-Kα radiation is used.

[0012] The present invention further provides a process for preparing crystalline Form I of the methanesulfonate salt of compound of formula (I), comprising: The compound of formula (I) is dissolved in a single or mixed solvent and stirred until completely dissolved, and then methanesulfonic acid is slowly added with stirring, followed by stirring to precipitate crystalline Form I.

[0013] In one embodiment of the present invention, the single or mixed solvent is selected from the group consisting of isopropanol, methanol, ethanol, tetrahydrofuran, dichloromethane, 1,4-dioxane, toluene, acetone, ethyl acetate, acetonitrile, methyl tert-butyl ether, 2-methyltetrahydrofuran, dimethyl sulfoxide, and water.

[0014] In one embodiment of the present invention, the single or mixed solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, dichloromethane, 1,4-dioxane, and isopropanol / ethanol mixed solution.

[0015] In one embodiment of the present invention, the ratio of the isopropanol / ethanol mixed solution is selected from the range of 1:1 to 6:1, preferably the ratio is selected from the range of 2:1 to 5:1, more preferably the ratio is selected from the range of 2:1 to 3:1.

[0016] In one embodiment of the present invention, when the single or mixed solvent is selected from isopropanol and 1,4-dioxane, the stirring is carried out under heating, and the heating temperature is 40°C to 60°C, preferably 45°C to 55°C.

[0017] In one embodiment of the present invention, the stirring is performed at room temperature or under heating, and the room temperature or heating conditions refer to 0°C to 70°C, preferably 10°C to 60°C. Preferably, the room temperature refers to 10°C to 30°C, preferably 15°C to 25°C, and the heating conditions refer to 40°C to 60°C, more preferably 45°C to 55°C.

[0018] In one embodiment of the present invention, the room temperature refers to 15°C to 25°C.

[0019] In one embodiment of the present invention, the heating refers to heating to 30°C or higher.

[0020] In one embodiment of the present invention, the amount of the single or mixed solvent is 20 to 30 times the volume of the compound of formula (I).

[0021] In one embodiment of the present invention, the amount of the single or mixed solvent is 5 to 50 times the volume of the compound of formula (I), preferably 6 to 40 times the volume, more preferably 7 to 35 times the volume, and even more preferably 8 to 25 times the volume.

[0022] The present invention provides crystalline Form II of the methanesulfonate salt of compound of formula (I), The crystalline form of the methanesulfonate salt of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide, a compound represented by formula (I), is crystalline form II, characterized in that powder X-ray diffraction using Cu-Kα radiation at 2θ angles has characteristic peaks at 12.66±0.2°, 13.68±0.2°, 15.74±0.2°, 18.57±0.2°, 21.16±0.2°, and 22.19±0.2°. [ka]

[0023] In one embodiment of the present invention, crystalline Form II of the methanesulfonate salt of compound of Formula (I) exhibits characteristic peaks at 18.09±0.2°, 20.13±0.2°, 24.88±0.2°, and 26.31±0.2° in addition to the characteristic peaks described above, in powder X-ray diffraction at 2θ angles using Cu-Kα radiation.

[0024] In one embodiment of the present invention, crystalline Form II of the methanesulfonate salt of compound of Formula (I) exhibits characteristic peaks at 10.02±0.2°, 16.36±0.2°, and 29.41±0.2° in addition to the characteristic peaks described above, in powder X-ray diffraction at 2θ angles using Cu-Kα radiation.

[0025] In one embodiment of the present invention, crystalline Form II of the methanesulfonate salt of compound of Formula (I) exhibits a powder X-ray diffraction pattern essentially as shown in FIG. 3 using Cu-Kα radiation.

[0026] The present invention further provides a process for preparing crystalline Form II of the methanesulfonate salt of compound of formula (I), comprising: The compound of formula (I) is dissolved in isopropanol and stirred at room temperature until completely dissolved, and then methanesulfonic acid is slowly added with stirring, followed by stirring at room temperature to precipitate crystalline form II.

[0027] In one embodiment of the present invention, the room temperature refers to 10°C to 30°C, preferably 15°C to 25°C.

[0028] The present invention provides crystalline Form III of the methanesulfonate salt of compound of formula (I), The crystalline form of the methanesulfonate salt of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide, a compound represented by formula (I), i.e., crystalline form III, is characterized in that powder X-ray diffraction using Cu-Kα radiation at 2θ angles has characteristic peaks at 10.32±0.2°, 10.58±0.2°, 12.55±0.2°, 17.30±0.2°, 21.49±0.2°, 21.95±0.2°, and 24.22±0.2°. [ka]

[0029] In one embodiment of the present invention, crystalline Form III of the methanesulfonate salt of compound of formula (I) exhibits characteristic peaks at 9.47±0.2°, 13.04±0.2°, 20.66±0.2°, and 23.61±0.2° in addition to the characteristic peaks described above, in powder X-ray diffraction at 2θ angles using Cu-Kα radiation.

[0030] In one embodiment of the present invention, crystalline Form III of the methanesulfonate salt of compound of formula (I) exhibits characteristic peaks at 8.61±0.2°, 15.34±0.2°, and 25.71±0.2° in addition to the characteristic peaks described above, in powder X-ray diffraction at 2θ angles using Cu-Kα radiation.

[0031] In one embodiment of the present invention, crystalline Form III of the methanesulfonate salt of compound of Formula (I) exhibits a powder X-ray diffraction pattern essentially as shown in FIG. 4 when using Cu-Kα radiation.

[0032] The present invention further provides a process for preparing crystalline Form III of the methanesulfonate salt of compound of formula (I), which comprises dissolving and slurrying the methanesulfonate salt of compound of formula (I) in acetonitrile to precipitate crystalline Form III.

[0033] The present invention further provides a process for preparing crystalline Form III of methanesulfonate salt of compound of formula (I), which comprises dissolving crystalline Form I of methanesulfonate salt of compound of formula (I) in acetonitrile, slurrying the mixture, and precipitating crystalline Form III.

[0034] In one embodiment of the present invention, the slurrying is carried out at a temperature of 0°C to 70°C, and preferably, the temperature is selected from the range of 10°C to 60°C.

[0035] The present invention provides crystalline Form IV of the methanesulfonate salt of compound of formula (I): The crystalline form of the methanesulfonate salt of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide, a compound represented by formula (I), i.e., crystalline form IV, is characterized in that powder X-ray diffraction using Cu-Kα radiation at 2θ angles has characteristic peaks at 9.71±0.2°, 12.66±0.2°, 17.59±0.2°, 19.35±0.2°, 22.01±0.2°, 23.40±0.2°, and 24.77±0.2°. [ka]

[0036] In one embodiment of the present invention, crystalline Form IV of the methanesulfonate salt of compound of Formula (I) exhibits characteristic peaks at 15.11±0.2°, 22.34±0.2°, and 23.92±0.2° in addition to the characteristic peaks described above, in powder X-ray diffraction at 2θ angles using Cu-Kα radiation.

[0037] In one embodiment of the present invention, crystalline Form IV of the methanesulfonate salt of compound of Formula (I) exhibits characteristic peaks at 10.26±0.2°, 11.78±0.2°, and 12.45±0.2° in addition to the characteristic peaks described above, in powder X-ray diffraction at 2θ angles using Cu-Kα radiation.

[0038] In one embodiment of the present invention, crystalline Form IV of the methanesulfonate salt of compound of Formula (I) exhibits a powder X-ray diffraction pattern essentially as shown in FIG. 5 using Cu-Kα radiation.

[0039] The present invention further provides a process for preparing crystalline Form IV of the methanesulfonate salt of compound of formula (I), comprising dissolving and slurrying the methanesulfonate salt of compound of formula (I) in dichloromethane to precipitate Form IV.

[0040] The present invention further provides a process for preparing crystalline Form IV of methanesulfonate salt of compound of formula (I), which comprises dissolving and slurrying crystalline Form I of methanesulfonate salt of compound of formula (I) in dichloromethane to precipitate crystalline Form IV.

[0041] In one embodiment of the present invention, the slurrying is carried out at a temperature of 0°C to 70°C, preferably the temperature is selected from the range of 10°C to 60°C, more preferably the temperature is selected from the range of 10°C to 30°C, and even more preferably the temperature is selected from the range of 15°C to 25°C.

[0042] The present invention further provides pharmaceutical compositions comprising crystalline Form I or Form II or Form III or Form IV of the methanesulfonate salt of compound of formula (I) and one or more second therapeutically active agents.

[0043] The present invention further provides a pharmaceutical formulation comprising crystalline Form I, Form II, Form III or Form IV of the methanesulfonate salt of compound of formula (I).

[0044] In some embodiments of the invention, the drug formulation may include one or more pharmaceutical carriers.

[0045] The pharmaceutical carrier of the present invention can be one or more solid or liquid fillers suitable for human use.The pharmaceutical carrier preferably has sufficient purity and low toxicity, and is compatible with the compound provided by the present invention, and does not significantly reduce its efficacy.For example, the pharmaceutical carrier can be a filler, adhesive, disintegrant, lubricant, aqueous solvent or non-aqueous solvent, etc.

[0046] The pharmaceutical formulations according to the present invention can be prepared into any pharmaceutically acceptable dosage form, and a "therapeutically effective amount" of crystalline Form I, Form II, Form III, or Form IV of the methanesulfonate salt of the compound of formula (I) is administered to a patient or examinee in need of such treatment by any suitable administration route, such as oral, parenteral, rectal, or pulmonary administration. When used for oral administration, they can be prepared into tablets, capsules, pills, granules, etc. When used for parenteral administration, they can be prepared into injection solutions, sterile powders for injection, etc.

[0047] The present invention further provides use of crystalline Form I, II, III or IV of the methanesulfonate salt of compound of formula (I), or a drug formulation or composition containing crystalline Form I, II, III or IV, in the preparation of a drug for treating and / or preventing a related disease caused by an abnormality in a signaling pathway resulting from the abnormal expression of a TAM family kinase and / or CSF1R kinase receptor and / or its ligand.

[0048] In some embodiments of the present invention, the diseases mediated by abnormal expression of the TAM family kinases and / or CSF1R kinase receptors and / or their ligands include at least one of the following related diseases: tumors, tumor immunity, ectopic endometriosis, vascular disease / damage, psoriasis, visual disorders / lesions (due to causes such as macular degeneration, diabetes, and premature birth), kidney diseases, rheumatoid arthritis, osteoporosis, etc.

[0049] The present invention further provides use of Crystalline Form I or Crystalline Form II or Crystalline Form III or Crystalline Form IV of the methanesulfonate salt of compound of Formula (I), or a drug formulation or drug composition containing Crystalline Form I or Crystalline Form II or Crystalline Form III or Crystalline Form IV, in the preparation of a drug for the treatment and / or prevention of a disease associated with NTRK.

[0050] The present invention further provides a use of crystalline Form I, II, III, or IV of the methanesulfonate salt of compound of formula (I), or a drug formulation or composition comprising crystalline Form I, II, III, or IV, in the preparation of a drug for the treatment and / or prevention of NTRK-related diseases, particularly drug-resistant NTRK-related diseases produced by NTRK mutations, including, but not limited to, non-small cell lung cancer, colorectal cancer, mammary analog secretory carcinoma, sarcoma, astrocytoma, glioblastoma, Spitz-like melanoma, cholangiocarcinoma, papillary thyroid carcinoma, mammary secretory carcinoma, breast carcinoma-pathological type unknown, etc.

[0051] Details of the invention "Room temperature" as used herein refers to room temperature, which is usually 10°C to 30°C, more usually 15°C to 25°C.

[0052] The term "double volume" as used herein refers to the volume (mL) of a solvent required to dissolve 1 g of a substance. For example, if 20 mL of a solvent is required to dissolve 1 g of a compound of formula (I), it is referred to as 20 volumes.

[0053] The "ethanol" described in the present invention includes absolute ethanol and a mixed solution of ethanol and water, and the ethanol used in the present invention has a content of 95.0% or more.

[0054] "Methanol" according to the present invention is methanol with a content of ≧98%, including but not limited to analytically pure, technical grade, anhydrous methanol.

[0055] The term "therapeutically effective amount" as used herein refers to the amount of a crystalline form, composition, or pharmaceutical formulation of the compound that, when administered to a patient, is capable of at least alleviating the symptoms of the patient's disease. The actual amount, including the "therapeutically effective amount," will vary depending on several factors, including but not limited to, the specific disease being treated, the severity of the disease, the patient's physical condition and health, and the route of administration. A skilled physician can easily determine the appropriate amount using methods known in the medical field.

[0056] The excellent effects of the present invention Through the research of the present invention, it has been found that the crystalline form of the present invention has very good physicochemical properties and pharmaceutical stability, and is relatively greatly improved in terms of efficacy and pharmacokinetic properties, and is more advantageous in terms of drug discovery potential. [Brief explanation of the drawings]

[0057] [Figure 1] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline Form I of the compound of formula (I). [Figure 2] 1 is a differential scanning calorimetry (DSC) pattern of crystalline Form I of the compound of formula (I). [Figure 3] 1 is a powder X-ray diffraction (XRPD) pattern of crystalline Form II of the compound of formula (I). [Figure 4] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline Form III of the compound of formula (I). [Figure 5] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline Form IV of the compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0058] The above content of the present invention will be described in more detail below with reference to specific embodiments, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology realized based on the above content of the present invention belongs to the scope of the present invention.

[0059] The abbreviations used herein are as follows:

[0060] -Boc: tert-butoxycarbonyl group "RH": Relative Humidity "DMF": N,N-dimethylformamide "DCM": dichloromethane "DMSO": dimethyl sulfoxide "FaSSIF": Fasting artificial intestinal fluid "FeSSIF": artificial intestinal fluid during feeding

[0061] Preparation Example 1: Synthesis of intermediate 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid [ka]

[0062] Step 1: Synthesis of 2-isopropylhydrazine-1-carboxylic acid tert-butyl ester [ka] Hydrazine formic acid tert-butyl ester (20.0 g, 0.151 mol), acetone (9.26 g, 0.16 mol), acetic acid (2 mL), magnesium sulfate (10.0 g), and sodium triacetoxyborohydride (96.64 g, 0.456 mol) were added to dichloromethane (100 mL). The reaction was allowed to proceed overnight at room temperature. After complete reaction was confirmed by TLC, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give the product (25 g, yield: 95.6%).

[0063] Step 2: Synthesis of 2-(3-ethoxy-3-oxopropyl)-2-isopropylhydrazine-1-carboxylic acid tert-butyl ester [ka] 2-Isopropylhydrazine-1-carboxylic acid tert-butyl ester (19.0 g, 0.109 mmol) and ethyl acrylate (12.01 g, 0.12 mol) were added to ethanol (60 mL), heated at 80 °C, and reacted overnight. Complete reaction was confirmed by TLC. The mixture was concentrated under reduced pressure, extracted with water and ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (DCM:MeOH = 200:1 to 80:1) to give the product (24.2 g, yield: 81.0%).

[0064] Step 3: Synthesis of ethyl 3-(1-isopropylhydrazine)propionate [ka] 2-(3-Ethoxy-3-oxopropyl)-2-isopropylhydrazine-1-carboxylic acid tert-butyl ester (24.1 g, 0.088 mol) was added to dichloromethane (75 mL), cooled to 0° C. in an ice bath, trifluoroacetic acid (35 mL) was added, and the mixture was allowed to warm slowly to room temperature overnight. After TLC showed complete reaction, the mixture was concentrated under reduced pressure to give the product (18.9 g crude).

[0065] Step 4: Synthesis of ethyl 2-(4-fluorophenyl)-2-oxoacetate [ka] p-Fluoroiodobenzene (10.0 g, 0.0451 mol) was added to 2-methyltetrahydrofuran (10 mL) and cooled to 0 °C in an ice bath. Isopropylmagnesium chloride (2 mol / L, 24.78 mL, 0.049 mol) was added and stirred at 0 °C for 30 min. The reaction mixture was then added dropwise to a solution of diethyl oxalate (7.25 g, 0.0496 mol) in 2-methyltetrahydrofuran (50 mL). The mixture was allowed to warm to room temperature overnight. TLC showed complete reaction. The reaction mixture was added to aqueous citric acid, and the pH was maintained at 5-6. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 120:1 to 40:1) to give the product (8 g, yield: 90.5%).

[0066] Step 5: Synthesis of ethyl 3-(2-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethylene)-1-isopropylhydrazine)propionate [ka] Ethyl 2-(4-fluorophenyl)-2-oxoacetate (4.43 g, 22.6 mmol) and ethyl 3-(1-isopropylhydrazine)propionate (11.81 g crude product) were added to ethanol (10 mL) and heated at 80 °C overnight. TLC showed complete reaction. The mixture was filtered under suction, and the filtrate was extracted with water and ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 60:1 to 10:1) to give the product (2.3 g, yield: 28.9%).

[0067] Step 6: Synthesis of ethyl 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate [ka] Ethyl 3-(2-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethylene)-1-isopropylhydrazine)propionate (2.27 g, 6.45 mmol) was added to 2-methyltetrahydrofuran (10 mL) and cooled to 0 °C in an ice bath. Potassium tert-butoxide (1.81 g, 16.11 mmol) was added and the mixture was allowed to warm slowly to room temperature overnight. TLC showed the reaction was complete. The reaction mixture was added to aqueous citric acid, the pH was maintained at 5-6, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (1.27 g, yield: 64.5%).

[0068] Step 7: Synthesis of ethyl 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylate [ka] Ethyl 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (1.2 g, 3.92 mmol) and copper chloride dihydrate (2.67 g, 15.68 mmol) were added to acetonitrile (10 mL) and reacted at 80 °C for 4 hours. TLC showed the reaction was complete. The reaction mixture was extracted with water and ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 100:1 to 40:1) to give the product (730.0 mg, yield: 61.2%).

[0069] Step 8: Synthesis of 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid [ka] Ethyl 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylate (700.0 mg, 2.3 mmol) was added to a mixture of methanol (6 mL) and water (5 mL), followed by addition of lithium hydroxide monohydrate (284.4 mg, 6.91 mmol). The mixture was stirred at room temperature for 1 hour, and TLC showed complete reaction. The pH was adjusted to 2-3 with citric acid, and the precipitated solid was filtered under suction. The filter cake was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (600.0 mg, yield: 94.5%).

[0070] Example 1 Preparation of compound of formula (I) N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide [ka]

[0071] Step 1: Synthesis of 6,7-dimethoxy-4-((6-nitropyridin-3-yl)oxy)quinoline [ka] 6,7-Dimethoxyquinolin-4-ol (15.00 g, 73.10 mmol, 1.0 eq), 5-chloro-2-nitropyridine (11.60 g, 73.10 mmol, 1.0 eq), and K2CO3 (20.20 g, 146.11 mmol, 2.0 eq) were added to DMF (120 mL) and stirred overnight at 80 °C under nitrogen protection. After complete reaction was confirmed by TLC, the mixture was filtered. The filter cake was rinsed with dichloromethane and the filtrate was concentrated under reduced pressure. Dichloromethane (50 mL) was added and dissolved. The mixture was washed sequentially with distilled water (20 mL × 4) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1:9 to EA) to give the product (4.70 g, yield: 19.6%).

[0072] Step 2: Synthesis of 5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-amine [ka] 6,7-Dimethoxy-4-((6-nitropyridin-3-yl)oxy)quinoline (4.70 g, 14.36 mmol, 1.0 eq), reduced iron powder (4.81 g, 86.16 mmol, 6.0 eq), and NHCl (9.22 g, 172.32 mmol, 12.0 eq) were added to a mixture of ethanol (100 mL) and water (40 mL) and stirred at 80 °C for 4 h. After completion of the reaction, the mixture was filtered while still hot. The filter cake was rinsed with dichloromethane and the filtrate was concentrated under reduced pressure. The aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to give the product (4.07 g, 95.3% yield).

[0073] Step 3: Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide [ka] 1-Isopropyl-4-oxo-5-(4-fluorophenyl)-1,4-dihydropyridazine-3-carboxylic acid (149.0 mg, 0.54 mmol, 1.0 eq) and 5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-amine (192.4 mg, 0.65 mmol, 1.2 eq) were dissolved in anhydrous pyridine (2 mL) and stirred for 10 min. POCl3 was slowly added dropwise until the solid dissolved. After confirming the complete reaction by TLC, the mixture was concentrated under reduced pressure, dissolved in ethyl acetate (10 mL), washed sequentially with 1 mol / L hydrochloric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL), water (5 mL × 2), and saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered under suction, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to give the product (151 mg, yield: 50.4%).

[0074] 1 H NMR (400MHz, DMSO-d6) δ(ppm): 13.08 (s, 1H), 8.94 (s, 1H), 8.52-8.50 (d, 1H), 8.44-8.42 (t, 2H), 7.98-7.95 (m, 2H), 7.91-7.88 (q, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.37-7.33 (t, 2H), 6.60-6.58 (d, 1H), 4.80-4.74 (m, 1H), 3.96-3.95 (d, 6H), 1.54-1.53 ​​(d, 6H). Molecular formula:C 30 H 26 FN5O5 Molecular weight: 555.57 LC-MS (Pos, m / z) = 556.33 [M+H] + .

[0075] Example 2 Preparation of Crystalline Form I of the Methanesulfonate Salt of Compound of Formula (I) 0.56 g of the compound of formula (I) was weighed into a reaction flask, 5 mL of anhydrous methanol was added, and the mixture was stirred at room temperature for 0.5 h. Then, 78 μL of methanesulfonic acid was slowly added while stirring, and the mixture was stirred at room temperature for 20 h to allow crystallization. The mixture was filtered, and the filter cake was dried under vacuum at 50°C to obtain crystalline form I of the methanesulfonate salt.

[0076] The powder X-ray diffraction pattern of Form I, expressed in degrees 2θ (°) using Cu-Kα radiation, shows characteristic peaks at 8.13±0.2°, 14.78±0.2°, 21.82±0.2°, 22.24±0.2°, 23.91±0.2°, 24.24±0.2°, 25.19±0.2°, and 26.94±0.2°, as well as characteristic peaks at 11.11±0.2°, 17.37±0.2°, and 20.27±0.2°, and further characteristic peaks at 12.52±0.2°, 13.75±0.2°, and 19.13±0.2°. The XRPD analysis is shown in FIG. 1.

[0077] The melting temperature of crystalline form I was measured by differential scanning calorimetry to be about 261° C. to 263° C., as shown in FIG.

[0078] Example 3 Preparation of Crystalline Form I of the Methanesulfonate Salt of Compound of Formula (I) 0.56 g of the compound of formula (I) was weighed into a reaction flask, 5 mL of absolute ethanol was added, and the mixture was stirred at room temperature for 0.5 h. Then, 78 μL of methanesulfonic acid was slowly added while stirring, and the mixture was stirred at room temperature for 20 h to allow crystallization. The mixture was filtered, and the filter cake was dried under vacuum at 50°C to obtain crystalline form I of the methanesulfonate salt.

[0079] When Cu-Kα radiation was used, a powder X-ray diffraction pattern essentially as shown in FIG. 1 was obtained.

[0080] Example 4 Preparation of Crystalline Form I of the Methanesulfonate Salt of Compound of Formula (I) 0.56 g of the compound of formula (I) was weighed into a reaction flask, 5 mL of tetrahydrofuran was added, and the mixture was stirred at room temperature for 10 min. Then, 78 μL of methanesulfonic acid was slowly added while stirring, and the mixture was stirred at room temperature for 20 h to allow crystallization. The mixture was filtered, and the filter cake was dried under vacuum at 50°C to obtain crystalline form I of the methanesulfonate salt.

[0081] When Cu-Kα radiation was used, a powder X-ray diffraction pattern essentially as shown in FIG. 1 was obtained.

[0082] Example 5 Preparation of Crystalline Form I of the Methanesulfonate Salt of Compound of Formula (I) 0.56 g of the compound of formula (I) was weighed into a reaction flask, 5 mL of dichloromethane was added, and the mixture was stirred at room temperature for 10 min. Then, 78 μL of methanesulfonic acid was slowly added while stirring, and the mixture was stirred at room temperature for 20 h to allow crystallization. The mixture was filtered, and the filter cake was dried under vacuum at 50°C to obtain crystalline form I of the methanesulfonate salt.

[0083] When Cu-Kα radiation was used, a powder X-ray diffraction pattern essentially as shown in FIG. 1 was obtained.

[0084] Example 6 Preparation of Crystalline Form I of the Methanesulfonate Salt of Compound of Formula (I) 0.56 g of the compound of formula (I) was weighed into a reaction flask, and 7 mL of an isopropanol / ethanol mixed solution (isopropanol:ethanol = 5:2) was added. The mixture was stirred at room temperature for 20 min, and then 78 μL of methanesulfonic acid was slowly added while stirring. The mixture was stirred at room temperature for 20 h to allow crystallization, followed by filtration. The filter cake was dried under vacuum at 50°C to obtain crystalline Form I of the methanesulfonate salt.

[0085] When Cu-Kα radiation was used, a powder X-ray diffraction pattern essentially as shown in FIG. 1 was obtained.

[0086] Example 7 Preparation of Crystalline Form I of the Methanesulfonate Salt of Compound of Formula (I) 0.56 g of the compound of formula (I) was weighed into a reaction flask, 6 mL of isopropanol was added, and the mixture was stirred at 50°C for 0.5 hours. Then, 78 μL of methanesulfonic acid was slowly added while stirring. After stirring at 50°C for 2 hours, heating was stopped and the mixture was allowed to cool to room temperature while stirring. After stirring for 16 hours, the mixture was filtered, and the filter cake was dried under vacuum at 50°C to obtain crystalline Form I of the methanesulfonate salt.

[0087] When Cu-Kα radiation was used, a powder X-ray diffraction pattern essentially as shown in FIG. 1 was obtained.

[0088] Example 8 Preparation of Crystalline Form I of the Methanesulfonate Salt of Compound of Formula (I) 0.56 g of the compound of formula (I) was weighed into a reaction flask, 10 mL of 1,4-dioxane was added, and the mixture was stirred at 50°C for 0.5 hours. 78 μL of methanesulfonic acid was then slowly added while stirring. After stirring at 50°C for 2 hours, the mixture was turned off and allowed to cool to room temperature while stirring. After stirring for 16 hours, the mixture was filtered and the filter cake was dried under vacuum at 50°C to obtain crystalline Form I of the methanesulfonate salt. When Cu-Kα radiation was used, the powder X-ray diffraction pattern was essentially as shown in Figure 1.

[0089] Example 9 Preparation of Crystalline Form II of the Methanesulfonate Salt of Compound of Formula (I) 1.12 g of the compound of formula (I) was weighed into a reaction flask, 5 mL of isopropanol was added, and the mixture was stirred at room temperature for 0.5 hours. Then, 156 μL of methanesulfonic acid was slowly added while stirring, and the mixture was stirred at room temperature for 20 hours to allow crystallization. The mixture was filtered, and the filter cake was dried under vacuum at 50°C to obtain crystalline form II of the methanesulfonate salt.

[0090] The powder X-ray diffraction pattern of Form I, expressed in degrees 2θ (°) using Cu-Kα radiation, shows characteristic peaks at 12.66±0.2°, 13.68±0.2°, 15.74±0.2°, 18.57±0.2°, 21.16±0.2°, and 22.19±0.2°, as well as characteristic peaks at 18.09±0.2°, 20.13±0.2°, 24.88±0.2°, and 26.31±0.2°, and further characteristic peaks at 10.02±0.2°, 16.36±0.2°, and 29.41±0.2°. The XRPD analysis is shown in FIG. 3.

[0091] Example 10 Preparation of Crystalline Form III of the Methanesulfonate Salt of Compound of Formula (I) 1 g of crystalline form I of the methanesulfonate salt was weighed into a reaction flask, and 10 mL of acetonitrile was added thereto. The mixture was slurried at room temperature or 50°C for 24 hours, filtered, and the filter cake was dried under vacuum at 50°C to obtain crystalline form III of the methanesulfonate salt.

[0092] Powder X-ray diffraction of Form III using Cu-Kα radiation, expressed in 2θ angles (°), shows characteristic peaks at 10.32±0.2°, 10.58±0.2°, 12.55±0.2°, 17.30±0.2°, 21.49±0.2°, 21.95±0.2°, and 24.22±0.2°, as well as characteristic peaks at 9.47±0.2°, 13.04±0.2°, 20.66±0.2°, and 23.61±0.2°, and also characteristic peaks at 8.61±0.2°, 15.34±0.2°, and 25.71±0.2°. XRPD analysis is shown in Figure 4.

[0093] Example 11 Preparation of Crystalline Form IV of the Methanesulfonate Salt of Compound of Formula (I) 1 g of crystalline form I of the methanesulfonate salt was weighed into a reaction flask, and 30 mL of dichloromethane was added thereto. The mixture was slurried at room temperature for 24 hours, filtered, and the filter cake was dried under vacuum at 50°C to obtain crystalline form IV of the methanesulfonate salt.

[0094] Powder X-ray diffraction of Form IV using Cu-Kα radiation, expressed in degrees 2θ (°), shows characteristic peaks at 9.71±0.2°, 12.66±0.2°, 17.59±0.2°, 19.35±0.2°, 22.01±0.2°, 23.40±0.2°, and 24.77±0.2°, as well as characteristic peaks at 15.11±0.2°, 22.34±0.2°, and 23.92±0.2°, and further characteristic peaks at 10.26±0.2°, 11.78±0.2°, and 12.45±0.2°. XRPD analysis is shown in FIG. 5.

[0095] The present invention can be better understood by the following experimental examples. However, it will be readily understood by those skilled in the art that the contents described in the examples are merely for the purpose of illustrating the present invention and should not, and do not, limit the present invention as specifically described in the claims.

[0096] Experimental Example 1: Test of the inhibitory activity of the crystalline form of the present invention against AXL cells H1299 is a non-small cell lung cancer cell line.

[0097] Test article: A crystalline form of the methanesulfonate salt of the compound of formula (I) of the present invention, the structure of which is shown above.

[0098] Testing equipment: Protein electrophoresis device (Bio Rad), transfer device (Bio Rad), exposure device (Tanon), CO2 cell incubator (Thermo), etc.

[0099] Test Method: Plate H1299 cells in 6-well plates (containing 10% FBS 1640 medium, 5 × 10 cells per well). 5Cells were seeded into wells containing 1000 cells (containing 1000 cells) and cultured at 37°C and 5% CO2 for 18 hours. The cells were starved overnight and then treated with various concentrations of compounds. The final compound concentrations were 0.37, 1.1, 3.3, 10, and 30 nM, with a final DMSO content of 1‰. Negative control wells contained medium containing 1‰ DMSO. After incubation at 37°C and 5% CO2 for 60 minutes, hGAS6 (R&D, final concentration 200 ng / mL) was added to each well and incubated for another 60 minutes. Total cell protein was extracted and Western blot analysis was performed to detect the inhibitory activity of the compounds on cellular pAXL.

[0100] The test results are shown in Table 1.

[0101] [Table 1]

[0102] As can be seen from the experimental results in Table 1, the crystalline form of the methanesulfonate salt of compound of formula (I) of the present invention has a significant inhibitory effect on H1299 cell pAXL. The crystalline form of the methanesulfonate salt of compound of formula (I) can effectively inhibit AXL activity at the cellular level, and is therefore a good AXL inhibitor.

[0103] Experimental Example 2 PK evaluation of the crystalline form of the present invention in rats Animal Dosing and Sample Collection: For experimental purposes, Form I and Form II of the methanesulfonate salt of compound of formula (I) were suspended in 0.5% HPMC. The compound solutions were intragastrically administered to SD rats at a dose of 60 mg / kg, and blood was collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 48 h, 72 h, and 96 h.

[0104] The animals were immobilized, and their tails were heated in a water bath 10 min before each time point. Approximately 100 μL of blood was collected from the tail vein and placed into anticoagulant tubes containing EDTA-K2. Blood samples were centrifuged at 8000 rpm for 6 min at 4°C to obtain plasma samples. Plasma was prepared within 30 min of blood collection. Plasma was stored in a -80°C refrigerator prior to testing.

[0105] How to analyze the sample: The samples to be tested were removed from the -80°C refrigerator, allowed to thaw at room temperature, and then swirled for 5 minutes. 20 μL of plasma sample was accurately aspirated into a 1.5 mL centrifuge tube, and 200 μL of 100 ng / mL internal standard working solution (tolbutamide in methanol) was added and mixed uniformly. After swirling for 5 minutes, the tube was centrifuged at 12,000 rpm for 5 minutes. 50 μL of the supernatant was accurately aspirated and placed in a 96-well plate containing 150 μL of water per well. The tube was swirled for 5 minutes to mix uniformly, and then subjected to LC-MS / MS analysis.

[0106] Data processing methods: Analyst 1.6.3 (AB) was used to calculate the concentration of the test substance. The mean, standard deviation, coefficient of variation, and other parameters were calculated using Microsoft Excel (Analyst 1.6.3 directly outputs the results without calculations). PK parameters were calculated using Pharsight Phoenix 6.1 software (NCA). max is the median).

[0107] The results are shown in Table 2 below.

[0108] [Table 2]

[0109] As can be seen from the experimental results in Table 2, the crystalline form of methanesulfonate salt of the compound of formula (I) of the present invention has good pharmacokinetic properties and good potential for drug discovery.

[0110] Experimental Example 3: Stability test of the crystalline form of the present invention Test substance: Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV of the methanesulfonate salt of the compound of formula (I) of the present invention.

[0111] Method: Appropriate amounts of samples of crystalline form I, crystalline form II, crystalline form III, and crystalline form IV of the methanesulfonate salt of compound of formula (I) were taken and left open under conditions of high temperature (60°C), high humidity (RH 92.5%), and light irradiation (4500±500 Lux). Sampling was performed on the 5th, 10th, and 30th days, and the properties, purity, and changes in crystalline form of the samples were examined.

[0112] result: [Table 3]

[0113] Conclusion: The properties and purity of the methanesulfonate salt of the compound of formula (I) of the present invention, Form I, Form II, Form III, and Form IV, were left for 30 days under various conditions, and the samples showed good stability.

[0114] Experimental Example 4 Measurement of the solubility of the crystalline form of the present invention in test solutions with different pH values Test substance: Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV of methanesulfonate salt of the compound of formula (I)

[0115] Preparation of different pH buffers: (1) FaSSIF (pH 6.5): 1) 0.42 g of NaOH, 3.44 g of anhydrous NaH2PO4, and 6.19 g of NaCl were dissolved in approximately 0.9 L of pure water.

[0116] 2) The pH was adjusted to 6.5 using 1N NaOH or 1N HCl, and the buffer volume was made up to 1 L using purified water at room temperature.

[0117] 3) 2.24 g of FaSSIF powder was added to approximately 0.5 L of buffer solution and stirred until the powder was completely dissolved. The volume was made up to 1 L with buffer solution at room temperature and allowed to stand for 2 h before use.

[0118] (2) FeSSIF (pH 5.0): 1) 4.04g of NaOH, 8.65g of glacial acetic acid, and 11.87g of NaCl were dissolved in approximately 0.9L of pure water.

[0119] 2) The pH was adjusted to 5.0 using 1N NaOH or 1N HCl, and the buffer volume was made up to 1 L using purified water at room temperature.

[0120] 3) 11.2 g of FeSSIF powder was added to approximately 0.5 L of buffer solution and stirred until the powder was completely dissolved. The solution was then made up to 1 L with buffer solution at room temperature and allowed to stand for 2 h before being ready for use.

[0121] Testing Procedure: Appropriate amounts of the test samples were taken and placed in 10 mL PE tubes, and 10 mL each of FaSSIF (pH 6.5) buffer and FeSSIF (pH 5.0) buffer were added. The tubes were then placed in a thermostatic water bath shaker and shaken at 37°C for 24 hours. After 24 hours, the tubes were sampled, centrifuged, and the supernatant was collected and diluted, after which its solubility was measured.

[0122] The experimental results are as follows: [Table 4]

[0123] Conclusion: Compared with the compound of formula (I), the solubility of crystalline forms I, II, III and IV of the methanesulfonate salt in the test solutions of pH 5.0 and pH 6.5 was significantly improved.

[0124] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of the claims of the present invention.

Claims

1. A crystalline form of methanesulfonate salt of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide, a compound represented by formula (I), i.e., crystalline form I, is characterized in that, when powdered using Cu-Kα radiation and X-ray diffraction at 2θ angles, it has characteristic peaks at 8.13±0.2°, 14.78±0.2°, 21.82±0.2°, 22.24±0.2°, 23.91±0.2°, 24.24±0.2°, 25.19±0.2°, and 26.94±0.2°. Crystalline form I. 【Chemical 1】

2. The powder X-ray diffraction pattern measured at 2θ angles using Cu-Kα radiation is further characterized by having characteristic peaks at 11.11±0.2°, 17.37±0.2°, and 20.27±0.2°. Crystalline form I according to claim 1.

3. The powder X-ray diffraction pattern measured at 2θ angles using Cu-Kα radiation is further characterized by having characteristic peaks at 12.52±0.2°, 13.75±0.2°, and 19.13±0.2°. Crystalline form I according to claim 2.

4. 2. A process for preparing crystalline form I according to claim 1, comprising the steps of: Dissolving the compound of formula (I) in a single or mixed solvent and stirring until completely dissolved, then slowly adding methanesulfonic acid while stirring, and stirring to precipitate crystalline form I; The single or mixed solvent is selected from the group consisting of isopropanol, methanol, ethanol, tetrahydrofuran, dichloromethane, 1,4-dioxane, toluene, acetone, ethyl acetate, acetonitrile, methyl tert-butyl ether, 2-methyltetrahydrofuran, dimethyl sulfoxide, and water, or a mixture of two or more thereof. Preferably, the single or mixed solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, dichloromethane, 1,4-dioxane, and an isopropanol / ethanol mixed solution. Preparation method.

5. A crystalline form of methanesulfonate salt of the compound N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide represented by formula (I), i.e., crystalline form II, characterized in that powder X-ray diffraction using Cu-Kα radiation at 2θ angles has characteristic peaks at 12.66±0.2°, 13.68±0.2°, 15.74±0.2°, 18.57±0.2°, 21.16±0.2°, and 22.19±0.2°. Crystalline Form II. 【Chemistry 2】

6. The powder X-ray diffraction pattern measured at 2θ angles using Cu-Kα radiation is further characterized by having characteristic peaks at 18.09±0.2°, 20.13±0.2°, 24.88±0.2°, and 26.31±0.2°. Crystalline form II according to claim 5.

7. The powder X-ray diffraction using Cu-Kα radiation at 2θ angles is further characterized by having characteristic peaks at 10.02±0.2°, 16.36±0.2°, and 29.41±0.2°.

7. Crystalline Form II according to claim 6.

8. A crystalline form of methanesulfonate salt of the compound N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide represented by formula (I), i.e., crystalline form III, characterized in that powder X-ray diffraction using Cu-Kα radiation at 2θ angles has characteristic peaks at 10.32±0.2°, 10.58±0.2°, 12.55±0.2°, 17.30±0.2°, 21.49±0.2°, 21.95±0.2°, and 24.22±0.2°. Crystalline Form III. 【Chemistry 3】

9. The powder X-ray diffraction pattern measured at 2θ angles using Cu-Kα radiation is further characterized by having characteristic peaks at 9.47±0.2°, 13.04±0.2°, 20.66±0.2°, and 23.61±0.2°.

9. Crystalline Form III according to claim 8.

10. The powder X-ray diffraction pattern measured at 2θ angles using Cu-Kα radiation is further characterized by having characteristic peaks at 8.61±0.2°, 15.34±0.2°, and 25.71±0.2°.

10. Crystalline Form III according to claim 9.

11. A crystalline form of methanesulfonate salt of the compound N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide represented by formula (I), i.e., crystalline form IV, characterized in that powder X-ray diffraction using Cu-Kα radiation at 2θ angles has characteristic peaks at 9.71±0.2°, 12.66±0.2°, 17.59±0.2°, 19.35±0.2°, 22.01±0.2°, 23.40±0.2°, and 24.77±0.2°. Crystalline Form IV. 【Chemistry 4】

12. The powder X-ray diffraction pattern measured at 2θ angles using Cu-Kα radiation is further characterized by having characteristic peaks at 15.11±0.2°, 22.34±0.2°, and 23.92±0.2°.

12. Crystalline form IV according to claim 11.

13. The powder X-ray diffraction pattern measured at 2θ angles using Cu-Kα radiation is further characterized by having characteristic peaks at 10.26±0.2°, 11.78±0.2°, and 12.45±0.2°.

13. Crystalline form IV according to claim 12.

14. A pharmaceutical composition comprising crystalline form I according to any one of claims 1 to 3, or crystalline form II according to any one of claims 5 to 7, or crystalline form III according to any one of claims 8 to 10, or crystalline form IV according to any one of claims 11 to 13, and one or more second therapeutically active agents. Drug composition.

15. A drug formulation comprising crystalline form I according to any one of claims 1 to 3, or crystalline form II according to any one of claims 5 to 7, or crystalline form III according to any one of claims 8 to 10, or crystalline form IV according to any one of claims 11 to 13, and one or more pharmaceutical carriers. Drug formulations.

16. Use of crystalline form I according to any one of claims 1 to 3, or crystalline form II according to any one of claims 5 to 7, or crystalline form III according to any one of claims 8 to 10, or crystalline form IV according to any one of claims 11 to 13, or the drug composition according to claim 14, or the drug formulation according to claim 15, in the preparation of a drug for treating and / or preventing an associated disease caused by an abnormality in a signal transduction pathway caused by an abnormal expression of a TAM family kinase and / or a CSF1R kinase receptor and / or its ligand.

17. Use of crystalline form I according to any one of claims 1 to 3, or crystalline form II according to any one of claims 5 to 7, or crystalline form III according to any one of claims 8 to 10, or crystalline form IV according to any one of claims 11 to 13, or the drug composition according to claim 14, or the drug formulation according to claim 15, in the preparation of a drug for treating and / or preventing related diseases caused by NTRK.

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