Crystal of tricyclic compound and application thereof

Abstract

The invention belongs to the field of medicine, discloses a crystal of a tricyclic compound and application thereof, and particularly relates to a crystal of a tricyclic compound shown in a formula (I) or pharmaceutically acceptable salt of the tricyclic compound, a preparation method of the crystal and application of the crystal in preparation of drugs for treating diseases related to PDE3 and / or PDE4. # imgabs0 #

Description

[0001] This application is a divisional application of the following application: Application date January 15, 2021; Application number 202180008505.0; Invention name: "Crystallization of a PDE3 / PDE4 dual inhibitor and its application".

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the rights and priority of Chinese invention patent application No. 202010043882.5 filed with the State Intellectual Property Office of the People's Republic of China on January 15, 2020, the entire contents of which are hereby incorporated by reference into this document in their entirety. Technical Field

[0004] The present application relates to a crystal of a tricyclic compound and its application, specifically to a crystal as a PDE3 / PDE4 dual inhibitor, and its application in treating diseases related to PDE3 / PDE4, specifically to chronic obstructive pulmonary disease (COPD). Background Art

[0005] Phosphodiesterase (PDE) belongs to the superfamily enzyme system, which includes 11 families. Each family participates in different signal transduction and regulates different physiological processes. Among them, PDE3 is the main phosphodiesterase in human airway smooth muscle (ASM). Inhibition of PDE3 will increase the concentration of intracellular cAMP and relax bronchial smooth muscle. PDE4 plays a major regulatory role in the expression of pro-inflammatory and anti-inflammatory mediators. PDE4 inhibitors can inhibit the release of harmful mediators from inflammatory cells. Therefore, in principle, an inhibitor that inhibits both PDE3 and PDE4 will have both the bronchodilator effect (bronchodilation) of β-adrenergic receptor agonists and the anti-inflammatory effect (anti-inflammatory action) of inhaled glucocorticoids. The complementary dual-targeting functionality has a theoretical basis for greater efficacy than single targeting. It can achieve therapeutic effects that can only be achieved through combined medication through a single drug, overcome the defect that the physical and chemical properties of the drug components of combined medication cannot be fully matched, simplify the administration method, and facilitate quantitative administration.

[0006] Victoria Boswell et al, J. Pharmaco. Experi. Therap. 2006, 318, 840-848 and WO200005830 reported that compounds RPL554 and RPL565 have long-acting bronchodilator and anti-inflammatory effects, as well as physical and chemical properties such as poor solubility and high plasma clearance, and are suitable for inhalation administration. However, data also show that their PDE4 inhibitory activity is not satisfactory and the anti-inflammatory effect is not ideal, so it is necessary to develop compounds with good PDE3 / 4 inhibitory activity. It is generally hoped that drugs have excellent properties in the following aspects: drug activity, pharmacokinetics, bioavailability, hygroscopicity, melting point, stability, solubility, purity, easy preparation, etc., to meet the needs of drugs in production, storage and preparation, so it is necessary to develop crystals of compounds with PDE3 / 4 inhibitory activity.

[0007] Summary of the invention

[0008] In one aspect, the present application provides a crystal of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] In some embodiments, the present application provides a crystal of the compound of formula (I).

[0011] On the other hand, the present application also provides type A crystals of the compound of formula (I), which has diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.14±0.2°, 6.98±0.2°, 8.20±0.2° and 11.50±0.2°.

[0012] In some embodiments of the present application, the above-mentioned type A crystal has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 4.14±0.2°, 6.56±0.2°, 6.98±0.2°, 8.20±0.2°, 11.50±0.2°, 12.66±0.2°, 13.94±0.2° and 16.35±0.2°.

[0013] In some embodiments of the present application, the above-mentioned type A crystal has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 4.14±0.2°, 6.56±0.2°, 6.98±0.2°, 8.20±0.2°, 9.35±0.2°, 11.50±0.2°, 12.66±0.2°, 13.94±0.2°, 14.52±0.2°, 16.35±0.2°, 21.52±0.2° and 24.57±0.2°.

[0014] In some embodiments of the present application, the above-mentioned type A crystal has an X-ray powder diffraction pattern using Cu Kα radiation, which comprises 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks selected from the following 2θ angles: 4.14±0.2°, 6.56±0.2°, 6.98±0.2°, 8.20±0.2°, 9.35±0.2°, 11.50±0.2°, 12.66±0.2°, 13.94±0.2°, 14.52±0.2°, 16.35±0.2°, 21.52±0.2° and 24.57±0.2°.

[0015] In some embodiments of the present application, the above-mentioned type A crystal has an X-ray powder diffraction pattern using Cu Kα radiation, which comprises 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 4.14±0.2°, 6.56±0.2°, 6.98±0.2°, 8.20±0.2°, 11.50±0.2°, 12.66±0.2°, 13.94±0.2° and 16.35±0.2°.

[0016] In some embodiments of the present application, in the XRPD spectrum of the above-mentioned type A crystal using Cu Kα radiation, the peak position and relative intensity of the diffraction peak are shown in the following Table 1:

[0017] Table 1

[0018] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 4.14 34.6 13 19.80 10.4 2 6.56 56.0 14 20.67 10.3 3 6.98 100.0 15 21.52 16.4 4 8.20 60.0 16 21.93 4.0 5 9.35 27.1 17 22.33 4.0 6 11.50 73.0 18 22.91 8.2 7 12.66 27.2 19 23.94 9.5 8 13.94 41.8 20 24.57 14.0 9 14.52 12.3 21 25.16 7.5 10 16.05 4.5 22 27.75 9.0 11 16.35 41.1 23 29.17 7.2 12 18.87 7.7

[0019] In some embodiments of the present application, the above-mentioned type A crystal has an XRPD pattern using Cu Kα radiation as shown in Figure 1 shown.

[0020] In some embodiments of the present application, the above-mentioned type A crystal has an endothermic peak at 146.23±2°C and / or 162.19±2°C in its differential scanning calorimetry curve.

[0021] In some embodiments of the present application, the above-mentioned Type A crystal has a differential scanning calorimetry curve having an exothermic peak at 172.65±2°C and / or 241.73±2°C.

[0022] In some embodiments of the present application, the above-mentioned type A crystal has a differential scanning calorimetry curve with endothermic peaks at 146.23±2°C and 162.19±2°C, and with exothermic peaks at 172.65±2°C and 241.73±2°C.

[0023] In some embodiments of the present application, the above-mentioned type A crystal has a differential scanning calorimetry spectrum as shown in Figure 2 shown.

[0024] In some embodiments of the present application, the thermogravimetric analysis curve of the above-mentioned type A crystals shows a weight loss of 0.4611% at 118.40±2°C; a weight loss of 0.8796% between 118.40±2°C and 185.65±2°C; and a weight loss of 7.177% between 185.65±2°C and 260.07±2°C.

[0025] In some embodiments of the present application, the above-mentioned type A crystal has a thermogravimetric analysis spectrum as shown in Figure 3 shown.

[0026] On the other hand, the present application provides a method for preparing type A crystals, comprising the step of precipitating the compound of formula (I) from a methanol solvent.

[0027] In some embodiments, the above operation is performed at 40° C. with stirring.

[0028] On the other hand, the present application also provides type B crystals of the compound of formula (Ⅰ), which has diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 5.81±0.2°, 13.96±0.2°, 15.01±0.2°, 17.95±0.2° and 24.73±0.2°.

[0029] In some embodiments of the present application, the above-mentioned B-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 5.81±0.2°, 8.38±0.2°, 11.16±0.2°, 13.96±0.2°, 14.47±0.2°, 15.01±0.2°, 17.95±0.2°, 24.73±0.2° and 26.13±0.2°.

[0030] In some embodiments of the present application, the above-mentioned B-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 5.81±0.2°, 8.38±0.2°, 11.16±0.2°, 13.96±0.2°, 14.47±0.2°, 15.01±0.2°, 16.76±0.2°, 17.95±0.2°, 20.83±0.2°, 24.73±0.2° and 26.13±0.2°.

[0031] In some embodiments of the present application, the above-mentioned B-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 5.81±0.2°, 8.38±0.2°, 9.13±0.2°, 11.16±0.2°, 11.60±0.2°, 12.82±0.2°, 13.96±0.2°, 14.47±0.2°, 15.01±0.2°, 16.76±0.2°, 17.95±0.2°, 18.91±0.2°, 20.83±0.2°, 24.36±0.2°, 24.73±0.2°, 25.78±0.2° and 26.13±0.2°.

[0032] In some embodiments of the present application, the above-mentioned B-type crystal, in its X-ray powder diffraction pattern using Cu Kα radiation, comprises 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following 2θ angles: 5.81±0.2°, 8.38±0.2°, 9.13±0.2°, 11.16±0.2°, 11.60±0.2°, 12.82±0.2°, 13.96±0.2°, 14.47±0.2°, 15.01±0.2°, 16.76±0.2°, 17.95±0.2°, 18.91±0.2°, 20.83±0.2°, 24.36±0.2°, 24.73±0.2°, 25.78±0.2° and 26.13±0.2°.

[0033] In some embodiments of the present application, the above-mentioned B-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation, which comprises 5, 6, 7, 8, 9, 10 or 11 diffraction peaks selected from the following 2θ angles: 5.81±0.2°, 8.38±0.2°, 11.16±0.2°, 13.96±0.2°, 14.47±0.2°, 15.01±0.2°, 16.76±0.2°, 17.95±0.2°, 20.83±0.2°, 24.73±0.2° and 26.13±0.2°.

[0034] In some embodiments of the present application, the above-mentioned B-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation, which comprises 5, 6, 7, 8 or 9 diffraction peaks selected from the following 2θ angles: 5.81±0.2°, 8.38±0.2°, 11.16±0.2°, 13.96±0.2°, 14.47±0.2°, 15.01±0.2°, 17.95±0.2°, 24.73±0.2° and 26.13±0.2°.

[0035] In some embodiments of the present application, in the XRPD spectrum of the above-mentioned B-type crystal using Cu Kα radiation, the peak position and relative intensity of the diffraction peak are shown in Table 2 below:

[0036] Table 2

[0037] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 5.81 47.9 17 17.69 20.9 2 8.38 23.7 18 17.95 69.7 3 9.13 15.4 19 18.91 15.0 4 10.57 8.2 20 20.21 8.0 5 11.16 46.9 21 20.83 24.3 6 11.60 17.6 22 21.25 5.3 7 11.77 6.2 23 22.96 9.9 8 12.82 16.5 24 24.14 5.1 9 13.96 99.5 25 24.36 19.5 10 14.47 38.4 26 24.73 100.0 11 15.01 80.7 27 25.48 11.1 12 15.71 8.0 28 25.78 19.9 13 16.03 9.1 29 26.13 61.8 14 16.54 9.2 30 29.05 12.5 15 16.76 24.4 31 29.37 6.3 16 17.47 8.3

[0038] In some embodiments of the present application, the above-mentioned B-type crystal has an XRPD pattern using Cu Kα radiation as shown in Figure 4 shown.

[0039] In some embodiments of the present application, the above-mentioned Type B crystal has an exothermic peak at 247.70±2° C. in its differential scanning calorimetry curve.

[0040] In some embodiments of the present application, the above-mentioned type B crystal has a differential scanning calorimetry spectrum as shown in Figure 5 shown.

[0041] In some embodiments of the present application, the thermogravimetric analysis curve of the above-mentioned Type B crystals shows a weight loss of 0.4870% at 155.75±2°C; and a weight loss of 7.287% between 155.75±2°C and 262.18±2°C.

[0042] In some embodiments of the present application, the above-mentioned B-type crystal has a thermogravimetric analysis spectrum as shown in Figure 6 shown.

[0043] On the other hand, the present application provides a method for preparing type B crystals, comprising the step of precipitating the compound of formula (I) from a mixed solvent of ethanol and water.

[0044] In some embodiments, the above operation is performed at 40° C. with stirring.

[0045] On the other hand, the present application also provides type C crystals of the compound of formula (I), which has diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.57±0.2°, 6.41±0.2°, 7.18±0.2° and 14.34±0.2°.

[0046] In some embodiments of the present application, the above-mentioned C-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 4.57±0.2°, 6.41±0.2°, 7.18±0.2°, 11.58±0.2°, 12.84±0.2°, 13.21±0.2°, 14.34±0.2°, 16.05±0.2° and 23.41±0.2°.

[0047] In some embodiments of the present application, the above-mentioned C-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 4.57±0.2°, 6.41±0.2°, 7.18±0.2°, 9.07±0.2°, 11.58±0.2°, 12.84±0.2°, 13.21±0.2°, 14.34±0.2°, 16.05±0.2°, 18.15±0.2°, 19.26±0.2°, 20.85±0.2° and 23.41±0.2°.

[0048] In some embodiments of the present application, the above-mentioned C-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation, which comprises 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 diffraction peaks selected from the following 2θ angles: 4.57±0.2°, 6.41±0.2°, 7.18±0.2°, 9.07±0.2°, 11.58±0.2°, 12.84±0.2°, 13.21±0.2°, 14.34±0.2°, 16.05±0.2°, 18.15±0.2°, 19.26±0.2°, 20.85±0.2° and 23.41±0.2°.

[0049] In some embodiments of the present application, the above-mentioned C-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation, which comprises 4, 5, 6, 7, 8 or 9 diffraction peaks selected from the following 2θ angles: 4.57±0.2°, 6.41±0.2°, 7.18±0.2°, 11.58±0.2°, 12.84±0.2°, 13.21±0.2°, 14.34±0.2°, 16.05±0.2° and 23.41±0.2°.

[0050] In some embodiments of the present application, in the XRPD spectrum of the above-mentioned C-type crystal using Cu Kα radiation, the peak position and relative intensity of the diffraction peak are shown in Table 3 below:

[0051] Table 3

[0052] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 4.57 38.7 13 18.15 9.6 2 6.41 39.3 14 18.68 6.8 3 7.18 100.0 15 19.26 11.8 4 9.07 12.4 16 19.76 5.4 5 10.15 6.3 17 20.10 6.7 6 11.18 3.9 18 20.85 10.4 7 11.58 31.3 19 22.74 5.6 8 12.84 36.7 20 23.41 25.7 9 13.21 29.3 21 25.14 5.1 10 13.98 7.1 22 25.82 6.8 11 14.34 70.9 23 28.82 6.2 12 16.05 39.6

[0053] In some embodiments of the present application, the above-mentioned C-type crystal has an XRPD pattern using Cu Kα radiation as shown in Figure 7 shown.

[0054] In some embodiments of the present application, the above-mentioned C-type crystal has an exothermic peak at 152.26±2°C and / or 247.92±2°C in its differential scanning calorimetry curve.

[0055] In some embodiments of the present application, the above-mentioned C-type crystal has a differential scanning calorimetry spectrum as shown in Figure 8 shown.

[0056] In some schemes of the present application, the thermogravimetric analysis curve of the above-mentioned C-type crystals shows a weight loss of 1.1460% at 152.80±2°C; and a weight loss of 7.871% at 152.80±2°C to 262.77±2°C.

[0057] In some embodiments of the present application, the thermogravimetric analysis spectrum of the above-mentioned C-type crystal is as follows Fig. 9 shown.

[0058] On the other hand, the present application provides a method for preparing type C crystals, comprising the step of precipitating the compound of formula (I) from acetonitrile.

[0059] In some embodiments, the above operation is performed at 40° C. with stirring.

[0060] On the other hand, the present application provides a pharmaceutically acceptable salt of the compound of formula (I), wherein the pharmaceutically acceptable salt is sulfate, p-toluenesulfonate, methanesulfonate or maleate.

[0061] In another aspect, the present application provides a crystal of a salt of the compound of formula (I).

[0062] On the other hand, the present application also provides a sulfate of a compound of formula (I); in some embodiments, the sulfate of the compound of formula (I) is selected from a compound of formula (II),

[0063]

[0064] On the other hand, the present application also provides a crystal of a compound of formula (II), whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 4.84±0.2°, 9.58±0.2°, 11.97±0.2° and 14.75±0.2°.

[0065] In some embodiments of the present application, the crystals of the compound of the above formula (II) have diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu Kα radiation: 4.84±0.2°, 9.58±0.2°, 10.93±0.2°, 11.97±0.2°, 14.31±0.2°, 14.75±0.2°, 16.49±0.2° and 24.42±0.2°.

[0066] In some embodiments of the present application, the crystals of the compound of the above formula (II) have an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 4.84±0.2°, 9.58±0.2°, 10.93±0.2°, 11.97±0.2°, 12.72±0.2°, 13.93±0.2°, 14.31±0.2°, 14.75±0.2°, 16.49±0.2°, 17.91±0.2°, 19.25±0.2°, 19.90±0.2°, 20.57±0.2°, 24.42±0.2° and 25.70±0.2°.

[0067] In some embodiments of the present application, the crystals of the compound of formula (II) above have an X-ray powder diffraction pattern using Cu Kα radiation, comprising 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following 2θ angles: 4.84±0.2°, 9.58±0.2°, 10.93±0.2°, 11.97±0.2°, 12.72±0.2°, 13.93±0.2°, 14.31±0.2°, 14.75±0.2°, 16.49±0.2°, 17.91±0.2°, 19.25±0.2°, 19.90±0.2°, 20.57±0.2°, 24.42±0.2° and 25.70±0.2°.

[0068] In some embodiments of the present application, the crystals of the compound of the above formula (II) have an X-ray powder diffraction pattern using Cu Kα radiation, which comprises 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 4.84±0.2°, 9.58±0.2°, 10.93±0.2°, 11.97±0.2°, 14.31±0.2°, 14.75±0.2°, 16.49±0.2° and 24.42±0.2°.

[0069] In some embodiments of the present application, the crystals of the compound of formula (II) above, in the XRPD spectrum using Cu Kα radiation, the peak positions and relative intensities of the diffraction peaks are shown in Table 4 below:

[0070] Table 4

[0071] serial number 2θ angle (±0.2°) Relative Strength serial number 2θ angle (±0.2°) Relative Strength 1 4.84 88.1 15 19.90 18.8 2 7.42 4.7 16 20.57 10.7 3 9.58 76.3 17 21.21 4.2 4 10.26 5.6 18 22.50 9.3 5 10.93 26.6 19 22.97 5.2 6 11.97 90.1 20 23.57 5.1 7 12.72 13.6 21 24.42 39.4 8 13.93 15.1 22 24.39 6.2 9 14.31 24.4 23 25.70 10.5 10 14.75 100 24 27.31 7.7 11 16.49 20.9 25 27.70 4.5 12 17.91 17.2 26 29.42 8.8 13 18.44 8.7 27 32.23 4.8 14 19.25 10.5

[0072] In some embodiments of the present application, the crystal of the compound of formula (II) has an XRPD pattern using Cu Kα radiation as shown in Fig.10 shown.

[0073] On the other hand, the present application also provides a p-toluenesulfonate salt of a compound of formula (I); in some embodiments, the p-toluenesulfonate salt of the compound of formula (I) is selected from a compound of formula (III),

[0074]

[0075] On the other hand, the present application also provides a crystal of the compound of formula (III), whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 6.53±0.2°, 12.48±0.2° and 13.11±0.2°.

[0076] In some embodiments of the present application, the crystals of the compound of the above formula (III) have an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.53±0.2°, 10.87±0.2°, 12.48±0.2°, 13.11±0.2°, 16.58±0.2° and 25.03±0.2°.

[0077] In some embodiments of the present application, the crystals of the compound of the above formula (III) have an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.53±0.2°, 10.87±0.2°, 12.48±0.2°, 13.11±0.2°, 14.04±0.2°, 16.58±0.2°, 25.03±0.2°, 25.56±0.2° and 26.66±0.2°.

[0078] In some embodiments of the present application, the crystals of the compound of the above formula (III) have an X-ray powder diffraction pattern using Cu Kα radiation, comprising 3, 4, 5, 6, 7, 8 or 9 diffraction peaks selected from the following 2θ angles: 6.53±0.2°, 10.87±0.2°, 12.48±0.2°, 13.11±0.2°, 14.04±0.2°, 16.58±0.2°, 25.03±0.2°, 25.56±0.2° and 26.66±0.2°.

[0079] In some embodiments of the present application, the crystals of the compound of the above formula (III) have an X-ray powder diffraction pattern using Cu Kα radiation, comprising 3, 4, 5 or 6 diffraction peaks selected from the following 2θ angles: 6.53±0.2°, 10.87±0.2°, 12.48±0.2°, 13.11±0.2°, 16.58±0.2° and 25.03±0.2°.

[0080] In some embodiments of the present application, the crystals of the compound of formula (III) above, in the XRPD spectrum using Cu Kα radiation, the peak positions and relative intensities of the diffraction peaks are shown in Table 5 below:

[0081] Table 5

[0082] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 6.53 100 10 20.49 4.5 2 9.69 4.7 11 21.44 5.1 3 10.87 11.1 12 22.01 7.2 4 12.48 28.7 13 24.13 6.6 5 13.11 57.4 14 25.03 11.2 6 14.04 9.1 15 25.56 8.3 7 15.91 4.8 16 26.66 8.2 8 16.58 15.9 17 27.67 4.9 9 18.67 7.8 18 28.25 4.8

[0083] In some embodiments of the present application, the crystal of the compound of formula (III) has an XRPD pattern using Cu Kα radiation as shown in Fig.11 shown.

[0084] In some embodiments of the present application, the thermogravimetric analysis curve of the crystal of the compound of formula (III) above shows a weight loss of 1.785% at 148.23±2°C; and a weight loss of 5.790% between 148.23±2°C and 240.99±2°C.

[0085] In some embodiments of the present application, the crystal of the compound of formula (III) has a TGA spectrum as shown in Fig.12 shown.

[0086] On the other hand, the present application also provides a mesylate salt of a compound of formula (I); in some embodiments, the mesylate salt of the compound of formula (I) is selected from a compound of formula (IV),

[0087]

[0088] The present application also provides a crystal of the compound of formula (IV), whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 11.22±0.2°, 18.85±0.2°, 22.62±0.2° and 24.45±0.2°.

[0089] In some embodiments of the present application, the crystals of the compound of the above formula (IV) have diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 11.22±0.2°, 12.58±0.2°, 16.43±0.2°, 17.90±0.2°, 18.85±0.2°, 22.62±0.2°, 24.45±0.2° and 25.87±0.2°.

[0090] In some embodiments of the present application, the crystals of the compound of the above formula (IV) have diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 11.22±0.2°, 12.58±0.2°, 16.43±0.2°, 17.08±0.2°, 17.90±0.2°, 18.85±0.2°, 19.23±0.2°, 19.72±0.2°, 22.62±0.2°, 23.27±0.2°, 24.45±0.2° and 25.87±0.2°.

[0091] In some embodiments of the present application, the crystal of the compound of formula (IV) has a diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 11.22±0.2°, 12.58±0.2°, 13.88±0.2°, 15.49±0.2°, 16.04±0.2°, 16.43±0.2°, 17.08±0.2°, 17.90±0.2°, 18.54±0.2°, 18.85±0. 2°, 19.23±0.2°, 19.72±0.2°, 20.02±0.2°, 20.51±0.2°, 22.62±0.2°, 23.27±0.2°, 24.45±0.2°, 24.83±0.2°, 25.42±0.2°, 25.87±0.2°, 26.09±0.2° and 29.53±0.2°.

[0092] In some embodiments of the present application, the crystal of the compound of formula (IV) has an X-ray powder diffraction pattern using Cu Kα radiation, comprising 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following 2θ angles: 11.22±0.2°, 12.58±0.2°, 13.88±0.2°, 15.49±0.2°, 16.04±0.2°, 16.43±0.2°, 17.08±0.2°, 17.90±0.2°, 18.54±0.2°, 19.70±0.2°, 20.80±0.2°, 21.30±0.2°, 22.70±0.2°, 23.60±0.2°, 24.90±0.2°, 25.80±0.2°, 26.70±0.2°, 27.60±0.2°, 28.60±0.2°, 29. ±0.2°, 18.85±0.2°, 19.23±0.2°, 19.72±0.2°, 20.02±0.2°, 20.51±0.2°, 22.62±0.2°, 23.27±0.2°, 24.45±0.2°, 24.83±0.2°, 25.42±0.2°, 25.87±0.2°, 26.09±0.2° and 29.53±0.2°.

[0093] In some embodiments of the present application, the crystals of the compound of formula (IV) above have an X-ray powder diffraction pattern using Cu Kα radiation, comprising 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks selected from the following 2θ angles: 11.22±0.2°, 12.58±0.2°, 16.43±0.2°, 17.08±0.2°, 17.90±0.2°, 18.85±0.2°, 19.23±0.2°, 19.72±0.2°, 22.62±0.2°, 23.27±0.2°, 24.45±0.2° and 25.87±0.2°.

[0094] In some embodiments of the present application, the crystals of the compound of the above formula (IV) have an X-ray powder diffraction pattern using Cu Kα radiation, comprising 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 11.22±0.2°, 12.58±0.2°, 16.43±0.2°, 17.90±0.2°, 18.85±0.2°, 22.62±0.2°, 24.45±0.2° and 25.87±0.2°.

[0095] In some embodiments of the present application, the crystals of the compound of formula (IV) above, in the XRPD spectrum using Cu Kα radiation, the peak positions and relative intensities of the diffraction peaks are shown in Table 6 below:

[0096] Table 6

[0097] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 8.71 9.3 19 23.27 19.0 2 11.22 91.6 20 24.06 8.2 3 12.58 49.1 21 24.45 75.1 4 13.88 11.5 22 24.83 18.1 5 15.49 11.4 23 25.10 11.4 6 16.04 23.7 24 25.42 16.9 7 16.43 51.1 25 25.87 28.4 8 17.08 25.9 26 26.09 18.2 9 17.90 32.5 27 26.76 8.5 10 18.54 31.5 28 27.22 7.8 11 18.85 100.0 29 27.93 10.1 12 19.23 28.1 30 28.87 9.6 13 19.72 27.3 31 29.17 9.7 14 20.02 13.5 32 29.53 13.8 15 20.51 14.0 33 31.14 7.1 16 20.86 10.2 34 32.46 8.3 17 21.26 10.1 35 33.63 9.6 18 22.62 79.6 36 36.29 6.4

[0098] In some embodiments of the present application, the crystal of the compound of formula (IV) has an XRPD pattern using Cu Kα radiation as shown in Fig.13 shown.

[0099] In some embodiments of the present application, the crystals of the compound of formula (IV) have a differential scanning calorimetry curve with an endothermic peak at 191.35±2°C and / or an exothermic peak at 222.21±2°C.

[0100] In some embodiments of the present application, the crystal of the compound of formula (IV) has a differential scanning calorimetry spectrum as shown in Fig.14 shown.

[0101] In some embodiments of the present application, the thermogravimetric analysis curve of the crystal of the compound of formula (IV) above shows a weight loss of 5.427% at 168.57±2°C; a weight loss of 4.678% at 168.57±2°C to 192.84±2°C; and a weight loss of 4.621% at 192.84±2°C to 238.22±2°C.

[0102] In some embodiments of the present application, the crystals of the compound of formula (IV) have a thermogravimetric analysis spectrum such as Fig.15 shown.

[0103] On the other hand, the present application also provides a maleate salt of a compound of formula (I); in some embodiments, the maleate salt of the compound of formula (I) is selected from a compound of formula (V),

[0104]

[0105] On the other hand, the present application also provides a crystal of the compound of formula (V), whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.83±0.2°, 6.62±0.2°, 9.50±0.2° and 10.98±0.2°.

[0106] In some embodiments of the present application, the crystals of the compound of the above formula (V) have diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 5.83±0.2°, 6.62±0.2°, 9.50±0.2°, 10.98±0.2°, 17.16±0.2°, 19.05±0.2°, 24.71±0.2° and 25.16±0.2°.

[0107] In some embodiments of the present application, the crystals of the compound of the above formula (V) have an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 5.83±0.2°, 6.62±0.2°, 9.50±0.2°, 10.98±0.2°, 11.59±0.2°, 13.23±0.2°, 16.27±0.2°, 17.16±0.2°, 19.05±0.2°, 21.63±0.2°, 24.71±0.2° and 25.16±0.2°.

[0108] In some embodiments of the present application, the crystals of the compound of the above formula (V) have an X-ray powder diffraction pattern using Cu Kα radiation, comprising 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks selected from the following 2θ angles: 5.83±0.2°, 6.62±0.2°, 9.50±0.2°, 10.98±0.2°, 11.59±0.2°, 13.23±0.2°, 16.27±0.2°, 17.16±0.2°, 19.05±0.2°, 21.63±0.2°, 24.71±0.2° and 25.16±0.2°.

[0109] In some embodiments of the present application, the crystals of the compound of the above formula (V) have an X-ray powder diffraction pattern using Cu Kα radiation, comprising 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 5.83±0.2°, 6.62±0.2°, 9.50±0.2°, 10.98±0.2°, 17.16±0.2°, 19.05±0.2°, 24.71±0.2° and 25.16±0.2°.

[0110] In some embodiments of the present application, the crystals of the compound of formula (V) have a XRPD spectrum using Cu Kα radiation, and the peak positions and relative intensities of the diffraction peaks are shown in Table 7 below:

[0111] Table 7

[0112] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 5.83 12.3 10 19.72 2.8 2 6.62 100.0 11 21.00 3.3 3 9.50 11.7 12 21.63 4.1 4 10.98 14.7 13 24.71 8.9 5 11.59 3.8 14 25.16 8.2 6 13.23 4.3 15 26.39 3.6 7 16.27 4.1 16 28.75 2.3 8 17.16 10.2 17 30.55 2.0 9 19.05 9.5 18 33.27 3.2

[0113] In some embodiments of the present application, the crystal of the compound of formula (V) has an XRPD pattern using Cu Kα radiation as shown in Fig.16 shown.

[0114] In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal of the compound of formula (V) above shows a weight loss of 1.928% at 155.26±2°C.

[0115] In some embodiments of the present application, the crystals of the compound of formula (V) have a thermogravimetric analysis spectrum such as Fig.17 shown.

[0116] On the other hand, the present application provides a method for preparing a salt of the compound of formula (I), comprising mixing the compound of formula (I) with tetrahydrofuran, then adding an aqueous solution of an acid (or base), and separating to obtain the corresponding salt.

[0117] On the other hand, the present application provides a crystalline composition comprising the above-mentioned crystals, wherein the crystals account for more than 50% of the weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.

[0118] On the other hand, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0119]

[0120] The compound of formula (I) is prepared by the following method:

[0121] (1) Compound 1-2a is reacted to obtain compound BB-4;

[0122] (2) Compound BB-4 is reacted with 5-hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid to prepare a compound of formula (I).

[0123]

[0124] On the other hand, the present application provides a method for preparing a compound of formula (I), which comprises the above steps (1) and (2).

[0125] In another aspect, the present application provides a method for preparing compound 1-2a, comprising the following steps: reacting compound BB-1 with compound 1-1a to obtain compound 1-2a

[0126]

[0127] In another aspect, the present application provides compound 1-2a or a pharmaceutically acceptable salt thereof

[0128]

[0129] In another aspect, the present application provides a method for preparing compound BB-4, comprising the following steps:

[0130] (a) Compound BB-1 reacts with compound 1-1a to prepare compound 1-2a;

[0131] (b) Compound 1-2a is reacted to obtain compound BB-4;

[0132]

[0133] In another aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0134]

[0135] The compound of formula (I) is prepared by the following method:

[0136] (1') Compound BB-1 reacts with compound 1-1a to prepare compound 1-2a;

[0137] (2') Compound 1-2a is reacted to obtain compound BB-4;

[0138] (3') Compound BB-4 is reacted with 5-hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid to prepare a compound of formula (I);

[0139]

[0140]

[0141] In another aspect, the present application provides a method for preparing the compound of formula (I), which comprises the above steps (1'), (2') and (3').

[0142] In some embodiments, the preparation step of compound 1-2a is carried out in the presence of a solvent; in some embodiments, the solvent is selected from acetonitrile and water.

[0143] In some embodiments, the preparation step of compound 1-2a is carried out in the presence of a base; in some embodiments, the base is selected from lithium carbonate.

[0144] In some embodiments, compound 1-2a is prepared by the following method: compound BB-1 and compound 1-1a are dissolved in acetonitrile, and then lithium carbonate and water are added to react.

[0145] In some embodiments, the reaction temperature of the preparation step of compound 1-2a is 100°C.

[0146] In some embodiments, the reaction time of the preparation step of compound 1-2a is 70 hours.

[0147] In some embodiments, in the preparation step of compound 1-2a, the molar ratio of compound BB-1 to compound 1-1a is 1:6.

[0148] In some embodiments, the preparation step of compound BB-4 is carried out in the presence of hydrogen chloride.

[0149] In some embodiments, the preparation step of compound BB-4 is carried out in the presence of a solvent; in some embodiments, the solvent is selected from methanol.

[0150] In some embodiments, compound BB-4 is prepared by the following method: Compound 1-2a is reacted in a methanol solution of hydrogen chloride to obtain compound BB-4.

[0151] In some embodiments, the reaction temperature of the preparation step of compound BB-4 is 60°C.

[0152] In some embodiments, the reaction time of the preparation step of compound BB-4 is 2 hours.

[0153] In some embodiments, the preparation step of compound BB-4 further comprises the step of treating with petroleum ether and ethyl acetate after the reaction is completed.

[0154] In some embodiments, the step of preparing the compound of formula (I) via compound BB-4 is carried out in the presence of a solvent; in some embodiments, the solvent is selected from dichloromethane.

[0155] In some embodiments, the step of preparing the compound of formula (I) via compound BB-4 is carried out in the presence of a base; in some embodiments, the base is selected from triethylamine.

[0156] In some embodiments, the step of preparing the compound of formula (I) via compound BB-4 is carried out in the presence of a condensing agent; in some embodiments, the condensing agent is selected from HATU.

[0157] In some embodiments, in the step of preparing the compound of formula (I) through compound BB-4, the molar ratio of 5-hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid to compound BB-4 is 1:(1-1.2).

[0158] In some embodiments, the reaction temperature of the step of preparing the compound of formula (I) via compound BB-4 is 20°C.

[0159] In some embodiments, the reaction time of the step of preparing the compound of formula (I) via compound BB-4 is 16 hours.

[0160] In another aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0161]

[0162] The compound of formula (I) is prepared by the following method: Compound 1-4b is reacted to obtain a compound of formula (I)

[0163]

[0164] In another aspect, the present application provides a method for preparing a compound of formula (I), which comprises: reacting compound 1-4b to obtain a compound of formula (I).

[0165] In another aspect, the present application provides a method for preparing compound 1-4b, the method comprising: reacting compound BB-4 with compound 1-3b to obtain compound 1-4b

[0166]

[0167] In another aspect, the present application provides a method for preparing compound BB-4, the method comprising: reacting compound 1-1b to obtain compound BB-4

[0168]

[0169] In another aspect, the present application provides a method for preparing compound 1-1b, the method comprising: reacting compound BB-1 with compound a to obtain compound 1-1b

[0170]

[0171] wherein X is selected from halogen.

[0172] In some embodiments, X is selected from Cl or Br; In some embodiments, X is selected from Br.

[0173] In another aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0174]

[0175] The compound of formula (I) is prepared by the following method:

[0176] (i) Compound BB-4 reacts with compound 1-3b to prepare compound 1-4b;

[0177] (ii) Compound 1-4b is reacted to obtain a compound of formula (I).

[0178] In yet another aspect, the present application provides a method for preparing the compound of formula (I), which comprises step (i) and step (ii) as described above.

[0179] In another aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0180]

[0181] The compound of formula (I) is prepared by the following method:

[0182] (i') Compound 1-1b is reacted to obtain compound BB-4;

[0183] (ii') Compound BB-4 reacts with compound 1-3b to prepare compound 1-4b;

[0184] (iii') Compound 1-4b is reacted to obtain the compound of formula (I).

[0185] In yet another aspect, the present application provides a method for preparing the compound of formula (I), the method comprising step (i'), step (ii') and step (iii') as described above.

[0186] In another aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0187]

[0188] The compound of formula (I) is prepared by the following method:

[0189] (i") Compound BB-1 reacts with compound a to obtain compound 1-1b;

[0190] (ii") Compound 1-1b is reacted to obtain compound BB-4;

[0191] (iii”) Compound BB-4 reacts with compound 1-3b to prepare compound 1-4b;

[0192] (iv") Compound 1-4b is reacted to obtain a compound of formula (I);

[0193]

[0194] wherein X is selected from halogen.

[0195] In some embodiments, X is selected from Cl or Br; in some embodiments, X is selected from Br.

[0196] In yet another aspect, the present application provides a method for preparing a compound of formula (I), which comprises step (i"), step (ii"), step (iii") and step (iv") as described above.

[0197] In another aspect, the present application provides compound 1-1b or a pharmaceutically acceptable salt thereof

[0198]

[0199] In another aspect, the present application provides compound 1-4b or a pharmaceutically acceptable salt thereof

[0200]

[0201] In some embodiments, the preparation step of compound 1-1b is carried out in the presence of a solvent; in some embodiments, the solvent is selected from 2-butanone.

[0202] In some embodiments, the preparation step of compound 1-1b is carried out in the presence of a catalyst; in some embodiments, the catalyst is selected from potassium phosphate, such as anhydrous potassium phosphate.

[0203] In some embodiments, the preparation step of compound 1-1b is carried out in the presence of a co-solvent; in some embodiments, the co-solvent is selected from sodium iodide.

[0204] In some embodiments, the preparation of compound 1-1b is carried out in the presence of potassium phosphate and sodium iodide.

[0205] In some embodiments, in the preparation step of compound 1-1b, the molar ratio of compound BB-1 to compound a is 1:3.

[0206] In some embodiments, the reaction temperature of the preparation step of compound 1-1b is 90°C.

[0207] In some embodiments, the reaction time of the preparation step of compound 1-1b is 18 hours.

[0208] In some embodiments, the preparation step of compound BB-4 is carried out in the presence of a solvent; in some embodiments, the solvent is selected from tetrahydrofuran.

[0209] In some embodiments, the preparation step of compound BB-4 is performed in the presence of borane-dimethyl sulfide.

[0210] In some embodiments, the reaction temperature of the preparation step of compound BB-4 is 20-25°C.

[0211] In some embodiments, the reaction time of the preparation step of compound BB-4 is 18 hours.

[0212] In some embodiments, the preparation step of compound BB-4 comprises the following steps: adding compound 1-1b to a mixture of tetrahydrofuran and borane-dimethyl sulfide at 0° C., and then raising the temperature for reaction. In some embodiments, the temperature is raised to 20-25° C. for reaction.

[0213] In some embodiments, the preparation steps of compound BB-4 include the following steps: lowering the temperature (e.g., to 0°C) after a period of reaction (e.g., 18 hours); further, adding methanol after lowering the temperature; further, adjusting the pH value after adding methanol; further, concentrating the product after adjusting the pH value; further, purifying.

[0214] In some embodiments, in the step of adjusting the pH value after adding methanol, the pH value is adjusted to 2-3.

[0215] In some embodiments, in the step of adjusting the pH value after adding methanol, hydrochloric acid is used to adjust the pH value.

[0216] In some embodiments, in the preparation step of compound 1-4b, the molar ratio of compound BB-4 to compound 1-3b is 1:(1-1.5).

[0217] In some embodiments, the preparation step of compound 1-4b is carried out in the presence of a condensing agent; in some embodiments, the condensing agent is N,N-carbonyldiimidazole.

[0218] In some embodiments, the preparation of compound 1-4b comprises the following steps: compound 1-3b is first reacted with a condensing agent (eg, N,N-carbonyldiimidazole), and then reacted with compound BB-4 to obtain compound 1-4b.

[0219] In some embodiments, in the preparation step of compound 1-4b, the step of reacting compound 1-3b with an activating agent is carried out in the presence of a solvent; in some embodiments, the solvent is selected from dichloromethane.

[0220] In some embodiments, in the step of preparing compound 1-4b, the reaction temperature of the step of reacting compound 1-3b with an activating agent is 25°C.

[0221] In some embodiments, in the step of preparing compound 1-4b, the reaction time of the step of reacting compound 1-3b with an activating agent is 5 hours.

[0222] In some embodiments, in the preparation step of compound 1-4b, the step of reacting compound 1-3b with an activating agent and then reacting with compound BB-4 is carried out in the presence of a solvent; in some embodiments, the solvent is selected from DMF.

[0223] In some embodiments, in the preparation step of compound 1-4b, the reaction temperature of the step of reacting compound 1-3b with an activating agent and then reacting with compound BB-4 is 20-25°C.

[0224] In some embodiments, in the preparation step of compound 1-4b, the reaction time of the step of reacting compound 1-3b with an activating agent and then reacting with compound BB-4 is 18 hours.

[0225] In some embodiments, the steps of preparing compound 1-4b further include adding methanol for treatment after the reaction is completed.

[0226] In some embodiments, the step of preparing the compound of formula (I) via compound 1-4b is carried out in the presence of a solvent; in some embodiments, the solvent is selected from a mixed solvent of trifluoroacetic acid and acetic acid.

[0227] In some embodiments, the volume ratio of trifluoroacetic acid to acetic acid is 5:1.

[0228] In some embodiments, the reaction temperature of the step of preparing the compound of formula (I) via compound 1-4b is 90-100°C.

[0229] In some embodiments, the reaction time of the step of preparing the compound of formula (I) via compound 1-4b is 48 hours.

[0230] In some embodiments, the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a crystal, and the crystal is type A crystal of the compound of formula (I), type B crystal of the compound of formula (I) or type C crystal of the compound of formula (I).

[0231] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is sulfate, p-toluenesulfonate, methanesulfonate or maleate.

[0232] The compound BB-1 of the present application is prepared by the following method:

[0233]

[0234] On the other hand, the present application provides a method for preparing a crystal of a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising: preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof by any of the above-mentioned methods for preparing a compound of formula (I) or a salt thereof; and precipitating a compound of formula (I) or a pharmaceutically acceptable salt thereof from a solvent selected from the following: a mixed solvent of methanol, ethanol and water, acetonitrile, a mixed solvent of tetrahydrofuran and water. In some specific embodiments, the present application provides a method for preparing a crystal of a pharmaceutically acceptable salt of a compound of formula (I), comprising precipitating a salt of the compound of formula (I) from a mixed solvent of tetrahydrofuran and water. In other specific embodiments, the present application provides a method for preparing a crystal of a pharmaceutically acceptable salt of a compound of formula (I), comprising: mixing a compound of formula (I) with tetrahydrofuran, adding an aqueous solution of an acid (and or a base) thereto for reaction, and precipitating a salt of the compound of formula (I) from a mixed solvent of tetrahydrofuran and water in the form of crystals.

[0235] In another aspect, the present application provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound of formula (I) described in the present application or a pharmaceutically acceptable salt thereof, the above-mentioned crystal or a crystalline composition thereof. The pharmaceutical composition of the present application may contain or not contain a pharmaceutically acceptable excipient. In addition, the pharmaceutical composition of the present application may further include one or more other therapeutic agents.

[0236] On the other hand, the present application also provides a method for preventing or treating PDE3 and / or PDE4-related disorders in mammals, comprising administering a therapeutically effective amount of the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt thereof, a crystal thereof, a crystalline composition thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such prevention or treatment.

[0237] On the other hand, the present application also provides the use of the above-mentioned compound of formula (I) or its pharmaceutically acceptable salt, its crystal, its crystalline composition, or its pharmaceutical composition in the preparation of a drug for preventing or treating diseases related to PDE3 and / or PDE4.

[0238] On the other hand, the present application also provides the use of the compound of formula (I) or its pharmaceutically acceptable salt, its crystal, its crystalline composition, or its pharmaceutical composition for preventing or treating disorders associated with PDE3 and / or PDE4.

[0239] On the other hand, the present application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, a crystal thereof, a crystalline composition thereof, or a pharmaceutical composition thereof for preventing or treating a disorder associated with PDE3 and / or PDE4.

[0240] In some embodiments of the present application, the disorder associated with PDE3 and / or PDE4 is selected from asthma or chronic obstructive pulmonary disease (COPD).

[0241] Technical Effects

[0242] The compound of formula (I) of the present application has significant dual PDE3 and PDE4 inhibitory effects, and has significant inhibitory effects on TNF-α in human peripheral blood mononuclear cells (hPBMC), and also shows excellent anti-inflammatory effects in LPS (lipopolysaccharide)-induced rat acute lung injury model; has high in vivo plasma clearance rate, low oral plasma systemic exposure and low oral bioavailability, and good safety of local administration; has low inhibitory effects on five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450, and has no risk of drug-drug interaction; reduces the total number of BALF white blood cells, has significant anti-inflammatory effects, and has a low effective dose; and reduces the airway resistance index Penh.

[0243] The crystals of the compound of formula (I) of the present application and the crystals of the pharmaceutically acceptable salts thereof have advantages in terms of drug activity, pharmacokinetics, bioavailability, hygroscopicity, melting point, stability, solubility, purity, and ease of preparation, so as to meet the requirements of drug production, storage, transportation, and formulation.

[0244] In the preparation method of the compound of formula (I) of the present application, method 2 can obtain an aminoethyl substituted compound in one step, and the reaction system is clean, and no further reduction is required after the introduction of amide or cyano group in the traditional method. Method 3 uses non-genotoxic bromoacetamide to replace the genotoxic reagent bromoacetonitrile, which reduces the safety risk for drug synthesis development.

[0245] Definition and Description

[0246] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0247] It should be noted that in the powder X-ray diffraction spectrum, the position of the peak or the relative intensity of the peak may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, there may be an error in the position of the peak, and the measurement error of the 2θ value may be ±0.2°. Therefore, when determining each crystal form, this error should be taken into account, and the error is also within the scope of this application.

[0248] It should be noted that for the same crystal form, the position of the endothermic peak of DSC may be different due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, the position of the endothermic peak may have an error, which may be ±5°C or ±3°C. Therefore, when determining each crystal form, this error should be taken into account, and the error is also within the scope of this application.

[0249] The word "comprise" or "comprises" and its English variations such as comprises or comprising or equivalents should be understood as an open, non-exclusive meaning, i.e., "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0250] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0251] The term "pharmaceutically acceptable salt" includes, as pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like.

[0252] The term "pharmaceutically acceptable excipient" refers to an inert substance that is administered together with an active ingredient and is conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is acceptable for humans or animals (e.g., livestock) and is approved by the State Food and Drug Administration. Non-limiting examples of the excipient include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0253] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0254] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0255] Typical routes of administration of the crystals described herein or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0256] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0257] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0258] The therapeutic dose of the compounds of the present application may be determined, for example, based on the specific purpose of the treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. The term "treatment" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0259] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0260] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0261] The term "prevention" means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0262] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0263] The therapeutically effective amount of the crystals described herein is from about 0.0001 to 20 mg / Kg body weight / day, such as from 0.001 to 10 mg / Kg body weight / day.

[0264] The dosage frequency of the crystallization described herein is determined by the needs of the individual patient, for example, once or twice a day, or more times a day. Administration can be intermittent, for example, wherein during a period of several days, the patient receives a daily dose of the crystal form, and then during a period of several days or more days, the patient does not receive a daily dose of the crystal form.

[0265] Herein, singular terms include plural referents and vice versa unless the context clearly dictates otherwise.

[0266] Herein, unless otherwise indicated, each parameter value (including 2θ values, reaction conditions) is deemed to be modified by the term "about" to reflect the measurement error that exists for each value, for example, there is an error of ±5% relative to a given value.

[0267] For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

[0268] The present application will be described in detail below through examples, which do not imply any limitation to the present application.

[0269] The intermediate compounds of the present application can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0270] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0271] The present application will be described in detail below through examples, which do not imply any limitation to the present application.

[0272] All solvents used in this application were commercially available and used without further purification.

[0273] The solvents used in the present application can be obtained from commercial sources. The present application uses the following abbreviations: DMSO represents dimethyl sulfoxide; TsOH represents p-toluenesulfonic acid; MsOH represents methanesulfonic acid.

[0274] X-ray powder diffractometer (XRPD)

[0275] Instrument model: Bruker D8 advance X-ray diffractometer; Light tube: Cu, kα,

[0276] Differential Scanning Calorimeter (DSC)

[0277] Instrument model: TAQ2000 differential scanning calorimeter

[0278] Thermogravimetric analysis (TGA)

[0279] Instrument model: TAQ5000IR thermogravimetric analyzer BRIEF DESCRIPTION OF THE DRAWINGS

[0280] Figure 1 is the XRPD spectrum of type A crystal of the compound of formula (Ⅰ);

[0281] Figure 2 is the DSC spectrum of type A crystal of the compound of formula (Ⅰ);

[0282] Figure 3 is the TGA spectrum of type A crystal of the compound of formula (Ⅰ);

[0283] Figure 4 XRPD spectrum of type B crystal of the compound of formula (Ⅰ);

[0284] Figure 5 is the DSC spectrum of type B crystal of the compound of formula (I);

[0285] Figure 6 is the TGA spectrum of type B crystal of the compound of formula (I);

[0286] Figure 7 is the XRPD spectrum of type C crystal of the compound of formula (Ⅰ);

[0287] Figure 8 is the DSC spectrum of type C crystal of the compound of formula (I);

[0288] Fig. 9 is the TGA spectrum of type C crystal of the compound of formula (Ⅰ);

[0289] Fig.10 is the XRPD pattern of the crystal of the compound of formula (II);

[0290] Fig.11 is the XRPD pattern of the crystal of the compound of formula (III);

[0291] Fig.12 is the TGA spectrum of the crystal of the compound of formula (III);

[0292] Fig.13 is the XRPD pattern of the crystal of the compound of formula (IV);

[0293] Fig.14 is the DSC spectrum of the crystal of the compound of formula (IV);

[0294] Fig.15 is the TGA spectrum of the crystal of the compound of formula (IV);

[0295] Fig.16 is the XRPD pattern of the crystal of the compound of formula (V);

[0296] Fig.17 is a TGA spectrum of the crystal of the compound of formula (V);

[0297] Fig.18 It is a DVS diagram of type B crystal of the compound of formula (Ⅰ);

[0298] Fig.19 is the total number of leukocytes in BALF;

[0299] Fig. 20It is a lung function test (airway resistance index Penh) under methacholine MCh induction. DETAILED DESCRIPTION

[0300] In order to better understand the content of this application, further description is given below in conjunction with specific embodiments, but the specific implementation methods are not limitations on the content of this application.

[0301] Synthesis of intermediate BB-1

[0302]

[0303] Step 1: Synthesis of compound BB-1-2

[0304] Under nitrogen atmosphere, a mixture of compound BB-1-1 (21.10 g) and ethyl cyanoacetate (11.00 g, 10.38 mL) was stirred at 100 ° C for 16 hours. After the reaction was completed, the mixture was cooled to 70 ° C, and ethanol (30 mL) was slowly added dropwise, and a large amount of solid precipitated. Filter, and dry the filter cake under reduced pressure to obtain the product BB-1-2.

[0305] 1 H NMR (400MHz, DMSO-d6) δ = 8.26 (t, J = 5.2Hz, 1H), 6.86 (d, J = 8.0Hz, 1H), 6.79 (br s,1H),6.71(d,8.0Hz,1H),4.00(q,J=6.8Hz,2H),3.72(s,3H),3.59(s,2H ),3.31-3.23(m,2H),2.64(t,J=7.2Hz,2H),1.32(t,J=6.8Hz,3H).MS-ESI m / z:263.1[M+H] + .

[0306] Step 2: Synthesis of compound BB-1-3

[0307] Under nitrogen atmosphere, phosphorus oxychloride (379.50 g, 230.00 mL) was heated to 85 ° C, and compound BB-1-2 (26.00 g) was added in batches. The reaction mixture was stirred at 85 ° C for 2 hours. After the reaction was completed, most of the phosphorus oxychloride was removed by distillation under reduced pressure. Dichloromethane (200 mL) was added to the residue and washed with water (100 mL × 2). After the organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration and concentrated under reduced pressure. The crude product was purified by slurrying with ethyl acetate (20 mL) to obtain compound BB-1-3.

[0308] 1H NMR (400MHz, CD3OD) δ = 7.16 (s, 1H), 6.83 (s, 1H), 4.62 (s, 1H), 4.12 (q, J = 6.8Hz, 2H), 3 .86(s,3H),3.35(d,J=6.4Hz,2H),2.84(t,J=6.4Hz,2H),1.44(t,J=6.8Hz,3H).MS-ESI m / z:245.1[M+H] + .

[0309] Step 3: Synthesis of compound BB-1-4

[0310] At 0°C, compound BB-1-3 (1.00 g) was added in batches to 98% concentrated sulfuric acid (12.88 g, 128.69 mmol, 7.00 mL). The reaction mixture was stirred at 27°C for 3 hours. After the reaction was completed, the mixture was added to cold water (15 mL), and then sodium hydroxide aqueous solution (4 mol / L, 32 mL) was added dropwise to adjust the pH value to neutral, and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain compound BB-1-4.

[0311] MS-ESI m / z:263.1[M+H] + .

[0312] Step 4: Synthesis of compound BB-1-5

[0313] At 0°C, sodium (2.42 g) was added to ethanol (80 mL) in batches. After the mixture was stirred at 28°C for 0.5 hours, compound BB-1-4 (6.90 g) was added to the solution in batches and stirred at 80°C for 0.5 hours. Diethyl carbonate (9.32 g, 9.51 mL) was then added all at once, and the mixture was stirred at 80°C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, ice water (30 mL) was slowly added, and then the pH value was adjusted to neutral with dilute hydrochloric acid (2 mol / L, 53 mL). A large amount of solid precipitated and was filtered. The filter cake was purified by slurrying with ethanol (10 mL) to obtain compound BB-1-5.

[0314] 1 H NMR (400MHz, DMSO-d6) δ = 11.22 (br s, 1H), 7.35 (s, 1H), 6.95 (s, 1H), 6.22 (s, 1H), 4.09 (q, J = 6.8Hz, 2H), 3.90 (br s, 2H), 3.83 (s, 3H), 2.89 (br s,2H),1.35(t,J=6.8Hz,3H).MS-ESI m / z:289.1[M+H]+ .

[0315] Step 5: Synthesis of compound BB-1-6

[0316] Compound BB-1-5 (5.00 g) was dissolved in phosphorus oxychloride (30 mL) at room temperature. The reaction mixture was stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was completed, most of the solvent was removed by distillation under reduced pressure. Water (100 mL) was added and extracted with dichloromethane (150 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain compound BB-1-6. MS-ESI m / z: 306.9 [M + H] + .

[0317] Step 6: Synthesis of compound BB-1

[0318] Compound BB-1-6 (925.67 mg) was dissolved in isopropanol (8 mL) at room temperature, and 2,4,6-trimethylaniline (2.10 g) was added. The reaction mixture was stirred at 90 ° C for 15 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by slurrying with ethanol (6 mL) to obtain compound BB-1.

[0319] 1 H NMR(400MHz,DMSO-d6)δ=8.85(br s,1H),7.27(s,1H),6.97(s,1H),6.90(s,2H),6.45(s,1H),4.10(q,J=6.8Hz,2H),3.90(t,J=6.0H z,2H),3.86(s,3H),2.87(t,J=6.0Hz,2H),2.45(s,3H),2.11(s,6H),1.37(t,J=6.8Hz,3H).MS-ESI m / z:406.2[M+H] + .

[0320] Synthesis of compound BB-4

[0321]

[0322] Step 1: Synthesis of compound BB-4-1

[0323] Compound BB-1 (1.00 g) was dissolved in 2-butanone (35 mL) at room temperature, and 2-(2-bromoethyl)isoindoline-1,3-dione (3.76 g), potassium carbonate (3.07 g) and sodium iodide (2.22 g) were added in sequence. The reaction mixture was stirred at 85 ° C for 72 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated to remove most of the organic solvent, and water (30 mL) and ethyl acetate (25 mL × 3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1 to 3:1) to obtain compound BB-4-1.

[0324] MS-ESI m / z:579.3[M+H] + .

[0325] Step 2: Synthesis of compound BB-4

[0326] Compound BB-4-1 (500.00 mg) was dissolved in chloroform (3 mL) and ethanol (3 mL) at room temperature, and hydrazine hydrate (152.67 mg, 85% purity) was added. The mixture was stirred at 28 ° C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated to remove most of the organic solvent, and water (15 mL) and dichloromethane (15 mL × 3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain compound BB-4.

[0327] 1 H NMR (400MHz, DMSO-d6) δ = 6.95 (s, 1H), 6.85 (br s,2H),6.66(s,1H),5.31(s,1H),4.14(t,J=6.8Hz,2H),4.05(q,J=6.8Hz,2H) ,3.91(t,J=6.4Hz,2H),3.62(s,3H),2.90-2.86(m,4H),2.22(s,3H),1.95(br s,6H),1.33(t,J=6.8Hz,3H).MS-ESI m / z:449.2[M+H] + .

[0328] Example 1: Preparation of the compound of formula (I)

[0329] Method 1

[0330]

[0331] 5-Hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid (18.50 mg) was dissolved in DCM (1 mL) at 20°C, HATU (8.80 mg) and triethylamine (57.40 μL) were added thereto, and the mixture was stirred for 2 hours, followed by the addition of compound BB-4 (50 mg), and the mixture was stirred for 16 hours at the same temperature. The mixture was diluted to 10 mL with DCM, washed with water (30 mL*3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was separated and purified by prep-HPLC to obtain the target compound of formula (I) as a yellow solid.

[0332] 1 H NMR (400MHz, CD3OD) δ = 6.94 (s, 2H), 6.87 (s, 1H), 6.77 (s, 1H), 5.52 (s, 1H), 4.48 (t, J = 6.0Hz, 2H), 4.15 (s, 3H), 4.12-4.08 (m, 2H), 4 .01(t,J=6.0Hz,2H),3.87(t,J=6.0Hz,2H),3.69(s,3H),2.94(t,J=6.0Hz,2H),2.29(s,3H),2.06(s,6H),1.41(t,J=6.8Hz,3H).MS m / z[M+H] + 574.1.

[0333] Method 2

[0334]

[0335] Step 1: Preparation of compound 1-1a

[0336] N-Boc-ethanolamine (50g, 48.08mL) and p-toluenesulfonyl chloride (70.96g) were dissolved in methyl tert-butyl ether (500mL), potassium hydroxide (52.21g) was added thereto, and the temperature was raised to 80°C and refluxed for 4 hours. The mixture was cooled to room temperature, poured into an ice-water mixture (1000mL), and the organic phase was separated. The aqueous phase was extracted with methyl tert-butyl ether (100mL*2). The organic phases were combined, washed with cold water (1000mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain 28.5g of yellow oily liquid crude product 1-1a, which can be directly used in the next step without purification.

[0337] 1 H NMR (400MHz, CHLOROFORM-d) δ (ppm) 2.15 (s, 4H), 1.47 (s, 9H).

[0338] Step 2: Preparation of compound 1-2a

[0339] Compound BB-1 (2g) and compound 1-1a (4.24g) were dissolved in acetonitrile (17mL), lithium carbonate (2.19g) and water (3mL) were added thereto, and the temperature was raised to 100°C and stirred for 70 hours. The mixture was cooled and allowed to stand, and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to remove the solvent, and then mixed with 50mL of water, extracted with ethyl acetate (20mL*3), and the organic phases were combined, washed with 0.5M sodium hydroxide solution (100mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain 1.08g of the target compound 1-2a as a light yellow solid.

[0340] MS-ESI(m / z):549.2[M+1] +

[0341] 1 H NMR (400MHz, METHANOL-d4) δ (ppm) 6.91 (s, 2H), 6.85 (s, 1H), 6.75 (s, 1H), 5.49 (s, 1H), 4.36 (t, J = 5.9Hz, 2H), 4.09 (q, J = 7.0H z, 2H), 4.00 (t, J = 6.1Hz, 2H), 3.68 (s, 3H), 3.56-3.48 (m, 2H), 2.91 (t, J = 6.3Hz, 2H), 2.27 (s, 3H), 2.06 (s, 6H), 1.39 (s, 12H).

[0342] Step 3: Preparation of compound BB-4

[0343] Compound 1-2a (1 g) and 4M hydrogen chloride-methanol solution (20 mL) were mixed evenly and heated to 60°C and stirred for 2 hours. The mixture was concentrated under reduced pressure and the solvent was evaporated to obtain a light yellow oily liquid crude product. 20 mL of petroleum ether and 5 mL of ethyl acetate were added to the crude product, stirred for 30 minutes, filtered, and the solid was collected and dried to obtain a light yellow solid target compound BB-4 (810 mg, yield 91.63%).

[0344] 1 H NMR(400MHz,METHANOL-d4)δ(ppm)7.16(s,2H),6.98(s,1H),6.80(s,1H),5.68(s,1H),4.72(br s,2H),4.22(br s,2H),4.16(q,J=7.0Hz,2H),3.69(s,3H),3.48(br s,2H),3.08(br s,2H),2.37(s,3H),2.30(s,6H),1.43(t,J=7.0Hz,3H).

[0345] Step 4: Preparation of compound (I)

[0346] 5-Hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid (18.50 mg) was dissolved in DCM (1 mL) at 20°C, HATU (8.80 mg) and triethylamine (57.40 μL) were added thereto, and the mixture was stirred for 2 hours, followed by the addition of compound BB-4 (50 mg), and the mixture was stirred for 16 hours at the same temperature. The mixture was diluted to 10 mL with DCM, washed with water (30 mL*3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was separated and purified by prep-HPLC to obtain the target compound of formula (I) (22 mg, yield 37.2%) as a yellow solid.

[0347] MS-ESI(m / z):574.5[M+1] +

[0348] 1 H NMR(400MHz,METHANOL-d4)δ(ppm)6.94(s,2H),6.87(s,1H),6.75(s,1H),5.51(s,1H),4.47(br t,J=6.0Hz,2H),4.14(s,3H),4.10(q,J=7.0Hz,2H),4.01(br t,J=5.9Hz,2H),3.85(br t,J=5.9Hz,2H),3.68(s,3H),2.92(br t,J=6.0Hz,2H),2.29(s,3H),2.05(s,6H),1.41(t,J=6.9Hz,3H).

[0349] Method 3

[0350]

[0351] Step 1: Preparation of compound 1-1b

[0352] 2-Butanone (12L) was added to a 50L jacketed reactor at 20°C. Compound BB-1 (615g) and 2-bromoacetamide (612.4g) were added under stirring. Anhydrous potassium phosphate (1.57kg) and sodium iodide (665.4g) were then added to the system. The reaction mixture was heated to 90°C and stirred for 18 hours under nitrogen protection. After the reaction solution was cooled to room temperature, water (12L) was added thereto. After stirring for 1 hour, the solid obtained was filtered and dried in vacuo to obtain the target compound 1-1b (575g, yield 81.96%) as a yellow solid.

[0353] MS-ESI(m / z):463.23[M+1] +

[0354] 1 H NMR (400MHz, DMSO-d6) δ = 7.49 (br s, 1H), 7.06 (br s,1H),6.95(s,1H),6.82(s,2H),6.69(s,1H),5.33(s,1H),4.66(s,2H),4.07(q,J=6.9Hz,2H),3.91(br t,J=6.0Hz,2H),3.63(s,3H),2.90(br t,J=5.9Hz,2H),2.20(s,3H),1.92(s,6H),1.33(t,J=7.0Hz,3H).

[0355] Step 2: Preparation of compound BB-4

[0356] After adding tetrahydrofuran (8.6L) to a dry 50L jacketed kettle at 20°C, borane-dimethyl sulfide solution (10M, 950mL) was added dropwise to the kettle under stirring. After the addition was completed, the temperature was lowered to 0°C and compound 1-1b (440g) was added thereto. The cooling device was turned off, and the temperature was naturally returned to 20-25°C and the reaction was continued to stir for 18 hours. The reaction solution was cooled to 0°C, methanol (~1.5L) was added dropwise to quench until no bubbles were generated, and 3M hydrochloric acid solution (~800mL) was continued to be added dropwise to the reaction solution to adjust the pH to 2-3. The reaction solution was concentrated under reduced pressure to evaporate the solvent. The residue was dissolved with dichloromethane, and saturated sodium bicarbonate solution was added to adjust the pH value to 7-8. The liquids were separated, and the aqueous phase was extracted with dichloromethane (3000 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The concentrated product was separated and purified by flash column chromatography to obtain 125 g of the target compound BB-4.

[0357] MS-ESI(m / z):449.25[M+1] +

[0358] 1H NMR (400MHz, DMSO-d6) δ = 7.91 (br s, 2H), 6.96 (s, 1H), 6.87 (s, 2H), 6.69 (s, 1H), 5.35 (s, 1H), 4.41 (br t,J=5.8Hz,2H),4.07(q,J=6.8Hz,2H),3.92(br t,J=5.8Hz,2H),3.63(s,3H),3.21(br s,2H),2.90(br t,J=5.8Hz,2H),2.22(s,3H),1.98(s,6H),1.33(t,J=7.0Hz,3H).

[0359] Step 3: Preparation of compound 1-4b

[0360] Compound 1-3b (68.68 g) was dissolved in dichloromethane (700 mL) at 20°C, N,N-carbonyldiimidazole (61.56 g) was added thereto, and the mixture was stirred at 25°C for 5 hours. The mixture was washed with saturated brine (700 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (675 mL), and compound BB-4 (95 g) was added in batches. After the addition was completed, the mixture was stirred at 20-25°C for 18 hours. Methanol (675 mL) was added to the reaction solution, and the mixture was stirred for 1 hour and filtered to obtain the target compound 1-4b (120 g, yield 81.49%).

[0361] MS-ESI(m / z):694.33[M+1] +

[0362] 1 H NMR (400MHz, DMSO-d6) δ = 8.36 (t, J = 6.1Hz, 1H), 7.26 (d, J = 8.6Hz, 2H), 6.96-6.87 (m, 3H), 6.82 (s, 2H), 6.66 (s, 1H), 5.14 (s, 2H), 4.31 (br t,J=6.3Hz,2H),4.16(s,3H),4.06(q,J=6.8Hz,2H),3.86(br t,J=5.8Hz,2H),3.75-3.66(m,5H),3.62(s,3H),2.86(br t,J=5.9Hz,2H),2.21(s,3H),1.91(s,6H),1.33(t,J=6.9Hz,3H).

[0363] Step 4: Preparation of compound (I)

[0364] Compound 1-4b (120 g) was dissolved in a mixed solvent of trifluoroacetic acid (1000 mL) and glacial acetic acid (200 mL) at 20°C, heated to 90-100°C and stirred for 48 hours. The reaction solution was concentrated under reduced pressure to remove most of the solvent, the residue was dissolved in DCM (1000 mL) and the pH value was adjusted to 7-8 with a saturated sodium bicarbonate solution, the organic phase and the aqueous phase were separated, the aqueous phase was extracted with DCM (1000 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain the target compound of formula (I) (80 g, yield 80.60%).

[0365] MS-ESI(m / z):574.27[M+1] +

[0366] 1 H NMR (400MHz, DMSO-d6)δ=7.73-7.65(m,1H),6.94(s,1H),6.84(s,2H),6.66(s,1H),5.32(s,1H),4.35( t,J=6.1Hz,2H),4.12-4.01(m,5H),3.88(t,J=6.1Hz,2H),3.70(q,J=6.1Hz,2H),3.62(s,3H),2.87(br t,J=6.0Hz,2H),2.21(s,3H),1.93(s,6H),1.33(t,J=6.9Hz,3H),0.90-0.90(m,1H).

[0367] Example 2: Preparation of Type A Crystals of the Compound of Formula (I)

[0368] 50 mg of the compound of formula (I) was added to a 4 mL glass bottle, 1 mL of anhydrous methanol was added, and the temperature was raised to 40°C and stirred for 48 hours. The mixture was naturally cooled to room temperature, centrifuged to separate the solid, and vacuum dried to obtain 34 mg of solid, which was type A crystal. Its XRPD spectrum is shown in Figure 1 As shown in the DSC spectrum Figure 2 As shown in the TGA spectrum Figure 3 shown.

[0369] Example 3: Preparation of Type B Crystals of the Compound of Formula (I)

[0370] 50 mg of the compound of formula (I) was added to a 4 mL glass bottle, 1 mL of anhydrous ethanol and 0.2 mL of water were added thereto, and the temperature was raised to 40°C and stirred for 48 hours. The mixture was naturally cooled to room temperature, centrifuged to separate the solid, and vacuum dried to obtain 46 mg of solid, which was type B crystal. Its XRPD spectrum is shown in Figure 4 As shown in the DSC spectrum Figure 5 As shown in the TGA spectrum Figure 6 shown.

[0371] Example 4: Preparation of Type C Crystals of the Compound of Formula (I)

[0372] 50 mg of the compound of formula (I) was added to a 4 mL glass bottle, 1 mL of acetonitrile was added thereto, and the temperature was raised to 40°C and stirred for 48 hours. The mixture was naturally cooled to room temperature, centrifuged to separate the solid, and vacuum dried to obtain 37 mg of solid, which was type C crystal. Its XRPD spectrum is shown in Figure 7 As shown in the DSC spectrum Figure 8 As shown in the TGA spectrum Fig. 9 shown.

[0373] Example 5: Preparation of salts of compounds of formula (I)

[0374] 100 mg of the compound of formula (I) was added to a 4 mL glass bottle, 2 mL of anhydrous tetrahydrofuran was added thereto, and the mixture was heated to 70°C and stirred for 1 hour to fully dissolve, and then cooled to 40°C, and a solution of the corresponding acid or base (specific specifications and dosages are shown in Table 8) and 0.1 mL of water was added thereto, and the temperature was maintained and stirred for 12 hours. The mixture was centrifuged to separate the solid precipitate, and vacuum dried to obtain the solid, which is the corresponding salt of the crystalline form of the compound of formula (I).

[0375] Table 8 Preparation of each salt type

[0376]

[0377]

[0378] Example 6: Study on the stability of type B crystalline solid of compound of formula (I)

[0379] High performance liquid chromatography (HPLC)

[0380] The chromatographic conditions of the HPLC method are shown in the table below:

[0381] Chromatographic column: Zorbax SB C-18, 4.6 mm × 150 mm, 5 μm (PDS-HPLC-007)

[0382] Mobile phase A: 0.1% TFA in water

[0383] Mobile phase B: 100% ACN

[0384] Sample preparation: The sample was dissolved in a mixed solvent of acetonitrile and water (acetonitrile: water = 50:50 (v / v)).

[0385] Solid Stability Lofting Method

[0386] The stability of the compound placed under the following conditions was investigated, and samples were taken at different time points for content detection. About 5 mg of the B-type crystal of the compound of formula (I) was accurately weighed and placed in a dry and clean glass bottle, in duplicate, spread into a thin layer as the formal test sample, and placed under the test conditions of influencing factors (60°C), (relative humidity 92.5%), light (total illumination 1.2×10 6 Lux·hr / Near UV 200w·hr / m 2 ), (40℃, relative humidity 75%), (60℃, relative humidity 75%), the samples were completely exposed, covered with aluminum foil and pierced with small holes. Sampling and analysis were carried out at 5 days, 10 days, 1 month, 2 months and 3 months. The samples placed under the conditions of light (visible light 1200000Lux, ultraviolet 200W) were completely exposed at room temperature. The experimental results are shown in Table 9.

[0387] Table 9 Solid stability sample content analysis results (5d, 10d, 1M, 2M, 3M)

[0388] RRT / Norm% Total impurities% Day 0 0.11 60℃_5 days 0.10 60℃_10 days 0.11 92.5%RH_5 days 0.11 92.5%RH_10 days 0.10 Shade 0.11 illumination 0.10 40℃-75%RH-10 days 0.10 60℃-75%RH-10 days 0.10 40℃-75%RH-1 month 0.10 60℃-75%RH-1 month 0.10 40℃-75%RH-2 months 0.08 40℃-75%RH-3 months 0.09

[0389] It can be seen that the crystals of the compound of formula (I) of the present application have good stability under high temperature, high humidity or light conditions, and there is no growth of impurities during the test period.

[0390] Example 7: Hygroscopicity study of type B crystals of the compound of formula (I)

[0391] Instrument model: SMSDVS Advantage Dynamic Vapor Sorption Instrument

[0392] Test conditions: Take a sample (10-20 mg, type B crystal prepared in Example 3) and place it in a DVS sample tray for testing.

[0393] The detailed DVS parameters are as follows:

[0394] Temperature: 25℃

[0395] Balance: dm / dt = 0.01% / min (minimum: 10min, maximum: 180min)

[0396] Drying: Drying at 0% RH for 120 min

[0397] RH(%) test level: 10%

[0398] RH (%) test step range: 0%-90%-0%. The obtained dynamic vapor adsorption (DVS) graph is as follows: Fig.18 shown.

[0399] Depend on Fig.18It can be seen that the crystals of the compound of formula (I) of the present application have low hygroscopicity.

[0400] Experimental Example 1: In vitro detection of the inhibitory activity of compounds on PDE 3A enzyme

[0401] Purpose: To measure AMP / GMP expression based on fluorescence polarization, i.e. tracer AMP / GMP antibody binding to indicate enzyme activity.

[0402] Reagents:

[0403] Assay buffer solution: 10 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 0.01% Brij 35, 1 mM dithiothreitol (DTT), and 1% DMSO.

[0404] Enzyme: Recombinant human PDE3A (gene accession number NM_000921; amino acid 669) was expressed by baculovirus in Sf9 insect cells with an N-terminal GST tag, and its molecular weight = 84 kDa.

[0405] Substrate: 1 μM cAMP

[0406] Detection: AMP2 / GMP2 antibody and AMP2 / GMP2 AlexaFluor633 tracer.

[0407] Steps:

[0408] 1. Dissolve the recombinant human PDE3A enzyme and substrate (1 μM cAMP) in freshly prepared experimental buffer;

[0409] 2. Transfer the above PDE3A enzyme buffer solution into the reaction well;

[0410] 3. Add 100% DMSO-dissolved compounds to the PDE3A enzyme buffer solution reaction wells by acoustic technology (echo 550; nanoliter range) and incubate at room temperature for 10 minutes;

[0411] 4. Add the substrate buffer solution to the above reaction wells to start the reaction;

[0412] 5. Incubate at room temperature for 1 hour;

[0413] 6. Add the assay mixture ( The reaction was terminated with AMP2 / GMP2 antibody and AMP2 / GMP2 AlexaFluor 633 tracer) and incubated for 90 minutes with slow mixing. The fluorescence polarization measurement range was Ex / Em=620 / 688.

[0414] Data analysis: The fluorescence polarization signal was converted into nM by calculating the percentage of enzyme activity relative to the DMSO control according to the AMP / GMP standard curve and Excel software. Curve fitting was performed using GraphPad Prism (drawing medical icons). The experimental results are shown in Table 10.

[0415] Experimental Example 2: In vitro detection of the inhibitory activity of compounds on PDE 4B enzyme

[0416] Purpose: To measure AMP / GMP expression based on fluorescence polarization, i.e. tracer AMP / GMP antibody binding to indicate enzyme activity.

[0417] Reagents:

[0418] Assay buffer solution: 10 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 0.01% Brij 35, 1 mM DTT, and 1% DMSO.

[0419] Enzyme: Recombinant human PDE4B (gene accession number NM_002600; amino acid 305) was expressed by baculovirus in Sf9 insect cells with an N-terminal GST tag, and its molecular weight = 78 kDa.

[0420] Substrate: 1 μM cAMP

[0421] Detection: AMP2 / GMP2 antibody and AMP2 / GMP2 AlexaFluor633 tracer.

[0422] Steps:

[0423] 1. Dissolve the recombinant human PDE4B enzyme and substrate (1 μM cAMP) in freshly prepared experimental buffer;

[0424] 2. Transfer the above PDE4B enzyme buffer solution into the reaction well;

[0425] 3. Add 100% DMSO-dissolved compounds to the PDE4B enzyme buffer solution reaction wells by acoustic technology (Echo 550; nanoliter range) and incubate at room temperature for 10 minutes.

[0426] 4. Add the substrate buffer solution to the above reaction wells to start the reaction

[0427] 5. Incubate at room temperature for 1 hour

[0428] 6. Add the assay mixture ( The reaction was terminated with AMP2 / GMP2 antibody and AMP2 / GMP2 AlexaFluor 633 tracer) and incubated for 90 minutes with slow mixing. The fluorescence polarization measurement range was Ex / Em=620 / 688.

[0429] Data analysis: The fluorescence polarization signal was converted into nM according to the AMP / GMP standard curve and the % enzyme activity relative to the DMSO control calculated by Excel software. Curve fitting was performed using GraphPad Prism (drawing medical icons). The experimental results are shown in Table 10:

[0430] Table 10 Compound in vitro screening test results

[0431]

[0432] The compounds of the present application have significant dual PDE3 and PDE4 inhibitory effects.

[0433] Experimental Example 3: Beagle Dog Pharmacokinetic Study

[0434] Male beagles were selected as test animals in this study. The LC-MS / MS method was used to quantitatively determine the drug concentration in the plasma of beagles at different time points after intravenous injection or oral administration of the compound of formula (I) to evaluate the pharmacokinetic characteristics of the compound of formula (I) in beagles.

[0435] The clear solution of the compound of formula (I) was injected into two 10-12 kg beagles via the cephalic vein or saphenous vein, and the clear solution of the compound of formula (I) was gavage administered to two 10-12 kg beagles (fasted overnight). Approximately 500 μL of blood was collected from the peripheral vein of the animals at 0.0333, 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration, and transferred to a commercial centrifuge tube containing 0.85-1.15 mg of K2 EDTA*2H2O anticoagulant, and centrifuged at 4°C and 3000g for 10 minutes to obtain plasma. The blood drug concentration was determined by LC-MS / MS, and WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate relevant pharmacokinetic parameters using the non-compartmental linear logarithmic trapezoidal method.

[0436] Table 11 Pharmacokinetic parameters of compounds in beagle dogs

[0437]

[0438] The compounds of the present application have high in vivo plasma clearance, low oral plasma systemic exposure and low oral bioavailability.

[0439] Experimental Example 4: Inhibition of the activity of human liver microsomal cytochrome P450 isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4)

[0440] A total of five specific probe substrates of five CYP isozymes, namely, phenacetin (CYP1A2), diclofenac (CYP2C9), (S)-mephenytoin (CYP2C19), dextromethorphan (CYP2D6) and midazolam (CYP3A4), were incubated with human liver microsomes and the compound of formula (I), and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction, the samples were processed and the concentrations of five metabolites produced by specific substrates, including acetaminophen, 4'-hydroxydiclofenac, 4'-hydroxymephenytoin, dextrorphan, and 1'-hydroxymidazolam, were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) to calculate the corresponding half inhibitory concentration (IC 50 ).

[0441] Table 12 Inhibition parameters of the compounds of formula (I) on five CYP enzymes

[0442]

[0443] The compounds of the present application have low inhibitory effects on five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450.

[0444] Experimental Example 5: Study on the efficacy of the drug in the smoke-induced acute lung injury model in rats

[0445] Experimental animals

[0446] Male Sprague-Dawley rats (provided by Shanghai Slake Laboratory Animal Co., Ltd.), SPF grade, weighing about 200 g.

[0447] Experimental Procedure

[0448] 1. After arriving at the facility, the animals were fed for one week and randomly divided into 6 groups according to body weight;

[0449] 2. On the 1st to 3rd day of the experiment, the corresponding compound of each group was atomized for 30 minutes, and then the animals in the model group and each compound treatment group were exposed to cigarette smoke for 1 hour. After an interval of 4 hours, they were exposed to cigarette smoke again for 1 hour. The animals in the control group were exposed to cigarette smoke twice a day for 3 consecutive days.

[0450] 3. On the fourth day of the experiment, the corresponding compounds of each group were nebulized for 30 minutes. The animals in the model group and each compound treatment group were exposed to 150 μg / mL LPS by nebulization for 15 minutes, and 3 hours later (from the start of nebulization), they were exposed to smoke for 1 hour. The lung function (Penh and F) of the animals was tested again. After the animals were euthanized with CO2, the alveolar lavage fluid was collected for cell counting.

[0451] 4. Drug administration

[0452] Administration: Whole body exposure: The test compound and the reference compound were aerosolized using a nebulizer at the maximum aerosol rate (approximately 12 mL) for 30 minutes.

[0453] Dosing frequency: Nebulized drug or solvent 30 minutes before smoking every morning, and before LPS nebulization inhalation on the 4th day.

[0454] 5. Pharmacodynamic endpoint measurement

[0455] (1) Total white blood cell count in BALF (alveolar lavage fluid);

[0456] (2) Lung function test under methacholine (Mch) induction (airway resistance index Penh);

[0457] Table 13 Experimental groups

[0458] Group Number of animals Compound concentration of atomized solution Time of administration Model Group 10 - 30 minutes before the first smoking of the day Low dose group of compound of formula (I) 10 0.05mg / ml 30 minutes before the first smoking of the day High dose group of compound of formula (I) 10 0.15mg / ml 30 minutes before the first smoking of the day

[0459] The experimental results are shown in Fig.19 and Fig. 20 .

[0460] The compound of the present application can reduce the total number of BALF white blood cells and the airway resistance index Penh in the smoke-induced acute lung injury model in rats.

[0461] Experimental Example 6: In vitro detection of the inhibitory activity of compounds on TNF-α in human peripheral blood mononuclear cells

[0462] Experimental purpose: To express the anti-inflammatory activity of the test compound at the cellular level based on the level of TNF-α in human peripheral blood mononuclear cells (hPBMC).

[0463] Steps:

[0464] 1. Collect whole blood from normal subjects and use EDTA anticoagulation tubes for anticoagulation;

[0465] 2. Ficoll density gradient centrifugation was used to separate PBMCs, count the cells, and adjust the cell concentration to 2×10 6 / ml;

[0466] 3. U-bottom 96-well plate, add 2×10 cells to each well 5 , LPS1ng / ml, the compound of formula (I) was prepared into DMSO solutions with concentrations of 100μM, 10μM, 1μM, 100nM, 10nM, 1nM, 100pM, and 10pM, respectively, with 200μL system in each well;

[0467] 4. Cultivate for 24 hours and collect the supernatant;

[0468] 5.ELISA was used to detect the level of TNF-α in the supernatant, and Graphpad Prism software was used to fit the inhibition curve and calculate the IC 50 .

[0469] The experimental results are shown in Table 14:

[0470] Table 14 In vitro test results of compounds

[0471]

[0472] The compound of the present application has a significant inhibitory effect on TNF-α in human peripheral blood mononuclear cells (hPBMC).

Claims

1. Crystals of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

2. The crystal of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The crystal is a crystal of the compound of formula (I), and its X-ray powder diffraction pattern using Cu Kα radiation comprises 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 4.14±0.2°, 6.56±0.2°, 6.98±0.2°, 8.20±0.2°, 11.50±0.2°, 12.66±0.2°, 13.94±0.2° and 16.35±0.2°; or, its X-ray powder diffraction pattern using Cu The X-ray powder diffraction pattern of Kα radiation has diffraction peaks at the following 2θ angles: 4.14±0.2°, 6.98±0.2°, 8.20±0.2° and 11.50±0.2°; or, the diffraction peaks at the following 2θ angles: 4.14±0.2°, 6.56±0.2°, 6.98±0.2°, 8.20±0.2°, 11.50±0.2°, 12.66±0.2°, 13.94±0.2 ° and 16.35±0.2°; or, having diffraction peaks at the following 2θ angles: 4.14±0.2°, 6.56±0.2°, 6.98±0.2°, 8.20±0.2°, 9.35±0.2°, 11.50±0.2°, 12.66±0.2°, 13.94±0.2°, 14.52±0.2°, 16.35±0.2°, 21.52±0.2° and 24.57±0.2°; Alternatively, the crystals are crystals of the compound of formula (I), and its differential scanning calorimetry curve has an endothermic peak at 146.23±2°C and / or 162.19±2°C; or, its differential scanning calorimetry curve has an exothermic peak at 172.65±2°C and / or 241.73±2°C.

3. The crystal of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The crystal is a crystal of the compound of formula (I), and its X-ray powder diffraction pattern using Cu Kα radiation comprises 5, 6, 7, 8, 9, 10 or 11 diffraction peaks selected from the following 2θ angles: 5.81±0.2°, 8.38±0.2°, 11.16±0.2°, 13.96±0.2°, 14.47±0.2°, 15.01±0.2°, 16.76±0.2°, 17.95±0.2°, 20.83±0.2°, 24.73±0.2° and 26.13±0.2°; or, its X-ray powder diffraction pattern using Cu The X-ray powder diffraction pattern of Kα radiation has diffraction peaks at the following 2θ angles: 5.81±0.2°, 13.96±0.2°, 15.01±0.2°, 17.95±0.2° and 24.73±0.2°; or, has diffraction peaks at the following 2θ angles: 5.81±0.2°, 8.38±0.2°, 11.16±0.2°, 13.96±0.2°, 14.47±0.2°, 15.01±0.2°, 16.76±0.2°, 17.95±0.2°, 20.83±0.2°, 24.73±0.2° and 26. 13±0.2°; or, having diffraction peaks at the following 2θ angles: 5.81±0.2°, 8.38±0.2°, 9.13±0.2°, 11.16±0.2°, 11.60±0.2°, 12.82±0.2°, 13.96±0.2°, 14.47±0.2°, 15.01±0.2°, 16.76±0.2°, 17.95±0.2°, 18.91±0.2°, 20.83±0.2°, 24..36±0.2°, 24.73±0.2°, 25.78±0.2° and 26.13±0.2°.

4. The crystal of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 3, wherein: The crystals are crystals of the compound of formula (I), and the differential scanning calorimetry curve thereof has an exothermic peak at 247.70±2°C.

5. The crystal of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The crystal is a crystal of the compound of formula (I), and its X-ray powder diffraction pattern using Cu Kα radiation comprises 4, 5, 6, 7, 8 or 9 diffraction peaks selected from the following 2θ angles: 4.57±0.2°, 6.41±0.2°, 7.18±0.2°, 11.58±0.2°, 12.84±0.2°, 13.21±0.2°, 14.34±0.2°, 16.05±0.2° and 23.41±0.2°; or, its X-ray powder diffraction pattern using Cu The X-ray powder diffraction pattern of Kα radiation has diffraction peaks at the following 2θ angles: 4.57±0.2°, 6.41±0.2°, 7.18±0.2° and 14.34±0.2°; or, the diffraction peaks at the following 2θ angles: 4.57±0.2°, 6.41±0.2°, 7.18±0.2°, 11.58±0.2°, 12.84±0.2°, 13.21±0.2°, 14.34±0.2°, 16.05±0.2 ° and 23.41±0.2°; or, having diffraction peaks at the following 2θ angles: 4.57±0.2°, 6.41±0.2°, 7.18±0.2°, 9.07±0.2°, 11.58±0.2°, 12.84±0.2°, 13.21±0.2°, 14.34±0.2°, 16.05±0.2°, 18.15±0.2°, 19.26±0.2°, 20.85±0.2° and 23.41±0.2°.

6. The crystal of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 5, wherein: The crystals are crystals of the compound of formula (I), and the differential scanning calorimetry curve thereof has exothermic peaks at 152.26±2°C and / or 247.92±2°C.

7. The crystal of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The crystal is a crystal of a compound of formula (II) The X-ray powder diffraction pattern using Cu Kα radiation comprises 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 4.84±0.2°, 9.58±0.2°, 10.93±0.2°, 11.97±0.2°, 14.31±0.2°, 14.75±0.2°, 16.49±0.2° and 24.42±0.2°; or, the X-ray powder diffraction pattern using Cu Kα radiation comprises 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 4.84±0.2°, 9.58±0.2°, 10.93±0.2°, 11.97±0.2°, 14.31±0.2°, 14.75±0.2°, 16.49±0.2° and 24.42±0.2°; The X-ray powder diffraction pattern of Kα radiation has diffraction peaks at the following 2θ angles: 4.84±0.2°, 9.58±0.2°, 11.97±0.2° and 14.75±0.2°; or, has diffraction peaks at the following 2θ angles: 4.84±0.2°, 9.58±0.2°, 10.93±0.2°, 11.97±0.2°, 14.31±0.2°, 14.75±0.2°, 16.49±0.2° and 24.42±0.2°; or, The following diffraction peaks are present at 2θ angles: 4.84±0.2°, 9.58±0.2°, 10.93±0.2°, 11.97±0.2°, 12.72±0.2°, 13.93±0.2°, 14.31±0.2°, 14.75±0.2°, 16.49±0.2°, 17.91±0.2°, 19.25±0.2°, 19.90±0.2°, 20.57±0.2°, 24.42±0.2° and 25.70±0.2°; Alternatively, the crystal is a crystal of a compound of formula (III) The X-ray powder diffraction pattern using Cu Kα radiation comprises 3, 4, 5 or 6 diffraction peaks selected from the following 2θ angles: 6.53±0.2°, 10.87±0.2°, 12.48±0.2°, 13.11±0.2°, 16.58±0.2° and 25.03±0.2°; or, the X-ray powder diffraction pattern using Cu Kα radiation comprises 3, 4, 5 or 6 diffraction peaks selected from the following 2θ angles: 6.53±0.2°, 10.87±0.2°, 12.48±0.2°, 13.11±0.2°, 16.58±0.2° and 25.03±0.2°; The X-ray powder diffraction pattern of Kα radiation has diffraction peaks at the following 2θ angles: 6.53±0.2°, 12.48±0.2° and 13.11±0.2°; or, has diffraction peaks at the following 2θ angles: 6.53±0.2°, 10.87±0.2°, 12.48±0.2°, 13.11±0.2°, 16.58±0.2° and 25.03±0.2°; or, has diffraction peaks at the following 2θ angles: 6.53±0.2°, 10.87±0.2°, 12.48±0.2°, 13.11±0.2°, 14.04±0.2°, 16.58±0.2°, 25.03±0.2°, 25.56±0.2° and 26.66±0.2°; Alternatively, the crystal is a crystal of a compound of formula (IV) The X-ray powder diffraction pattern using CuKα radiation comprises 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 11.22±0.2°, 12.58±0.2°, 16.43±0.2°, 17.90±0.2°, 18.85±0.2°, 22.62±0.2°, 24.45±0.2° and 25.87±0.2°; or, the X-ray powder diffraction pattern using CuKα radiation comprises 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 11.22±0.2°, 12.58±0.2°, 16.43±0.2°, 17.90±0.2°, 18.85±0.2°, 22.62±0.2°, 24.45±0.2° and 25.87±0.2°; The X-ray powder diffraction pattern of Kα radiation has diffraction peaks at the following 2θ angles: 11.22±0.2°, 18.85±0.2°, 22.62±0.2° and 24.45±0.2°; or, has diffraction peaks at the following 2θ angles: 11.22±0.2°, 12.58±0.2°, 16.43±0.2°, 17.90±0.2°, 18.85±0.2°, 22. 62±0.2°, 24.45±0.2° and 25.87±0.2°; or, having diffraction peaks at the following 2θ angles: 11.22±0.2°, 12.58±0.2°, 16.43±0.2°, 17.08±0.2°, 17.90±0.2°, 18.85±0.2°, 19.23±0.2°, 19.72±0.2°, 22.62±0.2°, 23.27±0.2°, 24.45±0.2° and 25.87±0.2°; or, having diffraction peaks at the following 2θ angles: 11.22±0.2°, 12.58±0.2°, 13.88±0.2°, 15.49±0.2°, 16.04±0.2°, 16.43±0.2°, 17.08±0.2°, 17.90±0.2°, 18.54±0.2°. 2°, 18.85±0.2°, 19.23±0.2°, 19.72±0.2°, 20.02±0.2°, 20.51±0.2°, 22.62±0.2°, 23.27±0.2°, 24.45±0.2°, 24.83±0.2°, 25.42±0.2°, 25.87±0.2°, 26.09±0.2°, and 29.53±0.2°; Alternatively, the crystal is a crystal of a compound of formula (IV), and its differential scanning calorimetry curve has an endothermic peak at 191.35±2°C and / or an exothermic peak at 222.21±2°C; Alternatively, the crystal is a crystal of a compound of formula (V) The X-ray powder diffraction pattern using Cu Kα radiation comprises 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 5.83±0.2°, 6.62±0.2°, 9.50±0.2°, 10.98±0.2°, 17.16±0.2°, 19.05±0.2°, 24.71±0.2° and 25.16±0.2°; or, the X-ray powder diffraction pattern using Cu Kα radiation comprises 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 5.83±0.2°, 6.62±0.2°, 9.50±0.2°, 10.98±0.2°, 17.16±0.2°, 19.05±0.2°, 24.71±0.2° and 25.16±0.2°; The X-ray powder diffraction pattern of Kα radiation has diffraction peaks at the following 2θ angles: 5.83±0.2°, 6.62±0.2°, 9.50±0.2° and 10.98±0.2°; or, the diffraction peaks at the following 2θ angles: 5.83±0.2°, 6.62±0.2°, 9.50±0.2°, 10.98±0.2°, 17.16±0.2°, 19.05±0.2°, 24.71±0.2° and 25.16±0.2°; or, having diffraction peaks at the following 2θ angles: 5.83±0.2°, 6.62±0.2°, 9.50±0.2°, 10.98±0.2°, 11.59±0.2°, 13.23±0.2°, 16.27±0.2°, 17.16±0.2°, 19.05±0.2°, 21.63±0.2°, 24.71±0.2°, and 25.16±0.2°.

8. A crystalline composition comprising a crystal of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: The crystals account for more than 50%, or more than 80%, or more than 90%, or more than 95% of the weight of the crystalline composition.

9. A pharmaceutical composition comprising a therapeutically effective amount of a crystal of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 or a crystalline composition according to claim 8.

10. Use of a crystal of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, a crystalline composition according to claim 8, or a pharmaceutical composition according to claim 9 in the preparation of a medicament for treating asthma or chronic obstructive pulmonary disease.

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