Crystal Forms of Quinoline TGF-β1 Inhibitors

Abstract

The present invention belongs to the field of medicinal chemistry, and relates to crystal forms of quinoline TGF-β1 inhibitors, their preparation methods and uses. Specifically, it relates to crystal forms of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline of formula (I) and their preparation methods. The crystal forms can be used to prepare drugs for treating and / or preventing cancer, tissue hyperplasia diseases, fibrosis or inflammatory diseases.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to the crystal forms of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline, and their preparation methods and uses. Background Art

[0002] TGF-β (transforming growth factor-β) is a class of important cytokines. So far, 6 different subtypes (TGF-β1-6) have been discovered, with different homologies among them, and only 3 subtypes are expressed in mammals, namely TGF-β1, TGF-β2, and TGF-β3. It is a multifunctional growth factor superfamily with a wide range of biological activities, participating in early embryonic development, cartilage and bone formation, extracellular matrix synthesis, inflammation, interstitial fibrosis, regulation of immune and endocrine functions, and tumor formation and development. At the same time, these 3 isomers have similar structures, and their amino acid sequences have a high degree of homology. However, in their respective gene knockout mouse models, they show completely different phenotypes, suggesting that each isomer has specific and non-overlapping functions in vivo. Ligands of the TGF-β family can bind to receptors on the cell membrane surface to initiate the transmission of downstream signals within the cell.

[0003] TGF-β1 is the most common and important subtype of TGF-β, the most abundant subtype expressed in the liver, and also the strongest known liver fibrosis inducer, playing a crucial role in the development of chronic liver disease to end-stage liver disease (Yamazaki, et al. Digestive Disease, 2011, 29:284-288). A number of studies have shown that TGF-β1 and TGF-β receptors are usually highly expressed in liver-lesioned organs, blood vessels, and extracellular matrix. In the classical TGFβ-TGFβR-Smads pathway, TGF-β1 activates TGFβR1 (transforming growth factor-β receptor 1, ALK5) in the signal pathway, and then regulates the entire signal pathway to achieve the regulation of the expression of a series of target genes related to fibrosis and tumorigenesis and development. Currently, it is generally believed that the promoting effect of TGF-β on liver cancer is mainly manifested in promoting tumor cell metastasis, enhancing tumor cell immune escape, and inducing angiogenesis, etc. (Ling, et al. Current Pharmaceutical Biotechnology, 2011, 12:2190-2202).

[0004] Drug research targeting the TGF-β pathway has been carried out for many years. However, TGFβR1 inhibitors such as Galunisertib have shown certain cardiotoxicity in animal models (such as bleeding, functional degradation, inflammatory damage, etc.). The reason is that the target selectivity and specificity of such drugs are relatively low. While the drugs inhibit the kinase activation site of TGFβR1, they also have a strong inhibitory effect on other proteins with the same kinase region (such as p38α), thus resulting in many unexpected off-target toxic side effects. Therefore, there is still a need to develop more selective TGFβR1 inhibitors to specifically regulate the TGF-β signaling pathway for the treatment of TGF-β related diseases. Summary of the Invention

[0005] The inventors of the present invention have discovered a quinoline-based TGF-β1 inhibitor. The chemical structure of this inhibitor is shown in the following formula (I), and its chemical name is 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline (hereinafter referred to as "compound of formula (I)"):

[0006]

[0007] The inventors of the present invention have studied and found that the compound of formula (I) or its hydrate, solvate or crystal shows significant inhibitory activity against TGF-βR1 kinase and is very promising to be a therapeutic agent for TGF-βR1 related diseases.

[0008] Those skilled in the art know that the crystal form of a medicinally active compound often affects its properties such as chemical stability and solubility. Therefore, it is necessary to conduct in-depth research to find a crystal form suitable for medicinal use.

[0009] The object of the present invention is to provide a crystal form of a quinoline-based TGF-β1 inhibitor with good water solubility, high bioavailability and high stability. Specifically, the present invention provides a crystal form of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as shown in formula (I).

[0010]

[0011] The inventors of the present invention have carried out detections on the crystal form of the compound of formula (I) such as X-ray powder diffraction, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA).

[0012] In some embodiments, the X-ray powder diffraction pattern of crystalline form A of the compound of formula (I) of the present invention is shown in Figure 1 , using Cu-Kα radiation, the X-ray powder diffraction pattern is represented by 2θ angle, and it has characteristic peaks at about 3.7±0.2, 9.5±0.2, 14.2±0.2, 14.7±0.2.

[0013] Furthermore, the X-ray powder diffraction pattern of crystalline form A of the compound of formula (I) of the present invention has characteristic peaks at about 3.7±0.2, 9.5±0.2, 14.2±0.2, 14.7±0.2, 18.9±0.2, 24.1±0.2, 25.9±0.2.

[0014] Still further, the X-ray powder diffraction pattern of crystalline form A of the compound of formula (I) of the present invention has characteristic peaks at about 3.7±0.2, 6.2±0.2, 6.6±0.2, 7.0±0.2, 7.4±0.2, 9.5±0.2, 14.2±0.2, 14.7±0.2, 16.3±0.2, 18.9±0.2, 21.6±0.2, 22.2±0.2, 23.0±0.2, 24.1±0.2, 25.9±0.2.

[0015] Even further, the X-ray powder diffraction pattern of crystalline form A of the compound of formula (I) of the present invention has characteristic peaks at about 3.7±0.2, 6.2±0.2, 6.6±0.2, 7.0±0.2, 7.4±0.2, 9.5±0.2, 14.2±0.2, 14.7±0.2, 16.3±0.2, 18.2±0.2, 18.5±0.2, 18.9±0.2, 21.6±0.2, 22.2±0.2, 23.0±0.2, 24.1±0.2, 25.9±0.2, 27.2±0.2, 27.8±0.2, 29.7±0.2, 30.4±0.2, 32.9±0.2, 34.0±0.2.

[0016] Non-limitingly, in a specific embodiment, crystalline form A of the compound of formula (I) of the present invention has an X-ray powder diffraction pattern as shown in Figure 1 .

[0017] Non-limitingly, in a specific embodiment, the DSC pattern of crystalline form A of the compound of formula (I) of the present invention (see Figure 2 ) shows a sharp endothermic peak at 215.6 °C.

[0018] Non-limitingly, in a specific embodiment, crystalline form A of the compound of formula (I) of the present invention has an X-ray powder diffraction pattern as shown in Figure 3The thermogravimetric analysis (TGA) spectrum shown indicates that there is no obvious weight loss before 300 °C. The crystalline form A of the compound of formula (I) of the present invention has very good stability.

[0019] The present invention provides a method for preparing crystalline form A of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline represented by formula (I), which includes the steps of placing 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline in an organic solvent and filtering, wherein the form of the raw material 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline is not particularly limited, and any crystal or amorphous solid can be used. In some embodiments, the organic solvent is selected from dichloromethane, methyl isobutyl ketone (MIBK), isopropyl acetate, ethanol, isopropanol, toluene, tetrahydrofuran, chloroform, 1,4-dioxane, acetonitrile, n-heptane, dimethyl sulfoxide, N,N-dimethylacetamide, methyl tert-butyl ether (MTBE), ethyl formate. In some specific embodiments, for the method for preparing crystalline form A of the compound of formula (I) according to the present invention, the organic solvent is dichloromethane and heptane. In some specific embodiments, for the method for preparing crystalline form A of the compound of formula (I) according to the present invention, the organic solvent is dichloromethane and butyl acetate. In some specific embodiments, for the method for preparing crystalline form A of the compound of formula (I) according to the present invention, the organic solvent is tetrahydrofuran and MTBE. In some specific embodiments, for the method for preparing crystalline form A of the compound of formula (I) according to the present invention, the organic solvent is ethyl acetate and heptane. In some specific embodiments, for the method for preparing crystalline form A of the compound of formula (I) according to the present invention, the organic solvent is dichloromethane and heptane, and the volume ratio (V / V) of dichloromethane to heptane is about 1:1 - about 1:10, such as about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, etc. In some specific embodiments, for the method for preparing crystalline form A of the compound of formula (I) according to the present invention, crystalline form A is prepared by the method of anti-solvent dropping. In some specific embodiments, the method for preparing crystalline form A of the compound of formula (I) according to the present invention includes the step of adding dichloromethane to the compound of formula (I), and then adding n-heptane. In some specific embodiments, the method for preparing crystalline form A of the compound of formula (I) according to the present invention includes the step of adding dichloromethane to the compound of formula (I), and then adding n-heptane at a temperature of 40 ± 15 °C, preferably 45 ± 10 °C, more preferably 45 ± 5 °C.In some specific embodiments, the method for preparing crystalline form A of the compound of formula (I) of the present invention comprises adding dichloromethane to the compound of formula (I), and then dropping n-heptane at a rate of 50-150 mL / min, preferably 60-120 mL / min, more preferably 80-100 mL / min at a temperature of 40 ± 15 °C, preferably 45 ± 10 °C, more preferably 45 ± 5 °C.

[0020] In some embodiments, for the X-ray powder diffraction pattern of crystalline form B of the compound of formula (I) of the present invention, see Figure 4 , using Cu-Kα radiation, the X-ray powder diffraction pattern is expressed in terms of 2θ angle, and it has characteristic peaks at about 3.9 ± 0.2 and 15.8 ± 0.2.

[0021] Furthermore, the X-ray powder diffraction pattern of crystalline form B of the compound of formula (I) of the present invention has characteristic peaks at about 3.9 ± 0.2, 7.8 ± 0.2, 10.0 ± 0.2, 11.8 ± 0.2, and 15.8 ± 0.2.

[0022] Still further, the X-ray powder diffraction pattern of crystalline form B of the compound of formula (I) of the present invention has characteristic peaks at about 3.9 ± 0.2, 7.8 ± 0.2, 10.0 ± 0.2, 11.8 ± 0.2, 15.1 ± 0.2, 15.8 ± 0.2, and 23.9 ± 0.2.

[0023] Even further, the X-ray powder diffraction pattern of crystalline form B of the compound of formula (I) of the present invention has characteristic peaks at about 3.9 ± 0.2, 7.8 ± 0.2, 10.0 ± 0.2, 11.8 ± 0.2, 15.1 ± 0.2, 15.8 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.8 ± 0.2, 20.9 ± 0.2, 21.4 ± 0.2, 22.6 ± 0.2, 23.2 ± 0.2, 23.9 ± 0.2, 25.0 ± 0.2, 28.0 ± 0.2, 28.7 ± 0.2, 32.0 ± 0.2, and 37.7 ± 0.2.

[0024] Non-limitingly, in a specific embodiment, crystalline form B of the compound of formula (I) of the present invention has an X-ray powder diffraction pattern as shown in Figure 4 shown.

[0025] The present invention provides a method for preparing crystalline form B of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline represented by formula (I), which includes the steps of placing 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline in an organic solvent and filtering. Among them, the existence form of the raw material 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline is not particularly limited, and any crystal or amorphous solid can be used. In some embodiments, the organic solvent is selected from methyl isobutyl ketone (MIBK) and isopropyl acetate.

[0026] In some embodiments, for the X-ray powder diffraction pattern of crystalline form C of the compound of formula (I) of the present invention, see Figure 5 , using Cu-Kα radiation, the X-ray powder diffraction pattern is represented by the 2θ angle, and it has characteristic peaks at about 8.2±0.2 and 12.0±0.2.

[0027] Furthermore, the X-ray powder diffraction pattern of crystalline form C of the compound of formula (I) of the present invention has characteristic peaks at about 8.2±0.2, 12.0±0.2, 16.6±0.2, 19.2±0.2, and 24.1±0.2.

[0028] Without limitation, in a specific embodiment, crystalline form C of the compound of formula (I) of the present invention has an X-ray powder diffraction pattern as shown in Figure 5 .

[0029] The present invention provides a method for preparing crystalline form C of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline of formula (I) as described below, which comprises placing 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline in a solvent and filtering; wherein the form of the starting material 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline is not particularly limited, and any crystal or amorphous solid can be used; and wherein the solvent is selected from water and water-saturated ethyl acetate.

[0030] In some embodiments, for the X-ray powder diffraction pattern of crystalline form D of the compound of formula (I) of the present invention, see Figure 6 , using Cu-Kα radiation, the X-ray powder diffraction pattern is expressed in terms of 2θ angle, and it has characteristic peaks at about 7.1±0.2, 10.1±0.2, 14.2±0.2, 20.2±0.2, 21.4±0.2.

[0031] Furthermore, the X-ray powder diffraction pattern of crystalline form D of the compound of formula (I) of the present invention has characteristic peaks at about 7.1±0.2, 8.3±0.2, 10.1±0.2, 14.2±0.2, 15.1±0.2, 20.2±0.2, 21.4±0.2, 22.6±0.2.

[0032] Even further, the X-ray powder diffraction pattern of crystalline form D of the compound of formula (I) of the present invention has characteristic peaks at about 7.1±0.2, 8.3±0.2, 10.1±0.2, 11.0±0.2, 14.2±0.2, 15.1±0.2, 15.9±0.2, 16.1±0.2, 17.4±0.2, 18.9±0.2, 20.2±0.2, 21.4±0.2, 22.6±0.2, 23.4±0.2, 23.8±0.2, 24.6±0.2, 26.8±0.2, 27.4±0.2, 28.2±0.2, 30.6±0.2.

[0033] Without limitation, in a specific embodiment, crystalline form D of the compound of formula (I) of the present invention has an X-ray powder diffraction pattern as shown in Figure 6 .

[0034] The present invention provides a method for preparing crystalline form D of 4 - ((1 - cyclopropyl - 3 - (tetrahydro - 2H - pyran - 4 - yl) - 1H - pyrazol - 4 - yl)oxy) - 7 - (3 - (trifluoromethyl) - 5,6 - dihydro - [1,2,4]triazolo[4,3 - a]pyrazin - 7(8H) - yl)quinoline shown by formula (I), which includes the step of dissolving 4 - ((1 - cyclopropyl - 3 - (tetrahydro - 2H - pyran - 4 - yl) - 1H - pyrazol - 4 - yl)oxy) - 7 - (3 - (trifluoromethyl) - 5,6 - dihydro - [1,2,4]triazolo[4,3 - a]pyrazin - 7(8H) - yl)quinoline in organic solvent 1 and then adding organic solvent 2; wherein the existence form of the raw material 4 - ((1 - cyclopropyl - 3 - (tetrahydro - 2H - pyran - 4 - yl) - 1H - pyrazol - 4 - yl)oxy) - 7 - (3 - (trifluoromethyl) - 5,6 - dihydro - [1,2,4]triazolo[4,3 - a]pyrazin - 7(8H) - yl)quinoline is not particularly limited, and any crystal or amorphous solid can be used; the organic solvent 1 is selected from chloroform, and the organic solvent 2 is selected from methyl tert - butyl ether (MTBE), toluene and n - heptane. Preferably, the volume ratio of the organic solvent 1 to the organic solvent 2 is about 1:0.8 - 1:2; more preferably, the volume ratio of the organic solvent 1 to the organic solvent 2 is about 1:1.1 - 1:1.2; even more preferably, the volume ratio of the organic solvent 1 to the organic solvent 2 is about 3:3.5.

[0035] In some embodiments, for the X - ray powder diffraction pattern of crystalline form E of the compound of formula (I) of the present invention, see Figure 7 , using Cu - Ka radiation, representing the X - ray powder diffraction pattern by 2θ angle, which has characteristic peaks at about 4.9±0.2, 9.9±0.2, 15.0±0.2, 18.7±0.2.

[0036] Furthermore, the X - ray powder diffraction pattern of crystalline form E of the compound of formula (I) of the present invention has characteristic peaks at about 4.9±0.2, 6.9±0.2, 9.9±0.2, 15.0±0.2, 18.7±0.2.

[0037] Even further, the X - ray powder diffraction pattern of crystalline form E of the compound of formula (I) of the present invention has characteristic peaks at about 4.9±0.2, 6.9±0.2, 9.9±0.2, 15.0±0.2, 18.7±0.2, 20.1±0.2, 21.2±0.2, 30.4±0.2.

[0038] Furthermore, the X-ray powder diffraction pattern of crystalline form E of the compound of formula (I) of the present invention has characteristic peaks at about 4.9±0.2, 6.9±0.2, 9.9±0.2, 15.0±0.2, 18.7±0.2, 20.1±0.2, 21.2±0.2, 23.6±0.2, 30.4±0.2, 31.9±0.2, 38.9±0.2.

[0039] Without limitation, in a specific embodiment, crystalline form E of the compound of formula (I) of the present invention has an X-ray powder diffraction pattern as Figure 7 shown.

[0040] The present invention provides a method for preparing crystalline form E of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline of formula (I) as described above, which comprises dissolving 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline in organic solvent 3, and then adding organic solvent 4; wherein the existence form of the raw material 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline is not particularly limited, and any crystal or amorphous solid can be used; wherein organic solvent 3 is selected from dichloromethane, and organic solvent 4 is selected from methyl tert-butyl ether (MTBE). Preferably, the volume ratio of organic solvent 3 to organic solvent 4 is about 1:3 - 1:7; more preferably, the volume ratio of organic solvent 3 to organic solvent 4 is about 1:4 - 1:6; even more preferably, the volume ratio of organic solvent 3 to organic solvent 4 is about 1:5.

[0041] The crystalline forms A - E prepared by the method of the present invention do not contain or contain a low content of residual solvents, meet the limit requirements of the national pharmacopoeia for residual solvents in pharmaceutical products, and can be preferably used as pharmaceutical active ingredients.

[0042] On the other hand, the present invention provides an amorphous form of the compound of formula (I).

[0043] Without limitation, a typical example of the amorphous form of the compound of formula (I) of the present invention has an X-ray powder diffraction pattern as Figure 8 shown.

[0044] The present invention provides a method for preparing the amorphous form of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline of the present invention, which includes dissolving 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline in organic solvent 5, and then adding it to solvent 6; preferably, the organic solvent 5 is selected from 1,4-dioxane; the solvent 6 is selected from water.

[0045] Another aspect of the present invention provides a crystal composition, wherein the crystal form A, B, C, D or E of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline accounts for more than 50% by weight of the crystal composition, preferably more than 80% by weight, more preferably more than 90% by weight, and most preferably more than 95% by weight.

[0046] Another aspect of the present invention provides a pharmaceutical composition, which contains the crystal form of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline and a pharmaceutically acceptable carrier, preferably contains the crystal form A, B, C, D or E of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline and a pharmaceutically acceptable carrier.

[0047] Another aspect of the present invention provides a crystalline form of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline or a pharmaceutical composition comprising the crystalline form of the above compound. In particular, the use of the crystalline form A, B, C, D or E of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline or a pharmaceutical composition comprising the crystalline form A, B, C, D or E of the above compound in the preparation of a drug for treating and / or preventing cancer, tissue hyperplasia diseases, fibrosis or inflammatory diseases, wherein the conditions of the cancer, tissue hyperplasia diseases, fibrosis or inflammatory diseases include but are not limited to: melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, carcinoma and sarcoma of the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lung and ovary or leukemia, glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), sarcoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma or angioimmunoblastic lymphoma, liver fibrosis and chronic kidney disease.

[0048] It should be specifically noted here that the X-ray powder diffraction pattern is characteristic of a specific crystalline form. When determining whether it is the same as a known crystalline form, attention should be paid to the relative position of the peaks (i.e., 2θ) rather than their relative intensities. This is because the relative intensities of the spectrum (especially at low angles) will vary due to the preferred orientation effect caused by differences in crystal conditions, particle size or other measurement conditions, and the relative intensity of the diffraction peaks is not characteristic for the determination of the crystalline form. In addition, there may be a slight error in the 2θ value of the same crystalline form, about ±0.2°. Therefore, this error should be taken into account when determining each crystal structure. In the XRPD pattern, the peak position is usually represented by the 2θ angle or the interplanar spacing d value, and there is a simple conversion relationship between the two: d = λ / 2sinθ, where the d value represents the interplanar spacing, λ represents the wavelength of the X-ray, and θ is the diffraction angle. It should also be specifically pointed out that in the identification of a mixture, due to factors such as a decrease in content, some diffraction lines may be missing. At this time, it is not necessary to rely on all the spectral bands observed in a high-purity sample, and one spectral band may also be characteristic of a given crystal.

[0049] DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or crystal melting. For the same polymorph of the same compound, in consecutive analyses, the thermal transition temperature and melting point error are typically within about 5 °C. When we say that a compound has a given DSC peak or melting point, this refers to the DSC peak or melting point ±5 °C. It should be noted that for mixtures, their DSC peaks or melting points may vary over a wider range. In addition, since decomposition occurs during the melting of a substance, the melting temperature is related to the heating rate.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0051] "Hydrogen", "carbon", and "oxygen" in the compounds of the present invention include all their isotopes. Isotopes should be understood to include those atoms having the same atomic number but different mass numbers. For example, the isotopes of hydrogen include protium, tritium, and deuterium, and the isotopes of carbon include 13 C and 14 C, and the isotopes of oxygen include 16 O and 18 O, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 is the X-ray diffraction pattern of polymorph A of the compound of formula (I);

[0053] Figure 2 is the DSC pattern of polymorph A of the compound of formula (I);

[0054] Figure 3 is the TGA pattern of polymorph A of the compound of formula (I);

[0055] Figure 4 is the X-ray diffraction pattern of polymorph B of the compound of formula (I);

[0056] Figure 5 is the X-ray diffraction pattern of polymorph C of the compound of formula (I);

[0057] Figure 6 is the X-ray diffraction pattern of polymorph D of the compound of formula (I);

[0058] Figure 7 is the X-ray diffraction pattern of polymorph E of the compound of formula (I);

[0059] Figure 8 is the X-ray diffraction pattern of the amorphous form of the compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0060] The following representative embodiments are for better illustrating the present invention, rather than limiting the protection scope of the present invention. Materials used in the following embodiments are commercially available unless otherwise specified.

[0061] I. Test Instruments Used in Experiments

[0062] 1. X-ray Powder Diffraction Spectrum (XRPD)

[0063] Instrument Model: D8 Advance X-ray Diffractometer from Switzerland

[0064] Test Conditions: Copper Target, Tube Voltage 40 kV, Tube Current 40 mA

[0065] 2. Thermogravimetric Analysis (TGA)

[0066] Instrument Model: PERKINELMER TGA4000 Thermogravimetric Analyzer

[0067] Temperature Range: 30–300 °C

[0068] Heating Rate: 10 °C / min

[0069] 3. Differential Scanning Calorimetry (DSC)

[0070] Instrument Model: NETZSCH DSC 204 Differential Thermal Analyzer

[0071] Temperature Range: 40–250 °C

[0072] Heating Rate: 10 °C / min

[0073] Example 1 Preparation of 4-((1-Cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline

[0074]

[0075] Step 1: Preparation of 2-Bromo-1-(tetrahydro-2H-pyran-4-yl)ethan-1-one

[0076]

[0077] Under nitrogen protection, in a 1000 mL three-necked flask, methanol (100 mL) and 1-(tetrahydro-2H-pyran-4-yl)ethanone (20.0 g, 156 mmol) were successively added. The temperature was lowered to below -15 °C, and liquid bromine was slowly dropped in while maintaining the temperature below -15 °C. After dropping, the temperature was raised to 0 °C and the reaction was carried out for 45 min, then the temperature was raised to 10 °C and the reaction was carried out for 45 min. While maintaining the internal temperature below room temperature, 11 mol / L sulfuric acid (55 mL) was slowly dropped in. After dropping, the reaction was carried out overnight at room temperature. After monitoring the reaction to completion, ethyl acetate and aqueous sodium chloride solution were added for extraction. The organic layers were combined, and the pH value of the organic layer was adjusted to 7 - 8 with saturated sodium bicarbonate. The organic layers were combined and concentrated under reduced pressure to obtain 28.5 g of the title compound as a pale yellow solid, with a yield of 87.5%; MS(ESI) m / z 207.0[M+H] + 。

[0078] Step 2: Preparation of 2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl benzoate

[0079]

[0080] Benzoic acid (18.5 g, 151.4 mmol) was dissolved in N,N-dimethylformamide (DMF, 495 mL), potassium carbonate (38 g, 275.2 mmol) was added, and then 2-bromo-1-(tetrahydro-2H-pyran-4-yl)ethan-1-one (28.5 g, 137.6 mmol) was added to the system. The reaction was carried out overnight at room temperature. It was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phases were combined and concentrated under reduced pressure to obtain 30.0 g of the title compound as a pale yellow solid, with a yield of 88.2%; LC-MS m / z[M+H] + = 249。

[0081] Step 3: Preparation of (Z)-1-(dimethylamino)-3-oxo-3-(tetrahydro-2H-pyran-4-yl)prop-1-en-2-yl benzoate

[0082]

[0083] To 1,1-dimethoxy-N,N-dimethylmethanamine (795.15 mL, 5975.8 mmol), 2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl benzoate (95.0 g, 383 mmol) was added. The temperature was heated to 100 °C and the reaction was carried out for 2 h, then the temperature was raised to 106 °C and the reaction was carried out for 2 h. After monitoring the reaction to completion, it was restored to room temperature and concentrated to dryness under reduced pressure. Ethyl acetate and brine were added to the system for washing, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain 107.9 g of the title compound as a red solid, with a yield of 93.1%, which was directly used for the next step. LC-MS m / z[M+H]+ = 304。

[0084] Step 4: Preparation of 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl benzoate

[0085]

[0086] Add acetic acid (376.1 mL) and (Z)-1-(dimethylamino)-3-oxo-3-(tetrahydro-2H-pyran-4-yl)prop-1-en-2-yl benzoate (32.56 g, 107.46 mmol) into a 1000 mL reaction flask in sequence. Slowly add 80% hydrazine hydrate (37.6 mL) dropwise under an ice bath. After dropping, stir at room temperature overnight. Monitor until the reaction reaches the end point. Add ethyl acetate to the reaction solution, wash with water, combine the organic phases, wash with saturated sodium bicarbonate solution until the pH is 7 - 8, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure to obtain a yellow oil, and let it stand at room temperature overnight to obtain the yellow solid title compound, totaling 28.0 g, yield: 95.8%; LC-MS m / z [M + H] + = 273。

[0087] Step 5: Preparation of 1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl benzoate

[0088]

[0089] Add 2,2'-bipyridine (17.7 g, 113.2 mmol) and copper(II) acetate (20.6 g, 113.2 mmol) into 1,2-dichloroethane (250 mL) in sequence. React at 75 °C for 30 min. After cooling to room temperature, add cyclopropylboronic acid (17.5 g, 205.9 mmol), sodium carbonate (21.8 g, 205.9 mmol) and a solution of 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl benzoate (28.0 g, 102.9 mmol) in 1,2-dichloroethane (250 mL) in sequence. React at 75 °C for 4 h under an oxygen atmosphere. Monitor until the reaction reaches the end point. Cool to room temperature, filter with the aid of diatomaceous earth, wash the filter cake with ethyl acetate, concentrate the filtrate under reduced pressure to obtain the reddish-brown oily title compound, totaling 32.0 g, yield: 98.5%, directly used for the next step; LC-MS m / z [M + H] + = 313。

[0090] Step 6: Preparation of 1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ol

[0091]

[0092] To methanol (308 mL), add 1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl benzoate (32.0 g, 102.6 mmol), and react at room temperature for 2 h. Monitor until the reaction reaches the end point, concentrate under reduced pressure to remove part of the methanol, adjust the pH to 6 - 7 with 1 mol / L dilute hydrochloric acid, extract with dichloromethane, and combine the organic layers. Concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the yellow solid titled compound, a total of 9.0 g, yield: 45%; LC-MS m / z + = 209.

[0093] Step 7: Preparation of 7-bromo-4-chloroquinoline

[0094]

[0095] Add 4.50 kg of acetonitrile to a 50 L vertical jacketed reactor, start stirring, and successively add 7-bromo-4-hydroxyquinoline (1.80 kg, 8.03 mol) and 4.00 kg of acetonitrile. When the internal temperature drops below 10 °C, add phosphorus oxychloride (1.85 kg, 12.05 mol) dropwise. After the addition is complete, heat to reflux and stir for 1 - 3 hours. Monitor until the reaction reaches the end point, cool the system to below 5 °C, add 4 mol / L NaOH solution to adjust the pH to 7 - 8, add 42.00 kg of water, stir at room temperature for 1 - 2 hours, centrifuge the feed liquid, wash the filter cake with 5.00 kg of water, and dry under vacuum. Collect and weigh the solid to obtain the crude titled compound as a brown solid, a total of 1.73 kg, yield: 88.8%.

[0096] Add 14.4 kg of methyl tert-butyl ether and 1.73 kg of the crude 7-bromo-4-chloroquinoline to a 50 L vertical jacketed reactor successively, stir within the range of 50 ± 5 °C for 1 - 3 hours, filter while hot, wash the filter cake with methyl tert-butyl ether, concentrate the filtrate to dryness under reduced pressure, dry the obtained solid under vacuum, collect and weigh the solid after drying to obtain the refined titled compound as a yellow solid, a total of 1.54 kg, yield 89.0%.

[0097] Step 8: Preparation of 7-bromo-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline

[0098]

[0099] Add 8.40 kg of acetonitrile to a 30 L glass reactor, start stirring, and successively add 7-bromo-4-chloroquinoline (1.26 kg, 5.18 mol), cesium carbonate (1.69 kg, 5.18 mol), 1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ol (0.90 kg, 4.32 mol), and wash with 4.00 kg of acetonitrile. Under nitrogen protection, heat up to 70 ± 5 °C and stir for 2 - 3 hours, then raise the temperature to reflux for 2 - 3 hours. Cool down to 70 ± 5 °C and filter while it is hot. Wash the filter cake with dichloromethane. Concentrate the filtrate under reduced pressure to a viscous state, add 14.00 kg of water, stir, centrifuge, wash the filter cake with 3.00 kg of water, and dry it under vacuum at 50 ± 5 °C for 10 - 20 hours. After drying, collect and weigh the solid to obtain 1.88 kg of the crude product of the title compound as a brown solid, and the crude product yield is 100.0%.

[0100] Add 6.40 kg of heptane and 1.88 kg of the crude product 1 of 7-bromo-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline to a 10 L four-necked flask, and stir at 25 ± 5 °C for 3 - 5 hours. Filter, wash the filter cake with 1.40 kg of heptane, and dry it under vacuum at 50 ± 5 °C for 3 - 20 hours. After drying, collect and weigh the solid to obtain 1.68 kg of the crude product 2 of the title compound as a dark yellow solid, and the yield is 89.4%.

[0101] Add 4.70 kg of absolute ethanol and 1.68 kg of the crude product 2 of 7-bromo-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline to a 10 L four-necked flask, heat up to reflux, stir for 0.5 - 1 hour after it becomes clear, turn off the heating, and let it cool and crystallize naturally. When the internal temperature is lower than 30 °C, start the external circulation and stir at -10 - -5 °C for 1 - 3 hours. Centrifuge the material liquid, wash the filter cake with 0.4 kg of cold ethanol (-10 - -5 °C), and dry it under vacuum at 50 ± 5 °C for 10 - 20 hours. After drying, collect and weigh the solid to obtain 1.35 kg of the refined product of the title compound as a pale yellow solid, and the yield is 80.4%.

[0102] Step 9: Preparation of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine

[0103]

[0104] Add 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (1.20 kg, 5.25 mol) and 11.8 kg of acetonitrile to a 20 L four-necked flask. Start stirring, add sodium hydroxide (0.42 kg, 10.50 mol), 36.00 g of water, and stir vigorously at 25 ± 5 °C for 3 - 15 hours; filter, wash with acetonitrile, concentrate the filtrate under reduced pressure to dryness, add 0.5 g of seed crystals, and vacuum dry after solidification. After drying, collect and weigh the solid to obtain 0.92 kg of the white solid title compound, with a yield of 91.2%.

[0105] Step 10: Preparation of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline

[0106]

[0107] Add 7.10 kg of 1,4-dioxane to a 20 L four-necked flask. Start stirring, and successively add 7-bromo-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline (1.34 kg, 3.23 mol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.75 kg, 3.88 mol), potassium phosphate (K3PO4, 1.37 kg, 6.47 mol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 37.40 g, 65.00 mmol), and tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 29.6 g, 32.00 mmol). Protect with nitrogen and maintain a nitrogen atmosphere. Heat to 95 ± 5 °C and stir for 3 - 15 hours, turn off the heating, filter while hot when the internal temperature drops to 70 - 80 °C, wash with 1.6 kg of hot 1,4-dioxane (70 - 80 °C), slowly pour the mother liquor into ice water, add N-acetyl-L-cysteine, stir for 1 - 1.5 hours, centrifuge, wash with 5.00 kg of water, and vacuum dry. After drying, collect and weigh the solid to obtain 1.41 kg of the crude product 1 of the yellow solid title compound, with a yield of 83.1%.

[0108] Step 11: Purification of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline

[0109] Add 3.8 kg of ethyl acetate and 1.40 kg of crude product 1 of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline into a 10 L four-necked flask. Heat up to 55 ± 5 °C under nitrogen protection and stir for 2 - 4 hours. Naturally cool to an internal temperature below 30 °C, stir and crystallize at -5 to -10 °C for 1 - 3 hours, centrifuge, wash with 0.5 kg of cold ethyl acetate (-10 to -5 °C), and dry in vacuum to obtain 1.21 kg of crude product 2 of the title compound as a pale yellow solid. The yield is 85.8%.

[0110] Add 14.30 kg of anhydrous methanol and 1.20 kg of crude product 2 of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline into a 30 L glass reactor. Heat up to reflux and dissolve until clear under nitrogen protection. Add 0.12 kg of activated carbon and 0.12 kg Thiol. Reflux for 1 - 1.5 hours, filter while hot, wash with hot methanol (50 - 60 °C), concentrate the filtrate under reduced pressure, cool and crystallize at -10 to -5 °C for 1 - 3 hours, centrifuge, and wash with cold methanol (-10 to -5 °C). Dry in vacuum to obtain 1.03 kg of crude product 3 of the title compound as an off-white solid. The yield is 85.1%.

[0111] Add 9.50 kg of dichloromethane and 1.02 kg of crude product 3 of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline into a 10 L four-necked flask, and start stirring. After dissolving until clear, add 0.20 kg Thiol, stir, filter, wash with dichloromethane, slowly add 26.20 kg of heptane dropwise to the filtrate, stir for 10 - 15 hours, filter, wash the filter cake with 1.60 kg of heptane, and dry in vacuum to obtain 0.99 kg of the refined product of the title compound as a white solid. The yield is 97.1%. ESI-MS [M + H] + m / z: 526.3, 11H NMR (400 MHz, DMSO) δ 8.59 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 11.2 Hz, 1H), 7.94 (s, 1H), 7.64 (dd, J = 11.2, 2.4 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 6.56 (d, J = 5.2 Hz, 1H), 4.91 (s, 2H), 4.34 (t, J = 5.1 Hz, 2H), 4.02 (t, J = 5.2 Hz, 2H), 3.88–3.71 (m, 2H), 3.73–3.63 (m, 1H), 3.30–3.19 (m, 2H), 2.82–2.65 (m, 1H), 1.78–1.59 (m, 4H), 1.12–1.01 (m, 2H), 1.01–0.88 (m, 2H).

[0112] More than 50 condition crystal form screening experiments were carried out on the compound of formula (I) in Example 1 above, including evaporation experiments, crystal slurry experiments, cooling crystallization experiments, diffusion experiments, etc. Multiple better crystal forms with good stability, high solubility and small particle size were found. See the following examples for details.

[0113] Example 2: Preparation of Crystal Form A of the Compound of Formula (I)

[0114] 1: Weigh 60 mg of the compound of formula (I) respectively, add 0.5 mL of ethanol, isopropanol, toluene, tetrahydrofuran, chloroform, 1,4-dioxane, acetonitrile or n-heptane each, stir at 50 °C for 12 hours, filter, and take the solid for XRPD characterization. The characterization results show that these experimental crystal forms are crystal form A.

[0115] 2: Weigh an appropriate amount of the compound of formula (I) respectively, dissolve it in solvent A as shown in Table 1, then add solvent B dropwise in proportion, stir for about 5 h after the solid is precipitated, filter, dry the solid at room temperature for 12 hours, and take the solid for XRPD characterization. The characterization results show that these experimental crystal forms are crystal form A.

[0116] Table 1

[0117]

[0118] 3: Weigh 60 mg of the compound of formula (I) respectively, add 0.5 mL of toluene, tetrahydrofuran, chloroform or 1,4-dioxane each, stir at 50 °C for 12 hours, filter, leave the filtered mother liquor open, dry the solvent completely, then dry the solid in vacuum at room temperature, take samples for XRPD characterization. The characterization results show that each experimental crystal form is crystal form A.

[0119] 4: Ethanol, a methanol / chloroform mixed solvent (volume ratio of methanol to chloroform is 3:2), an isopropanol / acetonitrile mixed solvent (volume ratio of isopropanol to acetonitrile is 1:1), or an acetonitrile / water mixed solvent (volume ratio of acetonitrile to water is 9:1) was added to the compound of formula (I). Stir at 50 °C, let stand, take the supernatant, stir and crystallize at 5 °C for 4 hours, filter, dry, sample and perform XRPD characterization. The characterization results show that all the experimental crystal forms are crystal form A.

[0120] 5: Weigh about 600 mg of the compound of formula (I) respectively, add dichloromethane, and then dropwise add heptane at a rate of 80 - 100 mL / min at 45 ± 5 °C (the volume ratios of dichloromethane to heptane added are 1:2 (total volume 20V), 1:3 (total volume 27V), 1:4 (total volume 34V), or 1:5 (total volume 42V)), stir for 10 - 20 hours, filter, take the solid for XRPD characterization. The characterization results show that the experimental crystal forms are all crystal form A.

[0121] In addition, using dichloromethane / butyl acetate, tetrahydrofuran / MTBE, or ethyl acetate / heptane as solvents respectively, the obtained crystal form is crystal form A.

[0122] The X-ray diffraction pattern of crystal form A of the compound of formula (I) (see Figure 1 ), using Cu-Kα radiation, represents the X-ray powder diffraction pattern in terms of 2θ angle. There are characteristic peaks at about 3.7, 6.2, 6.6, 7.0, 7.4, 9.5, 14.2, 14.7, 16.3, 18.2, 18.5, 18.9, 21.6, 22.2, 23.0, 24.1, 25.9, 27.2, 27.8, 29.7, 30.4, 32.9, 34.0. The 2θ and the relative intensities of the peaks in Figure 1 are listed in Table 2.

[0123] The DSC characterization results of crystal form A of the compound of formula (I) are shown in Figure 2 . The test results show that the sample has a sharp endothermic peak at 215.6 °C.

[0124] The TGA characterization results of crystal form A of the compound of formula (I) are shown in Figure 3 . The results show that there is no obvious weight loss before 300 °C.

[0125] Table 2: Details of the XRPD pattern of crystal form A of the compound of formula (I)

[0126]

[0127] Crystal form A can be obtained by the reverse dropping method. Experiments show that these solvents have good solubility for the compound of formula (I), especially the combination of dichloromethane and heptane. The stability and solubility of crystal form A are very good.

[0128] Example 3: Preparation of Crystal Form B of the Compound of Formula (I)

[0129] 1: Weigh about 500 mg of the compound of formula (I), slurry it with ethyl acetate, filter, add the obtained solid to 5 mL of isopropanol, heat to 90 °C, add an additional 5 mL of isopropanol until it becomes clear, turn off the heating, and allow it to crystallize by natural cooling. Filter, and dry the filter cake in vacuo at room temperature. Characterize the obtained solid by XRPD. The characterization results show that the experimental crystal form is Crystal Form B.

[0130] 2: Weigh 60 mg of the compound of formula (I) respectively, add 0.5 mL of methyl isobutyl ketone or isopropyl acetate, stir at 50 °C for 12 hours, filter, and take the solid for XRPD characterization. The characterization results show that the experimental crystal form is Crystal Form B.

[0131] The X-ray diffraction pattern of Crystal Form B of the compound of formula (I) (see Figure 4 ), using Cu-Kα radiation, represents the X-ray powder diffraction pattern in terms of 2θ angle. Characteristic peaks are observed at approximately 3.9, 7.8, 10.0, 11.8, 15.1, 15.8, 18.8, 19.2, 19.8, 20.9, 21.4, 22.6, 23.2, 23.9, 25.0, 28.0, 28.7, 32.0, 37.7. Figure 4 The 2θ and the relative intensities of the peaks in

[0132] Table 3: Details of the XRPD Pattern of Crystal Form B of the Compound of Formula (I)

[0133]

[0134]

[0135] Example 4: Preparation of Crystal Form C of the Compound of Formula (I)

[0136] 1: Weigh 60 mg of the compound of formula (I), add 0.5 mL of water; or weigh 60 mg of the compound of formula (I), add a water-saturated ethyl acetate solution; then stir at 50 °C for 12 hours, filter, and take the solid for XRPD characterization. The characterization results show that the experimental crystal form is Crystal Form C.

[0137] 2: Weigh an appropriate amount of the compound of formula (I), dissolve it in chloroform, and then add isopropyl acetate dropwise, with the volume ratio of chloroform to isopropyl acetate being 3:3. After the solid precipitates, stir for about 5 h, filter, and dry the solid at room temperature for 12 hours. Take the solid for XRPD characterization. The characterization results show that the experimental crystal form is Crystal Form C.

[0138] The X-ray diffraction pattern of Crystal Form C of the compound of formula (I) (see Figure 5) Using Cu-Kα radiation, the X-ray powder diffraction pattern is represented by 2θ angle, and characteristic peaks are present at approximately 8.2, 12.0, 16.6, 19.2, and 24.1. The 2θ and the relative intensities of the peaks in Figure 5 are listed in Table 4.

[0139] Table 4: Details of the XRPD pattern of crystalline form C of the compound of formula (I)

[0140]

[0141] Example 5: Preparation of crystalline form D of the compound of formula (I)

[0142] 1: Weigh an appropriate amount of the compound of formula (I), dissolve it in chloroform, and then add methyl tert-butyl ether (MTBE) dropwise. The volume ratio of chloroform to MTBE is 3:3.5. After the solid precipitates, stir for about 5 h, filter, dry the solid at room temperature for 12 hours, and take the solid for XRPD characterization. The characterization result shows that the crystalline form in this experiment is crystalline form D.

[0143] 2: Weigh an appropriate amount of the compound of formula (I), dissolve it in chloroform, and then add toluene dropwise. The volume ratio of chloroform to toluene is 3:4. After the solid precipitates, stir for about 5 h, filter, dry the solid at room temperature for 12 hours, and take the solid for XRPD characterization. The characterization result shows that the crystalline form in this experiment is crystalline form D.

[0144] 3: Weigh an appropriate amount of the compound of formula (I), dissolve it in chloroform, and then add n-heptane dropwise. The volume ratio of chloroform to n-heptane is 3:6. After the solid precipitates, stir for about 5 h, filter, dry the solid at room temperature for 12 hours, and take the solid for XRPD characterization. The characterization result shows that the crystalline form in this experiment is crystalline form D.

[0145] The X-ray diffraction pattern of crystalline form D of the compound of formula (I) (see Figure 6 ), using Cu-Kα radiation, the X-ray powder diffraction pattern is represented by 2θ angle, and characteristic peaks are present at approximately 7.1, 8.3, 10.1, 11.0, 14.2, 15.1, 15.9, 16.1, 17.4, 18.9, 20.2, 21.4, 22.6, 23.4, 23.8, 24.6, 26.8, 27.4, 28.2, 30.6. The 2θ and the relative intensities of the peaks in Figure 6 are listed in Table 5.

[0146] Table 5: Details of the XRPD pattern of crystalline form D of the compound of formula (I)

[0147]

[0148] Example 6: Preparation of crystalline form E of the compound of formula (I)

[0149] Weigh an appropriate amount of the compound of formula (I), dissolve it in dichloromethane, and then add MTBE dropwise, where the volume ratio of dichloromethane to MTBE is 1:5. After a solid precipitates, stir for about 5 h, filter, dry the solid at room temperature for 12 h, and take the solid for XRPD characterization. The characterization results show that the crystal form in this experiment is crystal form E.

[0150] The X-ray diffraction pattern of crystal form E of the compound of formula (I) (see Figure 7 ), using Cu-Kα radiation, represents the X-ray powder diffraction pattern in terms of 2θ angle, and has characteristic peaks at approximately 4.9, 6.9, 9.9, 15.0, 18.7, 20.1, 21.2, 23.6, 30.4, 31.9, 38.9. The Figure 7 2θ and the relative intensities of the peaks are listed in Table 6.

[0151] Table 6: Details of the XRPD pattern of crystal form E of the compound of formula (I)

[0152]

[0153] Example 7: Preparation of amorphous substance

[0154] Weigh an appropriate amount of the compound of formula (I), dissolve it in 5 times the volume of 1,4-dioxane. After heating to dissolve completely, use a pipette to draw the 1,4-dioxane solution of the compound of formula (I) in batches and drop it into water. Take the solid for XRPD characterization. The characterization results show that the crystal form in this experiment is an amorphous form, and its X-ray diffraction pattern is as shown in Figure 8 .

[0155] Experimental Example 1 Evaluation of the in vitro ALK5 kinase activity of the compound

[0156] 1. Experimental materials

[0157] 1.1 Compounds

[0158] The compound of formula (I) in Example 1 was formulated into 10 mM with DMSO and then serially diluted to 3.333 μM, 1.111 μM, 370 nM, 123 nM, 41 nM, 14 nM, 4.6 nM, 1.5 nM, 0.5 nM.

[0159] 1.2 Reagents and instruments

[0160] Reagents: ALK5, purchased from Carna, Cat.No.09-141; p38α, purchased from Carna, Cat.No.04-152; TGFβR1 peptide, purchased from SignalChem, Cat.No.T36-58; dimethyl sulfoxide (DMSO), purchased from Sigma, USA; EDTA, purchased from Sigma, USA; ADP-Glo Kinase Assay, purchased from Promega, Cat.No.v9102 / 3, 1× kinase buffer (40 mM Tris, pH 7.5, 0.10% BSA, 20 mM MgCl2, 1 mM DTT), prepared before use.

[0161] Instruments: 2104 Multilabel Reader, purchased from Perkin Elmer, USA.

[0162] 2. Experimental methods

[0163] 2.1 Preparation of 1x kinase buffer

[0164] 1x assay buffer

[0165] 40 mM Tris, pH 7.5

[0166] 20 mM MgCl2

[0167] 0.10% BSA

[0168] 1 mM DTT

[0169] 2.2 Compound preparation

[0170] 2.2.1 Compound dilution

[0171] 2.2.1.1 Preparation of 50-fold compound: The final detection concentration of the compound is 10 μM, configured into a 50-fold concentration, i.e., 500 μM: Add 95 μl of 100% DMSO to the second well of a 96-well plate, and then add 5 μl of 10 mM compound solution to prepare a 1000 μM compound solution. Add 60 μl of 100% DMSO to other wells. Take 30 μl of the compound from the second well and add it to the third well, and perform 3-fold dilutions successively downwards for a total of 10 concentrations.

[0172] Dilution instrument: Automatic micropipette (Precision PRC384U).

[0173] 2.2.1.2 Transfer 100 nl of the compound to the reaction plate using echo.

[0174] 2.3 Kinase reaction

[0175] 2.3.1 Preparation of 2X kinase solution

[0176] Add kinase to 1X kinase buffer to form 2X enzyme solution. There is already 100 nl of compound dissolved in 100% DMSO in the 384-well reaction plate. Add 2.5 μl of 2X enzyme solution to the 384-well reaction plate. Incubate at room temperature for 10 minutes.

[0177] 2.3.2 Preparation of 2X substrate solution

[0178] Add FAM-labeled polypeptide and ATP to 1X kinase buffer to form 2X substrate solution. Add 2.5 μl of 2X substrate solution to the 384-well reaction plate.

[0179] 2.4 Kinase reaction

[0180] Incubate the 384-well plate at 28 °C for 120 minutes,

[0181] 2.5 Detection of reaction results

[0182] 2.5.1 Equilibrate the ADP-Glo reagent to room temperature.

[0183] 2.5.2 Transfer 5 μl of the reaction solution to a new well of a 384-well plate.

[0184] 2.5.3 Transfer 5 μl of ADP-Glo reagent to the well of the 384-well plate to terminate the reaction.

[0185] 2.5.4 Incubate at 28 °C for 120 minutes.

[0186] 2.5.5 Transfer 10 μl of the kinase detection reagent to each well, shake for 1 minute, and let stand at room temperature for 30 minutes.

[0187] 2.6 Data reading

[0188] Read the luminescence value of the sample on Envision.

[0189] 2.7 Curve fitting

[0190] 2.7.1 Copy the data of the luminescence readings from the Envision program

[0191] 2.7.2 Convert the luminescence reading values to the percentage of inhibition through the formula.

[0192] Percent inhibition = (max - sample RLU) / (max - min)*100. "min" is the fluorescence reading of the control sample without adding enzyme for the reaction; "max" is the fluorescence reading of the sample with DMSO as the control.

[0193] 2.7.3 Import the data into MS Excel and perform curve fitting using the XLFit excel add-in version 5.4.0.8. The fitting formula is: Y = Bottom + (Top - Bottom) / (1 + (IC 50 / X)^HillSlope), and the results are shown in Table 7.

[0194] Table 7

[0195]

[0196] As can be seen from the above experimental results, the compounds of the present invention have good inhibitory activity against ALK5 kinase, while having low inhibitory effect on p38α and high selectivity. It shows that the compounds of the present invention have lower side effects while producing higher efficacy.

[0197] Experimental Example 2 Evaluation of the Compound in vitro Cell Luciferase Assay

[0198] 1. Experimental Materials

[0199] Test compound: The compound of formula (I) in Example 1 was formulated into 4 mM with DMSO, and then serially diluted 4-fold to 20000.00 nM, 5000.00 nM, 1250.00 nM, 312.5 nM, 78.125 nM, 19.53 nM, 4.88 nM, 1.22 nM.

[0200] Luc-Smad2 / 3-NIH3T3 mouse fibroblasts (engineered to overexpress SMAD2, 3-responsive promoter) were gifted by the laboratory of China Pharmaceutical University.

[0201] Reagents: DMEM, purchased from Invitrogen, USA; FBS, purchased from Invitrogen, USA; DMSO, purchased from Sigma, USA; Glo Lysis Buffer, purchased from Progema, USA; Bright-Glo Luciferase assay system, purchased from Promega, USA; TGFβ, purchased from PeproTech, USA.

[0202] Instruments: MD SpectraMax M3 multi-functional microplate reader, purchased from Molecular Devices, USA.

[0203] 2. Experimental Methods

[0204] 2.1 Cell culture:

[0205] Cell resuscitation: Place the cells in a 37°C water bath to dissolve, then transfer them to 15 mL of pre-warmed medium, centrifuge at 1000 rpm for 5 minutes, discard the medium, resuspend the cells with 15 mL of fresh medium, transfer to a 10 cm culture dish, and culture in an incubator at 37°C and 5% CO2. Replace the fresh medium after 24 hours.

[0206] Cell passage: Transfer the above resuscitated cells to a 50 mL sterile centrifuge tube, centrifuge at 1000 rpm for 5 minutes, discard the medium, take the evenly dispersed cells for counting, adjust the appropriate cell concentration to 15 mL of fresh medium, add to a 10 cm culture dish, and culture in an incubator at 37°C and 5% CO2.

[0207] 2.2 Experimental procedures:

[0208] Day1: Seed cells (clear-bottom 96-well plate)

[0209] Luc-Smad2 / 3-NIH3T3 cells are normally cultured in a 10 cm culture dish until the confluence reaches 80%-90%. After digestion, collect them in a 15 mL centrifuge tube, centrifuge at 1000 xg for 5 minutes, remove the supernatant, resuspend with 1 mL of medium, dilute 10 times for counting, dilute the cells according to the counting result, and transfer 4x10 3 cells per well into a 96-well plate (add 100 μl of resuspended cells to each well).

[0210] Day2: Administer drugs to cells

[0211] Weigh 1-2 mg of the drug (pre-weighed in advance), and prepare a 4 mM stock solution using DMSO. After 24 hours, remove the medium. Dilute the drug with 2% FBS medium, add 100 μl of 1x drug solution, so that the final concentrations of the drug are 20000.00 nM, 5000.00 nM, 1250.00 nM, 312.5 nM, 78.125 nM, 19.53 nM, 4.88 nM, 1.22 nM respectively, and the final concentration of TGFβ1 in each well is 4 ng / mL. Dilute it with 2% FBS medium together with the compound.

[0212] Day3: Fluorescence detection experiment

[0213] Equilibrate the Glo Lysis Buffer, Bright-glo luciferase assay system, and cells to room temperature. Remove the cell supernatant, add 100 μl of Glo Lysis Buffer to each well, and gently shake to evenly dissolve the cells. Lyse the cells at room temperature for 5 mins. Then add 100 μl of Bright-glo luciferase assay system to each well, incubate at room temperature for 5 minutes, shake for 2 minutes, transfer 180 μl of the supernatant to a white-bottom 96-well plate, and detect the chemiluminescence signal with a detection condition of 1 s.

[0214] 2.3 Data processing: Use Graphpad Prism 5 software for non-linear curve fitting and data analysis to fit the IC 50 , and the experimental results are shown in Table 8.

[0215] Table 8

[0216]

[0217] As can be seen from the above experiments, the compounds of the present invention exhibit good inhibitory activity against the TGFβ-ALK5-SMAD2 / 3 signaling pathway in NIH3T3 cells and are very promising as therapeutic agents for various cancer-related diseases.

[0218] Although the present invention has been described in detail above, those skilled in the art understand that various modifications and changes can be made to the present invention without departing from the spirit and scope of the present invention. The scope of the rights of the present invention is not limited to the detailed description above but shall be attributed to the claims.

Claims

1. A 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline crystal form A, characterized in that The X-ray powder diffraction spectrum shows characteristic peaks at 2θ angles of 3.7±0.2, 9.5±0.2, 14.2±0.2, 14.7±0.2, 18.9±0.2, 24.1±0.2, and 25.9±0.

2.

2. Crystal Form B of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline, characterized in that The X-ray powder diffraction spectrum shows characteristic peaks at 2θ angles of 3.9±0.2, 7.8±0.2, 10.0±0.2, 11.8±0.2, and 15.8±0.

2.

3. Crystal form C of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline, characterized in that The X-ray powder diffraction spectrum shows characteristic peaks at 2θ angles of 8.2±0.2, 12.0±0.2, 16.6±0.2, 19.2±0.2, and 24.1±0.

2.

4. A 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline polymorph D, characterized in that The X-ray powder diffraction spectrum shows characteristic peaks at 2θ angles of 7.1±0.2, 8.3±0.2, 10.1±0.2, 14.2±0.2, 15.1±0.2, 20.2±0.2, 21.4±0.2, and 22.6±0.

2.

5. A 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline crystal form E, characterized in that The X-ray powder diffraction spectrum shows characteristic peaks at 2θ angles of 4.9±0.2, 6.9±0.2, 9.9±0.2, 15.0±0.2, and 18.7±0.

2.

6. An amorphous form of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline, which has an X-ray powder diffraction spectrum substantially as shown in Figure 8.

7. A crystalline composition, wherein the crystalline form A of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline according to claim 1, the crystalline form B of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline according to claim 2, the crystalline form C of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline according to claim 3, the crystalline form D of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline according to claim 4, or the crystalline form E of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline according to claim 5 accounts for more than 50% by weight of the crystalline composition.

8. The crystalline composition according to claim 7, wherein the crystalline form A of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 1, the crystalline form B of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 2, the crystalline form C of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 3, the crystalline form D of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 4, or the crystalline form E of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 5 accounts for more than 80% by weight of the crystalline composition.

9. The crystalline composition according to claim 7, wherein the crystalline form A of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 1, the crystalline form B of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 2, the crystalline form C of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 3, the crystalline form D of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 4, or the crystalline form E of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 5 accounts for more than 90% by weight of the crystalline composition.

10. The crystalline composition according to claim 7, wherein the crystalline form A of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 1, the crystalline form B of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 2, the crystalline form C of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 3, the crystalline form D of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 4, or the crystalline form E of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 5 accounts for more than 95% by weight of the crystalline composition.

11. A pharmaceutical composition comprising the crystalline form A of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 1, or the crystalline form B as described in claim 2, or the crystalline form C as described in claim 3, or the crystalline form D as described in claim 4, or the crystalline form E as described in claim 5, or the amorphous form as described in claim 6, and a pharmaceutically acceptable carrier.

12. Use of the crystalline form A of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline as described in claim 1, or the crystalline form B as described in claim 2, or the crystalline form C as described in claim 3, or the crystalline form D as described in claim 4, or the crystalline form E as described in claim 5, or the amorphous form as described in claim 6, or the crystalline composition as described in any one of claims 7-10, or the pharmaceutical composition as described in claim 11 in the preparation of a medicament for the treatment and / or prevention of cancer, tissue hyperplasia diseases, fibrosis or inflammatory diseases.

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