Crystals of substituted piperazine derivatives and their preparation method

Abstract

The present invention provides crystals of substituted piperazine derivatives and methods for preparing them. Specifically, the present invention provides crystalline forms A to I of the compound represented by formula (1) and methods for preparing them. [Formula 1] TIFF2025536416000031.tif25169

Description

[Technical Field]

[0001] The present invention relates to crystals of substituted piperazine derivatives and methods for preparing the same. Specifically, the present invention provides crystalline forms A to I of the compound represented by formula (1) and methods for preparing the same. [Background technology]

[0002] Adenosine diphosphate ribosylation (ADP-ribosylation) is a post-transcriptional protein modification process in which one or more adenosine diphosphate ribose (ADP-ribose) groups are embedded in the amino acid residues of proteins. ADP-ribosylation is a reversible process involved in physiological regulation, including cell signaling, DNA damage repair, transcription, gene expression regulation, and cell apoptosis. ADP-ribose is derived from the redox coenzyme nicotinamide adenine dinucleotide (NAD+), and the enzyme that mediates the embedded modification of ADP-ribose is ADP-ribosylase. In physiological response regulation, the N-glycosidic bond of NAD+ connecting the ADP-ribose molecule to the nicotinamide group is cleaved and captured to form a bond with the corresponding amino acid residue in the target protein. ADP-ribosylase can perform two types of modifications: mono-ADP-ribosylation and poly-ADP-ribosylation. When DNA is damaged or cells are stressed, PARPs are activated, increasing the amount of poly(ADP-ribose) and decreasing the amount of NAD+. For over a decade, PARP1 has been considered the only poly(ADP-ribose) polymerase in mammalian cells and is therefore the most studied enzyme. Scientists have identified 17 PARPs to date. MonoPARPs make up the majority of the PARP family and mediate important biological functions as well as various stress responses, such as the unfolded protein response, NF-κB signaling, antiviral response, and cytokine signaling. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (PARP-7) is a member of the MonoPARP family, and its expression is regulated by the aryl hydrocarbon receptor (AHR), which is activated by TCDD. AHR is a ligand-activated transcription factor that can mediate the toxic activity of many environmental toxins. AHR upregulates PARP-7 expression. PARP-7 interacts with the kinase TBK1, causing its ADP-ribosylation, leading to inhibition of TBK1 activity and downregulation of IFN-I (type I interferon) responses, thereby inhibiting the body's antiviral and tumor immune responses.Research into PARP-7 inhibitors is extremely important, as no clinical results have been reported so far.

[0003] PCT / CN2022 / 094124 discloses a piperazine derivative with the chemical name (S)-4-(trifluoromethyl)-5-((1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one, which offers a new treatment option for patients. [ka]

[0004] The crystalline form of a pharmaceutically active ingredient often affects the chemical and physical stability of the drug. Different crystalline forms, preparation methods, and storage conditions can alter the crystalline form of a compound, sometimes resulting in the formation of other crystalline forms. Amorphous drugs generally lack a regular crystalline structure and often suffer from drawbacks such as poor product stability, difficulty in filtration, tendency to clump, and poor flowability. Given the importance of crystalline form as well as the stability of solid dosage forms in clinical treatment, detailed investigation of the crystalline form of the compound (S)-4-(trifluoromethyl)-5-(1-(5-(5-trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]piperazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one is of great significance for the development of pharmaceuticals suitable for industrial production and with favorable biological activity. Summary of the Invention

[0005] The present invention provides a crystal of (S)-4-(trifluoromethyl)-5-(1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (compound (1)). The chemical structure of compound (1) is as follows: [ka]

[0006] The crystals of the present invention exhibit at least one of the advantages of good solubility, high stability, ease of processing, handling, and purification, improved oral bioavailability of the drug, extended shelf life of the drug, and ease of manufacture in various dosage forms.

[0007] The crystals of the present invention exhibit pharmaceutical advantages over the amorphous form of Compound (1). In particular, the crystals of the present invention have improved chemical and physical stability and are more suitable for the preparation of solid pharmaceutical formulations containing pharmacologically active ingredients.

[0008] The crystalline forms of the present invention are present at about 5% to about 100% by weight of the active pharmaceutical ingredient (API). In some embodiments, the crystalline forms of the present invention are present at about 10% to about 100% by weight of the API. In some embodiments, the crystalline forms of the present invention are present at about 15% to about 100% by weight of the API. In some embodiments, the crystalline forms of the present invention are present at about 20% to about 100% by weight of the API. In some embodiments, the crystalline forms of the present invention are present at about 25% to about 100% by weight of the API. In some embodiments, the crystalline forms of the present invention are present at about 30% to about 100% by weight of the API. In some embodiments, the crystalline forms of the present invention are present at about 35% to about 100% by weight of the API. In some embodiments, the crystalline forms of the present invention are present at about 40% to about 100% by weight of the API. In some embodiments, the crystalline forms of the present invention are present at about 45% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 50% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 55% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 60% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 65% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 70% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 75% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 80% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 85% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 90% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 95% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 98% to about 100% by weight of the API. In some embodiments, the crystalline form of the present invention is present at about 99% to about 100% by weight of the aAPI.In some embodiments, substantially all of the API is in a crystalline form of the present invention, ie, the API is substantially phase-pure crystalline.

[0009] Unless otherwise specified, the compound (1) of the present invention is an amorphous form of compound (1).

[0010] One embodiment of the crystal of the present invention is crystalline form A of compound (1), and the X-ray powder diffraction pattern of crystalline form A has characteristic diffraction peaks at the following 2θ positions: 10.389°±0.3°, 11.917°±0.3°, 12.912°±0.3°, 13.385°±0.3°, 14.054°±0.3°, 15.316°±0.3°, and 16.636°±0.3°.

[0011] Furthermore, the powder X-ray diffraction pattern of crystalline form A has characteristic diffraction peaks at the following 2θ positions: 6.716°±0.3°, 10.043°±0.3°, 10.389°±0.3°, 11.917°±0.3°, 12.912°±0.3°, 13.385°±0.3°, 14.054°±0.3°, 15.316°±0.3°, 16.636°±0.3°, 18.003°±0.3°, 20.014°±0.3°, 20.794°±0.3°, and 23.855°±0.3°.

[0012] Furthermore, the powder X-ray diffraction pattern of crystalline form A is substantially as shown in FIG.

[0013] The TGA curve of the crystalline form A according to the present invention is substantially as shown in FIG.

[0014] The DSC curve of the crystalline form A according to the present invention is substantially as shown in FIG.

[0015] The present invention also relates to a method for preparing crystalline form A, which comprises crystallizing the compound of formula (1) in a solvent ((1)-A) to obtain crystalline form A, wherein the solvent ((1)-A) is selected from acetonitrile, ethanol, n-propanol, acetone, and water, or a mixed solvent of acetonitrile, ethanol, n-propanol, acetone, and water in any ratio and in any combination.

[0016] Furthermore, the method for preparing crystalline form A includes adding the compound of formula (1) or a crude product thereof to a solvent ((1)-A-1), heating to dissolve the compound, adding solvents ((1)-A-2) and ((1)-A-3), and then continuously cooling and stirring the mixture, followed by allowing the mixture to stand to crystallize, thereby obtaining crystalline form A. In this method, the solvents ((1)-A-1), ((1)-A-2) and ((1)-A-3) are any one selected from acetonitrile, ethanol, n-propanol, acetone and water.

[0017] One embodiment of the crystal of the present invention is crystalline form B of compound (1), and the X-ray powder diffraction pattern of crystalline form B has characteristic diffraction peaks at the following 2θ positions: 6.498°±0.3°, 13.326°±0.3°, 21.229°±0.3°, 21.426°±0.3°, and 22.195°±0.3°.

[0018] Furthermore, the powder X-ray diffraction pattern of crystalline form B has characteristic diffraction peaks at the following 2θ positions: 6.498°±0.3°, 9.657°±0.3°, 11.420°±0.3°, 13.027°±0.3°, 13.326°±0.3°, 15.882°±0.3°, 19.075°±0.3°, 19.315°±0.3°, 20.669°±0.3°, 21.229°±0.3°, 21.426°±0.3°, 22.195°±0.3°, 23.118°±0.3°, and 23.362°±0.3°.

[0019] Furthermore, the powder X-ray diffraction pattern of crystalline form B is substantially as shown in FIG.

[0020] The present invention also relates to a process for preparing crystalline form B, which comprises slurrying the compound of formula (1) in a solvent ((1)-B) to obtain crystalline form B, wherein the solvent ((1)-B) is selected from n-hexane.

[0021] One embodiment of the crystal of the present invention is crystalline form C of compound (1), and the X-ray powder diffraction pattern of crystalline form C has characteristic diffraction peaks at the following 2θ positions: 19.066°±0.3°, 20.300°±0.3°, 20.978°±0.3°, and 21.616°±0.3°.

[0022] Furthermore, the powder X-ray diffraction pattern of crystalline Form C has characteristic diffraction peaks at the following 2θ positions: 6.790°±0.3°, 9.917°±0.3°, 11.533°±0.3°, 12.600°±0.3°, 13.556°±0.3°, 13.793°±0.3°, 14.275°±0.3°, 15.008°±0.3°, 16.452°±0.3°, 17.877°±0.3°, 19.066°±0.3°, 19.774°±0.3°, 20.300°±0.3°, 20.978°±0.3°, 21.616°±0.3°, 22.585°±0.3°, and 23.407°±0.3°.

[0023] Furthermore, the X-ray powder diffraction pattern of crystalline form C is substantially as shown in FIG.

[0024] The present invention also relates to a method for preparing crystalline form C, comprising crystallizing the compound of formula (1) in a solvent ((1)-C) to obtain crystalline form C, wherein the solvent ((1)-C) is selected from isopropyl acetate, n-hexane, or a mixed solvent of isopropyl acetate and n-hexane.

[0025] One embodiment of the crystal of the present invention is crystalline form D of compound (1), and the X-ray powder diffraction pattern of crystalline form D has characteristic diffraction peaks at the following 2θ positions: 6.646°±0.3° and 13.175°±0.3°.

[0026] Additionally, the powder X-ray diffraction pattern of crystalline form D exhibits characteristic diffraction peaks at the following 2θ positions: 6.646°±0.3°, 13.175°±0.3°, 13.489°±0.3°, 16.450°±0.3°, 20.950°±0.3°, 21.585°±0.3°, 22.369°±0.3°, 23.036°±0.3°, and 23.281°±0.3°.

[0027] Furthermore, the powder X-ray diffraction pattern of crystalline form D is substantially as shown in FIG.

[0028] The present invention also relates to a method for preparing crystalline form D, which comprises extracting compound of formula (1) with a solvent ((1)-D), concentrating, and drying under vacuum to obtain crystalline form D, wherein the solvent ((1)-D) is selected from ethyl acetate.

[0029] One embodiment of the crystal of the present invention is crystalline form E of compound (1), and the X-ray powder diffraction pattern of crystalline form E has characteristic diffraction peaks at the following 2θ positions: 18.227°±0.3°, 19.954°±0.3°, and 22.449°±0.3°.

[0030] Furthermore, the powder X-ray diffraction pattern of crystalline form E has characteristic diffraction peaks at the following 2θ positions: 8.129°±0.3°, 11.118°±0.3°, 11.360°±0.3°, 11.749°±0.3°, 13.482°±0.3°, 14.730°±0.3°, 18.227°, and 19.954°. ±0.3°, 20.712°±0.3°, 21.092°±0.3°, 22.449°±0.3°, 22.813°±0.3°, 24.399°±0.3°, 24.560°±0.3°, 25.923°±0.3°, 26.429°±0.3°, 27.060°±0.3°, 27.446°±0.3°.

[0031] Furthermore, the powder X-ray diffraction pattern of crystalline form E is substantially as shown in FIG.

[0032] The present invention also relates to a method for preparing crystalline form E, comprising crystallizing the compound of formula (1) in a solvent ((1)-E) to obtain crystalline form E, wherein the solvent ((1)-E) is selected from ethyl acetate, n-hexane, or a mixture of ethyl acetate and n-hexane.

[0033] One embodiment of the crystal of the present invention is crystalline form F of compound (1), and the X-ray powder diffraction pattern of crystalline form F has characteristic diffraction peaks at the following 2θ positions: 6.717°±0.3° and 13.484°±0.3°.

[0034] Furthermore, the powder X-ray diffraction pattern of crystalline form F has characteristic diffraction peaks at the following 2θ positions: 6.717°±0.3°, 9.812°±0.3°, 11.426°±0.3°, 12.501°±0.3°, 13.484°±0.3°, 14.915°±0.3°, 16.374°±0.3°, 16.884°±0.3°, 17.828°±0.3°, 18.975°±0.3°, 20.241°±0.3°, 20.902°±0.3°, 21.593°±0.3°, 22.506°±0.3°, and 22.918°±0.3°.

[0035] Furthermore, the powder X-ray diffraction pattern of crystalline form F is substantially as shown in FIG.

[0036] The TGA curve of crystalline form F according to the present invention is substantially as shown in FIG.

[0037] The DSC curve of the crystalline form F according to the present invention is substantially as shown in FIG.

[0038] The present invention also relates to a method for preparing crystalline form F, comprising crystallizing the compound of formula (1) in a solvent ((1)-F) to obtain crystalline form F, wherein the solvent ((1)-F) is selected from n-propanol, n-heptane, or a mixture of n-propanol and n-heptane.

[0039] One embodiment of the crystal of the present invention is crystalline form G of compound (1), and the X-ray powder diffraction pattern of crystalline form G has characteristic diffraction peaks at the following 2θ positions: 6.743°±0.3° and 13.503°±0.3°.

[0040] Furthermore, the powder X-ray diffraction pattern of crystalline form G has characteristic diffraction peaks at the following 2θ positions: 6.743°±0.3°, 13.503°±0.3°, 16.901°±0.3°, 18.996°±0.3°, 20.260°±0.3°, 20.920°±0.3°, and 21.604±0.3°.

[0041] Furthermore, the powder X-ray diffraction pattern of crystalline form G is substantially as shown in FIG.

[0042] The present invention also relates to a method for preparing crystalline form G, comprising crystallizing the compound of formula (1) in a solvent ((1)-G) to obtain crystalline form G, wherein the solvent ((1)-G) is selected from ethanol, n-heptane, or a mixture of ethanol and n-heptane.

[0043] One embodiment of the crystal of the present invention is crystalline form H of compound (1). The X-ray powder diffraction pattern of crystalline form H has characteristic diffraction peaks at the following 2θ positions: 12.366°±0.3°, 13.115°±0.3°, 14.359°±0.3°, 15.617°±0.3°, and 16.909°±0.3°.

[0044] Furthermore, the powder X-ray diffraction pattern of crystalline form H has characteristic diffraction peaks at the following 2θ positions: 6.514°±0.3°, 10.074°±0.3°, 10.684°±0.3°, 12.366°±0.3°, 13.115°±0.3°, 14.359°±0.3°, 15.617°±0.3°, 16.909°±0.3°, 19.839°±0.3°, 20.092°±0.3°, 20.687°±0.3°, and 22.919°±0.3°.

[0045] Furthermore, the powder X-ray diffraction pattern of crystalline form H is substantially as shown in FIG.

[0046] The TGA curve of the crystalline form H according to the present invention is substantially as shown in FIG.

[0047] The DSC curve of the crystalline form H according to the present invention is substantially as shown in FIG.

[0048] The present invention also relates to a method for preparing crystalline form H, comprising crystallizing the compound of formula (1) in a solvent ((1)-H) to obtain crystalline form H, wherein the solvent ((1)-H) is selected from any one of acetonitrile, ethanol, n-propanol, acetone, and water, or a mixed solvent of acetonitrile, ethanol, n-propanol, acetone, and water in any ratio and in any combination.

[0049] One embodiment of the crystal of the present invention is crystalline form I of compound (1), and the X-ray powder diffraction pattern of crystalline form I has characteristic diffraction peaks at the following 2θ positions: 4.968°±0.3°, 19.770°±0.3°, and 21.752°±0.3°.

[0050] Furthermore, the powder X-ray diffraction pattern of crystalline Form I has characteristic diffraction peaks at the following 2θ positions: 4.968°±0.3°, 8.863°±0.3°, 12.739°±0.3°, 13.896°±0.3°, 14.848°±0.3°, 18.840°±0.3°, 19.179°±0.3°, 19.770°±0.3°, 21.155°±0.3°, 21.752°±0.3°, and 24.053°±0.3°.

[0051] Furthermore, the powder X-ray diffraction pattern of crystalline Form I is substantially as shown in FIG.

[0052] The present invention also relates to a method for preparing crystalline form I, which comprises crystallizing the compound of formula (1) in a solvent ((1)-I) to obtain crystalline form I, wherein the solvent ((1)-I) is selected from acetonitrile, water, or a mixture of acetonitrile and water.

[0053] The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a crystalline compound according to the present invention and one or more pharmaceutically acceptable carriers or excipients.

[0054] The crystals of the present invention can be used as an active pharmaceutical ingredient, or a pharmaceutical composition containing the crystals as an active ingredient can be used for the treatment and / or prevention of cancer.

[0055] In one or more embodiments, the present invention provides for the use of the crystals of the present invention as an active pharmaceutical ingredient, or a pharmaceutical composition in which the crystals are used as an active ingredient for the treatment and / or prevention of solid tumors.

[0056] In one or more embodiments, the solid tumor of the invention is selected from non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, hormone receptor positive (HR+) breast cancer, colon cancer, or PARP7-amplified advanced solid tumors.

[0057] Powder X-ray diffraction patterns substantially identical to those disclosed in the present invention are also within the scope of the present invention.

[0058] It is understood that the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, as is well known in the field of differential scanning calorimetry (DSC), while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline compounds of the present invention are characterized by a DSC pattern having characteristic peak positions and have substantially the same properties as the DSC patterns provided in the accompanying drawings of the present invention, within a tolerance of ±3°C.

[0059] Unless stated to the contrary, terms used in the specification and claims have the following meanings:

[0060] The term "effective dose" refers to an amount of a compound that brings about a desired physiological or medical transformation in a tissue, system, or subject, and includes an amount of a compound that, when administered to a subject, is sufficient to prevent the occurrence of, or alleviate to some extent, one or more symptoms of the disorder or disease being treated.

[0061] "I C 50 " refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0062] The crystalline forms of the present invention can be analyzed using a variety of analytical techniques known to those skilled in the art, including, but not limited to, powder X-ray diffraction (XRD).

[0063] It is understood that the numerical values ​​described and protected by this invention are approximate values, and variations in the numerical values ​​may be due to instrument calibration, instrument error, crystal purity, crystal size, sample size, and other factors.

[0064] It is understood that the crystals of the present invention are not limited to having the same characteristic patterns as those shown in the drawings of the present invention, such as XRD. All crystalline forms having substantially the same or essentially the same characteristic patterns as those shown in the drawings are included within the scope of the present invention.

[0065] Various modifications and alterations of the present invention will become apparent to those skilled in the art from consideration of the disclosure of the specification and procedures in practicing the invention without departing from the scope and spirit of the invention.

[0066] Unless otherwise stated, abbreviations used in the specification and claims have the following meanings: [Table 1] [Brief explanation of the drawings]

[0067] [Figure 1] 1 is a powder X-ray diffraction pattern of crystalline form A. [Figure 2] 1 is a powder X-ray diffraction pattern of crystalline form B. [Figure 3] 1 is a powder X-ray diffraction pattern of crystalline form C. [Figure 4] 1 is an X-ray powder diffraction pattern of crystalline form D. [Figure 5] 1 is a powder X-ray diffraction pattern of crystalline form E. [Figure 6] 1 is a powder X-ray diffraction pattern of crystalline form F. [Figure 7] 1 is a powder X-ray diffraction pattern of crystalline form G. [Figure 8] 1 is a powder X-ray diffraction pattern of crystalline form H. [Figure 9] 1 is a powder X-ray diffraction pattern of crystalline form I. [Figure 10] 1 is a TGA thermogram of crystalline form A. [Figure 11] 1 is a DSC thermogram of crystalline form A. [Figure 12] 1 is a TGA thermogram of crystalline form F. [Figure 13] 1 is a DSC thermogram of crystalline form F. [Figure 14] 1 is a TGA thermogram of crystalline form H. [Figure 15] 1 is a DSC thermogram of crystalline form H. DETAILED DESCRIPTION OF THE INVENTION

[0068] The implementation process of the present invention and the beneficial effects achieved will be described in detail below through specific embodiments, which are intended to help readers better understand the essence and characteristics of the present invention, but are not intended to limit the scope of the present invention.

[0069] Unless otherwise specified in the embodiments, the solution refers to an aqueous solution.

[0070] Unless otherwise specified, the experimental conditions for crystallization were generally room temperature (20 to 30°C, 30 to 70% RH), and the solvent ratios are volume ratios.

[0071] Intermediate 1 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 1) 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka] [ka]

[0072] Step 1: 4,5-Dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one (1b) 4,5-Dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one Sodium hydride (11.82 g, 295.41 mmol, 1.5 equiv, 60%) was added in one portion to a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (1a, 50 g, 196.94 mmol, 1.0 equiv) in N,N-dimethylformamide (500 mL) at 0°C to 10°C, followed by the addition of 1-(chloromethyl)-4-methoxybenzene (46.06 g, 294.11 mmol, 1.49 equiv) at 0°C. After the addition was complete, the reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction solution was quenched by slowly pouring it into 1.0 L of ice-water mixture and extracted with dichloromethane (2 × 500 mL). The organic layers were combined and concentrated. The solid was washed with methanol (500 mL × 2) to give 1b as a yellow solid (48.4 g, 66% yield). LC-MS m / z(ESI)=375.00[M+1].

[0073] Step 2: 4-Bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one (1c) 4-Bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one 1b (48.4 g, 129.40 mmol, 1.0 equiv) and potassium hydroxide (21.78 g, 388.30 mmol, 3.00 equiv) were dissolved in methanol (417 mL), and the reaction solution was stirred at room temperature for 2 h. The resulting reaction mixture was concentrated to 80 mL and filtered to give the crude product. The resulting filter cake was slurried in water (160 mL) for 1 h and filtered to give 1c as a white solid (38.72 g, 92% yield). LC-MS m / z(ESI)=326.30[M+1].

[0074] Step 3: 5-Methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1d) 5-Methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one 1c (14 g, 43.04 mmol, 1.0 equiv) and CuI (4.10 g, 21.52 mmol, 0.50 equiv) were weighed into a 250 mL reaction flask and dissolved in N-methylpyrrolidone (72 mL). 2,2-Difluoro-2-(fluorosulfonyl)methyl acetate (16.4 mL, 129.11 mmol, 3.0 equiv) was slowly added. After the addition was complete, the reaction mixture was placed in a 100 °C oil bath and stirred for 3 h. After the reaction was complete, the reaction solution was quenched by adding 90 mL of water. The resulting solution was extracted with dichloromethane (3 × 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 1d as a white solid (12.1 g, 89% yield). LC-MS m / z(ESI)=315.10[M+1].

[0075] Step 4: 5-Hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1e) 5-Hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one Trimethylsilyl iodide (9.97 g, 50.07 mmol, 1.3 equiv) was added dropwise to 1d (12.1 g, 38.52 mmol, 1.0 equiv) in N,N-dimethylformamide (60 mL) at room temperature. The resulting reaction solution was stirred at 85 °C for 20 h. After completion of the reaction, the reaction mixture was quenched by adding 60 mL of water, and the resulting solution was extracted with dichloromethane (3 × 60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 1e as a white solid (10.4 g, 90% yield). LC-MS m / z(ESI)=301.07[M+1].

[0076] Step 5: 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 1) 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one At 0°C, oxalyl chloride (8.79 g, 69.32 mmol, 2.0 equiv) was slowly added dropwise to a solution of compound 1e (10.4 g, 34.66 mmol, 1.0 equiv) in N,N-dimethylformamide (52 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 8 hours. After the reaction was complete, the reaction solution was quenched by adding 550 mL of water. The mixture was filtered to give intermediate 1 as a white solid (11.04 g, 99%). LC-MS m / z(ESI)=319.68[M+1].

[0077] Intermediate 2 (S)-1-((5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (Intermediate 2) (S)-1-((5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine [ka] [ka]

[0078] Step 1: Ethyl 5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (2b) Ethyl-5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate. Ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (2a, 5.0 g, 24 mmol, 1.0 equiv) and p-methoxybenzyl bromide (4.2 mL, 28.8 mmol, 1.2 equiv) were weighed and dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (1.15 g, 28.8 mmol, 1.2 equiv) was added slowly in an ice bath. After the addition was complete, the reaction was allowed to stand at room temperature for 3 h. After the reaction was complete, water was added to quench the reaction, followed by ethyl acetate extraction. The product was dried over anhydrous sodium sulfate, and the organic phase was then spun down. The crude product was purified by flash column chromatography (dichloromethane:methanol = 20:1) to give 2b as a white solid (7.5 g, 92% yield). 1 H NMR (400MHz, DMSO-d6):δ 7.33-7.23(m, 2H), 7.14(s, 1H), 6.94-6.87(m, 2H), 4.62(s, 2H), 4.50-4.38(m, 2H), 4.28(q, 2H), 3.76-3.69(m, 5H), 1.29(t, 3H) LC-MS m / z(ESI)=330.10[M+1].

[0079] Step 2: (5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (2c) (5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol 2b (4.1 g, 12.5 mmol, 1.0 equiv) was weighed and dissolved in tetrahydrofuran (100 mL). Under nitrogen protection, a solution of lithium aluminum tetrahydride (50 mL, 50 mmol, 4.0 equiv) in tetrahydrofuran was slowly added dropwise in an ice bath. After the addition was complete, the temperature was raised to 70 °C and the reaction mixture was allowed to react for 10 min. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched in an ice-water bath, filtered, and the filtrate was spin-dried. The crude product was purified by flash column chromatography (dichloromethane:methanol = 10:1) to give 2c (2.45 g, 71% yield) as a yellow solid. LC-MS m / z(ESI)=274.10[M+1].

[0080] Step 3: (S)-1-((5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (Intermediate 2) (S)-1-((5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine 2c (864 mg, 3.16 mmol, 1.0 equiv) was added to a 25 mL reaction flask and dissolved in anhydrous N,N-dimethylformamide (18 mL). Under N protection, sodium hydride (300 mg, 7.51 mmol, 2.5 eq) was added in one portion at 0 °C. After the addition was complete, the reaction mixture was stirred at that temperature for 30 min. Then, tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide in N,N-dimethylformamide (18 mL) was slowly added dropwise to the reaction mixture. The temperature was maintained at 0 °C during the addition, and the reaction mixture was continuously stirred for 2 h. After the reaction was complete, the pH of the reaction mixture was adjusted to 3, and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was extracted with EA (3 × 120 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product, which was purified by column chromatography (dichloromethane:methanol=40:1) to give Intermediate 2 as a white solid (252 mg, 24% yield). LC-MS m / z(ESI)=331.50 [M+1].

[0081] Intermediate 3 (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 3) (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka] [ka]

[0082] Step 1: (S)-2-(4-methoxybenzyl)-5-((1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (3a) (S)-2-(4-Methoxybenzyl)-5-((1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one. Intermediate 2 (252 mg, 0.764 mmol, 1.0 eq) and intermediate 1 (291.4 mg, 0.916 mmol, 1.1 equiv) were weighed and placed in a 10 mL reaction flask. N,N-dimethylformamide (3.0 mL) was added to dissolve the mixture. N,N-diisopropylethylamine (0.5 mL, 3.06 mmol, 4.0 equiv) was then added. The mixture was stirred at 100 °C for 4 h. After completion of the reaction, the product was concentrated under vacuum, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1.5) to give 3a as a white solid (359.8 mg, 77% yield). LC-MS m / z(ESI)=613.62[M+1].

[0083] Step 2: (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 3) (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Trifluoroacetic acid (3.4 mL) and trifluoromethanesulfonic acid (0.42 mL, 4.7 mmol, 8.0 equiv) were added to a 10 mL reaction flask containing 3a (359.8 mg, 0.588 mmol, 1.0 equiv). After the addition was complete, the reaction solution was stirred at 25 °C for 1 h. The reaction solution was then stirred in an oil bath at 70 °C. After the reaction was complete, the reaction solution was quenched by adding 15 mL of water. The resulting solution was extracted with ethyl acetate (3 × 15 mL). The pH of the organic layer was adjusted to 8–9 with aqueous potassium carbonate. The organic layers were combined and concentrated in vacuo. The residue was purified by MPLC (water:acetonitrile = 1:1) to give intermediate 3 as a white solid (48 mg, 22% yield). 1 H NMR (400MHz, DMSO-d6) δ 12.46(s, 1H), 8.81(s, 2H), 7.90(s, 1H), 6.28(dd, 1H), 6.11(s, 1H), 5.01(s, 2H), 4.41(d, 2H), 4.32(t, 2H), 4.16(t, 3H), 3.55-3.45(m, 2H), 1.15(d, 3H). LC-MS m / z(ESI)=373.1[M+1].

[0084] Example 1: Preparation of Compound (1) (S)-4-(trifluoromethyl)-5-(1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (compound (1)) (S)-4-(trifluoromethyl)-5-(1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka] [ka] Intermediate 3 (48 mg, 0.13 mmol, 1.0 equiv) and 2-chloro-5-trifluoromethylpyrimidine (24 mg, 0.13 mmol, 1.0 equiv) were weighed and placed in a 10 mL reaction flask and dissolved in N,N-dimethylformamide (4.0 mL). N,N-Diisopropylethylamine (0.086 mL, 0.52 mmol, 4 equiv) was added and stirred at 90 °C for 1 hour. After completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was purified by MPLC (water:acetonitrile = 1:1) to give compound (1) as a white solid (40 mg, 59% yield). 1 H NMR (400MHz, DMSO-d6):δ 12.46(s, 1H), 8.81(s, 2H), 7.90(s, 1H), 6.28(dd, 1H), 6.11(s, 1H), 5.01(s, 2H), 4.41(d, 2H), 4.32(t, 2H), 4.16(t, 3H), 3.55-3.45(m, 2H), 1.15(d, 3H). LCMS m / z=519.40 [M+1].

[0085] Example 2: Preparation of compound crystalline form A Method 1: Compound (1) (7.8 g) was dissolved in acetonitrile (16 mL) with stirring at room temperature, and water (24 mL) was added. Crystallization was carried out at room temperature for 4 hours under stirring. The resulting solution was filtered, and the filter cake was dried under vacuum at 55°C to obtain crystalline form A.

[0086] Method 2: Under nitrogen protection, crude compound (1) (5.20 g) was added to acetonitrile (16.50 g) and dissolved at a temperature of 60 to 65°C over 0.5 hours. Water (52.43 g) and n-propanol (8.40 g) were added sequentially, and the mixture was heated to 65±5°C and dissolved over 0.5 hours. The temperature was lowered to 30±5°C and stirring was continued for 11 hours. The mixture was left for crystallization for 16 hours, and the temperature was further maintained at 25±5°C for 6 hours. The mixture was filtered, washed with water (6.09 g), and dried at 55±5°C for 16 hours to obtain crystalline form A.

[0087] Powder X-ray diffraction analysis: Crystalline Form A of compound (1) was characterized at room temperature using a Bruker D8 advance X-ray diffractometer with graphite monochromated Cu Kα radiation (λ = 1.54). The method parameters were as follows: current voltage: -40 mA, 40 Kv; step length: 0.02°; scan rate: 0.2 s / step; scan range: 3°-40°2θ. A powder diffraction pattern was obtained and the data analyzed. The powder X-ray diffraction data for Crystalline Form A are shown in Table 1.

[0088] [Table 2-1] [Table 2-2]

[0089] The powder X-ray diffraction pattern of crystalline form A of compound (1) is shown in FIG.

[0090] TGA and DSC analysis: Crystalline Form A of Compound (1) was subjected to thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), respectively. TGA and DSC were collected on a Mettler thermogravimetric analyzer (Mettler TGA / DSC 3+) and a Mettler differential scanning calorimeter (Mettler DSC 3), respectively. TGA and DSC test parameters are shown in Table 2. Test results are shown in Figures 10 and 11, respectively. The TGA thermogram shows a weight loss of 0.1737% upon heating to 105°C. The DSC thermogram shows an endothermic peak at 139.02°C.

[0091] [Table 3]

[0092] Example 3: Preparation of crystalline form B of compound (1) Compound (1) (10 g) prepared by reverse phase purification was dissolved in n-hexane (100 mL), slurried at room temperature for 2 hours, filtered, and the resulting solid was dried under vacuum at 55°C to obtain crystalline form B.

[0093] Powder X-ray diffraction analysis: Crystalline form B of compound (1) was characterized at room temperature using a Bruker D8 advance X-ray diffractometer with graphite monochromated Cu Kα radiation (λ = 1.54). The method parameters were as follows: current voltage: -40 mA, 40 Kv; step length: 0.02°; scan rate: 0.2 s / step; scan range: 3°-40°2θ. A powder diffraction pattern was obtained and the data analyzed. The powder X-ray diffraction data for crystalline form B are shown in Table 3.

[0094] [Table 4-1] [Table 4-2]

[0095] The powder X-ray diffraction pattern of crystalline form B of compound (1) is shown in FIG.

[0096] Example 4: Preparation of compound crystalline form C Compound (1) (5.1 g) was recovered and dissolved in IPAc (isopropyl acetate) (5 mL) at room temperature. The IPAc solution of compound (1) was slowly added dropwise to n-hexane (120 mL) while maintaining the temperature at room temperature. After the addition was complete, the mixture was heated to 60°C and stirred to dissolve. Then, the heating was stopped and the mixture was allowed to cool to room temperature, resulting in the precipitation of a white cohesive solid. The solid was filtered, and the filter cake was dried under vacuum at 55°C to obtain crystalline form C.

[0097] Powder X-ray diffraction analysis: Crystalline form C of compound (1) was characterized at room temperature using a Bruker D8 advance X-ray diffractometer with graphite monochromated Cu Kα radiation (λ = 1.54). The method parameters were as follows: current voltage: -40 mA, 40 Kv; step length: 0.02°; scan rate: 0.2 s / step; scan range: 3°-40°2θ. A powder diffraction pattern was obtained and the data analyzed. The powder X-ray diffraction data for crystalline form C are shown in Table 4.

[0098] [Table 5]

[0099] The powder X-ray diffraction pattern of crystalline form C of compound (1) is shown in FIG.

[0100] Example 5: Preparation of crystalline form D of compound (1) The crude product was purified by reverse phase chromatography using acetonitrile and water, concentrated, extracted with ethyl acetate, concentrated again, and dried under vacuum at 55°C to give compound (1) (34 g) as an off-white solid, which was confirmed to be crystalline form D by XRD.

[0101] Powder X-ray diffraction analysis: Crystalline form D of compound (1) was characterized at room temperature using a Bruker D8 advance X-ray diffractometer with graphite monochromated Cu Kα radiation (λ = 1.54). The method parameters were as follows: current voltage: -40 mA, 40 Kv; step length: 0.02°; scan rate: 0.2 s / step; scan range: 3°-40°2θ. A powder diffraction pattern was obtained and the data analyzed. The powder X-ray diffraction data for crystalline form D are shown in Table 5.

[0102] [Table 6-1] [Table 6-2]

[0103] The powder X-ray diffraction pattern of crystalline form D of compound (1) is shown in FIG.

[0104] Example 6: Preparation of crystalline form E of compound (1) Compound (1) (2.0 g) was added to a reaction flask, and ethyl acetate (4 mL) was added at room temperature and stirred to dissolve at 60°C. After that, n-hexane (6 mL) was added while maintaining the internal temperature at 60°C, and stirring was continued for 2 hours. A large amount of white floccule appeared, so the floccule was filtered, and the obtained filter cake was dried in vacuo at 55°C to obtain crystalline form E.

[0105] Powder X-ray diffraction analysis: Form E of compound (1) was characterized at room temperature using a Bruker D8 advance X-ray diffractometer with graphite monochromated Cu Kα radiation (λ = 1.54). The method parameters were as follows: current voltage: -40 mA, 40 Kv; step length: 0.02°; scan rate: 0.2 s / step; scan range: 3°-40°2θ. A powder diffraction pattern was obtained and the data analyzed. The powder X-ray diffraction data for Form E are shown in Table 6.

[0106] [Table 7-1] [Table 7-2]

[0107] The powder X-ray diffraction pattern of crystalline form E of compound (1) is shown in FIG.

[0108] Example 7: Preparation of crystalline form F of compound (1) Compound (1) (500 mg) was weighed and placed in a 50 mL reaction flask. 2 mL of n-propanol was added and the mixture was heated under reflux to dissolve. 2 mL of n-heptane was then added dropwise. The solution was allowed to become clear again, cooled to room temperature, and allowed to crystallize for 30 minutes. The mixture was then filtered, and the filter cake was dried under vacuum at 55°C for 9 hours to obtain crystalline form F (420 mg).

[0109] Powder X-ray diffraction analysis: Crystalline form F of compound (1) was characterized at room temperature using a Bruker D8 advance X-ray diffractometer with graphite monochromated Cu Kα radiation (λ = 1.54). The method parameters were as follows: current voltage: -40 mA, 40 Kv; step length: 0.02°; scan rate: 0.2 s / step; scan range: 3°-40°2θ. A powder diffraction pattern was obtained and the data analyzed. The powder X-ray diffraction data for crystalline form F are shown in Table 7.

[0110] [Table 8-1] [Table 8-2]

[0111] The powder X-ray diffraction pattern of crystalline form F of compound (1) is shown in FIG.

[0112] TGA and DSC analysis: Compound (1) crystalline form F was subjected to thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) under the same conditions as Compound (1) crystalline form A. The results are shown in Figures 12 and 13, respectively. The TGA thermogram shows a weight gain of 0.697% when heated to 105°C. The DSC thermogram shows an endothermic peak at 126.78°C.

[0113] Example 8: Preparation of crystalline form G of compound (1) Compound (1) (500 mg) was placed in a 50 mL reaction flask and 2 mL of ethanol was added. The mixture was heated to reflux, and after dissolution, 2 mL of n-heptane was added dropwise. After the solution became clear again, the temperature was lowered to room temperature and stirred for 60 minutes for crystallization. The resulting mixture was filtered, and the filter cake was dried under vacuum at 55°C for 9 hours to obtain 350 mg of a white solid (Crystal Form G of Compound (1)).

[0114] Powder X-ray diffraction analysis: The crystalline form G of compound (1) was characterized at room temperature by X-ray diffractometry (Bruker D8 advance) using graphite monochromated Cu Kα radiation (λ = 1.54). The method parameters were as follows: current voltage: -40 mA, 40 Kv; step length: 0.02°; scan rate: 0.2 s / step; scan range: 3°-40°2θ. The powder diffraction pattern was obtained and the data analyzed. The powder X-ray diffraction data for crystalline form G are shown in Table 8.

[0115] [Table 9-1] [Table 9-2]

[0116] The powder X-ray diffraction pattern of crystalline form G of compound (1) is shown in FIG.

[0117] Example 9: Preparation of crystalline form H of compound (1) The crude product of compound (1) (2.2 kg) was placed in a reactor, and acetonitrile (4.1 kg) was added at room temperature and stirred to dissolve. Water (7.8 kg) was then added and stirred for 20 hours to crystallize the mixture. An acetonitrile / HO mixed solvent (solvent ratio: acetonitrile 4.1 kg + HO 7.8 kg) was added and stirred for 1 hour. The mixture was then centrifuged, and the filter cake was dried under vacuum at 55°C to obtain crystalline form H of compound (1) (1.54 kg).

[0118] Powder X-ray diffraction analysis: Crystalline form H of compound (1) was characterized at room temperature using a Bruker D8 advance X-ray diffractometer with graphite monochromated Cu Kα radiation (λ = 1.54). The method parameters were as follows: current voltage: -40 mA, 40 Kv; step length: 0.02°; scan rate: 0.2 s / step; scan range: 3°-40°2θ. A powder diffraction pattern was obtained and the data analyzed. The powder X-ray diffraction data for crystalline form H are shown in Table 9.

[0119] [Table 10]

[0120] The powder X-ray diffraction pattern of crystalline form H of compound (1) is shown in FIG.

[0121] TGA and DSC analysis: Using the same test conditions as for crystalline form A of compound (1), crystalline form H of compound (1) was subjected to thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), respectively. The test results are shown in Figures 14 and 15, respectively. The TGA thermogram showed a weight loss of 0.6674% upon heating to 101.42°C, and the DSC thermogram showed an endothermic peak at 130.05°C.

[0122] Example 10: Preparation of Compound Crystalline Form I The crude product of compound (1) (60 g) was placed in a reaction flask, and acetonitrile (120 mL) was added at room temperature and stirred to dissolve the compound. Water (180 mL) was then added and stirred for 3 hours to induce crystallization. A mixed solvent of acetonitrile (120 mL) and HO (180 mL) was then added, and crystallization was continued for 2 hours. The mixture was filtered, and the filter cake was dried under vacuum at 55°C to obtain crystalline form I (40.5 g).

[0123] Powder X-ray diffraction analysis: Crystalline Form I of compound (1) was characterized at room temperature using a Bruker D8 advance X-ray diffractometer with graphite monochromated Cu Kα radiation (λ = 1.54). The method parameters were as follows: current voltage: -40 mA, 40 Kv; step length: 0.02°; scan rate: 0.2 s / step; scan range: 3°-40°2θ. A powder diffraction pattern was obtained and the data analyzed. The powder X-ray diffraction data for Crystalline Form I are shown in Table 10.

[0124] [Table 11-1] [Table 11-2]

[0125] The powder X-ray diffraction pattern of crystalline form I of compound (1) is shown in FIG.

[0126] Biological Embodiments 1. In vivo pharmacokinetic study The appropriate amount of compound was weighed, and a 1 mg / mL suspension was prepared using the weighed compound and 5% DMSO + 30% HP-β-CD. Male ICR mice were fasted overnight and then orally administered the compound. Blood was collected from the jugular plexus at 0, 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h. After anticoagulation with EDTA-K2, plasma was separated by centrifugation, and the drug substance concentration in the plasma was measured by LC / MS / MS.

[0127] As a result, it was shown that crystalline forms A, B, C, D, E, F, G, H and I of compound (1) all have good pharmacokinetic properties.

[0128] 2. Stability testing 2.1 Influence Factor Test 2.1.1 Lighting Test An appropriate amount of compound was weighed and placed in a suitable white, transparent, open container (such as a weighing bottle or a petri dish), which was then placed in a drug lighting stability test chamber with an illumination of 4,500 lx ± 500 lx. Samples were taken 5, 10, and 30 days after placement and tested.

[0129] 2.1.2 High-temperature test The appropriate amount of compound was weighed and placed in a suitable open container (such as a weighing bottle or culture dish), which was then placed in an electrically heated air-drying oven at 60° C. Samples were taken and tested 5, 10, and 30 days after installation.

[0130] 2.1.3 High humidity test An appropriate amount of compound was weighed and placed in a suitable open container (such as a weighing bottle or a Petri dish), which was then placed in a desiccator containing saturated KNO3 solution at a relative humidity of 92.5% and 72.5% at a temperature of 25°C ± 2°C. Samples were taken 5, 10, and 30 days after installation and tested.

[0131] 2.2 Accelerated testing An appropriate amount of compound was packaged in an inner packaging material (pharmaceutical low-density polyethylene film, bag) and an outer packaging material (polyester / aluminum / polyethylene pharmaceutical composite film, bag), and then tested at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%.

[0132] 2.3 Intermediate conditions An appropriate amount of compound was packaged in an inner packaging material (low-density polyethylene film for pharmaceutical use, bag) and an outer packaging material (polyester / aluminum / polyethylene pharmaceutical composite film, bag), and then tested at a temperature of 30°C ± 2°C and a relative humidity of 65% ± 5%.

[0133] 2.4 Long-term testing An appropriate amount of compound was packaged in an inner packaging material (low-density polyethylene film for pharmaceutical use, bag) and an outer packaging material (polyester / aluminum / polyethylene pharmaceutical composite film, bag), and then tested at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 5%.

[0134] As a result, it was shown that crystalline forms A, B, C, D, E, F, G, H, and I of compound (1) all have good physical and chemical stability.

[0135] In the specification of the present invention, specific embodiments are described in detail. Those skilled in the art should realize that the above embodiments are illustrative and cannot be understood as limiting the present invention. For those skilled in the art, under the circumstances where some improvements and modifications are made to the present invention without departing from the principle of the present invention, the technical solutions obtained by these improvements and modifications also belong to the protection scope of the claims of the present invention.

Claims

1. A crystal of the compound shown in the following formula (1). 【Chemistry 1】

2. The crystal according to Claim 1, wherein the crystal is of crystal form A, and the X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ positions: 10.389°±0.3°, 11.917°±0.3°, 12.912°±0.3°, 13.385°±0.3°, 14.054°±0.3°, 15.316°±0.3°, and 16.636°±0.3°.

3. The crystal according to Claim 1, wherein the crystal is of crystal form A, and the X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ positions: 6.716°±0.3°, 10.043°±0.3°, 10.389°±0.3°, 11.917°±0.3°, 12.912°±0.3°, 13.385°±0.3°, 14.054°±0.3°, 15.316°±0.3°, 16.636°±0.3°, 18.003°±0.3°, 20.014°±0.3°, 20.794°±0.3°, and 23.855°±0.3°.

4. The crystal according to claim 2 or 3, wherein the crystal is of crystal form A, and the X-ray powder diffraction pattern of crystal form A is as shown in Table 1' below. Table 1-1 Table 1-2

5. The crystal according to claim 2 or 3, wherein the crystal is of crystal form A, and the DSC thermogram shows that the peak value of the endothermic peak is 139.02°C ± 3°C.

6. A method for preparing crystal form A according to claim 2 or 3, A method for obtaining crystalline form A by crystallizing a compound represented by formula (1) in a solvent ((1)-A), wherein the solvent ((1)-A) is selected from one of acetonitrile, ethanol, n-propanol, acetone, and water, or is a mixed solvent in any ratio and any combination of acetonitrile, ethanol, n-propanol, acetone, and water.

7. The preparation method according to claim 6, wherein a compound represented by formula (1) or its crude product is added to solvent ((1)-A-1), the resulting system is heated to dissolve it, solvents ((1)-A-2) and ((1)-A-3) are added, the resulting system is heated to dissolve it, the system is continuously cooled and stirred, and then left to crystallize to obtain crystalline form A, where solvents ((1)-A-1), ((1)-A-2), and ((1)-A-3) are selected from acetonitrile, ethanol, n-propanol, acetone, and water.

8. The crystal according to claim 1, wherein the crystal is of crystal form B, and the X-ray powder diffraction pattern of crystal form B has characteristic diffraction peaks at the following 2θ positions: 6.498°±0.3°, 13.326°±0.3°, 21.229°±0.3°, 21.426°±0.3°, and 22.195°±0.3°.

9. The crystal according to claim 1, wherein the crystal is of crystal form B, and the powder X-ray diffraction pattern of crystal form B has characteristic diffraction peaks at the following 2θ positions: 6.498°±0.3°, 9.657°±0.3°, 11.420°±0.3°, 13.027°±0.3°, 13.326°±0.3°, 15.882°±0.3°, 19.075°±0.3°, 19.315°±0.3°, 20.669°±0.3°, 21.229°±0.3°, 21.426°±0.3°, 22.195°±0.3°, 23.118°±0.3°, and 23.362°±0.3°.

10. The crystal according to claim 8 or 9, wherein the crystal is of crystal form B, and the X-ray powder diffraction pattern of crystal form B is as shown in Table 3' below. Table 2-1 Table 2-2

11. A method for preparing crystal form B according to claim 8 or 9, A method is provided in which the compound represented by formula (1) is slurryed in solvent ((1)-B) to obtain crystalline form B, where solvent ((1)-B) is selected from n-hexane.

12. The crystal according to claim 1, wherein the crystal is of crystal form C, and the X-ray powder diffraction pattern of crystal form C has characteristic diffraction peaks at the following 2θ positions: 19.066°±0.3°, 20.300°±0.3°, 20.978°±0.3°, and 21.616°±0.3°.

13. The crystal is of crystal form C, and the powder X-ray diffraction pattern of crystal form C has characteristic diffraction peaks at the following 2θ positions, as described in Claim 1: 6.790°±0.3°, 9.917°±0.3°, 11.533°±0.3°, 12.600°±0.3°, 13.556°±0.3°, 13.793°±0.3°, 14 275°±0.3°, 15.008°±0.3°, 16.452°±0.3°, 17.877°±0.3°, 19.066°±0.3°, 19.774°±0.3°, 20.300°±0.3°, 20.978°±0.3°, 21.616°±0.3°, 22.585°±0.3°, 23.407°±0.3°.

14. The crystal according to claim 12 or 13, wherein the crystal is of crystal form C, and the X-ray powder diffraction pattern of crystal form C is as shown in Table 4' below. Table 3

15. A method for preparing the crystalline form C according to claim 12 or 13, A method comprising crystallizing the compound represented by (1) in solvent ((1)-C) to obtain crystalline form C, wherein the solvent ((1)-C) is selected from isopropyl acetate, n-hexane, or a mixed solvent of isopropyl acetate and n-hexane.

16. The crystal according to claim 1, wherein the crystal is of crystal form D, and the X-ray powder diffraction pattern of crystal form D has characteristic diffraction peaks at the following 2θ positions: 6.646°±0.3° and 13.175°±0.3°.

17. The crystal according to claim 1, wherein the crystal is of crystal form D, and the X-ray powder diffraction pattern of crystal form D has characteristic diffraction peaks at the following 2θ positions: 6.646°±0.3°, 13.175°±0.3°, 13.489°±0.3°, 16.450°±0.3°, 20.950°±0.3°, 21.585°±0.3°, 22.369°±0.3°, 23.036°±0.3°, and 23.281°±0.3°.

18. The crystal according to claim 16 or 17, wherein the crystal is of crystal form D, and the X-ray powder diffraction pattern of crystal form D is as shown in Table 5' below. Table 4-1 Table 4-2

19. A method for preparing crystal form D according to claim 16 or 17, A method comprising extracting the compound represented by (1) with solvent ((1)-D), concentrating and drying under vacuum to obtain crystalline form D, wherein the solvent ((1)-D) is selected from ethyl acetate.

20. The crystal according to claim 1, wherein the crystal is of crystal form E, and the X-ray powder diffraction pattern of crystal form E has characteristic diffraction peaks at the following 2θ positions: 18.227°±0.3°, 19.954°±0.3°, and 22.449°±0.3°.

21. The crystal according to claim 1, wherein the crystal is of crystal form E, and the X-ray powder diffraction pattern of crystal form E has characteristic diffraction peaks at the following 2θ positions: 8.129°±0.3°, 11.118°±0.3°, 11.360°±0.3°, 11.749°±0.3°, 13.482°±0.3°, 14.730°±0.3°, 18.227°± 0.3°, 19.954°±0.3°, 20.712°±0.3°, 21.092°±0.3°, 22.449°±0.3°, 22.813°±0.3°, 24.399°±0.3°, 24.560°±0.3°, 25.923°±0.3°, 26.429°±0.3°, 27.060°±0.3°, 27.446°±0.3°.

22. The crystal according to claim 20 or 21, wherein the crystal is of crystal form E, and the X-ray powder diffraction pattern of crystal form E is as shown in Table 6' below. Table 5-1 Table 5-2

23. A method for preparing crystal form E according to claim 20 or 21, A method for obtaining crystalline form E by crystallizing a compound represented by formula (1) in solvent ((1)-E), where solvent ((1)-E) is selected from ethyl acetate, n-hexane, or a mixed solvent of ethyl acetate and n-hexane.

24. The crystal according to claim 1, wherein the crystal is of crystal form F, and the X-ray powder diffraction pattern of crystal form F has characteristic diffraction peaks at the following 2θ positions: 6.717°±0.3° and 13.484°±0.3°.

25. The crystal according to claim 1, wherein the crystal is of crystal form F, and the X-ray powder diffraction pattern of crystal form F has characteristic diffraction peaks at the following 2θ positions: 6.717°±0.3°, 9.812°±0.3°, 11.426°±0.3°, 12.501°±0.3°, 13.484°±0.3°, 14.915°±0.3°, 16.374°±0.3°, 16.884°±0.3°, 17.828°±0.3°, 18.975°±0.3°, 20.241°±0.3°, 20.902°±0.3°, 21.593°±0.3°, 22.506°±0.3°, 22.918°±0.3°, 23.412°±0.3°.

26. The crystal according to claim 24 or 25, wherein the crystal is of crystal form F, and the X-ray powder diffraction pattern of crystal form F is as shown in Table 7' below. Table 6-1 Table 6-2

27. ​​The crystal according to claim 24 or 25, wherein the crystal is of crystal form F, and the DSC thermogram shows that the peak value of the endothermic peak is 126.78°C ± 3°C.

28. A method for preparing the crystal form F according to claim 24 or 25, A method comprising crystallizing the compound represented by (1) in a solvent ((1)-F) to obtain crystalline form F, wherein the solvent ((1)-F) is selected from n-propanol, n-heptane, or a mixed solvent of n-propanol and n-heptane.

29. The crystal according to claim 1, wherein the crystal is of crystal form G, and the X-ray powder diffraction pattern of crystal form G has characteristic diffraction peaks at the following 2θ positions: 6.743°±0.3° and 13.503°±0.3°.

30. The crystal according to claim 1, wherein the crystal is of crystal form G, and the X-ray powder diffraction pattern of crystal form G has characteristic diffraction peaks at the following 2θ positions: 6.743°±0.3°, 13.503°±0.3°, 16.901°±0.3°, 18.996°±0.3°, 20.260°±0.3°, 20.920°±0.3°, and 21.604°±0.3°.

31. The crystal according to claim 29 or 30, wherein the crystal is of crystal form G, and the X-ray powder diffraction pattern of crystal form G is as shown in Table 8' below. Table 7-1 Table 7-2

32. A method for preparing the crystalline form G according to claim 29 or 30, A method comprising crystallizing the compound represented by (1) in solvent ((1)-G) to obtain crystalline form G, wherein the solvent ((1)-G) is selected from ethanol, n-heptane, or a mixed solvent of ethanol and n-heptane.

33. The crystal according to claim 1, wherein the crystal is of crystal form H, and the X-ray powder diffraction pattern of crystal form H has characteristic diffraction peaks at the following 2θ positions: 12.366°±0.3°, 13.115°±0.3°, 14.359°±0.3°, 15.617°±0.3°, 16.909°±0.3°.

34. The crystal according to claim 1, wherein the crystal is of crystal form H, and the X-ray powder diffraction pattern of crystal form H has characteristic diffraction peaks at the following 2θ positions: 6.514°±0.3°, 10.074°±0.3°, 10.684°±0.3°, 12.366°±0.3°, 13.115°±0.3°, 14.359°±0.3°, 15.617°±0.3°, 16.909°±0.3°, 19.839°±0.3°, 20.092°±0.3°, 20.687°±0.3°, 22.919°±0.3°.

35. The crystal according to claim 33 or 34, wherein the crystal is of crystal form H, and the X-ray powder diffraction pattern of crystal form H is as shown in Table 9' below. Table 8

36. The crystal according to claim 33 or 34, wherein the crystal is of crystal form H, and the DSC thermogram shows that the peak value of the endothermic peak is 130.05°C ± 3°C.

37. A method for preparing the crystalline form H according to claim 33 or 34, A method comprising crystallizing the compound represented by (1) in a solvent ((1)-H) to obtain crystalline form H, where the solvent ((1)-H) is selected from acetonitrile, ethanol, n-propanol, acetone, and water, or a mixed solvent in any ratio and any combination of acetonitrile, ethanol, n-propanol, acetone, and water.

38. The crystal according to claim 1, wherein the crystal is of crystal form I, and the X-ray powder diffraction pattern of crystal form I has characteristic diffraction peaks at the following 2θ positions: 4.968°±0.3°, 19.770°±0.3°, and 21.752°±0.3°.

39. The crystal according to claim 1, wherein the crystal is of crystal form I, and the X-ray powder diffraction pattern of crystal form I has characteristic diffraction peaks at the following 2θ positions: 4.968°±0.3°, 8.863°±0.3°, 12.739°±0.3°, 13.896°±0.3°, 14.848°±0.3°, 18.840°±0.3°, 19.179°±0.3°, 19.770°±0.3°, 21.155°±0.3°, 21.752°±0.3°, and 24.053°±0.3°.

40. The crystal according to claim 38 or 39, wherein the crystal is of crystal form I, and the X-ray powder diffraction pattern of crystal form I is as shown in Table 10' below. Table 9-1 Table 9-2

41. A method for preparing crystal form I according to claim 38 or 39, A method comprising crystallizing the compound represented by (1) in solvent ((1)-I) to obtain crystalline form I, where solvent ((1)-I) is selected from acetonitrile, water, or a mixed solvent of acetonitrile and water.

42. A pharmaceutical composition comprising a therapeutically effective amount of the crystals described in any one of claims 1, 2, 3, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 29, 30, 33, 34, 38, and 39, and a pharmaceutically acceptable carrier or excipient.

43. Use of the crystals according to any one of claims 1, 2, 3, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 29, 30, 33, 34, 38, and 39 in the preparation of a medicament for treating and / or preventing cancer.

44. Use of the pharmaceutical composition according to claim 42 in the preparation of a pharmaceutical for treating and / or preventing cancer.

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