Crystals of dual PDE3 / PDE4 inhibitors and their uses

Abstract

The present invention relates to a crystalline tricyclic compound of formula (I) or a pharmaceutically acceptable salt thereof, a method for preparing the same, and its use in a medicament for treating PDE3 and / or PDE4-related diseases. TIFF2023512471000065.tif43170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from Chinese Invention Patent Application No. 202010043882.5, filed with the China State Intellectual Property Office on January 15, 2020, which is incorporated herein by reference in its entirety.

[0002] This application relates to crystals as dual PDE3 / PDE4 inhibitors and their use in the treatment of PDE3 / PDE4 related disorders, specifically chronic obstructive pulmonary disease (COPD). [Background technology]

[0003] Phosphodiesterase (PDE) is a superfamily of enzymes that includes 11 families, each of which is involved in different signal transduction and regulates different physiological processes. Among them, PDE3 is the main phosphodiesterase in human airway smooth muscle (ASM), and inhibition of PDE3 increases the intracellular cAMP concentration and relaxes bronchial smooth muscle. PDE4 plays a major regulatory role in the expression of pro-inflammatory and anti-inflammatory mediators, and PDE4 inhibitors can inhibit the release of harmful mediators from inflammatory cells. Therefore, inhibitors that have inhibitory effects on both PDE3 and PDE4 have the bronchodilation effect of β-adrenergic receptor agonists and the anti-inflammatory action of inhaled glucocorticoids. Theoretically, the functional complementation of dual targets has a greater effect than a single target, allowing a single drug to achieve therapeutic effects that could previously only be achieved through combined administration, eliminating the drawback that the physical and chemical properties of the component drugs in a combined administration cannot be completely compatible, making the administration method easier and favoring administration at a fixed dose.

[0004] Victoria Boswell et al, J.Pharmaco.Experi.Therap.2006,318,840-848, WO200005830 reported compounds RPL554 and RPL565, which have long-term bronchodilatory and anti-inflammatory effects, and have physical and chemical properties such as poor solubility and high plasma clearance, making them suitable for inhalation administration, but the data show that their inhibitory activity against PDE4 is unsatisfactory and their anti-inflammatory effect is poor, so it is necessary to develop a compound that also has good PDE3 / 4 inhibitory activity. In general, in order to meet the requirements for drug production, storage and formulation, etc., excellent properties are required in terms of drug activity, pharmacokinetics, bioavailability, hygroscopicity, melting point, stability, solubility, purity, ease of production, etc., so it is necessary to develop a crystal of a compound with PDE3 / 4 inhibitory activity. [ka] [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. WO200005830 [Non-patent literature]

[0006] [Non-Patent Document 1] Victoria Boswell et al,J.Pharmaco.Experi.Therap.2006,318,840-848. Summary of the Invention [Problem to be solved by the invention]

[0007] In one aspect of the present application, there is provided a crystal of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. [ka] [Means for solving the problem]

[0008] In some embodiments, a crystal of a compound of Formula (I) is provided.

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

[0010] In some embodiments of the present application, the A-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation having 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°.

[0011] In some embodiments of the present application, the A-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation having 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°, and 24.57±0.2°.

[0012] In some embodiments of the present application, the A-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation that includes 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°, and 24.57±0.2°.

[0013] In some embodiments of the present application, the A-type 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°, and 16.35±0.2°.

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

[0015] In some embodiments of the present application, the A-type crystal has an XRPD pattern using Cu Kα radiation as shown in FIG.

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

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

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

[0019] In some embodiments of the present application, the Type A crystal has a differential scanning calorimetry curve as shown in FIG.

[0020] In some embodiments of the present application, the thermogravimetric analysis curve of the A-type crystals is 0.4611% weight loss at 118.40±2°C, 0.8796% weight loss at 118.40±2°C to 185.65±2°C, and 7.177% weight loss at 185.65±2°C to 260.07±2°C.

[0021] In some embodiments of the present application, the A-type crystal has a thermogravimetric analysis curve as shown in FIG.

[0022] In another aspect of the present application, there is provided a method for preparing Form A crystals, comprising precipitating the compound of formula (I) from a methanol solvent.

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

[0024] In another embodiment of the present application, there is further provided a B-type crystal of compound of formula (I), which has an X-ray powder diffraction pattern using Cu Kα radiation having 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°.

[0025] In some embodiments of the present application, the B-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation having 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°, and 26.13±0.2°.

[0026] In some embodiments of the present application, the B-type crystal has an X-ray powder diffraction pattern using Cu Kα radiation having 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°.

[0027] In some embodiments of the present application, the B-type crystal has, in an X-ray powder diffraction pattern using Cu Kα radiation, 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°, and 26.13±0.2°.

[0028] In some embodiments of the present application, the B-type crystals are The X-ray powder diffraction pattern using Kα radiation contains 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°, and 26.13±0.2°.

[0029] 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, 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°, and 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 B-type crystals have the peak positions and relative intensities of diffraction peaks in an XRPD pattern using Cu Kα radiation as shown in Table 2 below. [Table 2]

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

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

[0034] In some embodiments of the present application, the B-type crystals have a differential scanning calorimetry curve as shown in FIG.

[0035] In some embodiments of the present application, the thermogravimetric analysis curve of the B-type crystals 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 B-type crystals have a thermogravimetric analysis curve as shown in FIG.

[0037] In another aspect of the present application, there is provided a method for preparing type B crystals, comprising precipitating a compound of formula (I) from a mixed solvent of ethanol and water.

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

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

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

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

[0042] 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, 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°.

[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°, and 23.41±0.2°.

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

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

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

[0047] In some embodiments of the present application, the C-type crystal has a differential scanning calorimetry curve as shown in FIG.

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

[0049] In some embodiments of the present application, the C-type crystal has a thermogravimetric analysis curve as shown in FIG.

[0050] In another aspect of the present application, there is provided a method for preparing crystals of Form C, comprising precipitating the compound of formula (I) from acetonitrile.

[0051] In some embodiments, the step is carried out at 40° C. with stirring.

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

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

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

[0055] In another embodiment of the present application, there is further provided a crystal of the compound of formula (II) having 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°, 11.97±0.2°, and 14.75±0.2°.

[0056] In some embodiments of the present application, the crystal of the compound of formula (II) has an X-ray powder diffraction pattern using Cu Kα radiation having 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°, and 24.42±0.2°.

[0057] In some embodiments of the present application, the crystal of the compound of formula (II) has an X-ray powder diffraction pattern using Cu Kα radiation having 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°, and 25.70±0.2°.

[0058] In some embodiments of the present application, the crystal of the compound of formula (II) has an X-ray powder diffraction pattern using Cu Kα radiation that 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°, and 25.70±0.2°.

[0059] In some embodiments of the present application, the crystal of the compound of formula (II) 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 4.84±0.2°, 9.58±0.2°, 10.93±0.2°, 11.97±0.2°, 14.31±0.2°, 14.75±0.2°, 16.49±0.2°, and 24.42±0.2°.

[0060] In some embodiments of the present application, the crystals of the compound of formula (II) have diffraction peak positions and relative intensities in an XRPD pattern using Cu Kα radiation 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.

[0062] In another aspect of the present application, there is further provided a p-toluenesulfonic acid salt of a compound of formula (I). In some embodiments, the p-toluenesulfonic acid salt of a compound of formula (I) is selected from a compound of formula (III). [ka]

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

[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 having 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 having 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 crystals of the compound of formula (III) have diffraction peak positions and relative intensities in an 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.

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

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

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

[0073] The present application further provides a crystal of the compound of formula (IV) having an X-ray powder diffraction pattern using Cu Kα radiation with 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 crystal of the compound of formula (IV) has an X-ray powder diffraction pattern using Cu Kα radiation having 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 crystal of the compound of formula (IV) has an X-ray powder diffraction pattern using Cu Kα radiation having 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 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°, 19.2 It has diffraction peaks at 3±0.2°, 19.72±0.2°, 20.02±0.2°, 20.51±0.2°, 22.62±0.2°, 23.27±0.2°, 24.45±0.2°, 24.83±0.2°, 25.42±0.2°, 25.87±0.2°, 26.09±0.2°, and 29.53±0.2°.

[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 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°, 20.03±0.2°, 20.04±0.2°, 20.05±0.2°, 20.06±0.2°, 20.08±0.2°, 20.09±0.2°, 20.13±0.2°, 20.11±0.2°, 20.12±0.2°, 20.1 ... The diffraction peaks include 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks at 2θ angles selected from among 2.09±0.2°, 20.51±0.2°, 22.62±0.2°, 23.27±0.2°, 24.45±0.2°, 24.83±0.2°, 25.42±0.2°, 25.87±0.2°, 26.09±0.2°, and 29.53±0.2°.

[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 that 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°, and 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 that 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, in which the 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 FIG.

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

[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 FIG.

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

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

[0086] In another aspect of the present application, there is further provided a maleate salt of a compound of formula (I). In some embodiments, the maleate salt of a compound of formula (I) is selected from a compound of formula (V). [ka]

[0087] In another embodiment of the present application, there is further provided a crystal of compound of formula (V), having an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at 2θ angles of 5.83±0.2°, 6.62±0.2°, 9.50±0.2°, and 10.98±0.2°.

[0088] 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 having diffraction peaks 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 crystal of the compound of formula (V) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks 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 that 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°, and 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 that 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°, and 25.16±0.2°.

[0092] In some embodiments of the present application, the crystals of the compound of formula (V) have the peak positions and relative intensities of diffraction peaks in an XRPD pattern using Cu Kα radiation as shown in Table 7 below. [Table 7]

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

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

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

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

[0097] In a further aspect of the present application, there is provided a crystal composition comprising said crystals, said crystals comprising at least 50% by weight of the crystal composition, preferably at least 80%, more preferably at least 90%, and most preferably at least 95%.

[0098] In another aspect of the present application, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof. [ka] The compound of formula (I) can be prepared by the following method. (1) Compound BB-4 is obtained by reaction of compound 1-2a. (2) Compound BB-4 is reacted with 5-hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid to obtain compound of formula (I). [ka]

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

[0100] In a further aspect of the present application, there is provided a method for preparing compound 1-2a, comprising reacting compound BB-1 with compound 1-1a to obtain compound 1-2a. [ka]

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

[0102] In a further aspect of the present application, there is provided a method for preparing compound BB-4, comprising the steps of: (a) Compound BB-1 is reacted with compound 1-1a to obtain compound 1-2a. (b) Reaction of compound 1-2a to give compound BB-4. [ka]

[0103] In a further aspect of the present application there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof. [ka] The compound of formula (I) can be prepared by the following method. (1') Compound BB-1 is reacted with compound 1-1a to obtain compound 1-2a. (2') Compound BB-4 is obtained by reaction of compound 1-2a. (3') Reaction of compound BB-4 with 5-hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid to obtain compound of formula (I). [ka]

[0104] In a further aspect of the present application, there is provided a method for producing a compound of formula (I), comprising the steps (1'), (2') and (3').

[0105] In some embodiments, the step of obtaining compound 1-2a is carried out in the presence of a solvent, hi 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: Compound BB-1 and compound 1-1a are dissolved in acetonitrile, and then lithium carbonate and water are added to react with each other.

[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, obtaining compound BB-4 is performed 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: Compound 1-2a is reacted 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 comprises treating with petroleum ether and ethyl acetate after completion of 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, hi 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, hi 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, hi 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 for obtaining the compound of formula (I) from compound BB-4 is 20°C.

[0122] In some embodiments, the reaction time for 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 pharma- ceutically acceptable salt thereof. [ka] The compound of formula (I) may be prepared by the following method: Reaction of compound 1-4b gives compound of formula (I). [ka]

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

[0125] In a further aspect of the present application, there is provided a method for preparing compound 1-4b, comprising reacting compound BB-4 with compound 1-3b to obtain compound 1-4b. [ka]

[0126] In a further aspect of the present application, there is provided a method for preparing compound BB-4, comprising reacting compound 1-1b to obtain compound BB-4. [ka]

[0127] In a further aspect of the present application, there is provided a method for preparing compound 1-1b, comprising reacting compound BB-1 with compound a to obtain compound 1-1b. [ka] where X is selected from halogens.

[0128] In some embodiments, X is selected from Cl, 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 pharma- ceutically acceptable salt thereof. [ka] The compound of formula (I) can be prepared by the following method. (i) Compound BB-4 is reacted with compound 1-3b to give compound 1-4b. (ii) Reaction of compound 1-4b to give compound of formula (I).

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

[0131] In a further aspect of the present application there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof. [ka] The compound of formula (I) can be prepared by the following method. (i') Compound BB-4 is obtained by reaction of compound 1-1b. (ii') Compound BB-4 is reacted with compound 1-3b to give compound 1-4b. (iii') Reaction of compound 1-4b to give compound of formula (I).

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

[0133] In a further aspect of the present application there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof. [ka] The compound of formula (I) can be prepared by the following method. (i'') Compound BB-1 is reacted with compound a to obtain compound 1-1b. (ii'') Reaction of compound 1-1b to give compound BB-4. (iii'') Compound BB-4 is reacted with compound 1-3b to give compound 1-4b. (iv'') Reaction of compound 1-4b to give compound of formula (I). [ka] where X is selected from halogens.

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

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

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

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

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

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

[0140] In some embodiments, obtaining compound 1-1b is carried out in the presence of a co-solvent, hi 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 for 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, obtaining compound BB-4 is performed 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 dimethylsulfide.

[0147] In some embodiments, the reaction temperature in 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-dimethylsulfide at 0° C., and then reacting at elevated temperature. In some embodiments, the reaction is carried out at elevated temperature of 20-25° C.

[0150] In some embodiments, the step of obtaining compound BB-4 includes a step of lowering the temperature (e.g., lowering to 0° C.) after reacting for a predetermined time (e.g., 18 hours). It further includes a step of adding methanol after lowering the temperature. It further includes a step of adjusting the pH after adding methanol. It further includes a step of concentrating the product after adjusting the pH. It further includes a step of purifying.

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

[0152] In some embodiments, the step of adjusting the pH after adding methanol includes adjusting the pH with hydrochloric acid.

[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, hi some embodiments, the condensing agent is N,N-carbonyldiimidazole.

[0155] In some embodiments, the preparation of compound 1-4b involves reacting compound 1-3b first with a condensing agent (eg, N,N-carbonyldiimidazole) and then with compound BB-4 to give compound 1-4b.

[0156] In some embodiments, the step of reacting compound 1-3b with an activating agent to obtain compound 1-4b is carried out in the presence of a solvent, in some embodiments, the solvent is selected from dichloromethane.

[0157] In some embodiments, the reaction temperature in the step of reacting compound 1-3b with an activating agent to obtain compound 1-4b is 25°C.

[0158] In some embodiments, the reaction time for the step of reacting compound 1-3b with an activating agent in the step of obtaining compound 1-4b is 5 hours.

[0159] In some embodiments, in the step of obtaining compound 1-4b, after compound 1-3b is reacted with an activating agent, 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, the reaction temperature in the step of reacting compound 1-3b with an activating agent and then with compound BB-4 is 20 to 25°C.

[0161] In some embodiments, in the step of obtaining compound 1-4b, the reaction time of the step of reacting compound 1-3b with an activating agent and then with compound BB-4 is 18 hours.

[0162] In some embodiments, the step of obtaining compound 1-4b further comprises the step of treating with methanol after completion of the reaction.

[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, hi some embodiments, the solvent is selected from a mixture 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 in the step of obtaining the compound of formula (I) from compound 1-4b is 90 to 100°C.

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

[0167] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a crystal of the compound of formula (I), and the crystal is a type A crystal of a compound of formula (I), a type B crystal of a compound of formula (I), or a type C crystal of a compound of formula (I).

[0168] In some embodiments, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein the pharma- ceutically acceptable salt is a sulfate salt, a p-toluenesulfonate salt, a mesylate salt, or a maleate salt.

[0169] The compound BB-1 of the present application can be obtained by the following method. [ka]

[0170] In another aspect of the present application, a method for producing a crystal of a compound of formula (I) or a pharma- ceutically acceptable salt thereof is provided, comprising producing a compound of formula (I) or a pharma- ceutically acceptable salt thereof by any of the methods for producing a compound of formula (I) or a salt thereof, and precipitating the compound of formula (I) or a pharma- ceutically acceptable salt thereof from a solvent selected from a mixture of methanol, ethanol and water, acetonitrile, and tetrahydrofuran and water. In some specific embodiments of the present application, a method for producing a crystal of a pharma- ceutical acceptable salt of a compound of formula (I) is provided, comprising precipitating a salt of the compound of formula (I) from a mixture of tetrahydrofuran and water. In some specific embodiments of the present application, a method for producing a crystal of a pharma- ceutical acceptable salt of a compound of formula (I) is provided, comprising mixing the compound of formula (I) and tetrahydrofuran, adding an aqueous solution of an acid (and / or base) to react with the compound, and precipitating the salt of the compound of formula (I) in the form of a crystal from a mixture of tetrahydrofuran and water.

[0171] In a further aspect of the present application, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) described herein or a pharma- ceutically acceptable salt thereof, said crystal or a crystalline composition thereof. The pharmaceutical composition of the present application may or may not contain a pharma- ceutically acceptable additive. In addition, the pharmaceutical composition of the present application may further comprise one or more other therapeutic agents.

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

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

[0174] In another aspect of the present application, there is further provided a use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, a crystal thereof, a crystalline 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 a compound of formula (I) or a pharma- ceutically 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, chronic obstructive pulmonary disease (COPD). Effect of the Invention

[0177] The compound of formula (I) of the present application has a clear dual inhibitory effect on PDE3 and PDE4, and also has a clear inhibitory effect on TNF-α in human peripheral blood mononuclear cells (hPBMC). It has shown excellent anti-inflammatory effects in a lipopolysaccharide (abbreviated as LPS)-induced rat acute lung injury model. It has high in vivo plasma clearance, low plasma exposure and bioavailability when administered orally, and high safety when administered locally. It has a low inhibitory effect on five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) of human liver microsome-derived cytochrome P450, and has no risk of drug interactions. It has a clear anti-inflammatory effect, such as reducing the total number of white blood cells in BALF, and has a low minimum effective dose. It can reduce the airway resistance index Penh.

[0178] The crystals of the compound of formula (I) and the crystals of the pharma- ceutically acceptable salts thereof of the present application have advantages in pharmacological activity, pharmacokinetics, bioavailability, hygroscopicity, melting point, stability, solubility, purity, ease of preparation, etc., and therefore meet the requirements for the production, storage, transportation, formulation, etc. of drugs.

[0179] In the present invention, method 2 can obtain amine ethyl-substituted compounds in one step, and the reaction system is clean, without the need for the introduction of amide or cyano groups followed by reduction as in the conventional methods.Method 3 uses non-genotoxic bromoacetamide instead of the genotoxic reagent bromoacetonitrile, thereby reducing the safety risks associated with drug synthesis and development.

[0180] "Definitions and Explanations" Unless otherwise specified, the following terms and expressions used herein have the following meanings: Certain expressions or terms are to be understood in their ordinary sense, and not as indefinite or unclear, unless otherwise defined. When trade names are mentioned herein, they refer to the corresponding products or their active ingredients.

[0181] In addition, in the X-ray powder diffraction pattern, the peak position or the relative intensity of the peak may vary depending on the measuring device, measuring method / conditions, etc. In any determined crystalline 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 crystalline forms, the error should be taken into consideration, and those within the error are included in the scope of the present application.

[0182] In addition, even for the same crystal form, the position of the endothermic peak in DSC may differ depending on the measurement device, measurement method / conditions, etc. Any determined crystal form may have 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, the error should be taken into consideration, and those within the error are included in the scope of the present application.

[0183] The term "comprise", similar terms and English equivalents, such as "comprises", "comprising" or the like, are to be understood as open, non-exclusive expressions, such as "including, but not limited to," meaning that the invention may include unspecified elements, components or steps in addition to the listed elements, components or steps.

[0184] The term "pharmacologically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are medically determined to be suitable for use in contact with human or animal tissue, not toxic or irritating, and not likely to cause an allergic reaction or other problem or complication, and for which the benefit-to-risk ratio is reasonable.

[0185] With respect to the term "pharmaceutically acceptable salts," 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 excipient" refers to an inert substance administered together with an active ingredient to facilitate administration of the active ingredient, including, but not limited to, any glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved for use in humans or animals (e.g. livestock) by the China Food and Drug Administration. Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0187] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharma- ceutical acceptable excipients, which facilitate administration of the compounds of the present application to a living body.

[0188] The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharma- ceutically acceptable excipients, and may be prepared, for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

[0189] Exemplary routes of administration of the crystals or pharmaceutical compositions thereof described herein include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous.

[0190] The pharmaceutical compositions of the present application may be manufactured by conventional methods well known in the art, for example, by mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, lyophilizing or the like.

[0191] In some embodiments, the pharmaceutical composition is for oral administration. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharma- ceutical acceptable additives well known in the art. With such additives, the compound of the present application can be formulated as a tablet, pill, sugar-coated agent, capsule, liquid, gel, syrup, suspension, etc., for oral administration to a patient.

[0192] The therapeutic dose of the compound of the present application is determined by the purpose of treatment, the manner of administration of the compound, the health condition of the patient, the judgment of the prescribing physician, etc. The proportion or concentration of the compound of the present application in a pharmaceutical composition does not necessarily vary and is determined by various factors, such as dosage, chemical properties (e.g., hydrophobicity), and route of administration. The term "treatment" refers to the administration of a compound or formulation described in the present application to improve or eliminate a disease or one or more symptoms associated with said disease, and includes the following: (i) inhibiting a disease or disease state, i.e., reducing its progression; (ii) alleviating the disease or disease state, i.e., causing the disease or disease state to be eliminated.

[0193] The term "prevention" refers to the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the appearance of a disease or disease state in a mammal, particularly when a mammal susceptible to the disease state has not been diagnosed with the disease state.

[0194] The term "therapeutically effective amount" when applied to a drug or pharmacologically active agent refers to a sufficient dose of a drug or its formulation to obtain a desired effect without toxicity. The effective amount is determined by the age and general condition of the subject to be administered, and varies depending on the type of active substance. In practical administration, a person skilled in the art can appropriately determine the effective amount by performing routine experiments.

[0195] Therapeutically effective amounts of the crystals described herein are 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 dose and frequency of administration of the crystals described herein will be determined by the condition of the patient, for example, once or twice daily, or multiple times per day. Administration may be intermittent, for example, administering a daily dose of the crystalline form to the patient for a number of days and then not administering a daily dose of the crystalline form to the patient for the same number of days or for a longer period of time.

[0197] In this specification, singular terms cover plural referents and vice versa, unless expressly stated otherwise.

[0198] In this specification, unless otherwise specified, all parameter values ​​(including 2θ angle and reaction conditions) are considered to be modified with the term "about" to include error in the value due to measurement, etc., and have an error of, for example, ±5% from the stated value.

[0199] Herein, for the purposes of explanation and disclosure, patents, patent applications, or existing publications are incorporated by reference in their entirety. These publications are provided because they were published prior to the filing date of this application. Any statement as to the disclosure date of such documents or representation of their contents is based on the information known to the applicants and does not constitute an admission that the disclosure dates of such documents or the contents thereof are correct. Furthermore, the incorporation of such publications into this specification does not constitute an admission that such publications are common general knowledge in the art in all applicable countries.

[0200] Next, the present application will be described in detail with reference to examples, which are not intended to limit the present application in any way.

[0201] The intermediate compounds of the present application can be prepared by a variety of synthetic methods familiar to those of skill in the art, including the specific embodiments described below, embodiments in combination with other chemical synthetic methods, and alternative permutations familiar to those of skill in the art, and preferred embodiments include, but are not limited to, the examples of the present application.

[0202] The chemical reactions of certain embodiments of the present application are carried out in suitable solvents, which are suitable for the chemical transformations of the present application and the reagents and raw materials used. In order to obtain the compounds of the present application, it may be necessary for a person skilled in the art to select or modify synthetic steps or reaction processes in light of existing embodiments.

[0203] Next, the present application will be described in detail with reference to examples, which are not intended to limit the present application in any way.

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

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

[0206] X-ray powder diffractometer (XRPD) Instrument model: Bruker D8 advance X-ray diffractometer, radiation source: Cu Kα (λ=1.54056Å). 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 the drawings]

[0207] [Figure 1] FIG. 1 is an XRPD pattern of crystalline form A of the compound of formula (I). [Diagram 2] FIG. 2 is a DSC curve of the A-type crystals of the compound of formula (I). [Diagram 3] FIG. 3 is a TGA curve of the A-type crystals of the compound of formula (I). [Figure 4] FIG. 4 is an XRPD pattern of the B-type crystals of compound of formula (I). [Diagram 5] FIG. 5 is a DSC curve of the B-type crystals of the compound of formula (I). [Figure 6] FIG. 6 is a TGA curve of the B-type crystals of the compound of formula (I). [Figure 7] FIG. 7 is an XRPD pattern of the C-type crystals of compound of formula (I). [Figure 8] FIG. 8 is a DSC curve of the C-type crystals of the compound of formula (I). [Figure 9] FIG. 9 is a TGA curve of the C-type crystals of the compound of formula (I). [Figure 10] FIG. 10 is an XRPD pattern of the crystals of the compound of formula (II). [Figure 11] FIG. 11 is an XRPD pattern of the crystals of the compound of formula (III). [Figure 12] FIG. 12 is a TGA curve of the crystals of the compound of formula (III). [Figure 13] FIG. 13 is an XRPD pattern of the crystals of the compound of formula (IV). [Figure 14] FIG. 14 is a DSC curve of the crystals of the compound of formula (IV). [Figure 15] FIG. 15 is a TGA curve of the crystals of the compound of formula (IV). [Figure 16] FIG. 16 is an XRPD pattern of the crystals of compound of formula (V). [Figure 17] FIG. 17 is a TGA curve of the crystals of the compound of formula (V). [Figure 18] FIG. 18 is a DVS curve of the B-type crystals of the compound of formula (I). [Figure 19] FIG. 19 shows the total number of leukocytes in BALF. [Figure 20] FIG. 20 shows the measurement of pulmonary function (airway resistance index Penh) under methacholine (Mch) induction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0208] In the following, in order to provide a better understanding of the present application, further explanation will be given using specific examples, but these specific embodiments are not intended to be limiting of the present application. EXAMPLES

[0209] Synthesis of intermediate BB-1 [ka] [ka]

[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 the reaction was completed, the mixture was cooled to 70° C. and ethanol (30 mL) was slowly added dropwise to precipitate a large amount of solid. After filtration, the cake was dried under reduced pressure to obtain product BB-1-2. 1 H NMR (400MHz, DMSO-d 6 )δ=8.26(t,J=5.2Hz,1H),6.86(d,J=8.0Hz,1H),6.79(br s,1H),6.71(d,8.0Hz,1H),4.00(q,J=6.8Hz,2H),3.72(s,3H),3.59(s,2H),3.31~3.23(m,2H),2.64(t,J=7.2Hz,2H),1.32(t,J=6.8Hz,3H). MS-ESI m / z: 263.1 [M+H] + .

[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 the reaction was completed, 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 x 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 purified by pulping with ethyl acetate (20 mL) to obtain compound BB-1-3. 1 H NMR (400MHz, CD 3 OD)δ=7.16(s,1H),6.83(s,1H),4.62(s,1H),4.12(q,J=6.8Hz,2H),3.86( s,3H),3.35(d,J=6.4Hz,2H),2.84(t,J=6.4Hz,2H),1.44(t,J=6.8Hz,3H). MS-ESI m / z: 245.1 [M+H] + .

[0212] Step 3: Synthesis of compound BB-1-4 Compound BB-1-3 (1.00 g) was added in portions to 98% concentrated sulfuric acid (12.88 g, 128.69 mmol, 7.00 mL) at 0° C. The reaction mixture was stirred at 27° C. for 3 hours. After the reaction was completed, the mixture was added to cold water (15 mL), and then aqueous sodium hydroxide solution (4 mol / L, 32 mL) was added dropwise to adjust the pH to neutral, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 Sodium (2.42 g) was added to ethanol (80 mL) in several portions at 0° C. 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 stirred at 80° C. for 30 minutes. Then, diethyl carbonate (9.32 g, 9.51 mL) was added at once, and the mixture was continued to be stirred at 80° C. for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, ice water (30 mL) was slowly added, and then the pH was adjusted to neutral with dilute hydrochloric acid (2 mol / L, 53 mL) to precipitate a large amount of solid matter, which was filtered to obtain a cake, which was pulped with ethanol (10 mL) and purified to obtain compound BB-1-5. 1 H NMR (400MHz, DMSO-d 6 )δ=11.22(br s,1H),7.35(s,1H),6.95(s,1H),6.22(s,1H),4.09(q,J=6.8Hz,2H),3.90(br s,2H),3.83(s,3H),2.89(br s,2H),1.35(t,J=6.8Hz,3H). MS-ESI m / z: 289.1 [M+H] + .

[0214] Step 5: Synthesis of compound BB-1-6 Compound BB-1-5 (5.00 g) was dissolved in phosphoryl trichloride (30 mL) at room temperature. The reaction mixture was stirred at 100° C. for 16 hours under a nitrogen atmosphere. After the reaction was completed, most of the solvent was removed by distillation under reduced pressure. Water (100 mL) was added and extracted with dichloromethane (150 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 Compound BB-1-6 (925.67 mg) was dissolved in isopropanol (8 mL) at room temperature, and 2,4,6-trimethylaniline (2.10 g) was added. The reaction mixture was stirred at 90° C. for 15 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a residue, which was purified by pulping with ethanol (6 mL) to obtain compound BB-1. 1 H NMR (400MHz, DMSO-d 6 )δ=8.85(br s,1H),7.27(s,1H),6.97(s,1H),6.90(s,2H),6.45(s,1H),4.10(q,J=6.8Hz,2H),3.90(t,J=6 .0Hz,2H),3.86(s,3H),2.87(t,J=6.0Hz,2H),2.45(s,3H),2.11(s,6H),1.37(t,J=6.8Hz,3H). MS-ESI m / z: 406.2 [M+H] + .

[0216] Synthesis of compound BB-4 [ka] [ka]

[0217] Step 1: Synthesis of compound BB-4-1 Compound BB-1 (1.00 g) was dissolved in 2-butanone (35 mL) at room temperature, and 2-(2-bromoethyl)isoindoline-1,3-dione (3.76 g), potassium carbonate (3.07 g), and sodium iodide (2.22 g) were added in this order. The reaction mixture was stirred at 85° C. for 72 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated to remove most of the organic solvent, water (30 mL) was added, and the mixture was extracted with ethyl acetate (25 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain a residue, which 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 Compound BB-4-1 (500.00 mg) was dissolved in chloroform (3 mL) and ethanol (3 mL) at room temperature, and hydrazine hydrate (152.67 mg, purity 85%) was added. The mixture was stirred at 28°C for 16 hours under nitrogen atmosphere. After the reaction was completed, the mixture was concentrated to remove most of the organic solvent, water (15 mL) was added, and extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain compound BB-4. 1 H NMR (400MHz, DMSO-d 6 )δ=6.95(s,1H),6.85(br s,2H),6.66(s,1H),5.31(s,1H),4.14(t,J=6.8Hz,2H),4.05(q,J=6.8Hz,2H) ,3.91(t,J=6.4Hz,2H),3.62(s,3H),2.90-2.86(m,4H),2.22(s,3H),1.95(br s,6H),1.33(t,J=6.8Hz,3H). MS-ESI m / z: 449.2 [M+H] + .

[0219] Example 1: Preparation of Compound of Formula (I) Method 1: [ka]

[0220] 5-Hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid (18.50 mg) was dissolved in DCM (1 mL) at 20° C., HATU (8.80 mg) and triethylamine (57.40 μL) were added and stirred for 2 hours, and then compound BB-4 (50 mg) was added and stirred 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 remove the solvent by evaporation 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 (400MHz, CD 3 OD)δ=6.94(s,2H),6.87(s,1H),6.77(s,1H),5.52(s,1H),4.48(t,J=6.0Hz,2H),4.15(s,3H),4.12-4.08(m,2H),4.01(t, J=6.0Hz,2H),3.87(t,J=6.0Hz,2H),3.69(s,3H),2.94(t,J=6.0Hz,2H),2.29(s,3H),2.06(s,6H),1.41(t,J=6.8Hz,3H). MS m / z: 574.1 [M+H] + .

[0221] [ka]

[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 the temperature was raised to 80° C. and refluxed for 4 hours. The mixture was cooled to room temperature and 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 organic phases were combined, washed with cold water (1000 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure and the solvent was removed by evaporation to obtain 28.5 g of a yellow oily liquid as the crude product of 1-1a, which can be used directly in the next step reaction without purification. 1 H NMR (400 MHz, CHCl 3 -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 the temperature was raised to 100 ° C. and stirred for 70 hours. The mixture was cooled and left to stand, filtered to remove precipitates, and the filtrate was concentrated under reduced pressure and the solvent was removed by evaporation, then mixed with 50 mL of water and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 0.5 M sodium hydroxide solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure to obtain a 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] + . 1 H NMR (400MHz, MeOH-d 4)δ(ppm)6.91(s,2H),6.85(s,1H),6.75(s,1H),5.49(s,1H),4.36(t,J=5.9Hz,2H),4.09(q,J=7.0Hz,2H),4.00( t,J=6.1Hz,2H),3.68(s,3H),3.56~3.48(m,2H),2.91(t,J=6.3Hz,2H),2.27(s,3H),2.06(s,6H),1.39(s,12H).

[0224] Step 3: Preparation of compound BB-4 Compound 1-2a (1g) and 4M hydrogen chloride-methanol solution (20mL) were mixed homogeneously, then heated to 60°C and stirred for 2 hours. The mixture was concentrated under reduced pressure and the solvent was removed by evaporation to obtain a pale yellow oily liquid as the crude product. 20mL of petroleum ether and 5mL of ethyl acetate were added to the crude product, stirred for 30 minutes, filtered, and the solid was collected and dried to obtain a pale yellow solid as the target compound BB-4 (810mg, yield 91.63%). 1 H NMR (400MHz, MeOH-d 4 )δ(ppm)7.16(s,2H),6.98(s,1H),6.80(s,1H),5.68(s,1H),4.72(br s,2H),4.22(br s,2H),4.16(q,J=7.0Hz,2H),3.69(s,3H),3.48(br s,2H),3.08(br s,2H),2.37(s,3H),2.30(s,6H),1.43(t,J=7.0Hz,3H).

[0225] Step 4: Preparation of Compound (I) 5-Hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid (18.50 mg) was dissolved in DCM (1 mL) at 20°C, HATU (8.80 mg) and triethylamine (57.40 μL) were added and stirred for 2 hours, and then compound BB-4 (50 mg) was added and stirred for 16 hours while maintaining the temperature. The mixture was diluted to 10 mL with DCM, washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to remove the solvent by evaporation to obtain a crude product. The crude product was purified by prep-HPLC to obtain the target compound of formula (I) (22 mg, yield 37.2%) as a yellow solid. MS-ESI(m / z):574.5[M+1] + . 1 H NMR (400MHz, MeOH-d 4 )δ(ppm)6.94(s,2H),6.87(s,1H),6.75(s,1H),5.51(s,1H),4.47(br t,J=6.0Hz,2H),4.14(s,3H),4.10(q,J=7.0Hz,2H),4.01(br t,J=5.9Hz,2H),3.85(br t,J=5.9Hz,2H),3.68(s,3H),2.92(br t,J=6.0Hz,2H),2.29(s,3H),2.05(s,6H),1.41(t,J=6.9Hz,3H).

[0226] Method 3: [ka]

[0227] Step 1: Preparation of compound 1-1b 2-Butanone (12 L) was added to a 50 L jacketed reactor at 20°C. Compound BB-1 (615 g) and 2-bromoacetamide (612.4 g) were added with stirring. Anhydrous potassium phosphate (1.57 kg) and sodium iodide (665.4 g) were then added to the reaction system. The reaction mixture was heated to 90°C under nitrogen protection and stirred for 18 hours. The reaction solution was cooled to room temperature, water (12 L) was added, and the mixture was stirred for 1 hour, filtered to obtain a solid, which was then dried in vacuum 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 (400MHz, DMSO-d 6 )δ=7.49(br s,1H),7.06(br s,1H),6.95(s,1H),6.82(s,2H),6.69(s,1H),5.33(s,1H),4.66(s,2H),4.07(q,J=6.9Hz,2H),3.91(br t,J=6.0Hz,2H),3.63(s,3H),2.90(br t,J=5.9Hz,2H),2.20(s,3H),1.92(s,6H),1.33(t,J=7.0Hz,3H).

[0228] Step 2: Preparation of compound BB-4 Tetrahydrofuran (8.6 L) was added to a dry 50 L jacketed reaction vessel at 20°C, and then borane·dimethylsulfide solution (10 M, 950 mL) was added dropwise to the reaction vessel while stirring. After the addition was completed, the temperature was lowered to 0°C, compound 1-1b (440 g) was added, the cooling device was turned off, and the reaction was continued for 18 hours while stirring after the temperature naturally returned to 20-25°C. The reaction solution was cooled to 0°C, and methanol (about 1.5 L) was added dropwise to quench until no bubbles were generated, and then 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 and the solvent was removed by evaporation. The residue was dissolved in dichloromethane, and then saturated sodium bicarbonate solution was added to adjust the pH to 7-8. The liquids were separated, and the aqueous phase was extracted with dichloromethane (3000 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The concentrated product was purified by high-performance 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-d 6 )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 Compound 1-3b (68.68 g) was dissolved in dichloromethane (700 mL) at 20°C, N,N-carbonyldiimidazole (61.56 g) was added, and the mixture was stirred at 25°C for 5 hours. The mixture was washed with saturated saline (700 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (675 mL), and compound BB-4 (95 g) was added in several portions. After the addition, the mixture was stirred at 20-25°C for 18 hours. Methanol (675 mL) was added to the reaction solution, which 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-d 6 )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) Compound 1-4b (120 g) was dissolved in a mixed solvent of trifluoroacetic acid (1000 mL) and glacial acetic acid (200 mL) at 20 ° C., heated to 90-100 ° C., and stirred for 48 hours. The reaction solution was concentrated under reduced pressure to remove most of the solvent, the residue was dissolved in DCM (1000 mL) and adjusted to pH 7-8 with saturated sodium bicarbonate solution, the organic phase and the aqueous phase were separated by liquid separation, the aqueous phase was extracted with DCM (1000 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and the solvent was removed by evaporation to obtain the target compound of formula (I) (80 g, yield 80.60%). MS-ESI(m / z):574.27[M+1] + . 1 H NMR (400MHz, DMSO-d 6 )δ=7.73~7.65(m,1H),6.94(s,1H),6.84(s,2H),6.66(s,1H),5.32(s,1H),4.35(t,J=6.1Hz ,2H),4.12~4.01(m,5H),3.88(t,J=6.1Hz,2H),3.70(q,J=6.1Hz,2H),3.62(s,3H),2.87(br t,J=6.0Hz,2H),2.21(s,3H),1.93(s,6H),1.33(t,J=6.9Hz,3H),0.90~0.90(m,1H).

[0231] Example 2: Preparation of A-type crystals of 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, and the temperature was raised to 40°C and stirred for 48 hours. The mixture was naturally cooled to room temperature, and the solid was separated by centrifugation and dried in vacuum to obtain 34 mg of a solid as A-type crystals. The XRPD pattern, DSC curve, and TGA curve are shown in Figure 1, Figure 2, and Figure 3, respectively.

[0232] Example 3: Preparation of B-type crystals of 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, and the temperature was raised to 40°C and stirred for 48 hours. The mixture was naturally cooled to room temperature, and the solid was separated by centrifugation and dried in vacuum to obtain 46 mg of a solid as B-type crystals. The XRPD pattern, DSC curve, and TGA curve are shown in Figure 4, Figure 5, and Figure 6, respectively.

[0233] Example 4: Preparation of C-type crystals of 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, and the temperature was raised to 40°C and stirred for 48 hours. The mixture was naturally cooled to room temperature, and the solid was separated by centrifugation and dried in vacuum to obtain 37 mg of a solid as C-type crystals. The XRPD pattern, DSC curve, and TGA curve are shown in Figures 7, 8, and 9, respectively.

[0234] Example 5: Preparation of salts of compounds of formula (I) 100mg of compound of formula (I) was added to a 4mL glass bottle, 2mL of anhydrous tetrahydrofuran was added, and the mixture was heated to 70℃ and stirred for 1 hour to dissolve it fully, cooled to 40℃, and a solution prepared with the corresponding acid or base (see Table 8 for specifications and amounts) and 0.1mL of water was added, and the mixture was stirred for 12 hours while maintaining the temperature. The mixture was centrifuged to separate the solid precipitate, and dried in vacuum to obtain a solid, which was the corresponding salt of compound of formula (I) in crystalline form. [Table 8] TIFF0007648635000041.tif174170

[0235] Example 6: Study on the Solid Stability of B-Type Crystals of Compound of Formula (I) High-performance liquid chromatography (HPLC) For the HPLC method configuration, see below. Column: Zorbax SB C-18, 4.6 mm x 150 mm, 5 μm (PDS-HPLC-007). Mobile phase A: 0.1% TFA in water. Mobile phase B: 100% ACN. Sample preparation: The sample was dissolved in a mixed solvent of acetonitrile and water (acetonitrile:water=50:50 (V:V)).

[0236] Static methods for studying the stability of solids: The stability of the compound was examined when it was left to stand under the following conditions, and samples were taken at different time points to measure the content. Approximately 5 mg of B-type crystals of the compound of formula (I) were accurately weighed and placed in a dry, clean glass bottle. The two samples were spread thinly as duplicate samples to serve as the official test samples. The samples were then placed under the influencing factor test conditions (60°C), (relative humidity 92.5%), light (total illuminance 1.2×10 6 Lux·hr / Near UV range 200W·hr / m 2), (40°C, 75% relative humidity), and (60°C, 75% relative humidity) were left to ensure the samples were fully exposed, covered with aluminum foil, and small holes were drilled. Samples were taken and analyzed at 5 days, 10 days, 1 month, 2 months, and 3 months. The samples left under light conditions (visible light 1,200,000 Lux, ultraviolet 200 W) were fully exposed at room temperature. See Table 9 for experimental results. [Table 9]

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

[0238] Example 7: Study on the hygroscopicity of B-type crystals of compound of formula (I) Instrument model: SMS DVS Advantage Dynamic Vapor Sorption Instrument Measurement conditions: A sample (10 to 20 mg, B-type crystal produced in Example 3) was placed on a DVS sample tray and measured.

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

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

[0241] Experimental Example 1: In vitro measurement of the inhibitory activity of compounds against the PDE3A enzyme Experimental objective: To measure the expression of AMP / GMP by fluorescence polarization, thus tracking the binding of AMP / GMP antibodies and indicating enzyme activity.

[0242] reagent: Experimental buffer solution: 10mM Tris-HCl (pH7.5), 5mM MgCl 2 , 0.01% Brij 35, 1 mM dithiothreitol (DTT), 1% DMSO.

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

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

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

[0246] Data analysis: Based on the AMP / GMP standard curve, the percent enzyme activity was calculated from the fluorescence polarization signal relative to the DMSO control using software Excel and converted to nM. Curve fitting was performed using GraphPad Prism (for medical graphing). Experimental results are shown in Table 10.

[0247] Experimental Example 2: In vitro measurement of the inhibitory activity of compounds against the PDE4B enzyme Experimental objective: To measure the expression of AMP / GMP by fluorescence polarization, thus tracking the binding of AMP / GMP antibodies and indicating enzyme activity.

[0248] reagent: Experimental buffer solution: 10mM Tris-HCl (pH7.5), 5mM MgCl 2 , 0.01%Brij 35, 1mM DTT, 1%DMSO.

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

[0250] Substrate: 1μM cAMP. Measurements: Transcreener® AMP2 / GMP2 antibody and AMP2 / GMP2 AlexaFluor633 were tracked.

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

[0252] Data analysis: Based on the AMP / GMP standard curve, the percent enzyme activity was calculated from the fluorescence polarization signal relative to the DMSO control using software Excel and converted to nM. Curve fitting was performed using GraphPad Prism (for medical graphing). Experimental results are shown in Table 10. [Table 10]

[0253] The compounds of the present application have a clear 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 in vivo pharmacokinetic properties of compound of formula (I) in beagle dogs were evaluated by quantitatively measuring the plasma drug concentrations at different time points after intravenous injection or oral gavage of compound of formula (I) to beagle dogs using LC-MS / MS.

[0255] The clear solution of the compound of formula (I) was injected into the body of two beagle dogs weighing 10 to 12 kg via the cephalic vein or the great saphenous vein, and the clear solution of the compound of formula (I) was administered orally by force to two beagle dogs weighing 10 to 12 kg (fasted overnight). All animals were given blood samples of about 500 μL from a peripheral vein at 0.0333 hours, 0.0833 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration, and 0.85 to 1.15 mg of K were administered. 2 EDTA 2H 2The samples were transferred to anticoagulant centrifuge tubes containing O and centrifuged at 3000 g for 10 min at 4° C. Plasma was collected. Blood drug concentrations were measured by LC-MS / MS, and relevant pharmacokinetic parameters were calculated using the noncompartmental model with linear unit method using pharmacokinetic software WinNonlin™ Version 6.3 (Pharsight, Mountain View, CA). [Table 11]

[0256] The compounds of the present application have high in vivo plasma clearance and low plasma exposure and bioavailability upon oral administration.

[0257] Experimental Example 4: Inhibitory effect on isoenzymes of cytochrome P450 derived from human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) Five specific probe substrates for five CYP isoenzymes, namely phenacetin (CYP1A2), diclofenac (CYP2C9), (S)-mephenytoin (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4), were co-incubated with human liver microsomes and the compound of formula (I), respectively, and nicotinamide adenine dinucleotide phosphate reduced form (NADPH) was added to initiate the reaction. After the reaction was completed, the samples were processed and the concentrations of five metabolic products generated by specific substrates, namely acetaminophen, 4'-hydroxydiclofenac, 4'-hydroxymephenytoin, dextrorphan, and 1'-hydroxymidazolam, were quantitatively measured by liquid chromatography tandem mass spectrometry (LC-MS / MS) to obtain the corresponding half-inhibitory concentrations (IC 50 ) was calculated. [Table 12]

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

[0259] Experimental Example 5: Pharmacodynamic study in passive smoking-induced acute lung injury model in rats Experimental animals: Male SPF standard Sprague-Dawley rats (provided by Shanghai Sprague-Dawley Laboratory Animal Co., Ltd.) were used, weighing approximately 200 g.

[0260] Testing Procedure: 1. After being admitted to the facility, the animals were kept for one week to allow them to adapt to the environment, and then randomly divided into six groups based on their body weight. 2. On the first to third days of the experiment, the target compound was administered by aerosol to each group for 30 minutes, and then the animals in the model group and each compound treatment group were exposed to passive smoking for 1 hour, and then exposed to passive smoking again for 1 hour at an interval of 4 hours. They were exposed to cigarette smoke twice a day for three consecutive days. The control group animals were exposed to air in a room. 3. On the fourth day of the experiment, the target compound was administered to each group by aerosol for 30 minutes, and the animals in the model group and each compound treatment group were exposed to 150 μg / mL LPS by aerosol inhalation for 15 minutes. Three hours after the start of aerosol administration, the animals were exposed to passive smoking for one hour, and the animal pulmonary function (Penh, F) was measured, and CO 2 The animals were euthanized with 5% CO and then alveolar lavage fluid was collected for cell counting.

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

[0262] Frequency of administration: Every morning, either the aerosolized or solvent was administered for 30 minutes before passive smoking, and on the fourth day, the aerosolized administration was administered before inhalation of LPS aerosolized.

[0263] 5. Pharmacodynamic endpoint measurements (1) Total white blood cell count in BALF (bronchoalveolar lavage fluid). (2) Measurement of pulmonary function under methacholine (Mch)-induced hypertension (airway resistance index Penh). [Table 13]

[0264] See Figs. 19 and 20 for the experimental results.

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

[0266] Experimental Example 6: In vitro measurement of the inhibitory activity of compounds against TNF-α in human peripheral blood mononuclear cells Experimental Objective: To demonstrate the cellular level anti-inflammatory activity of test compounds on TNF-α levels in human peripheral blood mononuclear cells (hPBMC).

[0267] procedure: 1. Whole blood was collected from healthy subjects and anticoagulated in an EDTA anticoagulant tube. 2. PBMCs were isolated by Ficoll density gradient centrifugation, counted, and the cell concentration was adjusted to 2 × 10 6 / mL. 3. 2 x 10 cells per well of a U-bottom 96-well plate 5 The compounds of formula (I) were prepared in DMSO at concentrations of 100 μM, 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 100 pM, and 10 pM, and each well had a reaction volume of 200 μL. 4. After culturing for 24 hours, the supernatant was collected. 5. Measure TNF-α levels in the supernatants by ELISA and fit inhibition curves using the software Graphpad Prism to calculate IC 50 was calculated.

[0268] See Table 14 for experimental results. [Table 14]

[0269] The compounds of the present application have obvious inhibitory effects on TNF-α in human peripheral blood mononuclear cells (hPBMC). Some embodiments are given below. Item 1 A crystal of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. [ka] Section 2 A crystal of the compound of formula (I), having 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°, and 16.35±0.2°, or The X-ray powder diffraction pattern using Kα radiation has diffraction peaks at 2θ angles of 4.14±0.2°, 6.98±0.2°, 8.20±0.2°, and 11.50±0.2°, or 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°. Item 3. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to item 1, having 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°, and 24.57±0.2°. Section 3 Item 3. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to item 1 or 2, which is a crystal of the compound of formula (I), and has an XRPD pattern using Cu Kα radiation as shown in FIG. Section 4 Item 4. A crystal of the compound of formula (I) or a crystalline pharma- ceutically acceptable salt thereof according to any one of Items 1 to 3, which has an endothermic peak at 146.23±2°C and / or 162.19±2°C in a differential scanning calorimetry curve, or has an exothermic peak at 172.65±2°C and / or 241.73±2°C in a differential scanning calorimetry curve. Section 5 A crystal of the compound of formula (I), having an X-ray powder diffraction pattern using Cu Kα radiation that includes 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°, and 26.13±0.2°, or The X-ray powder diffraction pattern using 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°, or 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°, or Item 3. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to item 1, having diffraction peaks at θ 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°, and 26.13±0.2°. Section 6 Item 6. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to item 1 or 5, which is a crystal of the compound of formula (I), and has an XRPD pattern using Cu Kα radiation as shown in FIG. Section 7 Item 7. A crystal of the compound of formula (I) or a crystalline pharma- ceutically acceptable salt thereof according to any one of items 1, 5, and 6, which is a crystal of the compound of formula (I) and has an exothermic peak at 247.70±2°C in a differential scanning calorimetry curve. Section 8 A crystal of the compound of formula (I), having 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°, and 23.41±0.2°, or The X-ray powder diffraction pattern using Kα radiation has diffraction peaks at 2θ angles of 4.57±0.2°, 6.41±0.2°, 7.18±0.2°, and 14.34±0.2°, or 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°. Item 3. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to item 1, having 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°. Section 9 Item 9. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to item 1 or 8, which is a crystal of the compound of formula (I), and has an XRPD pattern using Cu Kα radiation as shown in FIG. Section 10 Item 10. A crystal of the compound of formula (I) or a crystalline pharma- ceutically acceptable salt thereof according to any one of items 1, 8, and 9, which has an exothermic peak at 152.26±2°C and / or 247.92±2°C in a differential scanning calorimetry curve. Section 11 A crystal of a compound of formula (II), [ka] The X-ray powder diffraction pattern using Cu Kα radiation contains 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°, and 24.42±0.2°, or The X-ray powder diffraction pattern using Kα radiation has diffraction peaks at 2θ angles of 4.84±0.2°, 9.58±0.2°, 11.97±0.2°, and 14.75±0.2°, or has 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°, and 24.42 .... Item 3. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to item 1, having diffraction peaks at the following angles: 9.58±0.2°, 10.93±0.2°, 11.97±0.2°, 12.72±0.2°, 13.93±0.2°, 14.31±0.2°, 14.75±0.2°, 16.49±0.2°, 17.91±0.2°, 19.25±0.2°, 19.90±0.2°, 20.57±0.2°, 24.42±0.2°, and 25.70±0.2°. Section 12 Item 12. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to item 1 or 11, which is a crystal of the compound of formula (II), and has an XRPD pattern using Cu Kα radiation as shown in FIG. Section 13 A crystal of a compound of formula (III),

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Claims

1. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】

2. A crystal of the compound of formula (I), which has an X-ray powder diffraction pattern using Cu Kα radiation containing 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°, and 16.35±0.2°, or a crystal of the compound of formula (I) ... an X-ray powder diffraction pattern using Kα radiation has diffraction peaks at 2θ angles of 4.14±0.2°, 6.98±0.2°, 8.20±0.2°, and 11.50±0.2°, or 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°; Or a crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1, having 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°, and 24.57±0.2°.

3. The crystal of the compound of formula (I) has an XRPD pattern using Cu Kα radiation as shown in FIG.

3. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1 or 2, which is as shown in

4. A crystal of the compound of formula (I) or a crystalline pharma- ceutically acceptable salt thereof according to any one of claims 1 to 3, which is a crystal of the compound of formula (I), and which has an endothermic peak at 146.23±2°C and / or 162.19±2°C in a differential scanning calorimetry curve, or has an exothermic peak at 172.65±2°C and / or 241.73±2°C in a differential scanning calorimetry curve.

5. A crystal of the compound of formula (I), wherein the X-ray powder diffraction pattern using Cu Kα radiation includes 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°, and 26.13±0.2°, or The X-ray powder diffraction pattern using 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°, or 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°, or 2. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1, having diffraction peaks at 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°, and 26.13±0.2°.

6. The crystal of the compound of formula (I) is shown in FIG. 4 below.

6. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1 or 5, which is as shown in

7. A crystal of the compound of formula (I) or a crystalline pharma- ceutically acceptable salt thereof according to any one of claims 1, 5, and 6, which is a crystal of the compound of formula (I) and has an exothermic peak at 247.70±2°C in a differential scanning calorimetry curve.

8. A crystal of the compound of formula (I), which has an X-ray powder diffraction pattern using Cu Kα radiation containing 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°, and 23.41±0.2°, or an X-ray powder diffraction pattern using Kα radiation has diffraction peaks at 2θ angles of 4.57±0.2°, 6.41±0.2°, 7.18±0.2°, and 14.34±0.2°, or 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°; Or a crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1, having 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°.

9. The crystal of the compound of formula (I) is shown in FIG. 7 below.

9. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1 or 8, which is as shown in

10. A crystal of the compound of formula (I) or a crystalline pharma- ceutically acceptable salt thereof according to any one of claims 1, 8, and 9, which is a crystal of the compound of formula (I) and has an exothermic peak at 152.26±2°C and / or 247.92±2°C in a differential scanning calorimetry curve.

11. A crystal of a compound of formula (II), 【Chemistry 2】 an 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°, and 24.42±0.2°; or The X-ray powder diffraction pattern using Kα radiation has diffraction peaks at 2θ angles of 4.84±0.2°, 9.58±0.2°, 11.97±0.2°, and 14.75±0.2°, or has 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°, and 24.42±0.2°, or has diffraction peaks at 2θ angles of 4.84±0.2°, 2. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1, having diffraction peaks at 9.58±0.2°, 10.93±0.2°, 11.97±0.2°, 12.72±0.2°, 13.93±0.2°, 14.31±0.2°, 14.75±0.2°, 16.49±0.2°, 17.91±0.2°, 19.25±0.2°, 19.90±0.2°, 20.57±0.2°, 24.42±0.2°, and 25.70±0.2°.

12. A crystal of a compound of formula (III), 【Chemistry 3】 The X-ray powder diffraction pattern using Cu Kα radiation includes three, four, five, or six 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°, or the X-ray powder diffraction pattern using CuKα radiation has diffraction peaks at 2θ angles of 6.53±0.2°, 12.48±0.2°, and 13.11±0.2°, or 2. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1, having 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°, or having 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°.

13. A crystal of a compound of formula (IV), 【Chemistry 4】 an X-ray powder diffraction pattern using Cu Kα radiation 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°; or The X-ray powder diffraction pattern using 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°, or or has 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 and 25.87±0.2°, or having 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. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1, having diffraction peaks at the following positions: 20.02±0.2°, 20.51±0.2°, 22.62±0.2°, 23.27±0.2°, 24.45±0.2°, 24.83±0.2°, 25.42±0.2°, 25.87±0.2°, 26.09±0.2°, and 29.53±0.2°.

14. A crystal of the compound of formula (IV) or a crystal of a pharma- ceutically acceptable salt thereof according to claim 1 or 13, wherein the differential scanning calorimetry curve has an endothermic peak at 191.35±2°C and / or an exothermic peak at 222.21±2°C.

15. A crystal of a compound of formula (V), 【Chemistry 5】 an X-ray powder diffraction pattern using Cu Kα radiation 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°, and 25.16±0.2°; or An X-ray powder diffraction pattern using Kα radiation has diffraction peaks at 2θ angles of 5.83±0.2°, 6.62±0.2°, 9.50±0.2°, and 10.98±0.2°, or has diffraction peaks 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°; 2. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1, having diffraction peaks 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°.

16. A pharma- ceutically acceptable salt of a compound of formula (I), said pharma- ceutically acceptable salt being a sulfate, a p-toluenesulfonate, a mesylate or a maleate; 【Chemistry 6】 A pharma- ceutically acceptable salt of the compound of formula (I).

17. The sulfate salt of the compound of formula (I) is selected from the compound of formula (II), 【Chemistry 7】 The p-toluenesulfonic acid salt of the compound of formula (I) is selected from the compound of formula (III): 【Chemistry 8】 The mesylate salt of the compound of formula (I) is selected from the compound of formula (IV): 【Chemistry 9】 or The maleate salt of the compound of formula (I) is selected from the compound of formula (V): 【Chemistry 10】 17. A pharma- ceutically acceptable salt of a compound of formula (I) according to claim 16.

18. A crystalline composition comprising a crystal of a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 15, wherein said crystal comprises 50% or more, or 80% or more, or 90% or more, or 95% or more by weight of said crystalline composition.

19. A pharmaceutical composition comprising a therapeutically effective amount of a crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 15, a pharma- ceutically acceptable salt of the compound of formula (I) according to claim 16 or 17, or a crystalline composition according to claim 18.

20. A method for producing a compound of formula (I), comprising producing a compound of formula (I) by method 1 or method 2, The method 1 includes: (1) reacting a compound 1-2a to obtain a compound BB-4; and (2) reacting the compound BB-4 with 5-hydroxy-3-methyl-1,2,3-triazole-4-carboxylic acid to obtain a compound of formula (I). 【Chemistry 11】 The method 2 comprises reacting compound 1-4b to obtain a compound of formula (I): 【Chemistry 12】 Methods for preparing compounds of formula (I).

21. The compound of formula (I) is prepared by Method 1, except that compound BB-1 is reacted with compound 1-1a to give compound 1-2a; 【Chemistry 13】 21. The method of claim 20.

22. The compound of formula (I) is prepared by method 2, except that compound BB-4 is reacted with compound 1-3b to give compound 1-4b; 【Chemistry 14】 21. The method of claim 20.

23. Compound BB-4 is obtained by reacting compound 1-1b. 【Chemistry 15】 23. The method of claim 20 or 22.

24. Compound BB-1 is reacted with compound a to obtain compound 1-1b, 【Chemistry 16】 24. The method of claim 23, wherein X is selected from halogens, or X is selected from Cl and Br, or X is selected from Br.

25. 18. A process for preparing a pharma- ceutically acceptable salt of a compound of formula (I) according to claim 16 or 17, comprising mixing the compound of formula (I) with tetrahydrofuran, followed by adding an aqueous solution of an acid, and isolating to obtain the corresponding pharma- ceutically acceptable salt.

26. Precipitating the compound of formula (I) or a pharma- ceutically acceptable salt thereof from a solvent selected from methanol, a mixed solvent of ethanol and water, acetonitrile, and a mixed solvent of tetrahydrofuran and water; Alternatively, the compound of formula (I) is mixed with tetrahydrofuran, and an aqueous solution of an acid and / or a base is added thereto to cause a reaction, thereby precipitating the salt of the compound of formula (I) in the form of crystals from a mixed solvent of tetrahydrofuran and water. A method for producing a crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 15, comprising:

27. A crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 15, a pharma- ceutically acceptable salt of the compound of formula (I) according to claim 16 or 17, a crystalline composition according to claim 18, or a pharmaceutical composition according to claim 19, for use in the prophylaxis or treatment of a PDE3- and / or PDE4-related disease, optionally selected from asthma, and a PDE3- and / or PDE4-related disease.

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