Crystals of fused tricyclic derivatives or pharma- ceutically acceptable salts thereof

Abstract

The present application discloses a crystal of a fused tricyclic derivative or a pharma- ceutically acceptable salt thereof, and in particular, discloses a crystal of a compound of formula (I), a crystal of a pharma- ceutically acceptable salt thereof, and a method for preparing and using the same. TIFF2025510061000027.tif41170

Description

[Technical field]

[0001] (See related applications.) This application claims priority to the following:

[0002] This application claims priority to and the benefit of Chinese patent application No. 2022103077974, filed with the State Intellectual Property Office of China on March 25, 2022, the entire contents of which are incorporated herein by reference.

[0003] The present application relates to crystals of fused tricyclic derivatives or pharma- ceutically acceptable salts thereof and a method for preparing the same, as well as the use of said crystals in the manufacture of a medicament for treating diseases associated with the M3 receptor and β2 receptor. [Background technology]

[0004] Bronchodilators play an important role in the treatment of respiratory diseases (e.g., chronic obstructive pulmonary disease and asthma). β-adrenergic receptor agonists and muscarinic receptor antagonists are known bronchodilators that are widely used in clinical applications. Currently, β-adrenergic receptor agonists available via inhalation include short-acting drugs such as salbutamol and terbutaline, and long-acting drugs such as salmeterol, formoterol, vilanterol and indacaterol. These drugs produce bronchodilator effects by stimulating the adrenergic receptors of airway smooth muscle, and can reverse the bronchoconstrictor response to various mediators (e.g., acetylcholine). Currently available inhaled muscarinic antagonists include short-acting ipratropium bromide or oxitropium bromide, and long-acting tiotropium bromide. These drugs can produce bronchodilator effects by reducing vagal cholinergic activity of airway smooth muscle. These drugs can improve lung function, improve quality of life, and alleviate the exacerbation of the disease. Clinical practice has shown that the combination of β2 agonists and M3 antagonists is more effective in treating chronic obstructive pulmonary disease (COPD) than either component alone. At present, combination preparations of muscarinic receptor antagonists and β2 adrenergic receptor agonists have been prepared in clinical practice for the treatment of asthma and moderate to severe COPD. Such combination preparations mainly include Anoro Ellipta (umeclidinium bromide / vilanterol), Ultibro Breezhaler (glycopyrronium bromide / indacaterol) and Duaklir (aclidinium bromide + formoterol fumarate), etc. The combination preparation has a better therapeutic effect than the single preparation, but the preparation is more demanding.

[0005] A single molecule with dual activity at muscarinic M3 and β2-adrenergic receptors (MABA) is more likely to exhibit synergistic drug targeting effects due to its matching pharmacokinetic properties compared to two-component combinations, and shows related advantages in combination. It is also easier to obtain triple combination therapy by formulating it with other therapeutic agents (e.g., inhaled glucocorticoids). Therefore, novel drugs that simultaneously have activity as β2-receptor agonists and muscarinic receptor antagonists and are suitable for the treatment of respiratory diseases (e.g., asthma, COPD) are believed to be of great clinical value and significance. Summary of the Invention

[0006] The present application provides a crystal of the compound of formula (I). [ka]

[0007] The present application, [ka] The present invention provides a crystalline form of compound of formula (I), A, having an X-ray powder diffraction pattern with diffraction peaks at 2θ angles of 12.65±0.20° and 24.06±0.20°.

[0008] In some embodiments of the present application, the crystalline A of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern with diffraction peak positions and relative intensities as shown in Table 1.

[0009] [Table 1] In some embodiments of the present application, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern as shown in FIG.

[0010] In some embodiments of the present application, crystalline A of the compound of formula (I) has a weight loss of 2.40% at 120.0° C. in a thermogravimetric analysis curve (TGA).

[0011] In some embodiments of the present application, the crystalline A of the compound of formula (I) has a TGA pattern as shown in FIG.

[0012] In some embodiments of the present application, crystalline A of the compound of formula (I) has an endothermic peak onset at 140.5° C. in a differential scanning calorimetry curve (DSC).

[0013] In some embodiments of the present application, the crystalline A of the compound of formula (I) has a DSC pattern as shown in FIG.

[0014] In some embodiments of the present application, crystalline A of the compound of formula (I) may exist as a crystalline solvate.

[0015] The present application further provides a method for preparing crystalline A of compound of formula (I), comprising the step of triturating compound of formula (I) in acetonitrile, and further comprising the step of isolating.

[0016] In some embodiments of the present application, the crystalline form A of the compound of formula (I) is (1) dispersing / suspending a compound of formula (I) in acetonitrile and triturating it; (2) continuing to triturate the solid in acetonitrile after filtration; and (3) filtering and drying.

[0017] In some embodiments of the present application, in step (2) above, trituration is performed under heating conditions, and preferably the trituration temperature is 50°C.

[0018] In some embodiments of the present application, the crystalline form A of the compound of formula (I) is Step (1) of adding methanol to the crystals C of the compound of formula (I) and suspending and stirring the mixture; and (2) drying.

[0019] The present application provides a crystalline form of compound of formula (I), B, which has an X-ray powder diffraction pattern having a diffraction peak at a 2θ angle of 12.66±0.20°.

[0020] In some embodiments of the present application, the crystalline B of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern with diffraction peak positions and relative intensities as shown in Table 2.

[0021] [Table 2] In some embodiments of the present application, the crystalline B of the compound of formula (I) has an X-ray powder diffraction pattern as shown in FIG.

[0022] In some embodiments of the present application, crystalline B of the compound of formula (I) has a weight loss of 6.24% at 150.0° C. in a thermogravimetric analysis curve (TGA).

[0023] In some embodiments of the present application, the crystalline B of the compound of formula (I) has a TGA pattern as shown in FIG.

[0024] In some embodiments of the present application, crystalline B of the compound of formula (I) has endothermic peaks at 65.3° C. and 156.3° C., respectively, in a differential scanning calorimetry (DSC) curve.

[0025] In some embodiments of the present application, the crystalline B of the compound of formula (I) has a DSC pattern as shown in FIG.

[0026] In some embodiments of the present application, the crystalline form B of the compound of formula (I) may exist as a crystalline solvate.

[0027] The present application further provides a method for producing crystalline B of compound of formula (I), comprising the steps of suspending and stirring the compound of formula (I) in tetrahydrofuran, followed by a heating and cooling cycle, and further comprising a separation step.

[0028] In some embodiments of the present application, crystalline B of the compound of formula (I) of the present application is Step (1) of adding tetrahydrofuran to a crystal C of the compound of formula (I) and suspending and stirring the mixture; (2) performing a heating and cooling cycle; and (3) drying.

[0029] The present application further provides Crystalline C of compound of formula (I), having an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 7.77±0.20°, 8.70±0.20°, 11.49±0.20°, 18.22±0.20°, and 23.39±0.20°.

[0030] In some embodiments of the present application, the crystalline C of the compound of formula (I) has an X-ray powder diffraction pattern, expressed in terms of 2θ angles, of at least five, six, seven, or eight diffraction peaks selected from 7.77±0.20°, 8.70±0.20°, 11.49±0.20°, 13.45±0.20°, 18.22±0.20°, 19.82±0.20°, 21.88±0.20°, and 23.39±0.20°.

[0031] In some embodiments of the present application, crystalline C of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 7.77±0.20°, 8.70±0.20°, 11.49±0.20°, 13.45±0.20°, 18.22±0.20°, 19.82±0.20°, 21.88±0.20°, and 23.39±0.20°.

[0032] In some embodiments of the present application, the crystalline C of the compound of formula (I) has an X-ray powder diffraction pattern expressed in terms of 2θ angles, which includes at least 12, 13, 14, 15, or 16 diffraction peaks selected from 7.77±0.20°, 8.70±0.20°, 9.97±0.20°, 10.64±0.20°, 11.49±0.20°, 13.45±0.20°, 15.55±0.20°, 18.22±0.20°, 19.82±0.20°, 20.37±0.20°, 21.88±0.20°, 23.39±0.20°, 23.99±0.20°, 27.29±0.20°, 27.75±0.20°, and 31.35±0.20°.

[0033] In some embodiments of the present application, the crystalline C of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 7.77±0.20°, 8.70±0.20°, 9.97±0.20°, 10.64±0.20°, 11.49±0.20°, 13.45±0.20°, 15.55±0.20°, 18.22±0.20°, 19.82±0.20°, 20.37±0.20°, 21.88±0.20°, 23.39±0.20°, 23.99±0.20°, 27.29±0.20°, 27.75±0.20°, and 31.35±0.20°.

[0034] In some embodiments of the present application, the crystalline C of the compound of formula (I) has an X-ray powder diffraction pattern of 7.77±0.20°, 8.70±0.20°, 9.97±0.20°, 10.64±0.20°, 11.49±0.20°, 12.28±0.20°, 12.71±0.20°, 13.45±0.20°, 13.84±0.20°, 14.82±0.20°, 15.55±0.20°, 16.89±0.20°, 17.39±0.20°, 18.22±0.20°, 19.22±0.20°, 20.22±0.20°, 21.22±0.20°, 22.22±0.20°, 23.22±0.20°, 24.22±0.20°, 25.22±0.20°, 26.22±0.20°, 27.22±0.20°, 28.22±0.20°, 29.22±0.20°, 30.22±0.20°, 31.22±0.20°, 32.22±0.20°, 33.22±0.20°, 34.22±0.20°, 35.22±0.20°, 36.22±0.20°, 37.22±0.20°, 38.22±0.20°, 39.22±0.20°, 40.22±0.20°, 41.22±0.20°, 42. The sample has diffraction peaks at 2θ angles of 19.45±0.20°, 19.82±0.20°, 20.37±0.20°, 20.71±0.20°, 21.88±0.20°, 22.70±0.20°, 23.39±0.20°, 23.99±0.20°, 24.32±0.20°, 25.46±0.20°, 26.00±0.20°, 26.55±0.20°, 27.29±0.20°, 27.75±0.20°, and 31.35±0.20°.

[0035] In some embodiments of the present application, the crystalline C of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern with diffraction peak positions and relative intensities as shown in Table 3.

[0036] [Table 3] In some embodiments of the present application, the crystalline C of the compound of formula (I) has an X-ray powder diffraction pattern as shown in FIG.

[0037] In some embodiments of the present application, crystalline C of the compound of formula (I) has a weight loss of 6.86% at 80.0° C. in a thermogravimetric analysis curve (TGA).

[0038] In some embodiments of the present application, the crystalline C of the compound of formula (I) has a TGA pattern as shown in FIG.

[0039] In some embodiments of the present application, crystalline C of the compound of formula (I) has an endothermic peak at 112.2° C. in a differential scanning calorimetry (DSC) curve.

[0040] In some embodiments of the present application, the crystalline C of the compound of formula (I) has a DSC pattern as shown in FIG.

[0041] In some embodiments of the present application, crystalline C of the compound of formula (I) may exist as a crystalline solvate.

[0042] The present application further provides a method for preparing crystalline C of compound of formula (I), comprising the steps of triturating compound of formula (I) in a mixed solvent of acetonitrile and water, and further comprising the steps of isolating.

[0043] In some embodiments of the present application, in the mixed solvent of acetonitrile and water, the volume ratio of acetonitrile to water is 1:1 to 1:10.

[0044] In some embodiments of the present application, the volume ratio of acetonitrile to water in the mixed solvent of acetonitrile and water is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, or any range thereof.

[0045] In some embodiments of the present application, the volume ratio of acetonitrile to water in the mixed solvent of acetonitrile and water is 1:1 to 1:5.

[0046] In some embodiments of the present application, in the mixed solvent of acetonitrile and water, the volume ratio of acetonitrile to water is 1:3.

[0047] In some embodiments of the present application, crystalline C of the compound of formula (I) of the present application is (1) adding acetonitrile to the compound of formula (I) and triturating and stirring the mixture; (2) adding water and triturating / stirring; (3) filtering to collect the solids; (4) washing the solid obtained in step (3) with acetonitrile; and and (5) drying.

[0048] In some embodiments of the present application, crystalline C of the compound of formula (I) of the present application is (1) adding acetonitrile to the compound of formula (I) and triturating and stirring the mixture; (2) evaporating approximately two-thirds of the acetonitrile under reduced pressure, adding water, and triturating and stirring; (3) filtering to collect the solids; adding acetonitrile to the solid obtained in step (3) and triturating and stirring the mixture; and and (5) filtering and drying.

[0049] In some embodiments of the present application, the volume ratio of acetonitrile remaining in step (2) above to water is 1:3.

[0050] The present application further provides a crystalline form of compound of formula (I), D, having an X-ray powder diffraction pattern with diffraction peaks at 2θ angles of 5.56±0.20° and 13.84±0.20°.

[0051] In some embodiments of the present application, the peak positions and relative intensities of the diffraction peaks in the X-ray powder diffraction (XRPD) pattern of Crystal D are as shown in Table 4.

[0052] [Table 4] In some embodiments of the present application, the crystalline form D of the compound of formula (I) has an X-ray powder diffraction pattern as shown in FIG.

[0053] In some embodiments of the present application, crystalline D of the compound of formula (I) has a weight loss of 7.96% at 150.0° C. in a thermogravimetric analysis curve (TGA).

[0054] In some embodiments of the present application, the crystalline D of the compound of formula (I) has a TGA pattern as shown in FIG.

[0055] In some embodiments of the present application, crystalline D of the compound of formula (I) has an endothermic peak at 148.9° C. in a differential scanning calorimetry (DSC) curve.

[0056] In some embodiments of the present application, the crystalline D of the compound of formula (I) has a DSC pattern as shown in FIG.

[0057] In some embodiments of the present application, crystalline D of the compound of formula (I) may exist as a crystalline solvate.

[0058] The present application further provides a method for producing crystalline D of compound of formula (I), comprising the steps of suspending and stirring crystalline C of compound of formula (I) in tetrahydrofuran, and further comprising a separation step.

[0059] In some embodiments of the present application, crystalline D of the compound of formula (I) of the present application is Step (1) of adding tetrahydrofuran to a crystal C of the compound of formula (I) and suspending and stirring the mixture; and (2) drying.

[0060] The present application provides a crystalline form E of compound of formula (I), which has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, and 15.14±0.20°.

[0061] In some embodiments of the present application, the crystalline E of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, 15.14±0.20°, and 17.03±0.20°.

[0062] In some embodiments of the present application, the crystalline E of the compound of formula (I) has an X-ray powder diffraction pattern expressed in terms of 2θ angles, which includes at least five, six, seven, or eight diffraction peaks selected from 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, 11.86±0.20°, 15.14±0.20°, 17.03±0.20°, 19.07±0.20°, and 23.60±0.20°.

[0063] In some embodiments of the present application, the crystalline E of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, 11.86±0.20°, 15.14±0.20°, 17.03±0.20°, 19.07±0.20°, and 23.60±0.20°.

[0064] In some embodiments of the present application, the crystalline E of the compound of formula (I) has an X-ray powder diffraction pattern expressed in terms of 2θ angles, which includes at least 10, 11, 12, or 13 diffraction peaks selected from 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, 11.86±0.20°, 15.14±0.20°, 16.67±0.20°, 17.03±0.20°, 18.50±0.20°, 19.07±0.20°, 21.12±0.20°, 23.60±0.20°, 26.61±0.20°, and 29.58±0.20°.

[0065] In some embodiments of the present application, the crystalline E of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, 11.86±0.20°, 15.14±0.20°, 16.67±0.20°, 17.03±0.20°, 18.50±0.20°, 19.07±0.20°, 21.12±0.20°, 23.60±0.20°, 26.61±0.20°, and 29.58±0.20°.

[0066] In some embodiments of the present application, the crystalline E of the compound of formula (I) has an X-ray powder diffraction pattern of 4.25±0.20°, 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, 11.86±0.20°, 13.10±0.20°, 14.35±0.20°, 15.14±0.20°, 16.67±0.20°, 17.03±0.20°, 17.41±0.20°, 18.25±0.20°, 19.25±0.20°, 20.07±0.20°, 21.04±0.20°, 22.03±0.20°, 23.02±0.20°, 24.01±0.20°, 25.01±0.20°, 26.01±0.20°, 27.01±0.20°, 28.01±0.20°, 29.01±0.20°, 30.01±0.20°, 31.01±0.20°, 32.01±0.20°, 33.01±0.20°, 34.01±0.20°, 35.01±0.20°, 36.01±0.20°, 37.01±0.20°, 38.01±0.20°, 39.01±0.20°, 40.01±0.20°, 41.01±0.20°, 42.01±0.20°, 43.01±0.20°, 44. The sample has diffraction peaks at 2θ angles of 18.13±0.20°, 18.50±0.20°, 19.07±0.20°, 21.12±0.20°, 21.39±0.20°, 21.83±0.20°, 23.60±0.20°, 25.54±0.20°, 26.61±0.20°, 27.80±0.20°, 29.58±0.20°, and 30.59±0.20°.

[0067] In some embodiments of the present application, the crystalline E of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern with diffraction peak positions and relative intensities as shown in Table 5.

[0068] [Table 5] In some embodiments of the present application, the crystalline E of the compound of formula (I) has an X-ray powder diffraction pattern as shown in FIG.

[0069] In some embodiments of the present application, the crystalline E of the compound of formula (I) has a weight loss of 6.29% at 140.0° C. in a thermogravimetric analysis curve (TGA).

[0070] In some embodiments of the present application, the crystalline E of the compound of formula (I) has a TGA pattern as shown in FIG.

[0071] In some embodiments of the present application, crystalline E of the compound of formula (I) has endothermic peak values ​​at 120.0°C, 152.7°C, and 192.0°C, respectively, in a differential scanning calorimetry curve (DSC).

[0072] In some embodiments of the present application, the crystalline E of the compound of formula (I) has a DSC pattern as shown in FIG.

[0073] In some embodiments of the present application, the crystalline form E of the compound of formula (I) may exist as a crystalline solvate.

[0074] The present application further provides a method for preparing crystalline E of compound of formula (I) comprising the steps of triturating compound of formula (I) in methanol, and further comprising a separating step.

[0075] In some embodiments of the present application, the crystalline E of the compound of formula (I) of the present application is (1) triturating and stirring a compound of formula (I) in methanol; and (2) filtering and drying.

[0076] The present application further provides a crystalline form of compound of formula (I), F, having an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 9.50±0.20°, 15.79±0.20°, and 18.44±0.20°.

[0077] The present application further provides a crystalline form of compound of formula (I), F, having an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 9.50±0.20°, 13.34±0.20°, 15.79±0.20°, 18.44±0.20°, and 24.43±0.20°.

[0078] In some embodiments of the present application, the crystalline F of the compound of formula (I) has an X-ray powder diffraction pattern, expressed in terms of 2θ angles, of at least five, six, seven, or eight diffraction peaks selected from 9.50±0.20°, 13.34±0.20°, 15.79±0.20°, 18.44±0.20°, 19.97±0.20°, 21.27±0.20°, 21.80±0.20°, and 24.43±0.20°.

[0079] In some embodiments of the present application, the crystalline F of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 9.50±0.20°, 13.34±0.20°, 15.79±0.20°, 18.44±0.20°, 19.97±0.20°, 21.27±0.20°, 21.80±0.20°, and 24.43±0.20°.

[0080] In some embodiments of the present application, the crystalline F of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern with diffraction peak positions and relative intensities as shown in Table 6.

[0081] [Table 6] In some embodiments of the present application, the crystalline F of the compound of formula (I) has an X-ray powder diffraction pattern as shown in FIG.

[0082] In some embodiments of the present application, the crystalline F of the compound of formula (I) has a weight loss of 2.02% at 150.0° C. in a thermogravimetric analysis curve (TGA).

[0083] In some embodiments of the present application, the crystalline F of the compound of formula (I) has a TGA pattern as shown in FIG.

[0084] In some embodiments of the present application, crystalline F of the compound of formula (I) has endothermic peaks at 130.2°C, 151.6°C, and 190.9°C, respectively, in a differential scanning calorimetry (DSC) curve.

[0085] In some embodiments of the present application, the crystalline F of the compound of formula (I) has a DSC pattern as shown in FIG.

[0086] In some embodiments of the present application, the crystalline form F of the compound of formula (I) may exist as a crystalline solvate.

[0087] The present application further provides a method for preparing crystalline F of compound of formula (I), comprising the step of triturating crystalline E of compound of formula (I) in methanol, and further comprising the step of isolating.

[0088] In some embodiments of the present application, crystalline F of the compound of formula (I) of the present application is (1) triturating and stirring the crystalline E of the compound of formula (I) in methanol, cooling and filtering; Step (2) repeats the operation of step (1) three times; and (3) drying.

[0089] The present application provides a tartrate salt of the compound of formula (I). Preferably, the tartrate salt is in crystalline form.

[0090] In some embodiments of the present application, the tartrate salt of the compound of formula (I) is an L-tartrate salt or a D-tartrate salt, and preferably, the L-tartrate salt or the D-tartrate salt is in crystalline form.

[0091] In some embodiments of the present application, the D-tartrate salt of the compound of formula (I) has a molar ratio of the compound of formula (I) to D-tartaric acid of 1:0.9 to 1:1.1, preferably 1:0.9, 1:1 or 1:1.1.

[0092] In some embodiments of the present application, the D-tartrate salt of the compound of formula (I) is a compound of formula (II): [ka] In the formula (II), x is an integer of 0.9 to 1.1, and preferably 0.9, 1 or 1.1.

[0093] In some embodiments of the present application, the compound of formula (II) is in a crystalline form.

[0094] In some embodiments of the present application, the crystal of the compound of formula (II) may exist as a crystalline solvate.

[0095] In some embodiments of the present application, the L-tartrate salt of the compound of formula (I) has a molar ratio of the compound of formula (I) to L-tartaric acid of 1:0.9 to 1:1.1, preferably 1:0.9, 1:1 or 1:1.1.

[0096] In some embodiments of the present application, the L-tartrate salt of the compound of formula (I) is a compound of formula (III): [ka] In formula (III), y is an integer of 0.9 to 1.1, and preferably 0.9, 1 or 1.1.

[0097] In some embodiments of the present application, the compound of formula (III) is in a crystalline form.

[0098] In some embodiments of the present application, the crystal of the compound of formula (III) may exist as a crystalline solvate.

[0099] The present application further provides a crystalline form G of the compound of formula (II) above, which has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 11.64±0.20°, 18.51±0.20°, and 22.68±0.20°.

[0100] In some embodiments of the present application, the crystalline G of the compound of formula (II) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 4.62±0.20°, 11.64±0.20°, 13.24±0.20°, 18.51±0.20°, and 22.68±0.20°.

[0101] In some embodiments of the present application, the X-ray powder diffraction pattern of crystalline G of the compound of formula (II) contains at least 6, 7, or 8 diffraction peaks selected from 4.62±0.20°, 10.98±0.20°, 11.64±0.20°, 13.24±0.20°, 16.76±0.20°, 18.51±0.20°, 22.68±0.20°, and 23.52±0.20°, expressed in terms of 2θ angles.

[0102] In some embodiments of the present application, the crystalline G of the compound of formula (II) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 4.62±0.20°, 10.98±0.20°, 11.64±0.20°, 13.24±0.20°, 16.76±0.20°, 18.51±0.20°, 22.68±0.20°, and 23.52±0.20°.

[0103] In some embodiments of the present application, the crystalline G of the compound of formula (II) has an X-ray powder diffraction pattern expressed in terms of 2θ angles, which includes at least 12, 13, 14, 15, or 16 diffraction peaks selected from 4.62±0.20°, 9.80±0.20°, 10.98±0.20°, 11.64±0.20°, 12.63±0.20°, 13.24±0.20°, 13.79±0.20°, 15.28±0.20°, 16.76±0.20°, 18.51±0.20°, 19.62±0.20°, 21.62±0.20°, 22.68±0.20°, 23.52±0.20°, 25.04±0.20°, and 26.64±0.20°.

[0104] In some embodiments of the present application, the crystalline G of the compound of formula (II) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 4.62±0.20°, 10.98±0.20°, 11.64±0.20°, 13.24±0.20°, 13.79±0.20°, 15.28±0.20°, 16.76±0.20°, 18.51±0.20°, 19.62±0.20°, 22.68±0.20°, 23.52±0.20°, and 26.64±0.20°.

[0105] In some embodiments of the present application, the crystalline G of the compound of formula (II) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 4.62±0.20°, 9.80±0.20°, 10.98±0.20°, 11.64±0.20°, 12.63±0.20°, 13.24±0.20°, 13.79±0.20°, 15.28±0.20°, 16.76±0.20°, 18.51±0.20°, 19.62±0.20°, 21.62±0.20°, 22.68±0.20°, 23.52±0.20°, 25.04±0.20°, and 26.64±0.20°.

[0106] In some embodiments of the present application, the crystalline G of the compound of formula (II) has an X-ray powder diffraction pattern of 4.62±0.20°, 7.58±0.20°, 8.20±0.20°, 9.80±0.20°, 10.98±0.20°, 11.64±0.20°, 12.63±0.20°, 13.24±0.20°, 13.79±0.20°, 15.28±0.20°, 16.30±0.20°, 16.76±0.20°, 17.56±0.20°, 18.74±0.20°, 19.78±0.20°, 20.76±0.20°, 21.78±0.20°, 22.78±0.20°, 23.78±0.20°, 24.78±0.20°, 25.78±0.20°, 26.78±0.20°, 27.78±0.20°, 28.78±0.20°, 29.78±0.20°, 30.78±0.20°, 31.78±0.20°, 32.78±0.20°, 33.78±0.20°, 34.78±0.20°, 35.78±0.20°, 36.78±0.20°, 37.78±0.20°, 38.78±0.20°, 39.78±0.20°, 40.78±0.20°, 41.78±0.20°, 42.7 The sample has diffraction peaks at 2θ angles of 18.51±0.20°, 19.62±0.20°, 20.26±0.20°, 20.87±0.20°, 21.34±0.20°, 21.62±0.20°, 22.68±0.20°, 23.52±0.20°, 24.14±0.20°, 25.04±0.20°, 25.92±0.20°, 26.64±0.20°, 29.59±0.20°, and 30.18±0.20°.

[0107] In some embodiments of the present application, the crystalline G of the compound of formula (II) has the peak positions and relative intensities of the diffraction peaks in the X-ray powder diffraction (XRPD) pattern as shown in Table 7.

[0108] [Table 7] In some embodiments of the present application, the crystalline G of the compound of formula (II) has an X-ray powder diffraction pattern as shown in FIG.

[0109] In some embodiments of the present application, the crystalline G of the compound of formula (II) has a weight loss of 4.69% at 150.0° C. in a thermogravimetric analysis curve (TGA).

[0110] In some embodiments of the present application, the crystalline G of the compound of formula (II) has a TGA pattern as shown in FIG.

[0111] In some embodiments of the present application, the crystalline G of the compound of formula (II) has endothermic peak values ​​at 73.1°C, 124.5°C, and 184.4°C, respectively, in a differential scanning calorimetry curve (DSC).

[0112] In some embodiments of the present application, the crystalline G of the compound of formula (II) has a DSC pattern as shown in FIG.

[0113] In some embodiments of the present application, the crystalline form G of the compound of formula (II) may exist as a crystalline form of a solvate.

[0114] The present application further provides a method for preparing the crystalline form G of the compound of formula (II), comprising the steps of triturating the compound of formula (II) in ethanol, and further comprising the steps of isolating.

[0115] In some embodiments of the present application, the crystalline form G of the compound of formula (II) of the present application is Step (1) of reacting a compound of formula (I) with D-tartaric acid in the presence of dioxane and ethanol to obtain a compound of formula (II); step (2) of triturating the compound of formula (II) obtained in step (1) in ethanol; and (3) filtering and drying.

[0116] The present application further provides a crystalline form H of the compound of formula (III) above, which has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 11.56±0.20°, 18.64±0.20°, and 22.52±0.20°.

[0117] In some embodiments of the present application, crystalline H of the compound of formula (III) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 10.01±0.20°, 11.56±0.20°, 13.07±0.20°, 18.64±0.20°, and 22.52±0.20°.

[0118] In some embodiments of the present application, the X-ray powder diffraction pattern of crystalline H of the compound of formula (III) includes at least five, six, seven, or eight diffraction peaks selected from 10.01±0.20°, 11.56±0.20°, 13.07±0.20°, 14.17±0.20°, 18.64±0.20°, 20.06±0.20°, 22.52±0.20°, and 23.48±0.20°, expressed in terms of 2θ angles.

[0119] In some embodiments of the present application, crystalline H of the compound of formula (III) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 10.01±0.20°, 11.56±0.20°, 13.07±0.20°, 14.17±0.20°, 18.64±0.20°, 20.06±0.20°, 22.52±0.20°, and 23.48±0.20°.

[0120] In some embodiments of the present application, the crystalline H of the compound of formula (III) has an X-ray powder diffraction pattern, expressed in 2θ angles, of 4.29±0.20°, 10.01±0.20°, 10.89±0.20°, 11.56±0.20°, 13.07±0.20°, 14.17±0.20°, 14.80±0.20°, 15.66±0.20°, 16.07±0.20°, 17.07±0.20°, 18.07±0.20°, 19.07±0.20°, 20.07±0.20°, 21.07±0.20°, 22.07±0.20°, 23.07±0.20°, 24.07±0.20°, 25.07±0.20°, 26.07±0.20°, 27.07±0.20°, 28.07±0.20°, 29.07±0.20°, 30.07±0.20°, 31.07±0.20°, 32.07±0.20°, 33.07±0.20°, 34.07±0.20°, 35.07±0.20°, 36.07±0.20°, 37.07±0.20°, 38.07±0.20°, 39.07±0.20°, 40.07±0.20°, 41.07±0.20°, 42.07±0.20°, 43.07±0.20°, 44.07± The diffraction peaks include at least 12, 13, 14, 15, or 16 diffraction peaks selected from 16.75±0.20°, 16.37±0.20°, 18.64±0.20°, 20.06±0.20°, 22.52±0.20°, 23.48±0.20°, 24.80±0.20°, 25.98±0.20°, and 29.35±0.20°.

[0121] In some embodiments of the present application, the crystalline H of the compound of formula (III) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 4.29±0.20°, 10.01±0.20°, 10.89±0.20°, 11.56±0.20°, 13.07±0.20°, 14.17±0.20°, 16.37±0.20°, 18.64±0.20°, 20.06±0.20°, 22.52±0.20°, 23.48±0.20°, and 25.98±0.20°.

[0122] In some embodiments of the present application, the crystalline H of the compound of formula (III) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 4.29±0.20°, 10.01±0.20°, 10.89±0.20°, 11.56±0.20°, 13.07±0.20°, 14.17±0.20°, 14.80±0.20°, 15.66±0.20°, 16.37±0.20°, 18.64±0.20°, 20.06±0.20°, 22.52±0.20°, 23.48±0.20°, 24.80±0.20°, 25.98±0.20°, and 29.35±0.20°.

[0123] In some embodiments of the present application, the crystalline H of the compound of formula (III) has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 4.29±0.20°, 7.66±0.20°, 10.01±0.20°, 10.89±0.20°, 11.56±0.20°, 13.07±0.20°, 14.17±0.20°, 14.80±0.20°, 15.66±0.20°, 16.37±0.20°, 18.64±0.20°, 20.06±0.20°, 22.52±0.20°, 23.48±0.20°, 24.80±0.20°, 25.98±0.20°, 29.35±0.20°, and 34.55±0.20°.

[0124] In some embodiments of the present application, crystalline H of the compound of formula (III) has an X-ray powder diffraction (XRPD) pattern with diffraction peak positions and relative intensities as shown in Table 8.

[0125] [Table 8] In some embodiments of the present application, the compound of formula (III) above, crystalline H, has an X-ray powder diffraction pattern as shown in FIG.

[0126] In some embodiments of the present application, crystalline H of the compound of formula (III) has a weight loss of 4.21% at 160.0° C. in a thermogravimetric analysis curve (TGA).

[0127] In some embodiments of the present application, the crystalline H of the compound of formula (III) has a TGA pattern as shown in FIG.

[0128] In some embodiments of the present application, crystalline H of the compound of formula (III) has an endothermic peak at 176.4° C. in a differential scanning calorimetry (DSC) curve.

[0129] In some embodiments of the present application, the crystalline H of the compound of formula (III) has a DSC pattern as shown in FIG.

[0130] In some embodiments of the present application, the crystalline form H of the compound of formula (III) may exist as a crystalline solvate.

[0131] The present application further provides a method for preparing crystalline H of the compound of formula (III), comprising precipitating the compound of formula (III) in a mixed solvent of methanol and tetrahydrofuran, and further comprising a separating step.

[0132] In some embodiments of the present application, crystalline H of the compound of formula (III) of the present application is (1) reacting a compound of formula (I) with L-tartaric acid in the presence of methanol and tetrahydrofuran to obtain a compound of formula (III); (2) stirring, filtering and drying.

[0133] In another aspect, the present application provides a crystalline composition comprising Crystal A, Crystal B, Crystal C, Crystal D, Crystal E or Crystal F of compound of formula (I), Crystal G of compound of formula (II), or Crystal H of compound of formula (III), wherein said crystals account for 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more by weight of the crystalline composition.

[0134] In another aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline A, crystalline B, crystalline C, crystalline D, crystalline E or crystalline F of the compound of formula (I), the D-tartrate salt of the compound of formula (I), the compound of formula (II) or a crystalline G thereof, the L-tartrate salt of the compound of formula (I), the compound of formula (III) or a crystalline H thereof, or the above crystalline compositions. The pharmaceutical composition of the present application may or may not contain a pharma- ceutically acceptable adjuvant. The pharmaceutical composition of the present application may further contain one or more other therapeutic agents.

[0135] In a further aspect, the present application provides a method for treating chronic obstructive pulmonary disease, comprising administering a therapeutically effective amount of crystalline A, crystalline B, crystalline C, crystalline D, crystalline E or crystalline F of the compound of formula (I), the D-tartrate salt of the compound of formula (I), the compound of formula (II) or a crystalline G thereof, the L-tartrate salt of the compound of formula (I), the compound of formula (III) or a crystalline H thereof, or any of said crystalline compositions, or any of said pharmaceutical compositions, to an individual in need thereof.

[0136] In a further aspect, the present application provides use of crystalline A, crystalline B, crystalline C, crystalline D, crystalline E or crystalline F of the compound of formula (I), the D-tartrate salt of the compound of formula (I), the compound of formula (II) or a crystalline G thereof, the L-tartrate salt of the compound of formula (I), the compound of formula (III) or a crystalline H thereof, or any of said crystalline compositions, or any of said pharmaceutical compositions, in the manufacture of a medicament for treating chronic obstructive pulmonary disease.

[0137] In a further aspect, the present application provides use of crystalline A, crystalline B, crystalline C, crystalline D, crystalline E or crystalline F of the compound of formula (I), the D-tartrate salt of the compound of formula (I), the compound of formula (II) or a crystalline G thereof, the L-tartrate salt of the compound of formula (I), the compound of formula (III) or a crystalline H thereof, or said crystalline composition, or said pharmaceutical composition, in the treatment of chronic obstructive pulmonary disease.

[0138] In a further aspect, the present application provides crystalline A, crystalline B, crystalline C, crystalline D, crystalline E or crystalline F of the compound of formula (I), the D-tartrate salt of the compound of formula (I), the compound of formula (II) or a crystalline G thereof, the L-tartrate salt of the compound of formula (I), the compound of formula (III) or a crystalline H thereof, or the crystalline composition or the pharmaceutical composition for treating chronic obstructive pulmonary disease.

[0139] The compound of the present application and its crystals are easy to prepare, have excellent solubility, physical stability and chemical stability, and have good oral exposure and excellent pharmacokinetic properties, making them suitable for use as drugs.Specifically, the crystals C and E of the compound of formula (I) of the present application are highly stable, easy to prepare as drugs, have significant agonistic effect on β2 receptors and binding effect on M3 receptors, and can be used as bronchodilator agents to treat chronic obstructive pulmonary disease.

[0140] [Definition and Explanation] 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, not as open or unclear, unless specifically defined: When trade names are mentioned herein, they refer to the corresponding products or their active ingredients.

[0141] It is well known in the field of crystallography that for any given crystal morphology, the relative intensity of the diffraction peaks may change due to preferred orientation resulting from factors such as the crystal morphology. When the effect of preferred orientation is present, the peak intensity may change, but the diffraction peak position of the crystal will not change. It is also well known in the field of crystallography that for any given crystal, there may be a small error in the position of the peak. For example, the peak position may vary due to changes in temperature when analyzing the sample, movement of the sample, or calibration of the instrument, and the measurement error of the 2θ value may be about ±0.2°. Therefore, it is well known to those skilled in the art that such errors should be taken into account when identifying various crystal structures.

[0142] DSC measures the transition temperatures when a crystal undergoes a change in its crystal structure or absorbs or releases heat by melting. For the same type of crystal of the same type of compound, the error of thermal transition temperatures and melting points is typically within about 5°C or 3°C in consecutive analyses. When a compound is said to have a certain DSC peak or melting point, it means that the DSC peak or melting point is ±5°C or ±3°C. DSC provides an auxiliary method for distinguishing different crystals. Different crystal forms can be distinguished by their different transition temperature characteristics. For mixtures, the DSC peak or melting point may vary over a wider range. In addition, since decomposition occurs during the process of melting a substance, the melting temperature is related to the heating rate.

[0143] For the same crystal, the TGA weight loss temperature may vary depending on factors such as measurement equipment, measurement method / conditions, etc. For any particular crystal, there may be an error in the weight loss temperature, and the error may be about ±5°C, or about ±3°C.

[0144] In addition, when preparing crystals of a drug, in the process of contacting the drug molecules with the solvent molecules, due to external conditions or internal factors, the solvent molecules and the compound molecules will form a eutectic and remain in the solid substance, which inevitably produces solvates, specifically stoichiometric solvates and non-stoichiometric solvates. All of the above solvates are included within the scope of the present invention.

[0145] The above-mentioned "pharmaceutical acceptable adjuvant" refers to an inert substance that is administered together with an active ingredient and is advantageous to the administration of the active ingredient, and includes, but is not limited to, any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonicity agent, solvent or emulsifier approved by the China Food and Drug Administration for use in humans or animals (e.g., livestock).

[0146] The term "crystalline composition" refers to a mixture of a crystalline compound of Formula (I) or Formula (II) or Formula (III) of the present application together with other crystalline or amorphous or other impurities of said compound. For example, a crystalline composition of Crystal A of a compound of Formula (I) further comprises, in addition to Crystal A of a compound of Formula (I), other crystalline or amorphous or other impurities of a compound of Formula (I).

[0147] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharma- ceutical acceptable auxiliaries. Pharmaceutical compositions are intended for advantageous administration of the compounds of the present application to an organism.

[0148] The therapeutic dosage of the compounds of the present application can be determined according to the particular therapeutic use, the manner of administration of the compound, the health and condition of the patient, the judgment of the prescribing physician, etc. The proportion or concentration of the compounds of the present application in a pharmaceutical composition does not necessarily vary and will depend on a variety of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration.

[0149] The term "treatment" refers to the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with said disease; (i) inhibiting the disease or disease state, i.e., reducing its progression; (ii) Alleviating the disease or disease state, i.e., causing a reduction in the disease or disease state.

[0150] The term "therapeutically effective amount" refers to a dose of a compound of the present application that (i) treats a particular disease, condition, or disorder described herein, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder described herein, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The dose of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the state of the disease and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his or her own knowledge and the contents of this disclosure.

[0151] Unless otherwise required in this application, throughout this specification and the claims that follow, the terms "comprise" and its English variants, such as "comprises" and "comprising," are to be construed in their open-ended, inclusive sense, i.e., "including, but not limited to."

[0152] References throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in some embodiments" mean that at least one embodiment includes the relevant referenced particular element, structure, or feature described in that embodiment. Thus, the terms "in one embodiment" or "in an embodiment" or "in another embodiment" or "in some embodiments" appearing in different places throughout this specification do not necessarily refer to the same embodiment. Furthermore, the particular particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0153] As used in the specification and the appended claims, the singular articles "one," "one," and "one" (equivalent to the English terms "a," "an," and "the") should be understood to include plural objects unless otherwise specified. Thus, for example, a reaction involving a "catalyst" can include one catalyst or two or more catalysts. Additionally, the term "or" should be understood to generally include the meaning of "and / or" unless otherwise specified.

[0154] The intermediate compounds of the present application can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments that can be combined with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present application.

[0155] The chemical reactions in the specific embodiments of the present application were carried out in suitable solvents that should be compatible with the chemical transformations of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, those skilled in the art may need to modify or select synthetic steps or reaction flows based on the existing embodiments.

[0156] The conformation of 1,4-cyclohexyl in the structure of the compound of the present application is trans. For example, [ka] is tert-butyl trans(4-hydroxy-cyclohexyl)carbamate, and for example, the conformation of the cyclohexyl in the compound of formula (I) of the present application is trans.

[0157] The present application will be specifically described below with reference to examples, but these examples are not intended to limit the present application in any way.

[0158] All solvents used in this application are commercially available and can be used without further purification.

[0159] The solvents used in this application are commercially available.

[0160] This application uses the following abbreviations: Boc stands for tert-butoxycarbonyl, THF stands for tetrahydrofuran, DMSO stands for dimethylsulfoxide, Boc2O stands for di-tert-butyl dicarbonate, Bn stands for benzyl, Cbz stands for benzyloxycarbonyl, TBS stands for tert-butyldimethylsilyl, DIEA stands for N,N-diisopropylethylamine, DMF stands for N,N-dimethylformamide, i-PrOAc stands for isopropyl acetate, DIPEA stands for N,N-diisopropylethylamine, HEPES stands for 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid, NMS stands for N-methyl-scopolamine, PEI stands for polyethyleneimine, CbzCl stands for benzyl chloroformate, DCM represents dichloromethane, EA or EtOAc represents ethyl acetate, PE represents petroleum ether, MeOH represents methanol, Ru-(S,S)-Ms-DENEB represents {N-[(1S,2S)-2-[(R)-[2-[[1,2,3,4,5,6-η)-4-methylphenyl]methoxy]ethyl]amino]-1,2-diphenethylethylmethanesulfonamide}ruthenium(II) chloride, Xphos represents 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, Pd2(dba)3 represents bis(dibenzylideneacetone)palladium, MsCl represents methanesulfonyl chloride, and DIBAL-H represents diisobutylaluminum hydride.

[0161] Compounds are named according to conventions common in the field or the software ChemDraw®; commercially available compounds adopt the supplier's catalogue name.

[0162] Equipment and analytical methods 1.1. X-ray powder diffractometer (XRPD) method of the present application Device model number: X'Pert3 Test method: Approximately 10-20 mg of sample is used for XRPD detection.

[0163] Detailed XRPD parameters are as follows:

[0164] X-ray source: Cu, kα (Kα1=1.540598Å, Kα2=1.544426Å, Kα2 / Kα1 intensity ratio: 0.5) X-ray tube voltage: 45 kV, X-ray tube current: 40 mA Divergence slit: fixed 1 / 8deg 1st Soller slit: 0.04rad, 2nd Soller slit: 0.04rad Receiving slit: None, Anti-scattering slit: 7.5 mm Measurement time: 5 min Scanning angle range: 3~40° Step width angle: 0.0263° Step size: 46.665 seconds Sample disc rotation speed: 60 rpm 1.2. Differential Scanning Calorimetry (DSC) Method of the Present Application Model number: TA Q200 / Q2000 / 2500 differential scanning calorimeter Test method: The test is performed by placing a sample (approximately 1 to 5 mg) in an aluminum DSC sample pan and heating the sample from 25°C (room temperature) to decomposition at a heating rate of 10°C / min under N2 conditions of 50 mL / min.

[0165] 1.3. Thermogravimetric Analysis (TGA) Method of the Present Application Model number: TA Q5000 / 5500 Thermogravimetric Analyzer Test method: The test is performed by placing a sample (approximately 1 to 5 mg) in an aluminum TGA sample pan and heating the sample from room temperature to 350°C at a heating rate of 10°C / min under N2 conditions of 10 mL / min.

[0166] 1.4. Dynamic Vapor Sorption (DVS) Method of the Present Application Model number: SMS DVS Advantage Dynamic Vapor Sorption Apparatus Test conditions: Place the sample (10-15 mg) in a DVS sample pan and perform the test.

[0167] The detailed DVS parameters are as follows: Temperature: 25℃ Equilibrium: dm / dt=0.01% / min (minimum: 10min, maximum: 180min) Drying: Dry for 120 minutes at 0% RH RH(%) test gradient: 10% RH(%) test gradient range: 0%-90%-0%. [Brief description of the drawings]

[0168] [Figure 1] FIG. 1 is an XRPD pattern of Cu-Kα radiation of crystalline A of compound of formula (I).

[0169] [Diagram 2] 1 is a TGA pattern of crystalline A of compound of formula (I).

[0170] [Diagram 3] 1 is a DSC pattern of crystalline A of compound of formula (I).

[0171] [Figure 4] FIG. 2 is an XRPD pattern of Cu-Kα radiation of crystalline B of compound of formula (I).

[0172] [Diagram 5] 1 is a TGA pattern of crystalline B of compound of formula (I).

[0173] [Figure 6] 1 is a DSC pattern of crystalline B of compound of formula (I).

[0174] [Figure 7] FIG. 1 is an XRPD pattern of Cu-Kα radiation of crystalline C of compound of formula (I).

[0175] [Figure 8] 1 is a TGA pattern of crystalline C of compound of formula (I).

[0176] [Figure 9] 1 is a DSC pattern of crystalline C of compound of formula (I).

[0177] [Figure 10] FIG. 1 is an XRPD pattern of Cu-Kα radiation of crystalline D of compound of formula (I).

[0178] [Figure 11] 1 is a TGA pattern of crystalline D of compound of formula (I).

[0179] [Figure 12] 1 is a DSC pattern of crystalline D of compound of formula (I).

[0180] [Figure 13] FIG. 1 is an XRPD pattern of Cu-Kα radiation of crystalline E of compound of formula (I).

[0181] [Figure 14] 1 is a TGA pattern of crystalline E of compound of formula (I).

[0182] [Figure 15] 1 is a DSC pattern of crystalline E of compound of formula (I).

[0183] [Figure 16] FIG. 1 is an XRPD pattern of Cu-Kα radiation of crystalline F of compound of formula (I).

[0184] [Figure 17] 1 is a TGA pattern of crystalline F of compound of formula (I).

[0185] [Figure 18] 1 is a DSC pattern of crystalline F of compound of formula (I).

[0186] [Figure 19] FIG. 1 is an XRPD pattern of Cu-Kα radiation of crystalline G of compound of formula (II).

[0187] [Figure 20] 1 is a TGA pattern of crystalline G of compound of formula (II).

[0188] [Figure 21] 1 is a DSC pattern of crystalline G of compound of formula (II).

[0189] [Figure 22] FIG. 1 is an XRPD pattern of Cu-Kα radiation of crystalline H of compound of formula (III).

[0190] [Diagram 23] 1 is a TGA pattern of crystalline H of compound of formula (III).

[0191] [Figure 24] 1 is a DSC pattern of crystalline H of compound of formula (III).

[0192] [Diagram 25] 1 is a DVS pattern of crystalline C of compound of formula (I).

[0193] [Figure 26] FIG. 1 is an overlay of XRPD patterns of Cu-Kα radiation of crystalline C of compound of formula (I) before and after DVS testing.

[0194] [Figure 27] 1 is an overlay of XRPD patterns of crystalline E of compound of formula (I) before and after exposure to 94% RH. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0195] The present application will be described in detail below with reference to examples, but this does not limit the present application in any way. The present application, including specific embodiments, is described in detail in this specification. It is obvious to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0196] Reference Example 1 [ka] Synthesis Route: [ka]

[0197] Step 1: Synthesis of Compound 1-2 Compound 1-1 (15 g) was dissolved in acetic acid (75 mL) and water (75 mL), and sodium perborate (17.33 g) was added while stirring. The reaction solution was cooled to 0° C., and a solution of potassium iodide (18.70 g) in water (150 mL) was slowly added dropwise. The reaction solution was warmed to room temperature (25° C.) and stirred for 0.5 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with 500 mL of water. The solid was collected and concentrated to dryness under reduced pressure to obtain compound 1-2, which was used directly in the next step.

[0198] 1 H NMR (400MHz, CDCl3) δ:7.32(d,J=8.4Hz,1H), 6.30(d,J=8.4Hz,1H), 3.65(s,2H), 2.92-2.84(m,4H), 2.18-2.05(m,2H).

[0199] MS-ESI calculated value [M+H] + is 260 and the actual value is 260.0.

[0200] Step 2: Synthesis of compounds 1-3 Compound 1-2 (26.5 g) was dissolved in tetrahydrofuran (250 mL), and acetic anhydride (15.66 g) and diisopropylethylamine (26.44 g) were added. The reaction solution was heated to 45° C. and stirred for 16 hours. After the reaction was completed, the solution was diluted with 500 mL of ethyl acetate, washed with 500 mL of water and 500 mL of saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound 1-3, which was used directly in the next step.

[0201] MS-ESI calculated value [M+H] + is 302 and the actual value is 302.0.

[0202] Step 3: Synthesis of compounds 1-4 To a suspension of compound 1-3 (5 g) in acetic anhydride (50 mL) was added concentrated nitric acid (2.41 g, purity 65%) at 0°C. The reaction solution was stirred at 0-25°C for 2 hours. After the reaction was completed, the reaction solution was filtered and the filter cake was washed with 50 mL of petroleum ether. The solid was collected and concentrated to dryness under reduced pressure to give compound 1-4, which was used directly in the next step.

[0203] 1 H NMR (400MHz, CDCl3)δ:8.69(s,1H), 8.26(s,1H), 3.06-2.97(m,4H), 2.26-2.21(m,3H), 2.14(t,J=7.6Hz,2H).

[0204] MS-ESI calculated value [M+H] + is 347 and the actual value is 346.9.

[0205] Step 4: Synthesis of Compounds 1-5 Compound 1-4 (14.5 g) was dissolved in ethanol (400 mL), hydrochloric acid solution (6 M, 139.64 mL) was added, and the reaction mixture was heated to 85° C. and stirred for 72 hours. After the reaction was completed, most of the ethanol was removed under reduced pressure, and the precipitated solid was collected by filtration and concentrated to dryness under reduced pressure to give compound 1-5, which was used directly in the next step.

[0206] 1 H NMR (400MHz, CDCl3) δ: 8.38 (s, 1H), 5.96 (s, 2H), 3.03-2.83 (m, 4H), 2.28-2.09 (m, 2H).

[0207] MS-ESI calculated value [M+H] + is 305 and the actual value is 304.9.

[0208] Step 5: Synthesis of Compounds 1-6 Compound 1-5 (8.5 g) was dissolved in dimethyl sulfoxide (100 mL), and cuprous oxide (799.95 mg) and acetonitrile (3.86 g) were added. The reaction solution was heated to 130°C and stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into 750 mL of water, and extracted with ethyl acetate (350 mL x 2). The organic phases were combined, washed with saturated saline (350 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by flash silica gel column chromatography (eluent: ethyl acetate / petroleum ether, 0-30%) to obtain compound 1-6.

[0209] 1 H NMR(400MHz, CDCl3)δ:8.38(s,1H), 6.37(s,2H), 3.15(t,J=7.6Hz,2H), 2.84(t,J=7.6Hz,2H), 2.35-2.26(m,2H).

[0210] Step 6: Synthesis of Compounds 1-7 A mixture of cuprous chloride (6.25 g) and acetonitrile (470 mL) was heated to 65° C., tert-butyl nitrite (5.99 g) was added at once, and compound 1-6 (4.72 g) was added in several portions. The reaction solution was stirred at 65° C. for 0.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. Ethyl acetate (500 mL) and hydrochloric acid solution (6 M, 200 mL) were added to the residue and separated. The organic phase was washed with saturated saline (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was separated and purified by flash silica gel column chromatography (eluent: ethyl acetate / petroleum ether, 0-10%) to obtain compound 1-7.

[0211] 1 H NMR(400MHz, CDCl3)δ:8.01(s,1H), 3.28(t,J=7.6Hz,2H), 3.16(t,J=7.6Hz,2H), 2.31(t,J=7.6Hz,2H).

[0212] Step 7: Synthesis of Compounds 1-8 Compound 1-7 (3.74 g) was dissolved in tetrahydrofuran (150 mL), triethylamine (4.25 g) and 3-aminopropanol (3.79 g) were added, and the reaction solution was heated to 65° C. and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into 300 mL of water, and extracted with ethyl acetate (300 mL). The organic phase was washed with saturated saline (300 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was separated and purified by flash silica gel column chromatography (eluent: dichloromethane, 100%) to obtain compound 1-8.

[0213] 1 H NMR(400MHz,CDCl3)δ:8.66(s,1H), 8.37(s,1H), 3.90-3.75(m,4H), 3.29(t,J=7.2Hz,2 H), 3.04(t,J=7.6Hz,2H), 2.23-2.13(m,2H), 1.96-1.88(m,2H), 1.47(t,J=4.4Hz,1H).

[0214] MS-ESI calculated value [M+H] + is 262 and the actual value is 261.9.

[0215] Step 8: Synthesis of Compounds 1-9 Compound 1-8 (2.35 g) was dissolved in a mixture of methanol, tetrahydrofuran and water (135 mL, volume ratio: 1 / 1 / 1), reduced iron powder (3.01 g) and ammonium chloride (2.41 g) were added, and the reaction solution was heated to 70°C and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, concentrated to dryness under reduced pressure, and separated and purified by flash silica gel column chromatography (eluent: ethyl acetate / petroleum ether, 0-50%) to obtain compound 1-9.

[0216] 1 H NMR (400MHz, CDCl3) δ: 6.79 (s, 1H), 3.91-3.81 (m, 2H), 3.41 (s, 2H), 3.05-2.92 (m, 4H), 2.16-2.08 (m, 2H), 1.88-1.79 (m, 2H).

[0217] MS-ESI calculated value [M+H] + is 232 and the actual value is 232.0.

[0218] Step 9: Synthesis of Compounds 1-10 Compound 1-9 (2 g) was dispersed in hydrochloric acid solution (6 M, 14.41 mL) and the system was cooled to 0°C. A solution of sodium nitrite (894.94 mg) in water (8 mL) was slowly added dropwise at 0°C. The reaction solution was stirred at 0-25°C for 1 hour. After the reaction was completed, the reaction solution was separated into ethyl acetate (200 mL) and water (200 mL). The organic phase was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound 1-10, which was used directly in the next step.

[0219] MS-ESI calculated value [M+H] + is 243 and the actual value is 243.0.

[0220] Step 10: Synthesis of Compounds 1-11 Compound 1-10 (2 g) was dissolved in formic acid solution (80 mL, 75% purity) and nickel-aluminum alloy (3.54 g) was added. The reaction solution was heated to 90 °C and stirred for 16 hours. The reaction solution was filtered, the filtrate was collected, concentrated to dryness under reduced pressure, 200 mL of ethanol was added, and aqueous sodium hydroxide solution (2 M, 41.28 mL) was added while stirring. The reaction solution was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution was cooled in an ice bath, 2N hydrochloric acid solution was added to adjust the pH to 6-7, most of the methanol was removed under reduced pressure, and the mixture was extracted with ethyl acetate (250 mL × 2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound 1-11, which was used directly in the next step.

[0221] MS-ESI calculated value [M+H] + is 246 and the actual value is 246.0.

[0222] Step 11: Synthesis of Compounds 1-12 Compound 1-11 (250 mg) was dissolved in dichloromethane (20 mL), and triethylamine (309.41 mg) and methanesulfonyl chloride (233.51 mg) were added. The reaction solution was stirred at 25°C for 0.5 hours. Two pots were set up for the reaction. After the reaction was completed, the reaction solution was separated into dichloromethane (200 mL) and water (200 mL). The organic phase was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by flash silica gel column chromatography (eluent: methanol / dichloromethane, 0-2%) to obtain compound 1-12.

[0223] MS-ESI calculated value [M+H] + is 324 and the actual value is 324.0.

[0224] Step 12: Synthesis of compound 1-13-3 Compound 1-13-1 (11.09 g) dissolved in anhydrous toluene (100 mL) was added to compound 1-13-2 (10 mg) dissolved in anhydrous toluene, and then sodium hydride (872 mg, purity 60%) was added. The reaction solution was reacted for 2 hours while stirring at 155 ° C. The reaction solution was cooled to room temperature, quenched with 4% aqueous sodium bicarbonate solution (200 mL), extracted with ethyl acetate (200 mL × 2), the organic phase was combined, washed with saturated saline (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20: 1 to 6: 1) to obtain compound 1-13-3.

[0225] MS-ESI calculated value [M+H] + is 434 and the actual value is 434.1.

[0226] Step 13: Synthesis of Compounds 1-13 Compound 1-13-3 (400 mg) was dissolved in ethyl acetate (4 mL), and then hydrochloric acid-ethyl acetate solution (6.64 mL, 4 M) was added. The reaction solution was reacted for 2 hours with stirring at 25° C. The pH of the reaction solution was adjusted to about 8 with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated aqueous sodium carbonate (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product compound 1-13.

[0227] MS-ESI calculated value [M+H] + is 352 and the actual value is 352.1.

[0228] Step 14: Synthesis of Compounds 1-14 Compound 1-13 (200 mg) was dissolved in acetonitrile (20 mL), and diisopropylethylamine (220.62 mg), potassium iodide (141.69 mg), and compound 1-12 (184.00 mg) were added. The reaction solution was heated to 90°C and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the product was separated and purified by flash silica gel column chromatography (eluent: methanol / dichloromethane, 0-5%) to obtain compound 1-14.

[0229] MS-ESI calculated value [M+H] + is 579 and the actual value is 579.2.

[0230] Step 15: Synthesis of acetate salts of compounds 1-15 Compound 1-15-1 (2 g) was added to benzylamine (4.92 g). The reaction solution was stirred at 150°C with a microwave for 0.5 hours. The reaction solution was quenched with water (40 mL), extracted with ethyl acetate (40 mL x 3), and the organic phases were combined, washed with saturated saline (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 0:1, dichloromethane / methanol = 20:1 to 10:1) to obtain compound 1-15-2. MS-ESI calculated value [M+H] + is 401 and the actual value is 401.1.

[0231] Compound 1-15-2 (50 mg) was dissolved in DCM (1 mL), and then 2,6-lutidine (26.8 mg) and t-butyldimethylsilyl trifluoromethanesulfonate (36.30 mg) were added at 0° C. The reaction was stirred at 20° C. for 2 hours. The mixture was quenched with water (2 mL) and extracted with dichloromethane (2 mL×2). The organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product compound 1-15-3. MS-ESI calculated value [M+H] + is 515 and the actual value is 515.2.

[0232] Compound 1-15-3 (10 g) was dissolved in methanol (100 mL), and then acetic acid (1.67 mL) and Pd(OH)2 (2 g, 20%) were added. The reaction was stirred at 20° C. under hydrogen atmosphere (15 psi) for 16 hours. It was filtered and concentrated under reduced pressure to give the crude compound 1-15 acetate salt. MS-ESI calculated value [M+H] + is 335 and the actual value is 334.9.

[0233] Step 16: Synthesis of Compounds 1-16 Compound 1-14 (325 mg) and compound 1-15 (187.83 mg) were dissolved in methanol (10 mL) and tetrahydrofuran (8 mL). 4A molecular sieves (300 mg), diisopropylethylamine (217.73 mg) and sodium triacetylborohydride (595.09 mg) were added, and the reaction solution was stirred at 25°C for 3 hours. Sodium triacetylborohydride (595.09 mg) was further added, and the reaction solution was stirred at 25°C for 16 hours. Sodium triacetylborohydride (595.09 mg) was further added, and the reaction solution was stirred at 25°C for 3 hours. The reaction solution was concentrated to dryness, 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by flash silica gel column chromatography (eluent: methanol / dichloromethane, 0-10%) to obtain compound 1-16.

[0234] MS-ESI calculated value [M+H] + is 897 and the actual value is 897.5.

[0235] Step 17: Synthesis of the trifluoroacetate salt of the compound of formula (I) Compound 1-16 (213 mg) was dissolved in tetrahydrofuran (5 mL), triethylamine trihydrofluoride (191.35 mg) was added, and the reaction solution was stirred at 25 ° C for 16 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and separated by high performance liquid chromatography (column type: Welch Xtimate C18, length * inner diameter: 100 mm * 40 mm, 3 μm, preparation method: the crude product was dissolved in dimethyl sulfoxide and filtered with a 0.45 μm membrane filter to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.075% trifluoroacetic acid), gradient elution method (acetonitrile was gradient eluted from 17% to 57%, elution time was 8 minutes) to obtain the trifluoroacetate salt of the compound of formula (I).

[0236] 1 H NMR(400MHz,DMSO-d6)δ:10.86-10.34(m,2H), 9.87(s,1H), 9.43-9.01(m,2H), 8.15(d,J=9.6Hz,1H), 8.07(s, 1H), 7.47(d,J=4.0Hz,2H), 7.31(s,1H), 7.15(d,J=7.6Hz,1H), 7.07(s,2H), 7.03-6.76(m,3H), 6.53(d,J=9.6H) z,1H), 6.28(s,1H), 5.42(d,J=8.0Hz,1H), 4.78(s,3H), 4.38(s,2H), 3.36(s,4H), 3.19(s,2H), 3.09(s,2H), 2 .71(s,3H), 2.54(s,1H), 2.32(s,2H), 2.22(s,2H), 1.99(s,4H), 1.64(d,J=7.6Hz,2H), 1.46(d,J=10.8Hz,2H).

[0237] MS-ESI calculated value [M+H] + is 783 and the actual value is 783.4.

[0238] Step 18: Synthesis of Compounds of Formula (I) Compound 1-16 (6.26 g, 6.98 mmol) was dissolved in tetrahydrofuran (120 mL), and triethylamine trishydrofluoride (5.62 g, 34.89 mmol, 5.69 mL) was added. The mixture was stirred at 25° C. for 16 hours. After the reaction was completed, the supernatant was removed, and the solid was washed with 50 mL of tetrahydrofuran, and then concentrated to dryness under reduced pressure. The obtained solid was dispersed in a mixed solution of dichloromethane / methanol (700 mL, v / v=10 / 1) and a saturated sodium bicarbonate solution (400 mL), and stirred for 2 hours. The organic phase was separated, washed with 200 mL of deionized water, and then concentrated to dryness under reduced pressure to obtain the compound of formula (I).

[0239] 1 H NMR(400MHz,DMSO-d6)δ:8.13(d,J=10.0Hz,1H), 7.71(s,1H), 7.46(d,J=4Hz,2H), 7.24(brs,1H), 7. 07-7.04(m,3H), 6.98-6.96(m,2H), 6.89(d,J=8.0Hz,1H), 6.40(d,J=10.0Hz,1H), 5.37(brs,1H), 5.0 8-5.05(m,1H), 4.69-4.65(m,3H), 3.80(s,2H), 3.29-3.25(m,4H), 2.91(brt,J=7.6Hz,2H), 2.83-2.6 6(m,2H), 2.42-2.39(m,4H), 2.17-2.12(m,2H), 1.99-1.89(s,7H), 1.65(brs,2H), 1.34-1.32(m,4H).

[0240] MS-ESI calculated value [M+H] + is 783 and the actual value is 783.2.

[0241] Example 1: Preparation of Crystalline C of Compound of Formula (I) 100mL of acetonitrile was added to 5.46g of the compound of formula (I) obtained in step 18 of Reference Example 1, and the mixture was triturated and stirred at 25°C for 16 hours. Approximately two-thirds of the acetonitrile was evaporated under reduced pressure, 100mL of deionized water was added, and the mixture was triturated and stirred at 25°C for 15 minutes. The solid was collected by filtration. 100mL of acetonitrile was added to the obtained solid, and the mixture was triturated and stirred at 25°C for 4 hours. The solid was collected by filtration and dried in vacuum at 50°C for 16 hours. Crystal C of the compound of formula (I) was obtained, and its XRPD, TGA and DSC patterns are shown in Figures 7 to 9.

[0242] Example 2: Preparation of Crystalline A of Compound of Formula (I) Compound 1-16 (5 g, 5.57 mmol) was dissolved in tetrahydrofuran (100 mL), and triethylamine trishydrofluoride (4.49 g, 27.86 mmol, 4.54 mL) was added. The mixture was stirred at 25° C. for 16 hours. After the reaction was completed, the supernatant was removed, and the solid was washed with 100 mL of tetrahydrofuran, and then concentrated to dryness under reduced pressure. The obtained solid was dispersed in a mixed solution of dichloromethane / methanol (1500 mL, v / v=10 / 1) and a saturated sodium bicarbonate solution (800 mL), and stirred for 2 hours. The organic phase was separated, washed with 400 mL of deionized water, and then concentrated to dryness under reduced pressure to obtain a solid compound of formula (I). The obtained solid was stirred in 100 mL of acetonitrile at 25° C. for 16 hours. The solid was filtered off under suction, and the resulting solid was stirred in 100 mL of acetonitrile at 50° C. for 16 hours, filtered off under suction, and dried in vacuum at 50° C. for 16 hours to obtain crystalline A of the compound of formula (I). Its XRPD, TGA and DSC patterns are shown in FIGS. 1 to 3.

[0243] Example 3: Preparation of Crystalline E of Compound of Formula (I) 0.5 mL of methanol was added to 0.05 g of the compound of formula (I) obtained in step 18 of Reference Example 1, and the mixture was triturated and stirred at 65°C for 2 hours. The solid was collected by filtration. It was dried in vacuum at 40°C for 16 hours. Crystal E of the compound of formula (I) was obtained, and its XRPD, TGA and DSC patterns are shown in Figures 13 to 15.

[0244] Example 4: Preparation of Crystalline F of Compound of Formula (I) 2 mL of methanol was added to 0.1 g of the crystal E of the compound of formula (I), and the mixture was triturated and stirred at 65°C for 2 hours, cooled to room temperature, and then filtered to obtain a solid. The above process was repeated three times. The solid was collected by filtration. It was dried in vacuum at 40°C for 16 hours. The crystal F of the compound of formula (I) was obtained, and its XRPD, TGA and DSC patterns are shown in Figures 16 to 18.

[0245] Example 5: Screening of multiple crystals of the compound of formula (I) Crystal C of the compound of formula (I) can be obtained as a plurality of free crystals under the following conditions.

[0246] Crystal A: 0.5 mL of methanol was added to about 15.2 mg of Crystal C of the compound of formula (I), and the mixture was suspended and stirred at room temperature for about 4 days, and then dried at room temperature to obtain Crystal A.

[0247] Crystal B: Add 0.5 mL of tetrahydrofuran to about 15.1 mg of Crystal C of the compound of formula (I), suspend and stir at 40°C for about 7 days, then perform a heating and cooling cycle (50°C to 5°C, 0.1°C / min, 2 cycles), stir, and air-dry at room temperature for 1 day to obtain Crystal B, whose XRPD, TGA and DSC patterns are shown in Figures 4 to 6.

[0248] Crystal D: About 15.0 mg of Crystal C of the compound of formula (I) was added to 0.5 mL of tetrahydrofuran, and the mixture was suspended and stirred at room temperature for about 4 days, dried at room temperature for 2 days (the sample dried at room temperature was in a gel state), and further dried in vacuum at room temperature for 5 days to obtain a powdery solid, Crystal D. The XRPD, TGA and DSC patterns of the crystal D are shown in Figures 10 to 12.

[0249] Example 6: Preparation of Crystal G of Compound of Formula (II) [ka] 100 mg of the compound of formula (I) obtained in step 18 in Reference Example 1 was dissolved in 2 mL of a mixed solvent of dioxane / ethanol (1 / 1), and a solution obtained by dissolving 19 mg of D-tartaric acid in 1 mL of ethanol was added dropwise at room temperature to precipitate a white solid, which was then heated to 50-55°C and stirred for 4 hours. The solid was collected by filtration. 35 mg of the solid was triturated in 3 mL of ethanol at 50-55°C for 6 hours. The solid was collected by filtration and vacuum dried at 40°C for 14 hours to obtain crystalline G of the compound of formula (II). The XRPD, TGA and DSC patterns of the crystals are shown in Figures 19-21.

[0250] Example 7: Preparation of Crystalline H of Compound of Formula (III) [ka] 100 mg of the compound of formula (I) obtained in step 18 in Reference Example 1 was dissolved in 2 mL of a mixed solvent of methanol / tetrahydrofuran (1 / 1), and a solution of 19 mg of L-tartaric acid dissolved in 1 mL of methanol was added dropwise at room temperature to precipitate a white solid, which was then heated to 50° C. and stirred for 6 hours. The solid was collected by filtration and vacuum dried at 40° C. for 14 hours to obtain crystalline H of the compound of formula (III). The XRPD, TGA and DSC patterns are shown in Figures 22 to 24.

[0251] Test Example 1: Crystal stability test of crystalline C of compound of formula (I) under high humidity conditions After the crystalline C of the compound of formula (I) is left under different humidity conditions at room temperature, TGA is measured to initially evaluate the change in water content under different humidity conditions.The results are summarized in Table 9.The results show that the TGA weight loss of the compound of formula (I) after the crystalline C of the compound of formula (I) is left under two conditions increases slightly.

[0252] Then, the crystalline C of compound of formula (I) was subjected to a DVS test, and the results (Figure 25) showed that the water adsorption of the sample at 25°C / 80%RH was 7.84%, and the XRPD results (Figure 26) showed that the crystalline C of the sample was unchanged after the DVS test.

[0253] [Table 9]

[0254] Experimental conclusion: Crystal C of the compound of formula (I) of the present application is highly stable and easy to prepare into a drug.

[0255] Test Example 2: Crystal stability study of crystalline E of compound of formula (I) under high humidity conditions Crystal E of the compound of formula (I) was left at room temperature and 94% RH for 1 to 2 weeks, and then XRPD was measured to evaluate its solid stability in a high humidity environment. The results (Figure 27) show that the crystal did not change after the sample was left.

[0256] Experimental conclusion: Crystal E of the compound of formula (I) of the present application is highly stable and easy to prepare into a drug.

[0257] Biological Experiments: Experimental Example 1: Measurement of the agonistic effect of compounds on β1 receptors using the HTRF cAMP method Purpose of the Test: The β1 receptor is a G protein-coupled receptor, which is mainly coupled with Gs protein. When it is activated by binding with a ligand, it can increase the intracellular cAMP level by activating the activity of adenylate cyclase by Gs protein. In this experiment, the agonist activity of the compound against the in vitro β1 receptor is detected by the cAMP kit.

[0258] Testing Method: β1 cells (expressing human ADRB1 gene) from Beijing Aisip Biotechnology Co., Ltd. were grown under standard conditions, the cells were harvested and diluted with 1×Stimulation Buffer, 9 microliters of cell dilution was added to a white 384-well low volume plate, and 4000 cells were seeded in each well. Compounds were serially diluted 5-fold in DMSO to 10 concentrations. Before the experiment, the compounds serially diluted in DMSO were diluted 100-fold with 1×Stimulation Buffer to obtain the working solution of the compounds. The solvent DMSO concentration was 0.1%. Eu-cAMP and ULight®-anti-cAMP were diluted to working concentrations in Detection buffer, and 5 microliters were added to the corresponding experimental wells, and after incubation at room temperature for 1 hour, the readings were read at 665 nm and 620 nm with an excitation wavelength of 330 nm using a Biotek microplate reader. The activity of the compound was plotted against the ratio (665 / 620) and the compound concentration, and the EC 50 was calculated.

[0259] The experimental results are shown in Table 10.

[0260] [Table 10] Conclusion: The compounds of the present application have a certain agonistic effect on β1 receptors.

[0261] Experimental Example 2: Measurement of the agonistic effect of compounds on β2 receptors using the HTRF cAMP method Purpose of the Test: The β2 receptor is a G protein-coupled receptor, which is mainly coupled with Gs protein. When it is activated by binding with a ligand, it can increase the intracellular cAMP level by activating the activity of adenylate cyclase by Gs protein. In this experiment, the agonist activity of the compound against the in vitro β2 receptor is detected by the cAMP kit.

[0262] Testing Method: β2 cells (expressing human ADRB2 gene) from Beijing Aisip Biotechnology Co., Ltd. were grown under standard conditions, the cells were harvested and diluted with 1×Stimulation Buffer, 9 microliters of cell dilution were added to a white 3-8-4 well low volume plate, and 1000 cells were seeded in each well. Compounds were serially diluted 5-fold in DMSO and serially diluted to 10 concentrations. Before the experiment, the compounds serially diluted in DMSO were diluted 100-fold with 1×Stimulation Buffer to obtain the working solution of the compounds. The concentration of the solvent DMSO was 0.1%. Eu-cAMP and ULight®-anti-cAMP were diluted to the working concentration in Detection buffer, and 5 microliters were added to the corresponding experimental wells, and after incubation at room temperature for 1 hour, the readings were read at 665 nm and 620 nm with an excitation wavelength of 330 nm using a Biotek microplate reader. The activity of the compound was plotted against the ratio (665 / 620) and the compound concentration, and the EC 50 was calculated.

[0263] The experimental results are shown in Table 11.

[0264] [Table 11] Conclusion: The compounds of the present application have relatively strong or very strong agonistic effects on β2 receptors.

[0265] Experimental Example 3: M3 receptor affinity test Purpose of the Test: The M3 receptor is a G protein-coupled receptor, and in this experiment, the activity of a test compound against the in vitro M3 receptor is detected by competing with radioisotope-labeled NMS and a non-isotopically labeled test compound for the M3 binding site.

[0266] Testing Method: This experiment is carried out by the method of radioisotope affinity detection. The M3 receptor membrane protein prepared by the Biological Department of Yakult Co., Ltd. was adjusted to 10 μg / mL, and the compound was serially diluted 2.5-fold in DMSO to a total of 10 concentrations. The radioisotope 3H-NMS was adjusted to 0.2 nM in the experiment buffer (10 mM HEPES, 1 mM MgCl2, pH 7.40). In the formal experiment, the experimental system was 1 μL of the test compound, 100 μL of M3 receptor membrane protein, and 100 μL of the radioisotope, which was placed on a shaker at room temperature and reacted at 300 RPM for 2 hours. A GF / C plate (Perkin Elmer, part number 6055690) was pre-soaked with 0.3% PEI, and the membrane protein in the reaction solution was collected on the GF / C plate by filtration. The signal value was read by a Perkin Elmer Microbeta2 instrument, and the inhibition rate at each concentration point was expressed as a percentage.

[0267] The experimental results are shown in Table 12.

[0268] [Table 12] Conclusion: The compounds of the present application have relatively strong or very strong binding effect on M3 receptors.

[0269] Experimental Example 4: M2 receptor affinity test Purpose of the Test: The M2 receptor is a G protein-coupled receptor, and in this experiment, the activity of a test compound against the M2 receptor in vitro is detected by competing with radioisotope-labeled NMS and a non-isotopically labeled test compound for the M2 binding site.

[0270] Testing Method: M2 receptor membrane protein prepared by the Biological Department of Yakult Co., Ltd. was adjusted to 100μg / mL, and the compounds were serially diluted 2.5-fold in DMSO to a total of 10 concentrations. Radioisotope 3H-NMS was adjusted to 0.2nM in the experimental buffer (10mM HEPES, 1mM MgCl2, pH7.40). In the formal experiment, the experimental system consisted of 1μL of test compound, 100μL of M2 receptor membrane protein, and 100μL of radioisotope, which were reacted at 300RPM for 2 hours on a shaker at room temperature. GF / C plates (Perkin Elmer, part number 6055690) were pre-soaked with 0.3% PEI, and the membrane proteins in the reaction solution were collected on the GF / C plate by filtration. The signal values ​​were read using a Perkin Elmer Microbeta2 instrument, and the inhibition rate at each concentration point was expressed as a percentage.

[0271] The experimental results are shown in Table 13.

[0272] [Table 13] Conclusion: The compounds of the present application have relatively strong binding effect on M2 receptors.

Claims

1. A crystal of the compound of formula (I). 【Chemistry 1】

2. The X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 12.65±0.20° and 24.06±0.20°, Alternatively, the crystal of the compound of formula (I) according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal is as shown in Figure 1.

3. The X-ray powder diffraction pattern of the crystal has a diffraction peak at a 2θ angle of 12.66±0.20°, Alternatively, the crystal of the compound of formula (I) according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal is as shown in Figure 4.

4. The X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 7.77±0.20°, 8.70±0.20°, 11.49±0.20°, 18.22±0.20°, and 23.39±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal, expressed in terms of 2θ angles, includes at least 5, 6, 7, or 8 diffraction peaks selected from 7.77±0.20°, 8.70±0.20°, 11.49±0.20°, 13.45±0.20°, 18.22±0.20°, 19.82±0.20°, 21.88±0.20°, and 23.39±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 7.77±0.20°, 8.70±0.20°, 11.49±0.20°, 13.45±0.20°, 18.22±0.20°, 19.82±0.20°, 21.88±0.20°, and 23.39±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal, expressed in terms of 2θ angles, includes at least 12, 13, 14, 15, or 16 diffraction peaks selected from 7.77±0.20°, 8.70±0.20°, 9.97±0.20°, 10.64±0.20°, 11.49±0.20°, 13.45±0.20°, 15.55±0.20°, 18.22±0.20°, 19.82±0.20°, 20.37±0.20°, 21.88±0.20°, 23.39±0.20°, 23.99±0.20°, 27.29±0.20°, 27.75±0.20°, and 31.35±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 7.77±0.20°, 8.70±0.20°, 9.97±0.20°, 10.64±0.20°, 11.49±0.20°, 13.45±0.20°, 15.55±0.20°, 18.22±0.20°, 19.82±0.20°, 20.37±0.20°, 21.88±0.20°, 23.39±0.20°, 23.99±0.20°, 27.29±0.20°, 27.75±0.20°, and 31.35±0.20°; Alternatively, the crystal of the compound of formula (I) according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal is as shown in Figure 7.

5. The differential scanning calorimetry curve of the crystals has an endothermic peak at 112.2 ° C. Alternatively, the crystal of the compound of formula (I) according to claim 4, characterized in that the differential scanning calorimetry curve pattern of the crystal is as shown in Figure 9.

6. The X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 5.56±0.20° and 13.84±0.20°, Alternatively, the crystal of the compound of formula (I) according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal is as shown in Figure 10.

7. The X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, and 15.14±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, 15.14±0.20°, and 17.03±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal, expressed in terms of 2θ angles, includes at least 5, 6, 7, or 8 diffraction peaks selected from 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, 11.86±0.20°, 15.14±0.20°, 17.03±0.20°, 19.07±0.20°, and 23.60±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, 11.86±0.20°, 15.14±0.20°, 17.03±0.20°, 19.07±0.20°, and 23.60±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal, expressed in terms of 2θ angles, includes at least 10, 11, 12, or 13 diffraction peaks selected from 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, 11.86±0.20°, 15.14±0.20°, 16.67±0.20°, 17.03±0.20°, 18.50±0.20°, 19.07±0.20°, 21.12±0.20°, 23.60±0.20°, 26.61±0.20°, and 29.58±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 8.53±0.20°, 9.67±0.20°, 10.31±0.20°, 11.86±0.20°, 15.14±0.20°, 16.67±0.20°, 17.03±0.20°, 18.50±0.20°, 19.07±0.20°, 21.12±0.20°, 23.60±0.20°, 26.61±0.20°, and 29.58±0.20°; Alternatively, the crystal of the compound of formula (I) according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal is as shown in Figure 13.

8. The differential scanning calorimetry curve of the crystals has endothermic peak values ​​at 120.0 ° C, 152.7 ° C, and 192.0 ° C, respectively; Alternatively, the crystal of the compound of formula (I) according to claim 7, characterized in that the differential scanning calorimetry curve pattern of the crystal is as shown in Figure 15.

9. The X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 9.50±0.20°, 15.79±0.20°, and 18.44±0.20°, Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 9.50±0.20°, 13.34±0.20°, 15.79±0.20°, 18.44±0.20°, and 24.43±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal, expressed in terms of 2θ angles, includes at least 5, 6, 7, or 8 diffraction peaks selected from 9.50±0.20°, 13.34±0.20°, 15.79±0.20°, 18.44±0.20°, 19.97±0.20°, 21.27±0.20°, 21.80±0.20°, and 24.43±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 9.50±0.20°, 13.34±0.20°, 15.79±0.20°, 18.44±0.20°, 19.97±0.20°, 21.27±0.20°, 21.80±0.20°, and 24.43±0.20°; Alternatively, the crystal of the compound of formula (I) according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal is as shown in Figure 16.

10. A tartrate salt of the compound of formula (I) or a crystal thereof.

11. The tartrate salt of the compound of formula (I) or a crystal thereof is selected from the compound of formula (II) or a crystal thereof: 【Chemistry 2】 In (II), x is 0.9 to 1.1, preferably 0.9, 1 or 1.1; Alternatively, the tartrate salt of the compound of formula (I) or a crystal thereof is selected from a compound of formula (III) or a crystal thereof: 【Chemistry 3】 The tartrate salt of the compound of formula (I) or a crystal thereof according to claim 10, characterized in that in formula (III), y is 0.9 to 1.1, preferably 0.9, 1 or 1.

1.

12. The X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 11.64±0.20°, 18.51±0.20°, and 22.68±0.20°, Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 4.62±0.20°, 11.64±0.20°, 13.24±0.20°, 18.51±0.20°, and 22.68±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal, expressed in terms of 2θ angles, includes at least 6, 7, or 8 diffraction peaks selected from 4.62±0.20°, 10.98±0.20°, 11.64±0.20°, 13.24±0.20°, 16.76±0.20°, 18.51±0.20°, 22.68±0.20°, and 23.52±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 4.62±0.20°, 10.98±0.20°, 11.64±0.20°, 13.24±0.20°, 16.76±0.20°, 18.51±0.20°, 22.68±0.20°, and 23.52±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal, expressed in terms of 2θ angles, includes at least 12, 13, 14, 15, or 16 diffraction peaks selected from 4.62±0.20°, 9.80±0.20°, 10.98±0.20°, 11.64±0.20°, 12.63±0.20°, 13.24±0.20°, 13.79±0.20°, 15.28±0.20°, 16.76±0.20°, 18.51±0.20°, 19.62±0.20°, 21.62±0.20°, 22.68±0.20°, 23.52±0.20°, 25.04±0.20°, and 26.64±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 4.62±0.20°, 10.98±0.20°, 11.64±0.20°, 13.24±0.20°, 13.79±0.20°, 15.28±0.20°, 16.76±0.20°, 18.51±0.20°, 19.62±0.20°, 22.68±0.20°, 23.52±0.20°, and 26.64±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 4.62±0.20°, 9.80±0.20°, 10.98±0.20°, 11.64±0.20°, 12.63±0.20°, 13.24±0.20°, 13.79±0.20°, 15.28±0.20°, 16.76±0.20°, 18.51±0.20°, 19.62±0.20°, 21.62±0.20°, 22.68±0.20°, 23.52±0.20°, 25.04±0.20°, and 26.64±0.20°; Alternatively, the crystal of the compound of formula (II) according to claim 11, characterized in that the X-ray powder diffraction pattern of the crystal is as shown in Figure 19.

13. The X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 11.56±0.20°, 18.64±0.20°, and 22.52±0.20°, Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 10.01±0.20°, 11.56±0.20°, 13.07±0.20°, 18.64±0.20°, and 22.52±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal, expressed in terms of 2θ angles, includes at least 5, 6, 7, or 8 diffraction peaks selected from 10.01±0.20°, 11.56±0.20°, 13.07±0.20°, 14.17±0.20°, 18.64±0.20°, 20.06±0.20°, 22.52±0.20°, and 23.48±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 10.01±0.20°, 11.56±0.20°, 13.07±0.20°, 14.17±0.20°, 18.64±0.20°, 20.06±0.20°, 22.52±0.20°, and 23.48±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal, expressed in terms of 2θ angles, includes at least 12, 13, 14, 15, or 16 diffraction peaks selected from 4.29±0.20°, 10.01±0.20°, 10.89±0.20°, 11.56±0.20°, 13.07±0.20°, 14.17±0.20°, 14.80±0.20°, 15.66±0.20°, 16.37±0.20°, 18.64±0.20°, 20.06±0.20°, 22.52±0.20°, 23.48±0.20°, 24.80±0.20°, 25.98±0.20°, and 29.35±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 4.29±0.20°, 10.01±0.20°, 10.89±0.20°, 11.56±0.20°, 13.07±0.20°, 14.17±0.20°, 16.37±0.20°, 18.64±0.20°, 20.06±0.20°, 22.52±0.20°, 23.48±0.20°, and 25.98±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 4.29±0.20°, 10.01±0.20°, 10.89±0.20°, 11.56±0.20°, 13.07±0.20°, 14.17±0.20°, 14.80±0.20°, 15.66±0.20°, 16.37±0.20°, 18.64±0.20°, 20.06±0.20°, 22.52±0.20°, 23.48±0.20°, 24.80±0.20°, 25.98±0.20°, and 29.35±0.20°; Alternatively, the crystal of the compound of formula (III) according to claim 11, characterized in that the X-ray powder diffraction pattern of the crystal is as shown in Figure 22.

14. A crystalline composition comprising a crystal of the compound of formula (I) according to any one of claims 1 to 9, or a tartrate salt of the compound of formula (I) according to any one of claims 10 to 13, or a crystal thereof.

15. A pharmaceutical composition comprising a crystal of the compound of formula (I) according to any one of claims 1 to 9, a tartrate salt of the compound of formula (I) according to any one of claims 10 to 13 or a crystal thereof, or a crystal composition according to claim 14.

16. Use of a crystal of the compound of formula (I) according to any one of claims 1 to 9, a tartrate salt of the compound of formula (I) according to any one of claims 10 to 13 or a crystal thereof, a crystal composition according to claim 14, or a pharmaceutical composition according to claim 15, in the manufacture of a medicament for treating chronic obstructive pulmonary disease.

17. A method for producing the crystals of the compound of formula (I) according to claim 4, comprising the step of triturating the compound of formula (I) in a mixed solvent of acetonitrile and water, Alternatively, the method further comprises the step of separating: Alternatively, the manufacturing method includes: Step (1) of adding acetonitrile to the compound of formula (I) and triturating and stirring; (2) adding water and triturating / stirring; (3) filtering to collect the solids; Step (4) of washing the solid obtained in step (3) with acetonitrile; and (5) drying.

18. A method for producing the crystals of the compound of formula (I) according to claim 7, comprising the step of triturating the compound of formula (I) in methanol, Alternatively, the method further comprises the step of separating: Alternatively, the manufacturing method includes: Step (1) of triturating and stirring a compound of formula (I) in methanol; and (2) filtering and drying.

Images