Crystal of PDE3 / PDE4 dual inhibitor and use thereof

Abstract

To provide a crystal of a compound having PDE3 / 4 inhibitory activity.SOLUTION: There are provided a crystal of a tricyclic compound as shown in formula (I) or a pharmaceutically acceptable salt thereof and a preparation method therefor, and the use thereof in a drug for treating PDE3- and / or PDE4-related diseases.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to related applications In this application, the priority of Chinese Patent Application for Invention No. 202010043882.5, filed with the China National Intellectual Property Administration on January 15, 2020, is claimed, and it is incorporated herein by reference in its entirety.

[0002] This application relates to a crystal as a PDE3 / PDE4 dual inhibitor and its use in the treatment of PDE3 / PDE4 - related diseases, specifically chronic obstructive pulmonary disease (COPD).

Background Art

[0003] Phosphodiesterase (PDE) is a superfamily of enzymes containing 11 families, and each family is involved in different signal transmissions and regulates different physiological processes. Among them, PDE3 is the main phosphodiesterase in human airway smooth muscle (ASM). Inhibiting PDE3 increases the intracellular cAMP concentration and relaxes bronchial smooth muscle. PDE4 plays a major regulatory role in the expression of inflammatory mediators and anti - inflammatory mediators, and PDE4 inhibitors can inhibit the release of harmful mediators from inflammatory cells. Therefore, an inhibitor having an inhibitory effect on both PDE3 and PDE4 has the bronchodilation effect of β - adrenergic receptor agonists and the anti - inflammatory action by inhalation of glucocorticoids. The functional complementarity of the dual targets theoretically has a greater effect than a single target, realizes the therapeutic effect that could only be obtained by conventional combination administration with a single drug, eliminates the drawback that the physical and chemical properties of the component drugs in combination administration cannot be fully compatible, makes the administration method easier, and is advantageous for administration at a certain dose.

[0004] Victoria Boswell et al, J.Pharmaco.Experi.Therap. 2006, 318, 840 - 848, and WO200005830 reported compounds RPL554 and RPL565, which have long - term bronchodilation and anti - inflammatory effects. However, due to their physical and chemical properties such as poor solubility and high plasma clearance, they are suitable for inhalation administration. However, it was found from the data that their inhibitory activity against PDE4 was unsatisfactory and the anti - inflammatory effect was not good. Therefore, it is necessary to develop compounds with good PDE3 / 4 inhibitory activity. Generally, in order to meet the requirements regarding drug manufacturing, storage, and formulation, excellent properties are required in terms of drug activity, pharmacokinetics, bioavailability, hygroscopicity, melting point, stability, solubility, purity, ease of manufacture, etc. Therefore, it is necessary to develop crystals of compounds having PDE3 / 4 inhibitory activity.

Chemical formula

Prior art documents

Patent documents

[0005]

Patent Document 1

Non - patent documents

[0006]

Non - patent Document 1

Summary of the invention

Problems to be solved by the invention

[0007] In one aspect of the present application, crystals of a compound of formula (I) or a pharmaceutically acceptable salt thereof are provided.

Chemical formula

Means for Solving the Problem

[0008] In some embodiments, crystals of the compound of formula (I) are provided.

[0009] In another aspect of the present application, furthermore, there is provided Form A crystals of the compound of formula (I) having diffraction peaks at 2θ angles of 4.14 ± 0.2°, 6.98 ± 0.2°, 8.20 ± 0.2°, 11.50 ± 0.2° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0010] In some embodiments of the present application, the Form A crystals have diffraction peaks at 2θ angles of 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°, 16.35 ± 0.2° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0011] In some embodiments of the present application, the Form A crystals have diffraction peaks at 2θ angles of 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°, 24.57 ± 0.2° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0012] In some embodiments of the present application, the Form A crystals contain 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks at 2θ angles selected from 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°, 24.57 ± 0.2° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0013] In some embodiments of the present application, the Type A crystal has an X-ray powder diffraction pattern using Cu Kα radiation that includes 4, 5, 6, 7, or 8 diffraction peaks at 2θ angles selected from 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°, 16.35±0.2°.

[0014] In some embodiments of the present application, the peak positions and relative intensities of the diffraction peaks in the XRPD pattern of the Type A crystal using Cu Kα radiation are as shown in Table 1 below.

Table 1

[0015] In some embodiments of the present application, the XRPD pattern of the Type A crystal using Cu Kα radiation is as shown in Figure 1.

[0016] In some embodiments of the present application, the Type A crystal has an endothermic peak in the differential scanning calorimetry curve at 146.23±2°C and / or 162.19±2°C.

[0017] In some embodiments of the present application, the Type A crystal has an exothermic peak in the differential scanning calorimetry curve at 172.65±2°C and / or 241.73±2°C.

[0018] In some embodiments of the present application, the Type A crystal has an endothermic peak in the differential scanning calorimetry curve at 146.23±2°C and 162.19±2°C, and an exothermic peak at 172.65±2°C and 241.73±2°C.

[0019] In some embodiments of the present application, the differential scanning calorimetry curve of the Type A crystal is as shown in Figure 2.

[0020] In some embodiments of the present application, the thermogravimetric analysis curve of the Type A crystal shows a weight loss of 0.4611% at 118.40 ± 2 °C, a weight loss of 0.8796% from 118.40 ± 2 °C to 185.65 ± 2 °C, and a weight loss of 7.177% from 185.65 ± 2 °C to 260.07 ± 2 °C.

[0021] In some embodiments of the present application, the thermogravimetric analysis curve of the Type A crystal is as shown in Figure 3.

[0022] In another aspect of the present application, there is provided a method for producing a Type A crystal, including the step of precipitating the compound of formula (I) from a methanol solvent.

[0023] In some embodiments, the step is carried out with stirring at 40 °C.

[0024] In another aspect of the present application, there is further provided a Type B crystal of the compound of formula (I) having diffraction peaks at 2θ angles of 5.81 ± 0.2 °, 13.96 ± 0.2 °, 15.01 ± 0.2 °, 17.95 ± 0.2 °, 24.73 ± 0.2 ° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0025] In some embodiments of the present application, the Type B crystal has diffraction peaks at 2θ angles of 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 °, 26.13 ± 0.2 ° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0026] In some embodiments of the present application, the Type B crystal has diffraction peaks at 2θ angles of 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 °, 26.13 ± 0.2 ° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0027] In some embodiments of the present application, the B-type crystal has X-ray powder diffraction patterns using Cu Kα radiation with diffraction peaks at 2θ angles of 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°, 26.13±0.2°.

[0028] In some embodiments of the present application, the B-type crystal has X-ray powder diffraction patterns using Cu Kα radiation, including 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks at 2θ angles selected from 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°, 26.13±0.2°.

[0029] In some embodiments of the present application, the B-type crystal has X-ray powder diffraction patterns using Cu Kα radiation, including 5, 6, 7, 8, 9, 10 or 11 diffraction peaks at 2θ angles selected from 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°, 26.13±0.2°.

[0030] In some embodiments of the present application, the B-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation that includes 5, 6, 7, 8, or 9 diffraction peaks at 2θ angles selected from 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°.

[0031] In some embodiments of the present application, the peak positions and relative intensities of the diffraction peaks in the XRPD pattern of the B-type crystal using Cu Kα radiation are as shown in Table 2 below.

Table 2

[0032] In some embodiments of the present application, the XRPD pattern of the B-type crystal using Cu Kα radiation is as shown in Figure 4.

[0033] In some embodiments of the present application, the B-type crystal has an endothermic peak in the differential scanning calorimetry curve at 247.70±2 °C.

[0034] In some embodiments of the present application, the differential scanning calorimetry curve of the B-type crystal is as shown in Figure 5.

[0035] In some embodiments of the present application, the thermogravimetric analysis curve of the B-type crystal shows a weight loss of 0.4870% at 155.75±2 °C and a weight loss of 7.287% from 155.75±2 °C to 262.18±2 °C.

[0036] In some embodiments of the present application, the thermogravimetric analysis curve of the B-type crystal is as shown in Figure 6.

[0037] In another aspect of the present application, there is provided a method for producing a B-type crystal, which includes the step of precipitating a compound of formula (I) from a mixed solvent of ethanol and water.

[0038] In some embodiments, the step is carried out with stirring at 40°C or below.

[0039] In another aspect of the present application, further provided is a C-type crystal of the compound of formula (I) having diffraction peaks at 2θ angles of 4.57 ± 0.2°, 6.41 ± 0.2°, 7.18 ± 0.2°, and 14.34 ± 0.2° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0040] In some embodiments of the present application, the C-type crystal has diffraction peaks at 2θ angles of 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° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0041] In some embodiments of the present application, the C-type crystal has diffraction peaks at 2θ angles of 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° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0042] In some embodiments of the present application, the C-type crystal contains 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 diffraction peaks at 2θ angles selected from 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° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0043] In some embodiments of the present application, the C-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation that includes 4, 5, 6, 7, 8, or 9 diffraction peaks at 2θ angles selected from 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°, 23.41 ± 0.2°.

[0044] In some embodiments of the present application, the peak positions and relative intensities of the diffraction peaks in the XRPD pattern of the C-type crystal using Cu Kα radiation are as shown in Table 3 below.

Table 3

[0045] In some embodiments of the present application, the XRPD pattern of the C-type crystal using Cu Kα radiation is as shown in Figure 7.

[0046] In some embodiments of the present application, the C-type crystal has a differential scanning calorimetry curve with an exothermic peak at 152.26 ± 2 °C and / or 247.92 ± 2 °C.

[0047] In some embodiments of the present application, the differential scanning calorimetry curve of the C-type crystal is as shown in Figure 8.

[0048] In some embodiments of the present application, the thermogravimetric analysis curve of the C-type crystal has a weight loss of 1.1460% at 152.80 ± 2 °C and a weight loss of 7.871% from 152.80 ± 2 °C to 262.77 ± 2 °C.

[0049] In some embodiments of the present application, the thermogravimetric analysis curve of the C-type crystal is as shown in Figure 9.

[0050] In another aspect of the present application, there is provided a method for producing a C-type crystal, which includes the step of precipitating the compound of formula (I) from acetonitrile.

[0051] In some embodiments, the step is performed with stirring at 40°C or below.

[0052] In another aspect of the present application, a pharmaceutically acceptable salt of the compound of formula (I) is provided, and the pharmaceutically acceptable salt is a sulfate, p-toluenesulfonate, mesylate or maleate.

[0053] In another aspect of the present application, crystals of a salt of the compound of formula (I) are provided.

[0054] In another aspect of the present application, further, a sulfate of the compound of formula (I) is provided. In some embodiments, the sulfate of the compound of formula (I) is selected from the compounds of formula (II).

Chemical formula

[0055] In another aspect of the present application, further, an X-ray powder diffraction pattern using Cu Kα radiation provides crystals of the compound of formula (II) having diffraction peaks at 2θ angles of 4.84±0.2°, 9.58±0.2°, 11.97±0.2°, 14.75±0.2°.

[0056] In some embodiments of the present application, the crystals of the compound of formula (II) have an X-ray powder diffraction pattern using Cu Kα radiation with diffraction peaks at 2θ angles of 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°, 24.42±0.2°.

[0057] In some embodiments of the present application, for the crystal of the compound of formula (II), the X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at 2θ angles of 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°, 25.70±0.2°.

[0058] In some embodiments of the present application, for the crystal of the compound of formula (II), the X-ray powder diffraction pattern using Cu Kα radiation includes 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks at 2θ angles selected from 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°, 25.70±0.2°.

[0059] In some embodiments of the present application, for the crystal of the compound of formula (II), the X-ray powder diffraction pattern using Cu Kα radiation includes 4, 5, 6, 7 or 8 diffraction peaks at 2θ angles selected from 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°, 24.42±0.2°.

[0060] In some embodiments of the present application, for the crystal of the compound of formula (II), the peak positions and relative intensities of the diffraction peaks in the XRPD pattern using Cu Kα radiation are as shown in Table 4 below.

Table 4

[0061] 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.

[0062] In another aspect of the present application, furthermore, a p-toluenesulfonate of the compound of formula (I) is provided. In some embodiments, the p-toluenesulfonate of the compound of formula (I) is selected from the compounds of formula (III).

Chemical formula

[0063] In another aspect of the present application, furthermore, a crystal of a compound of formula (III) having diffraction peaks in an X-ray powder diffraction pattern using Cu Kα radiation at 2θ angles of 6.53±0.2°, 12.48±0.2°, and 13.11±0.2° is provided.

[0064] In some embodiments of the present application, the crystal of the compound of formula (III) has an X-ray powder diffraction pattern using Cu Kα radiation with diffraction peaks at 2θ angles of 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°.

[0065] In some embodiments of the present application, the crystal of the compound of formula (III) has an X-ray powder diffraction pattern using Cu Kα radiation with diffraction peaks at 2θ angles of 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°.

[0066] In some embodiments of the present application, the crystal of the compound of formula (III) has an X-ray powder diffraction pattern using Cu Kα radiation that includes 3, 4, 5, 6, 7, 8, or 9 diffraction peaks at 2θ angles selected from 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°.

[0067] In some embodiments of the present application, the crystal of the compound of formula (III) has an X-ray powder diffraction pattern using Cu Kα radiation that includes 3, 4, 5, or 6 diffraction peaks at 2θ angles selected from 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°.

[0068] In some embodiments of the present application, the crystal of the compound of formula (III) has the peak positions and relative intensities of the diffraction peaks in the XRPD pattern using Cu Kα radiation as shown in Table 5 below. [Table 5]

[0069] 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.

[0070] In some embodiments of the present application, the thermogravimetric analysis curve of the crystal of the compound of formula (III) has a weight loss of 1.785% at 148.23 ± 2°C and a weight loss of 5.790% at 148.23 ± 2°C to 240.99 ± 2°C.

[0071] In some embodiments of the present application, the crystal of the compound of formula (III) has a TGA curve as shown in FIG. 12.

[0072] In another aspect of the present application, furthermore, a mesylate salt of the compound of formula (I) is provided. In some embodiments, the mesylate salt of the compound of formula (I) is selected from the compounds of formula (IV).

Chemical formula

[0073] In the present application, furthermore, crystals of the compound of formula (IV) are provided, the X-ray powder diffraction pattern of which using Cu Kα radiation has diffraction peaks at 2θ angles of 11.22 ± 0.2°, 18.85 ± 0.2°, 22.62 ± 0.2°, and 24.45 ± 0.2°.

[0074] In some embodiments of the present application, the crystals of the compound of formula (IV) have an X-ray powder diffraction pattern using Cu Kα radiation with diffraction peaks at 2θ angles of 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°.

[0075] In some embodiments of the present application, the crystals of the compound of formula (IV) have an X-ray powder diffraction pattern using Cu Kα radiation with diffraction peaks at 2θ angles of 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°.

[0076] 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 with diffraction peaks at 2θ angles of 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°, 29.53±0.2°.

[0077] 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 and includes 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks at 2θ angles selected from 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°, 29.53±0.2°.

[0078] 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 and includes 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks at 2θ angles selected from 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°, 25.87±0.2°.

[0079] 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, which includes 4, 5, 6, 7, or 8 diffraction peaks at 2θ angles selected from 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°.

[0080] In some embodiments of the present application, the crystal of the compound of formula (IV) has an XRPD pattern using Cu Kα radiation, and the peak positions and relative intensities of the diffraction peaks are as shown in Table 6 below.

Table 6

[0081] 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 Figure 13.

[0082] In some embodiments of the present application, the crystal of the compound of formula (IV) has a differential scanning calorimetry curve with an endothermic peak at 191.35±2 °C and / or an exothermic peak at 222.21±2 °C.

[0083] In some embodiments of the present application, the crystal of the compound of formula (IV) has a differential scanning calorimetry curve as shown in Figure 14.

[0084] In some embodiments of the present application, the thermogravimetric analysis curve of the crystal of the compound of formula (IV) shows a weight loss of 5.427% at 168.57±2 °C, a weight loss of 4.678% from 168.57±2 °C to 192.84±2 °C, and a weight loss of 4.621% from 192.84±2 °C to 238.22±2 °C.

[0085] In some embodiments of the present application, the crystal of the compound of formula (IV) has a thermogravimetric analysis curve as shown in Figure 15.

[0086] In another aspect of the present application, furthermore, maleate salts of the compounds of formula (I) are provided. In some embodiments, the maleate salts of the compounds of formula (I) are selected from the compounds of formula (V).

Chemical formula

[0087] In another aspect of the present application, furthermore, crystals of the compound of formula (V) having diffraction peaks in the X-ray powder diffraction pattern using Cu Kα radiation at 2θ angles of 5.83±0.2°, 6.62±0.2°, 9.50±0.2°, and 10.98±0.2° are provided.

[0088] In some embodiments of the present application, the crystals of the compound of formula (V) have diffraction peaks in the X-ray powder diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0089] In some embodiments of the present application, the crystals of the compound of formula (V) have diffraction peaks in the X-ray powder diffraction pattern using Cu Kα radiation at 2θ angles of 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°.

[0090] In some embodiments of the present application, the crystal of the compound of formula (V) has an X-ray powder diffraction pattern using Cu Kα radiation, which includes 4, 5, 6, 7, 8, 9, 10, 11, or 12 diffraction peaks at 2θ angles selected from 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°, 25.16 ± 0.2°.

[0091] In some embodiments of the present application, the crystal of the compound of formula (V) has an X-ray powder diffraction pattern using Cu Kα radiation, which includes 4, 5, 6, 7, or 8 diffraction peaks at 2θ angles selected from 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°, 25.16 ± 0.2°.

[0092] In some embodiments of the present application, the peak positions and relative intensities of the diffraction peaks in the XRPD pattern of the crystal of the compound of formula (V) are as shown in Table 7 below.

Table 7

[0093] In some embodiments of the present application, the XRPD pattern of the crystal of the compound of formula (V) using Cu Kα radiation is as shown in Figure 16.

[0094] In some embodiments of the present application, the thermogravimetric analysis curve of the crystal of the compound of formula (V) shows a weight loss of 1.928% at 155.26 ± 2 °C.

[0095] In some embodiments of the present application, the thermogravimetric analysis curve of the crystal of the compound of formula (V) is as shown in Figure 17.

[0096] In another aspect of the present application, there is provided a method for producing a salt of the compound of formula (I), which comprises mixing the compound of formula (I) with tetrahydrofuran, and then adding an aqueous solution of an acid (or a base), followed by separation to obtain the corresponding salt.

[0097] In a further aspect of the present application, there is provided a crystalline composition comprising the crystals, wherein the crystals account for 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more of the weight of the crystalline composition.

[0098] In another aspect of the present application, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0099] In another aspect of the present application, there is provided a method for producing a compound of formula (I) comprising steps (1) and (2).

[0100] In a further aspect of the present application, there is provided a method for producing compound 1-2a, which comprises a step of obtaining compound 1-2a by reacting compound BB-1 with compound 1-1a.

Chemical formula

[0101] In a further aspect of the present application, there is provided compound 1-2a or a pharmaceutically acceptable salt thereof.

Chemical formula

[0102] In a further aspect of the present application, a method for producing compound BB-4 is provided, which includes the following steps. (a) Reacting compound BB-1 with compound 1-1a to obtain compound 1-2a. (b) Reacting compound 1-2a to obtain compound BB-4.

Chemical formula

[0103] In a further aspect of the present application, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

Chemical formula

Chemical formula

[0104] In a further aspect of the present application, a method for producing a compound of formula (I) is provided, which includes step (1’), step (2’), and step (3’).

[0105] In some embodiments, the step of obtaining compound 1-2a is carried out in the presence of a solvent. In some embodiments, the solvent is selected from acetonitrile and water.

[0106] In some embodiments, the step of obtaining compound 1-2a is carried out in the presence of a base. In some embodiments, the base is selected from lithium carbonate.

[0107] In some embodiments, compound 1-2a is obtained by the following method. Dissolve compound BB-1 and compound 1-1a in acetonitrile, and then add lithium carbonate and water and react them.

[0108] In some embodiments, the reaction temperature for the step of obtaining compound 1-2a is 100 °C.

[0109] In some embodiments, the reaction time for the step of obtaining compound 1-2a is 70 hours.

[0110] In some embodiments, in the step of obtaining compound 1-2a, the molar ratio of compound BB-1 to compound 1-1a is 1:6.

[0111] In some embodiments, the step of obtaining compound BB-4 is carried out in the presence of hydrogen chloride.

[0112] In some embodiments, the step of obtaining compound BB-4 is carried out in the presence of a solvent. In some embodiments, the solvent is selected from methanol.

[0113] In some embodiments, compound BB-4 is obtained by the following method. React compound 1-2a in a methanol solution of hydrogen chloride to obtain compound BB-4.

[0114] In some embodiments, the reaction temperature for the step of obtaining compound BB-4 is 60 °C.

[0115] In some embodiments, the reaction time for the step of obtaining compound BB-4 is 2 hours.

[0116] In some embodiments, the step of obtaining compound BB-4 further includes a step of treating with petroleum ether and ethyl acetate after the reaction.

[0117] In some embodiments, the step of obtaining the compound of formula (I) from compound BB-4 is carried out in the presence of a solvent. In some embodiments, the solvent is selected from dichloromethane.

[0118] In some embodiments, the step of obtaining the compound of formula (I) from compound BB-4 is carried out in the presence of a base. In some embodiments, the base is selected from triethylamine.

[0119] In some embodiments, the step of obtaining the compound of formula (I) from compound BB-4 is carried out in the presence of a condensing agent. In some embodiments, the condensing agent is selected from HATU.

[0120] In some embodiments, in the step of obtaining the compound of formula (I) from 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 to 1.2).

[0121] In some embodiments, the reaction temperature in the step of obtaining the compound of formula (I) from compound BB-4 is 20 °C.

[0122] In some embodiments, the reaction time in the step of obtaining the compound of formula (I) from compound BB-4 is 16 hours.

[0123] In a further aspect of the present application, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0124] In a further aspect of the present application, there is provided a method for preparing a compound of formula (I) comprising obtaining the compound of formula (I) by reacting compound 1-4b.

[0125] In a further aspect of the present application, there is provided a method for producing compound 1-4b, which comprises obtaining compound 1-4b by reacting compound BB-4 with compound 1-3b.

Chem.

[0126] In a further aspect of the present application, there is provided a method for producing compound BB-4, which comprises obtaining compound BB-4 by reacting compound 1-1b.

Chem.

[0127] In a further aspect of the present application, there is provided a method for producing compound 1-1b, which comprises obtaining compound 1-1b by reacting compound BB-1 with compound a.

Chem.

[0128] In some embodiments, X is selected from Cl and Br. In some embodiments, X is selected from Br.

[0129] In a further aspect of the present application, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Chem.

[0130] In a further aspect of the present application, there is provided a method for producing a compound of formula (I) comprising steps (i) and (ii).

[0131] In a further aspect of the present application, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof. [Chemical formula] The compound of formula (I) is prepared by the following method. (i’) Obtaining compound BB-4 by reacting compound 1-1b. (ii’) Obtaining compound 1-4b by reacting compound BB-4 with compound 1-3b. (iii’) Obtaining the compound of formula (I) by reacting compound 1-4b.

[0132] In a further aspect of the present application, there is provided a method for preparing a compound of formula (I) comprising the steps (i’), (ii’), and (iii’).

[0133] In a further aspect of the present application, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof. [Chemical formula] The compound of formula (I) is prepared by the following method. (i’’) Obtaining compound 1-1b by reacting compound BB-1 with compound a. (ii’’) Obtaining compound BB-4 by reacting compound 1-1b. (iii’’) Obtaining compound 1-4b by reacting compound BB-4 with compound 1-3b. (iv’’) Obtaining the compound of formula (I) by reacting compound 1-4b. [Chemical formula] Here, X is selected from halogens.

[0134] In some embodiments, X is selected from Cl and Br. In some embodiments, X is selected from Br.

[0135] In a further aspect of the present application, there is provided a method for producing a compound of formula (I) comprising the steps (i''), (ii''), (iii''), and (iv'').

[0136] In a further aspect of the present application, there is provided compound 1-1b or a pharmaceutically acceptable salt thereof.

Chemical formula

[0137] In a further aspect of the present application, there is provided compound 1-4b or a pharmaceutically acceptable salt thereof.

Chemical formula

[0138] In some embodiments, the step of obtaining compound 1-1b is carried out in the presence of a solvent. In some embodiments, the solvent is selected from 2-butanone.

[0139] In some embodiments, the step of obtaining compound 1-1b is carried out in the presence of a catalyst. In some embodiments, the catalyst is selected from potassium phosphate, for example, anhydrous potassium phosphate.

[0140] In some embodiments, the step of obtaining compound 1-1b is carried out in the presence of a co-solvent. In some embodiments, the co-solvent is selected from sodium iodide.

[0141] In some embodiments, the preparation of compound 1-1b is carried out in the presence of potassium phosphate and sodium iodide.

[0142] In some embodiments, in the step of obtaining compound 1-1b, the molar ratio of compound BB-1 to compound a is 1:3.

[0143] In some embodiments, the reaction temperature in the step of obtaining compound 1-1b is 90 °C.

[0144] In some embodiments, the reaction time for the step of obtaining Compound 1-1b is 18 hours.

[0145] In some embodiments, the step of obtaining Compound BB-4 is carried out in the presence of a solvent. In some embodiments, the solvent is selected from tetrahydrofuran.

[0146] In some embodiments, the step of obtaining Compound BB-4 is carried out in the presence of borane dimethyl sulfide.

[0147] In some embodiments, the reaction temperature for the step of obtaining Compound BB-4 is 20 - 25 °C.

[0148] In some embodiments, the reaction time for the step of obtaining Compound BB-4 is 18 hours.

[0149] In some embodiments, the step of obtaining Compound BB-4 includes adding Compound 1-1b to a mixture of tetrahydrofuran and borane dimethyl sulfide at 0 °C, and then raising the temperature to carry out the reaction. In some embodiments, the temperature is raised to 20 - 25 °C for the reaction.

[0150] In some embodiments, the step of obtaining Compound BB-4 includes lowering the temperature (for example, to 0 °C) after reacting for a predetermined time (for example, 18 hours). Further, it further includes adding methanol after lowering the temperature. Further, it further includes adjusting the pH after adding methanol. Further, it further includes a step of concentrating the product after pH adjustment. Further, it further includes a purification step.

[0151] In some embodiments, in the step of adjusting the pH after adding the methanol, the pH is adjusted to 2 - 3.

[0152] In some embodiments, in the step of adjusting the pH after adding the methanol, hydrochloric acid is used to adjust the pH.

[0153] In some embodiments, in the step of obtaining Compound 1-4b, the molar ratio of Compound BB-4 to Compound 1-3b is 1:(1 to 1.5).

[0154] In some embodiments, the step of obtaining Compound 1-4b is carried out in the presence of a condensing agent. In some embodiments, the condensing agent is N,N-carbonyldiimidazole.

[0155] In some embodiments, the preparation of Compound 1-4b includes the step in which Compound 1-3b first reacts with a condensing agent (e.g., N,N-carbonyldiimidazole), and then reacts with Compound BB-4 to obtain Compound 1-4b.

[0156] In some embodiments, in the step of obtaining Compound 1-4b, the step in which Compound 1-3b reacts with an activator is carried out in the presence of a solvent. In some embodiments, the solvent is selected from dichloromethane.

[0157] In some embodiments, in the step of obtaining Compound 1-4b, the reaction temperature of the step in which Compound 1-3b reacts with an activator is 25°C.

[0158] In some embodiments, in the step of obtaining Compound 1-4b, the reaction time of the step in which Compound 1-3b reacts with an activator is 5 hours.

[0159] In some embodiments, in the step of obtaining Compound 1-4b, after Compound 1-3b reacts with an activator, the step of further reacting with Compound BB-4 is carried out in the presence of a solvent. In some embodiments, the solvent is selected from DMF.

[0160] In some embodiments, in the step of obtaining Compound 1-4b, after Compound 1-3b reacts with an activator, the reaction temperature for further reacting with Compound BB-4 is 20 to 25 °C.

[0161] In some embodiments, in the step of obtaining Compound 1-4b, after Compound 1-3b reacts with an activator, the reaction time for further reacting with Compound BB-4 is 18 hours.

[0162] In some embodiments, in the step of obtaining Compound 1-4b, after the reaction is completed, the step of adding methanol for treatment is further included.

[0163] In some embodiments, the step of obtaining the compound of formula (I) from 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.

[0164] In some embodiments, the volume ratio of trifluoroacetic acid to acetic acid is 5:1.

[0165] In some embodiments, the reaction temperature for obtaining the compound of formula (I) from Compound 1-4b is 90 to 100 °C.

[0166] In some embodiments, the reaction time for obtaining the compound of formula (I) from Compound 1-4b is 48 hours.

[0167] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is such that the compound of formula (I) is a crystal, and the crystal is a Form A crystal of the compound of formula (I), a Form B crystal of the compound of formula (I), or a Form C crystal of the compound of formula (I).

[0168] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is such that the pharmaceutically acceptable salt is a sulfate, p-toluenesulfonate, mesylate, or maleate.

[0169] The compound BB-1 of the present application is obtained by the following method. [Chemical formula]

[0170] In another aspect of the present application, as a method for producing crystals of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound of formula (I) or a pharmaceutically acceptable salt thereof is produced by any of the methods for producing the compound of formula (I) or a salt thereof, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is precipitated from a solvent selected from a mixed solvent of methanol, ethanol and water, acetonitrile, and a mixed solvent of tetrahydrofuran and water. The method is provided. In some specific embodiments of the present application, a method for producing crystals of a pharmaceutically acceptable salt of the compound of formula (I) is provided, which includes precipitating a salt of the compound of formula (I) from a mixed solvent of tetrahydrofuran and water. In some specific embodiments of the present application, a method for producing crystals of a pharmaceutically acceptable salt of the compound of formula (I) is provided, which includes mixing the compound of formula (I) and tetrahydrofuran, adding an aqueous solution of an acid (and / or base) to react, and precipitating a salt of the compound of formula (I) in crystal form from a mixed solvent of tetrahydrofuran and water.

[0171] In a further aspect of the present application, a pharmaceutical composition is provided that includes a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the present application, the crystal or a crystal composition thereof. The pharmaceutical composition of the present application may or may not include a pharmaceutically acceptable additive. Further, the pharmaceutical composition of the present application may further include one or more other therapeutic agents.

[0172] In another aspect of the present application, further provided is a method for preventing or treating PDE3- and / or PDE4-related diseases in a mammal, preferably a human, which includes administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the crystal, the crystal composition, or the pharmaceutical composition thereof to a mammal in need of prevention or treatment.

[0173] In another aspect of the present application, there is further provided the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, a crystal thereof, a crystal composition thereof, or a pharmaceutical composition thereof in the manufacture of a drug for preventing or treating a PDE3- and / or PDE4-related disease.

[0174] In another aspect of the present application, there is further provided the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, a crystal thereof, a crystal composition thereof, or a pharmaceutical composition thereof for preventing or treating a PDE3- and / or PDE4-related disease.

[0175] In another aspect of the present application, there is further provided the compound of formula (I) or a pharmaceutically acceptable salt thereof, a crystal thereof, a crystal composition thereof, or a pharmaceutical composition thereof for preventing or treating a PDE3- and / or PDE4-related disease.

[0176] In some embodiments of the present application, the PDE3- and / or PDE4-related disease is selected from asthma and chronic obstructive pulmonary disease (COPD).

Advantages of the Invention

[0177] The compound of formula (I) of the present application has an obvious dual inhibitory effect on PDE3 and PDE4, and also has an obvious inhibitory effect on TNF-α in human peripheral blood mononuclear cells (hPBMC). It shows excellent anti-inflammatory effects in a lipopolysaccharide (LPS)-induced rat acute lung injury model. It has a high in vivo plasma clearance, low plasma exposure and bioavailability by oral administration, and high safety by local route administration. It has a low inhibitory effect on five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) of cytochrome P450 derived from human liver microsomes, and there is no risk of drug interaction. It has obvious anti-inflammatory effects such as reducing the total number of white blood cells in BALF, and the minimum effective dose is low. It can reduce the airway resistance index Penh.

[0178] Crystals of the compound of formula (I) of the present application and crystals of pharmaceutically acceptable salts thereof have advantages in terms of drug activity, pharmacokinetics, bioavailability, hygroscopicity, melting point, stability, solubility, purity, ease of manufacture, etc., thus meeting the requirements regarding drug manufacture, storage, transportation, and formulation.

[0179] In the method for producing the compound of formula (I) of the present application, Method 2 can obtain an aminoethyl-substituted compound in one step, the reaction system is clean, and there is no need to introduce an amide or cyano group and then reduce it as in the conventional method. In Method 3, since a non-genotoxic bromoacetamide is used instead of the genotoxic reagent bromoacetonitrile, the safety risks related to drug synthesis and development are reduced.

[0180] "Definitions and Explanations" Unless otherwise specified, the following terms and expressions used in this specification have the following meanings. For a specific expression or term, if there is no specific definition, it should not be regarded as uncertain or unclear, but should be understood in its ordinary meaning. When a trade name is described in this specification, it refers to the corresponding product or its active ingredient.

[0181] In the X-ray powder diffraction pattern, the peak position or the relative peak intensity may vary depending on the measuring device, measuring method / conditions, etc. For any determined crystal form, there may be an error in the peak position, and the measurement error of the 2θ angle may be ±0.2°. Therefore, when determining various crystal forms, this error should be considered, and those within the error are included in the scope of the present application.

[0182] In addition, even for the same crystal form, the appearance position of the endothermic peak in DSC may vary depending on the measuring device, measuring method / conditions, etc. For any determined crystal form, there may be an error in the position of the endothermic peak, and the error may be ±5°C or ±3°C. Therefore, when determining various crystal forms, this error should be considered, and those within the error are included in the scope of the present application.

[0183] The term "comprise", similar terms and their English equivalents, such as comprises, comprising or the like, are understood as open and non-exclusive expressions of "including... but not limited to", meaning that in addition to the recited elements, components or steps, other elements, components or steps not specified may also be included.

[0184] The term "pharmaceutically acceptable" is used for compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human or animal tissue, are medically determined to be non-toxic and non-irritating, and do not cause allergic reactions, other problems or complications, and for which the benefit-to-risk ratio is reasonable.

[0185] Regarding the term "pharmaceutically acceptable salt", examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and the like.

[0186] The term "pharmaceutically acceptable additive" refers to an inert substance that is administered together with the active ingredient to facilitate the administration of the active ingredient, and includes, but is not limited to, any flow promoter, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent approved by the China National Food and Drug Administration for use in humans or animals (e.g., livestock). Non-limiting examples of the excipients include calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0187] The term "pharmaceutical composition" refers to a mixture comprising one or more compounds of the present application or salts thereof and pharmaceutically acceptable additives. The pharmaceutical composition is for facilitating the administration of the compound of the present application to a living body.

[0188] The pharmaceutical composition of the present application may be produced by combining the compound of the present application with a suitable pharmaceutically acceptable additive, and may be produced, for example, as a solid, semi-solid, liquid or gaseous preparation, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, etc.

[0189] Typical routes of administration of the crystal or its pharmaceutical composition described in the present application include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.

[0190] The pharmaceutical composition of the present application may be produced by methods well known in the art, such as ordinary methods of mixing, dissolving, granulating, sugar coating, pulverizing, emulsifying, freeze-drying, etc.

[0191] In some embodiments, the pharmaceutical composition is for oral administration. In the case of oral administration, the active compound can be mixed with pharmaceutically acceptable additives well known in the art to produce the pharmaceutical composition. By such additives, the compound of the present application is formulated as tablets, pills, sugar-coated agents, capsules, liquids, gels, syrups, suspensions, etc. for oral administration to patients.

[0192] The therapeutic dose of the compound of the present application is determined by the purpose of treatment, the mode of administration of the compound, the health status of the patient, the judgment of the prescribing physician, etc. The ratio or concentration of the compound of the present application in the pharmaceutical composition is not necessarily constant and is determined by various factors such as the dose, chemical properties (e.g., hydrophobicity), route of administration, etc. The term "treatment" means administering the compound or formulation described in the present application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes the following. (i) inhibiting a disease or disease state, i.e., suppressing its progression; (ii) alleviating a disease or disease state, i.e., eliminating the disease or disease state.

[0193] The term "prevention" means administering the compounds or formulations described in the present application to prevent a disease or one or more symptoms associated with said disease, and includes the following. Preventing the occurrence of a disease or disease state in a mammal, particularly including prevention when a mammal prone to said disease state has not been diagnosed with said disease state.

[0194] When used with respect to a drug or a pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient dosage of the drug or its formulation that is non-toxic and can achieve the desired effect. Said effective amount is determined by the age and general condition of the administration subject and varies depending on the type of active substance. In actual administration, those skilled in the art can appropriately determine the effective amount through normal tests.

[0195] The therapeutically effective amount of the crystal described in the present application is from about 0.0001 to 20 mg / kg body weight / day, for example, from 0.001 to 10 mg / kg body weight / day.

[0196] The dosage and frequency of administration of the crystal described in the present application are determined according to the condition of the patient, for example, once or twice a day, or multiple times a day. Administration may be intermittent, for example, administering the daily dose of the crystalline form to the patient for a certain number of days, and then not administering the daily dose of the crystalline form to the patient for the same number of days or a longer period.

[0197] In this specification, unless otherwise clearly specified, singular terms cover cases with multiple referents, and vice versa.

[0198] In this specification, unless otherwise explained, the values of each parameter (including 2θ angle, reaction conditions, etc.) are considered to be modified by the term "about" so as to include errors in values due to measurement, etc., for example, there is an error of ±5% with respect to the described value.

[0199] For the purposes of explanation and disclosure in this specification, patents, patent applications or existing publications are incorporated by reference in their entirety. Since these publications were published before the filing date of this application, they can be provided. The statements regarding the publication dates of these documents or the descriptions of their contents are based on the information available to the applicant and do not constitute an admission that the publication dates or the contents of these documents are correct. Moreover, in all target countries, the incorporation of these publications into this specification does not recognize that such publications have become common general knowledge in this field.

[0200] Next, the present application will be described in detail using examples. The examples are not intended to impose any limitations on the present application.

[0201] The intermediate compounds of the present application include the following specific embodiments, embodiments combined with other chemical synthesis methods, and alternative replacement forms well-known to those skilled in the art. The preferred embodiments include, but are not limited to, the examples of the present application, and can be prepared by various synthesis methods well-known to those skilled in the art.

[0202] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, and the solvent is suitable for the chemical changes of the present application and the reagents and raw materials used. In order to obtain the compounds of the present application, in some cases, those skilled in the art need to select or change the synthesis steps or reaction processes based on the existing embodiments.

[0203] Next, the present application will be described in detail using examples. The examples are not intended to impose any limitations on the present application.

[0204] All solvents used in the present application are commercially available products and can be used without purification.

[0205] The solvents used in the present application may be commercially available products. The abbreviations used in the present application and their meanings are as follows. DMSO is dimethyl sulfoxide. TsOH is p-toluenesulfonic acid. MsOH is methanesulfonic acid.

[0206] Powder X-ray Diffraction (X-ray powder diffractometer, XRPD) Instrument model: Bruker D8 advance X-ray diffractometer, radiation source: Cu Kα (λ = 1.54056 Å). Differential Scanning Calorimetry (Differential Scanning Calorimeter, DSC) Instrument model: TA Q2000 differential scanning calorimeter. Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) Instrument model: TA Q5000IR thermogravimetric analyzer.

Brief Description of Drawings

[0207]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Mode for Carrying Out the Invention

[0208] Next, for a further understanding of the content of the present application, further explanations will be given using specific examples. However, these specific embodiments are not limitations on the content of the present application.

Examples

[0209] Synthesis of Intermediate BB-1

Chemical Formula

Chemical Formula

[0210] Step 1: Synthesis of Compound BB-1-2 Under a 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 completion of the reaction, the mixture was cooled to 70 °C, and ethanol (30 mL) was slowly added dropwise, upon which a large amount of solid precipitated. The mixture was filtered, and the cake was dried under reduced pressure to obtain Product BB-1-2. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.26 (t, J = 5.2 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.79 (br s, 1H), 6.71 (d, 8.0 Hz, 1H), 4.00 (q, J = 6.8 Hz, 2H), 3.72 (s, 3H), 3.59 (s, 2H), 3.31 - 3.23 (m, 2H), 2.64 (t, J = 7.2 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H). MS-ESI m / z: 263.1 [M+H] + 。

[0211] Step 2: Synthesis of Compound BB-1-3 Under a nitrogen atmosphere, phosphoryl trichloride (379.50 g, 230.00 mL) was heated to 85 °C, and compound BB-1-2 (26.00 g) was added in several portions. The reaction mixture was reacted for 2 hours with stirring at 85 °C. After completion of the reaction, most of the phosphoryl trichloride was removed by distillation under reduced pressure. Dichloromethane (200 mL) was added to the residue, and it was washed with water (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The crude product was obtained and pulped and purified with ethyl acetate (20 mL) to obtain compound BB-1-3. 1 1H NMR (400 MHz, CD3OD) δ = 7.16 (s, 1H), 6.83 (s, 1H), 4.62 (s, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.35 (d, J = 6.4 Hz, 2H), 2.84 (t, J = 6.4 Hz, 2H), 1.44 (t, J = 6.8 Hz, 3H). MS-ESI m / z: 245.1 [M+H] + 。

[0212] Step 3: Synthesis of Compound BB-1-4 At 0 °C, compound BB-1-3 (1.00 g) was added to 98% concentrated sulfuric acid (12.88 g, 128.69 mmol, 7.00 mL) in several portions. The reaction mixture was stirred at 27 °C for 3 hours. After completion of the reaction, the mixture was added to cold water (15 mL), and then an aqueous sodium hydroxide solution (4 mol / L, 32 mL) was added dropwise to adjust the pH to neutral, followed by extraction with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain compound BB-1-4. MS-ESI m / z: 263.1 [M+H] + 。

[0213] Step 4: Synthesis of compound BB-1-5 At 0 °C, sodium (2.42 g) was added to ethanol (80 mL) in several portions. After the mixture was stirred at 28 °C for 30 minutes, compound BB-1-4 (6.90 g) was added to the solution in several portions, and the mixture was stirred at 80 °C for 30 minutes. Subsequently, diethyl carbonate (9.32 g, 9.51 mL) was added all at once, and the mixture was continuously stirred at 80 °C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, ice water (30 mL) was slowly added, and then the pH was adjusted to neutral with dilute hydrochloric acid (2 mol / L, 53 mL) to precipitate a large amount of solid. The solid was filtered to obtain a cake, which was pulped with ethanol (10 mL) and purified to obtain compound BB-1-5. 1 H NMR (400 MHz, DMSO-d6) δ = 11.22 (br s, 1H), 7.35 (s, 1H), 6.95 (s, 1H), 6.22 (s, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.90 (br s, 2H), 3.83 (s, 3H), 2.89 (br s, 2H), 1.35 (t, J = 6.8 Hz, 3H). MS-ESI m / z: 289.1 [M+H] + 。

[0214] Step 5: Synthesis of compound BB-1-6 At room temperature, compound BB-1-5 (5.00 g) was dissolved in phosphoryl trichloride (30 mL). Under a nitrogen atmosphere, the reaction mixture was stirred at 100 °C for 16 hours. After completion of the reaction, most of the solvent was removed by distillation under reduced pressure. Water (100 mL) was added, and the mixture was extracted with dichloromethane (150 mL × 2). The combined organic phases were 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] + 。

[0215] Step 6: Synthesis of compound BB-1 At room temperature, compound BB-1-6 (925.67 mg) was dissolved in isopropanol (8 mL), and 2,4,6-trimethylaniline (2.10 g) was added. Under a nitrogen atmosphere, the reaction mixture was stirred at 90 °C for 15 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a residue, which was pulped and purified with ethanol (6 mL) to obtain compound BB-1. 1 H NMR (400 MHz, 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 = 6.8 Hz, 2H), 3.90 (t, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.87 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H), 2.11 (s, 6H), 1.37 (t, J = 6.8 Hz, 3H). MS-ESI m / z: 406.2 [M+H] + 。

[0216] Synthesis of compound BB-4

Chemical formula

Chemical formula

[0217] Step 1: Synthesis of compound BB-4-1 At room temperature, compound BB-1 (1.00 g) was dissolved in 2-butanone (35 mL), 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 this order. Under a nitrogen atmosphere, the reaction mixture was stirred at 85 °C for 72 hours. After completion of the reaction, the mixture was concentrated to remove most of the organic solvent, water (30 mL) was added, and the mixture was extracted with ethyl acetate (25 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1 to 3:1) to obtain compound BB-4-1. MS-ESI m / z: 579.3 [M+H] + 。

[0218] Step 2: Synthesis of compound BB-4 At room temperature, compound BB-4-1 (500.00 mg) was dissolved in chloroform (3 mL) and ethanol (3 mL), and hydrazine hydrate (152.67 mg, purity 85%) was added. Under a nitrogen atmosphere, the mixture was stirred at 28 °C for 16 hours. After completion of the reaction, the mixture was concentrated to remove most of the organic solvent, water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain compound BB-4. 1 H NMR (400 MHz, DMSO-d6) δ = 6.95 (s, 1H), 6.85 (br s, 2H), 6.66 (s, 1H), 5.31 (s, 1H), 4.14 (t, J = 6.8 Hz, 2H), 4.05 (q, J = 6.8 Hz, 2H), 3.91 (t, J = 6.4 Hz, 2H), 3.62 (s, 3H), 2.90 - 2.86 (m, 4H), 2.22 (s, 3H), 1.95 (br s, 6H), 1.33 (t, J = 6.8 Hz, 3H). MS-ESI m / z: 449.2 [M+H] + 。

[0219] Example 1: Production of the compound of formula (I) Method 1: [Chemistry]

[0220] At 20 °C, 5-hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid (18.50 mg) was dissolved in DCM (1 mL), HATU (8.80 mg) and triethylamine (57.40 μL) were added, and the mixture was stirred for 2 hours. Subsequently, compound BB-4 (50 mg) was added, and stirring was continued for 16 hours while maintaining the 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 drying agent, and the filtrate was concentrated under reduced pressure to evaporate the solvent to obtain a crude product. The crude product was purified by prep-HPLC to obtain the target compound of formula (I) as a yellow solid. 1 H NMR (400 MHz, CD3OD) δ = 6.94 (s, 2H), 6.87 (s, 1H), 6.77 (s, 1H), 5.52 (s, 1H), 4.48 (t, J = 6.0 Hz, 2H), 4.15 (s, 3H), 4.12 - 4.08 (m, 2H), 4.01 (t, J = 6.0 Hz, 2H), 3.87 (t, J = 6.0 Hz, 2H), 3.69 (s, 3H), 2.94 (t, J = 6.0 Hz, 2H), 2.29 (s, 3H), 2.06 (s, 6H), 1.41 (t, J = 6.8 Hz, 3H). MS m / z: 574.1 [M + H] + 。

[0221] [Chemistry]

[0222] Step 1: Preparation of Compound 1-1a N-Boc-ethanolamine (50 g, 48.08 mL), p-toluenesulfonyl chloride (70.96 g) were dissolved in methyl tert-butyl ether (500 mL), potassium hydroxide (52.21 g) was added, and then 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 (1000 mL), and the organic phase was separated. The aqueous phase was extracted with methyl tert-butyl ether (100 mL × 2). The combined organic phases were washed with cold water (1000 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to evaporate the solvent to obtain 28.5 g of a yellow oily liquid as the crude product of 1-1a, and the crude product could be directly used in the next-step reaction without purification. 1 H NMR (400 MHz, CHCl3-d) δ (ppm) 2.15 (s, 4H), 1.47 (s, 9H).

[0223] Step 2: Preparation of Compound 1-2a Compound BB-1 (2 g) and Compound 1-1a (4.24 g) were dissolved in acetonitrile (17 mL), lithium carbonate (2.19 g) and water (3 mL) were added, and then the temperature was raised to 100 °C and stirred for 70 hours. The mixture was cooled and allowed to stand, filtered to remove the precipitate, and the filtrate was concentrated under reduced pressure to evaporate the solvent. After that, it was mixed with 50 mL of water and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with 0.5 M sodium hydroxide solution (100 mL), then dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 1.08 g of a pale yellow solid as the target compound 1-2a. MS-ESI (m / z): 549.2 [M+1] + 。 11H NMR (400 MHz, MeOH-d4) δ (ppm) 6.91 (s, 2H), 6.85 (s, 1H), 6.75 (s, 1H), 5.49 (s, 1H), 4.36 (t, J = 5.9 Hz, 2H), 4.09 (q, J = 7.0 Hz, 2H), 4.00 (t, J = 6.1 Hz, 2H), 3.68 (s, 3H), 3.56 - 3.48 (m, 2H), 2.91 (t, J = 6.3 Hz, 2H), 2.27 (s, 3H), 2.06 (s, 6H), 1.39 (s, 12H).

[0224] Step 3: Preparation of Compound BB-4 Compound 1-2a (1 g) and 4 M hydrogen chloride-methanol solution (20 mL) were uniformly mixed and then heated to 60 °C and stirred for 2 hours. The mixture was concentrated under reduced pressure to evaporate and remove the solvent, obtaining a pale yellow oily liquid as the crude product. 20 mL of petroleum ether and 5 mL of ethyl acetate were added to the crude product, stirred for 30 minutes and then filtered to collect the solid, which was dried to obtain a pale yellow solid as the target compound BB-4 (810 mg, yield 91.63%). 1 1H NMR (400 MHz, MeOH-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 = 7.0 Hz, 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 = 7.0 Hz, 3H).

[0225] Step 4: Preparation of Compound (I) At 20 °C, 5-hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid (18.50 mg) was dissolved in DCM (1 mL), HATU (8.80 mg) and triethylamine (57.40 μL) were added, and the mixture was stirred for 2 hours. Subsequently, compound BB-4 (50 mg) was added, and stirring was continued for 16 hours while maintaining the 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 evaporate the solvent to obtain a crude product. The crude product was purified by prep-HPLC to obtain the target compound as a yellow solid of formula (I) (22 mg, yield 37.2%). MS-ESI (m / z): 574.5 [M+1] + 。 1 H NMR (400 MHz, MeOH-d4) δ (ppm) 6.94 (s, 2H), 6.87 (s, 1H), 6.75 (s, 1H), 5.51 (s, 1H), 4.47 (br t, J = 6.0 Hz, 2H), 4.14 (s, 3H), 4.10 (q, J = 7.0 Hz, 2H), 4.01 (br t, J = 5.9 Hz, 2H), 3.85 (br t, J = 5.9 Hz, 2H), 3.68 (s, 3H), 2.92 (br t, J = 6.0 Hz, 2H), 2.29 (s, 3H), 2.05 (s, 6H), 1.41 (t, J = 6.9 Hz, 3H).

[0226] Method 3:

Chemical formula

[0227] Step 1: Preparation of compound 1-1b At 20 °C, 2-butanone (12 L) was added to a 50 L reaction vessel equipped with a jacket. While stirring, compound BB-1 (615 g) and 2-bromoacetamide (612.4 g) were added. Then, potassium phosphate anhydrous (1.57 kg) and sodium iodide (665.4 g) were added to the reaction system. The reaction mixture was heated to 90 °C under nitrogen protection and stirred for 18 hours. After the reaction solution was cooled to room temperature, water (12 L) was added, and after stirring for 1 hour, it was filtered to obtain a solid, which was dried in vacuo to obtain the target compound 1-1b as a yellow solid (575 g, yield 81.96%). MS-ESI (m / z): 463.23 [M+1] + 。 1 H NMR (400 MHz, 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 = 6.9 Hz, 2H), 3.91 (br t, J = 6.0 Hz, 2H), 3.63 (s, 3H), 2.90 (br t, J = 5.9 Hz, 2H), 2.20 (s, 3H), 1.92 (s, 6H), 1.33 (t, J = 7.0 Hz, 3H).

[0228] Step 2: Preparation of compound BB-4 After adding tetrahydrofuran (8.6 L) to a dried 50 L reaction vessel with a jacket at 20 °C, a borane·dimethyl sulfide solution (10 M, 950 mL) was added dropwise to the reaction vessel while stirring. After the addition was complete, the temperature was lowered to 0 °C, compound 1-1b (440 g) was added, the cooling device was turned off, and after the temperature naturally returned to 20 - 25 °C, the reaction was continued with stirring for 18 hours. The reaction solution was cooled to 0 °C, methanol (about 1.5 L) was added dropwise to quench it until no bubbles were generated, and then a 3 M hydrochloric acid solution (about 800 mL) was added dropwise to the reaction solution to adjust the pH to 2 - 3. The reaction solution was concentrated under reduced pressure to evaporate and remove the solvent. The residue was dissolved in dichloromethane, then a saturated sodium bicarbonate solution was added to adjust the pH to 7 - 8, liquid separation was performed, 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, concentrated under reduced pressure, and the concentrated product was purified by high-speed column chromatography to obtain 125 g of the target compound BB-4. MS-ESI(m / z):449.25[M+1] + 。 1 H 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).

[0229] Step 3: Preparation of Compound 1-4b At 20 °C, compound 1-3b (68.68 g) was dissolved in dichloromethane (700 mL), and N,N-carbonyldiimidazole (61.56 g) was added. The mixture was stirred at 25 °C for 5 hours. It was washed with saturated brine (700 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was added to DMF (675 mL) and dissolved, and compound BB-4 (95 g) was added in several portions. After completion, 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%). MS-ESI(m / z): 694.33[M+1] + 。 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).

[0230] Step 4: Preparation of compound (I) At 20 °C, compound 1-4b (120 g) was dissolved in a mixed solvent of trifluoroacetic acid (1000 mL) and glacial acetic acid (200 mL), 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 was adjusted to 7 - 8 with saturated sodium bicarbonate solution. The organic and aqueous phases were separated by liquid separation. The aqueous phase was extracted with DCM (1000 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to evaporate the solvent to obtain the target compound of formula (I) (80 g, yield 80.60%). MS-ESI(m / z): 574.27[M+1] + 。 1 1H NMR (400 MHz, 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 = 6.1 Hz, 2H), 4.12~4.01 (m, 5H), 3.88 (t, J = 6.1 Hz, 2H), 3.70 (q, J = 6.1 Hz, 2H), 3.62 (s, 3H), 2.87 (br t, J = 6.0 Hz, 2H), 2.21 (s, 3H), 1.93 (s, 6H), 1.33 (t, J = 6.9 Hz, 3H), 0.90~0.90 (m, 1H).

[0231] Example 2: Preparation of Form A Crystal of the Compound of Formula (I) 50 mg of the compound of formula (I) was added to a 4 mL glass bottle, 1 mL of anhydrous methanol was added, the temperature was raised to 40 °C, and the mixture was stirred for 48 hours. It was cooled to room temperature by natural cooling, the solid was separated by centrifugation, and dried in vacuo to obtain 34 mg of a solid as Form A crystal. The XRPD pattern, DSC curve, and TGA curve are as shown in Figure 1, Figure 2, and Figure 3, respectively.

[0232] Example 3: Preparation of Form B Crystal of the Compound of Formula (I) 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, the temperature was raised to 40 °C, and the mixture was stirred for 48 hours. It was cooled to room temperature by natural cooling, the solid was separated by centrifugation, and dried in vacuo to obtain 46 mg of a solid as Form B crystal. The XRPD pattern, DSC curve, and TGA curve are as shown in Figure 4, Figure 5, and Figure 6, respectively.

[0233] Example 4: Preparation of Form C Crystal of the Compound of Formula (I) 50 mg of the compound of formula (I) was added to a 4 mL glass bottle, 1 mL of acetonitrile was added, the temperature was raised to 40 °C, and the mixture was stirred for 48 hours. It was cooled to room temperature by natural cooling, the solid was separated by centrifugation, and dried in vacuo to obtain 37 mg of a solid as Form C crystal. The XRPD pattern, DSC curve, and TGA curve are as shown in Figure 7, Figure 8, and Figure 9, respectively.

[0234] Example 5: Preparation of Salt of the Compound of Formula (I) Add 100 mg of the compound of formula (I) to a 4 mL glass bottle, add 2 mL of anhydrous tetrahydrofuran, heat to 70 °C, stir for 1 hour to dissolve completely, cool to 40 °C, and add a solution prepared with the corresponding acid or base (see Table 8 for specifications and dosages) and 0.1 mL of water. Then, continue stirring for 12 hours while maintaining the temperature. Centrifuge the mixture to separate the solid precipitate, and vacuum dry to obtain a solid, which was the corresponding salt in the crystalline form of the compound of formula (I).

Table 8

[0235] Example 6: Study on the stability of the solid of the B - type crystal of the compound of formula (I) High - performance liquid chromatography (HPLC) Refer to the following for the composition of the HPLC method. Column: Zorbax SB C - 18, 4.6 mm×150 mm, 5 μm (PDS - HPLC - 007). Mobile phase A: 0.1% TFA in water. Mobile phase B: 100% ACN. Sample preparation: Dissolve the sample in a mixed solvent of acetonitrile and water (acetonitrile: water = 50:50 (V:V)).

[0236] Static method for examining the stability of the solid: The stability of the compound when standing under the following conditions was examined, and samples were taken at different times to measure the content. Accurately weigh about 5 mg of the B - type crystal of the compound of formula (I), put it into a dry and clean glass bottle, and use it as a double - sample. The thinly spread one was used as the formal test sample. Under the influencing factor test conditions (60 °C), (relative humidity 92.5%), light (total illuminance 1.2×10 6 Lux·hr / near - ultraviolet region 200 W·hr / m 2)、(40 °C, relative humidity 75%), (60 °C, relative humidity 75%), and left to stand still so that the samples were fully exposed, covered with aluminum foil and small holes were made. Samples were taken and analyzed at 5 days, 10 days, 1 month, 2 months, and 3 months. The samples left to stand still under light (visible light 1200000 Lux, ultraviolet 200 W) conditions were fully exposed at room temperature. Refer to Table 9 for the experimental results.

Table 9

[0237] As can be seen from the above, the crystals of the compound of formula (I) in the present application have good stability under high temperature, high humidity or light conditions, and no impurities increased during the test.

[0238] Example 7: Study on the hygroscopicity of the B-type crystal of the compound of formula (I) Apparatus model: SMS DVS Advantage dynamic vapor sorption measurement apparatus Measurement conditions: The sample (10 - 20 mg, B-type crystal produced in Example 3) was placed on the DVS sample tray for measurement.

[0239] The detailed DVS parameters are as follows. Temperature: 25 °C. Equilibrium: dm / dt = 0.01% / min (minimum 10 minutes, maximum 180 minutes). Drying: Dried for 120 minutes under 0% RH. RH (%) measurement step: 10%. RH (%) measurement step range: 0% - 90% - 0%. The final dynamic vapor sorption (DVS) curve is as shown in Figure 18.

[0240] As can be seen from Figure 18, the crystals of the compound of formula (I) in the present application have low hygroscopicity.

[0241] Experimental Example 1: In vitro measurement of the inhibitory activity of the compound against PDE3A enzyme Experimental purpose: Measure the expression of AMP / GMP by fluorescence polarization, that is, track the binding of the AMP / GMP antibody to show enzyme activity.

[0242] Reagents: Experimental buffer solution: 10 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 0.01% Brij 35, 1 mM dithiothreitol (DTT), 1% DMSO.

[0243] Enzyme: Recombinant human PDE3A (gene accession number NM_000921, amino acid 669 terminus) was expressed with an N-terminal GST tag in a baculovirus of Sf9 insect cells, and its molecular weight was 84 kDa.

[0244] Substrate: 1 μM cAMP. Measurement: Transcreener® AMP2 / GMP2 antibody and AMP2 / GMP2 AlexaFluor633 were tracked.

[0245] Procedure: 1. Recombinant human PDE3A enzyme and substrate (1 μM cAMP) were each dissolved in freshly prepared experimental buffer solution. 2. The PDE3A enzyme buffer solution was transferred to the reaction well. 3. Using an acoustic method (echo 550, accuracy nanoliter), a compound dissolved in 100% DMSO was added to the reaction well containing the PDE3A enzyme buffer solution and incubated at room temperature for 10 minutes. 4. The substrate buffer solution was added to the reaction well to initiate the reaction. 5. Incubated at room temperature for 1 hour. 6. The measurement mixture (Transcreener® AMP2 / GMP2 antibody and AMP2 / GMP2 AlexaFluor633 tracking) was added to stop the reaction and incubated for 90 minutes while mixing gently. The measurement range of fluorescence polarization was Ex / Em = 620 / 688.

[0246] Data analysis: Based on the AMP / GMP standard curve, the percentage of enzyme activity relative to the DMSO control was calculated from the fluorescence polarization signal using the software Excel and converted to nM. Curve fitting was performed using GraphPad Prism (for medical graph creation). Refer to Table 10 for the experimental results.

[0247] Experimental Example 2: In Vitro Measurement of the Inhibitory Activity of Compounds against PDE4B Enzyme Experimental purpose: Measure the expression of AMP / GMP by fluorescence polarization, that is, track the binding of the AMP / GMP antibody to indicate enzyme activity.

[0248] Reagents: Experimental buffer solution: 10 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 0.01% Brij 35, 1 mM DTT, 1% DMSO.

[0249] Enzyme: Recombinant human PDE4B (gene accession number NM_002600, amino acid 305 terminus) with an N-terminal GST tag was expressed in the baculovirus of Sf9 insect cells, and the molecular weight was 78 kDa.

[0250] Substrate: 1 μM cAMP. Measurement: Tracked the Transcreener® AMP2 / GMP2 antibody and AMP2 / GMP2 AlexaFluor633.

[0251] Procedure: 1. The recombinant human PDE4B enzyme and the substrate (1 μM cAMP) were each dissolved in freshly prepared experimental buffer solution. 2. The PDE4B enzyme buffer solution was transferred to the reaction wells. 3. Using an acoustic technique (echo 550, accuracy nanoliter), a compound dissolved in 100% DMSO was added to the reaction wells containing the PDE4B enzyme buffer solution and incubated at room temperature for 10 minutes. 4. The substrate buffer solution was added to the reaction wells to initiate the reaction. 5. Incubated at room temperature for 1 hour. 6. The reaction was stopped by adding a measurement mixture (Transcreener® AMP2 / GMP2 antibody and AMP2 / GMP2 AlexaFluor633 tracer), and incubated for 90 minutes with gentle mixing. The measurement range of fluorescence polarization was Ex / Em = 620 / 688.

[0252] Data analysis: Based on the AMP / GMP standard curve, the percentage of enzyme activity relative to the DMSO control was calculated from the fluorescence polarization signal using the software Excel and converted to nM. Curve fitting was performed using GraphPad Prism (for medical graph creation). Refer to Table 10 for the experimental results.

Table 10

[0253] The compounds of the present application have an obvious dual inhibitory effect on PDE3 and PDE4.

[0254] Experimental Example 3: Pharmacokinetic Study in Beagle Dogs In this study, male Beagle dogs were used as test animals, and the plasma drug concentrations of the compound of formula (I) at different time points after intravenous injection or forced oral administration to Beagle dogs were quantitatively measured by LC-MS / MS method, so as to evaluate the in vivo pharmacokinetic characteristics of the compound of formula (I) in Beagle dogs.

[0255] A clear solution of the compound of formula (I) was injected into the bodies of two beagle dogs weighing 10 - 12 kg via the cephalic vein or the great saphenous vein, and a clear solution of the compound of formula (I) was forcibly administered orally to two beagle dogs weighing 10 - 12 kg (fasted overnight). Approximately 500 μL of blood was collected from the peripheral vein of all animals at 0.0333 h, 0.0833 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration and transferred to an anticoagulant centrifuge tube containing 0.85 - 1.15 mg of K2EDTA·2H2O. Plasma was collected by centrifugation at 3000 g for 10 minutes at 4°C. The blood drug concentration was measured by the LC-MS / MS method, and the relevant pharmacokinetic parameters were calculated by the non-compartmental model × linear trapezoidal method using the pharmacokinetic software WinNonlin™ Version 6.3 (Pharsight Corporation, Mountain View, California).

Table 11

[0256] The compound of the present application has a high in vivo plasma clearance and low plasma exposure and bioavailability following oral administration.

[0257] Experimental Example 4: Inhibitory effect on the activities of cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) derived from human liver microsomes Phenacetin (CYP1A2), Diclofenac (CYP2C9), (S)-Mephenytoin (CYP2C19), Dextromethorphan (CYP2D6), and Midazolam (CYP3A4), which are five specific probe substrates for five CYP isoenzymes, were incubated with human liver microsomes and the compound of formula (I), respectively. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction was completed, the samples were processed and the concentrations of five metabolites, Acetaminophen, 4’-Hydroxydiclofenac, 4’-Hydroxymephenytoin, Dextrorphan, and 1’-Hydroxymidazolam, which were generated from the specific substrates, were quantitatively measured by liquid chromatography tandem mass spectrometry (LC-MS / MS) to calculate the corresponding half maximal inhibitory concentration (IC 50 ).

Table 12

[0258] The compounds of the present application have a low inhibitory effect on five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) of cytochrome P450 derived from human liver microsomes.

[0259] Experimental Example 5: Pharmacodynamic study in a rat model of acute lung injury induced by passive smoking Experimental animals: Male SPF-grade Sprague-Dawley rats (provided by Shanghai Slack Experimental Animal Co., Ltd.) were used, and their body weight was about 200 g.

[0260] Experimental procedure: 1. After the animals were accepted into the facility, they were bred for 1 week to adapt to the environment and then randomly divided into 6 groups according to their body weight. 2. On the 1st to 3rd days of the experiment, in each group, the test compound was nebulized for 30 minutes, and then the animals in the model group and each compound-treated group were exposed to passive smoking for 1 hour, and then exposed to passive smoking for another 1 hour at 4-hour intervals. They were exposed to tobacco smoke twice a day for 3 consecutive days. The control group animals were exposed to air indoors. 3. On the 4th day of the experiment, in each group, the test compound was nebulized for 30 minutes, and the animals in the model group and each compound-treated group were exposed to 150 μg / mL of LPS by nebulization inhalation for 15 minutes. Three hours after the start of nebulization administration, they were exposed to passive smoking for 1 hour. The animal lung function (Penh, F) was measured, and after euthanizing the animals with CO2, the alveolar lavage fluid was collected for cell counting.

[0261] 4. Administration treatment Administration method: Using a nebulization device for whole-body exposure, the test compound and the reference compound were nebulized for 30 minutes at the maximum nebulization rate (about 12 mL).

[0262] Administration frequency: Nebulized for 30 minutes before passive smoking every morning or the solvent was administered, and it was administered before LPS nebulization inhalation on the 4th day.

[0263] 5. Measurement of pharmacodynamic endpoints (1) Total number of white blood cells in BALF (alveolar lavage fluid). (2) Measurement of lung function under methacholine (Mch) induction (airway resistance index Penh).

Table 13

[0264] Refer to Figure 19 and Figure 20 for the experimental results.

[0265] The compound of the present application can reduce the total number of white blood cells in BALF and the airway resistance index Penh in a passive smoking-induced rat acute lung injury model.

[0266] Experimental Example 6: In vitro measurement of the inhibitory activity of the compound against TNF-α in human peripheral blood mononuclear cells Experimental purpose: To demonstrate 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).

[0267] Procedure: 1. Whole blood was collected from healthy donors and anticoagulated with an EDTA anticoagulation tube. 2. PBMCs were separated by Ficoll density gradient centrifugation, counted, and the cell concentration was adjusted to 2×10 6 / mL. 3. 2×10 5 cells and 1 ng / mL of LPS were added to each well of a U-bottom 96-well plate. The compound of formula (I) was prepared in DMSO solutions at concentrations of 100 μM, 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 100 pM, and 10 pM, respectively. Each well had a reaction system of 200 μL. 4. After culturing for 24 hours, the supernatant was collected. 5. The level of TNF-α in the supernatant was measured by ELISA, and the inhibition curve was fitted with the software Graphpad Prism to calculate the IC 50 .

[0268] Refer to Table 14 for the experimental results.

Table 14

[0269] The compound of the present application has an obvious inhibitory effect on TNF-α in human peripheral blood mononuclear cells (hPBMC).

[0270] Some embodiments are shown below. Item 1 Crystals of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

1. A crystal of the compound of formula (I), wherein the X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at 2θ angles of 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°.

2. A crystal of the compound of formula (I), in which an X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at 2θ angles of 5.81±0.2°, 13.96±0.2°, 15.01±0.2°, 17.95±0.2° and 24.73±0.2°.

3. The crystal according to claim 2, wherein the X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at 2θ angles of 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°.

4. A crystal of the compound of formula (I), wherein the X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at 2θ angles of 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°.

5. A crystalline composition comprising a crystal of the compound of formula (I) according to any one of claims 1 to 4, A crystalline composition, wherein the crystals comprise 50% or more, or 80% or more, or 90% or more, or 95% or more by weight of the crystalline composition.

6. A pharmaceutical composition comprising a therapeutically effective amount of a crystal of the compound of formula (I) according to any one of claims 1 to 4, or a crystal composition comprising said crystal.

7. A pharmaceutical composition comprising a therapeutically effective amount of a crystal of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a crystal composition comprising said crystal.

8. and / or further comprising a pharma- ceutically acceptable excipient; said additives being selected from glidants, diluents, preservatives, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonicity agents, solvents and emulsifiers; and / or said additives being selected from calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin and polyethylene glycols; and / or The pharmaceutical composition of claim 7 , wherein the additive is a sugar.

9. may be prepared as a solid, semi-solid, liquid or gaseous formulation; and / or The pharmaceutical composition according to claim 7, which may be prepared as a powder, or a suspension, injection, inhalant, gel, microsphere and aerosol.

10. 8. The pharmaceutical composition of claim 7, which may be prepared as a formulation to be administered via a route of administration selected from oral, topical, inhalation, parenteral or intranasal.

11. 1. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, said excipient being selected from a glidant, a diluent, a preservative, a surfactant, a wetting agent, a dispersing agent, a disintegrating agent, a suspending agent, a stabilizer, an isotonic agent, a solvent or an emulsifying agent.

12. said additives being selected from calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin and polyethylene glycols; and / or The pharmaceutical composition of claim 11 , wherein the additive is a sugar.

13. may be prepared as a solid, semi-solid, liquid or gaseous formulation; and / or 12. The pharmaceutical composition of claim 11, which may be formulated as an inhalant.

14. A therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient; may be formulated as a solid or liquid formulation; and / or The pharmaceutical composition may be prepared as an inhalant.

15. A therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient; The pharmaceutical composition may be prepared as an inhalant.

16. A therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient; The pharmaceutical composition may be prepared as pills, capsules, powders, granules, suspensions, injections, inhalants, gels, microspheres and aerosols.

17. comprising a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition may be prepared as a powder or a suspension.

18. The pharmaceutical composition according to any one of claims 11 to 17, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is present in crystalline form.

19. A method for producing the pharmaceutical composition according to any one of claims 7 to 17, comprising the steps of: The process, wherein said pharmaceutical composition is produced by using mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying or lyophilizing processes.

20. A process for preparing a compound of formula (I), comprising reacting compound 1-4b to obtain a compound of formula (I).

21. 21. The method of claim 20, comprising reacting compound BB-4 with compound 1-3b to obtain compound 1-4b.

22. The method of claim 21, wherein the compound BB-4 is prepared by the following reaction:

23. The compound or a pharma- ceutically acceptable salt thereof:

24. 24. Use of a compound according to claim 23, or a pharma- ceutically acceptable salt thereof, in the manufacture of a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

25. Use of the crystal according to any one of claims 1 to 4, a crystal composition or pharmaceutical composition comprising said crystal, or the pharmaceutical composition according to any one of claims 7 to 17, in the manufacture of a medicament for treating asthma or chronic obstructive pulmonary disease.

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