Crystal form of isoquinolinone compound and preparation method thereof

Abstract

The invention relates to a crystal form of an isoquinolinone compound and a preparation method thereof. Specifically, the invention provides a crystal form of a compound as shown in a formula (I) and a preparation method of the crystal form. # imgabs0 #

Description

A crystal form of an isoquinolinone compound and a preparation method thereof

[0001] This application claims the benefit of Chinese Patent Application No. 2022113360457, filed on October 28, 2022. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present disclosure relates to a crystal form of an isoquinolinone compound and a preparation method thereof. Specifically, a crystal form of a compound as shown in Formula I and a preparation method thereof are provided. Background Art

[0003] Phosphodiesterases (PDEs) belong to a superfamily of enzymes encompassing 11 families, each involved in distinct signaling pathways and regulating distinct physiological processes. PDE3 hydrolyzes both cAMP and cGMP, but its cAMP hydrolysis capacity is approximately ten times greater than that of cGMP. PDE3 has two genetic isoforms: PDE3A and PDE3B, located on chromosomes 11 and 12, respectively. PDE3A is further divided into three isoforms, PDE3A1, PDE3A2, and PDE3A3, depending on their start codons. These isoforms are primarily distributed in the heart, platelets, vascular smooth muscle, and oocytes, regulating cardiac contractility, platelet aggregation, vascular smooth muscle contraction, oocyte maturation, and renin release. PDE3B has only one isoform, PDE3B1, primarily distributed in adipocytes, hepatocytes, spermatocytes, and pancreas. It regulates the signaling of insulin, insulin-like growth factor, and leptin, playing a crucial role in metabolic diseases such as obesity and diabetes. The main PDE3 selective inhibitors include cilostazol, cilostazolamide, milrinone, amrinone, enoximone and cyanoguanidine.

[0004] For example, amrinone can inhibit PDE3 activity, increase the concentration of cAMP in myocardial cells, and increase intracellular Ca 2+ Concentration, thereby fully exerting its positive inotropic effect. Amrinone also acts directly on vascular smooth muscle cells, dilating blood vessels, increasing myocardial contractility, reducing pulmonary artery pressure, and restoring cardiopulmonary function. It is of great value in the treatment of chronic cor pulmonale combined with heart failure. In addition, cilostazol is clinically used to treat platelet aggregation, pulmonary hypertension (PAH), chronic obstructive pulmonary disease (COPD), intermittent claudication, and cerebral microvascular disease.

[0005] On the other hand, PDE4 is highly specific for cAMP and has four isoforms: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4 is involved in promoting physiological and pathological processes such as monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, vasodilation, and myocardial contraction, affecting central nervous system function, cardiovascular function, inflammation / immune system, and cell adhesion. PDE4 plays a major role in regulating the expression of pro- and anti-inflammatory mediators. PDE4 inhibitors can inhibit the release of harmful mediators from inflammatory cells.

[0006] Developing new molecules with both PDE3 and PDE4 inhibitory activity will have the bronchodilation effect of β-adrenergic receptor agonists and the anti-inflammatory effect of inhaled corticosteroids. The complementary dual targeting functions have better efficacy than single targets.

[0007] For example, RPL554 (9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1a]isoquinolin-4-one) is a dual-target PDE3 / PDE4 inhibitor disclosed in WO00 / 58308. Recent Phase II clinical data showed significant improvements in bronchiectasis and symptoms in patients with COPD. The drug was also well tolerated, with no significant adverse events, including mild cardiac events, nausea, and diarrhea. The drug's safety profile and limited systemic exposure are encouraging.

[0008] Developing new molecules with both PDE3 and PDE4 inhibitory activity will have the bronchodilation effect of β-adrenergic receptor agonists and the anti-inflammatory effect of inhaled corticosteroids. The complementary dual targeting functions have better efficacy than single targets.

[0009] Patent application PCT / CN2022 / 090175 provides a compound as shown in Formula I, whose chemical name is 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]isoquinolin-4-one, which has good PDE3 and PDE4 inhibitory activity.

[0010] Generally speaking, the crystal structure of a drug's active ingredient and its salt not only affects the physical and chemical stability of the drug itself, but also the ease of subsequent drug preparation and production costs. Differences in crystallization and storage conditions can lead to variations in the crystal structure of the compound and its salt, sometimes resulting in the formation of alternative crystalline forms. Therefore, considering the comprehensive considerations of stability, the difficulty of drug preparation processes, and production costs, in-depth research on the crystal form of the compound represented by Formula I is essential.

[0011] Summary of the Invention

[0012] The present disclosure provides a crystalline form of a compound represented by formula (I) and a preparation method thereof, wherein the chemical name of the compound represented by formula I is 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]isoquinolin-4-one,

[0013] The present disclosure provides an amorphous form of the compound represented by formula (I), wherein the X-ray powder diffraction pattern thereof has no obvious characteristic peak at a diffraction angle 2θ in the range of 2-45°.

[0014] The present disclosure further provides a method for preparing an amorphous form of a compound represented by formula (I), comprising the steps of: mixing the compound represented by formula (I) with benzyl alcohol, dissolving the mixture, and b) volatilizing and crystallizing the mixture.

[0015] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0016] In certain embodiments, the method for preparing the amorphous form of the compound of (I) described in the present disclosure further comprises a filtering, washing or drying step.

[0017] The present disclosure provides a crystalline form A of the compound represented by formula (I), which has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.6, 11.0, 14.4, 15.5, 17.9, 19.1 and 23.7.

[0018] In certain embodiments, Form A of the compound of Formula (I) has characteristic peaks at 4.6, 6.6, 10.1, 11.0, 14.4, 15.5, 17.9, 19.1, 22.8, and 23.7.

[0019] In certain embodiments, Form A of the compound of Formula (I) has characteristic peaks at 4.6, 6.6, 10.1, 11.0, 13.1, 14.4, 15.5, 17.1, 17.9, 19.1, 22.8, 23.7, and 25.9.

[0020] In certain embodiments, the X-ray powder diffraction pattern of Form A of the compound represented by formula (I) expressed at a diffraction angle of 2θ is shown in FIG2 .

[0021] The present disclosure provides a crystal form B of the compound represented by formula (I), which has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.6, 11.0, 12.7, 15.5, 19.1, 23.7 and 25.8.

[0022] In certain embodiments, the Form B of the compound of Formula (I) has characteristic peaks at 6.6, 10.0, 11.0, 11.7, 12.7, 15.5, 19.1, 23.7, 24.6 and 25.8.

[0023] In certain embodiments, Form B of the compound of Formula (I) has characteristic peaks at 6.6, 8.6, 10.0, 11.0, 11.7, 12.7, 15.5, 17.8, 19.1, 23.7, 24.6, 25.8 and 26.9.

[0024] In certain embodiments, the X-ray powder diffraction pattern of Form B of the compound represented by Formula (I) expressed in terms of a diffraction angle 2θ is shown in FIG3 .

[0025] The present disclosure further provides a method for preparing a crystalline form B of the compound represented by formula (I), comprising: a) mixing the compound represented by formula I with dichloromethane and dissolving the mixture; and b) volatilizing and crystallizing the mixture.

[0026] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0027] In certain embodiments, the method for preparing Form B of the compound of formula (I) described in the present disclosure further comprises steps such as filtering, washing or drying.

[0028] The present disclosure provides Form C of the compound represented by formula (I), which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with characteristic peaks at 6.6, 7.5, 10.1, 10.9, 15.6, 23.8 and 24.3.

[0029] In certain embodiments, Form C of the compound of Formula (I) has characteristic peaks at 6.6, 7.5, 10.1, 10.9, 13.8, 15.6, 20.7, 23.8, 24.3, and 24.7.

[0030] In certain embodiments, Form C of the compound of Formula (I) has characteristic peaks at 6.6, 7.5, 10.1, 10.9, 13.8, 15.6, 17.5, 19.3, 20.7, 23.8, 24.3, 24.7, and 27.0.

[0031] In certain embodiments, the X-ray powder diffraction pattern of Form C of the compound represented by Formula (I) expressed in terms of a diffraction angle 2θ is shown in FIG4 .

[0032] The present disclosure further provides a method for preparing a crystalline form of compound C represented by formula (I), comprising: a) mixing the compound represented by formula I with acetonitrile, methanol or a mixture thereof, and b) volatilizing and crystallizing.

[0033] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0034] In certain embodiments, the method for preparing Form C of the compound of formula (I) described in the present disclosure further comprises steps such as filtering, washing or drying.

[0035] The present disclosure provides a D-type crystal of the compound represented by formula (I), which has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5 and 24.2.

[0036] In certain embodiments, the D form of the compound represented by formula (I) has characteristic peaks at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5, 20.3, 24.2, 25.8 and 26.9.

[0037] In certain embodiments, the D form of the compound represented by formula (I) has characteristic peaks at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5, 20.3, 23.3, 24.2, 24.7, 25.1, 25.8 and 26.9.

[0038] In certain embodiments, the X-ray powder diffraction pattern of Form D of the compound represented by Formula (I) expressed in terms of a diffraction angle of 2θ is shown in FIG5 .

[0039] The present disclosure further provides a method for preparing the crystalline form D of the compound represented by formula (I), comprising:

[0040] Method 1: a) mixing the compound represented by Formula I with a solvent II, and dissolving the mixture with or without heating, wherein the solvent II is selected from one or more of propylene glycol methyl ether, 1,2-dichloroethane, ethyl acetate / ethanol, n-propanol, tetrahydrofuran / ethanol, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol / acetone, ethanol / isopropyl acetate, and acetonitrile / methanol / acetone; b) volatilizing and crystallizing;

[0041] Or method 2: a) mixing the compound represented by formula I with solvent III and dissolving it, wherein the solvent III is selected from one or more of ethanol, N-methylpyrrolidone, dichloromethane or acetonitrile / methanol; b) adding solvent IV to precipitate crystals, wherein the solvent IV is selected from one or more of methyl tert-butyl ether, n-heptane, water, acetone, and isopropyl acetate.

[0042] Or method 3: a) mixing the compound represented by formula I with a solvent V, wherein the solvent V is selected from one or more of water, acetone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-butanone, tetrahydrofuran, methyl isobutyl ketone, 1,4-dioxane, isopentanol, water / ethanol, water / isopropanol, water / acetone, methanol / water, ethyl acetate / n-heptane, o-xylene, isopropyl ether, and toluene; b) stirring and crystallizing.

[0043] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0044] In certain embodiments, the method for preparing the D-form of the compound of formula (I) described in the present disclosure further comprises steps such as filtration, washing or drying.

[0045] The present disclosure provides Form E of the compound represented by formula (I), which has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.3, 11.1, 12.8, 14.3, 17.9, 22.9 and 25.6.

[0046] In certain embodiments, the E form of the compound represented by formula (I) has characteristic peaks at 6.3, 11.1, 12.8, 14.3, 17.0, 17.9, 18.7, 22.9, 23.8 and 25.6.

[0047] In certain embodiments, the E form of the compound represented by formula (I) has characteristic peaks at 6.3, 11.1, 12.8, 14.3, 15.9, 17.0, 17.9, 18.7, 20.1, 22.9, 23.8 and 25.6.

[0048] In certain embodiments, the X-ray powder diffraction pattern of Form E of the compound represented by Formula (I) expressed in terms of a diffraction angle 2θ is shown in FIG6 .

[0049] The present disclosure further provides a method for preparing a crystalline form of compound E represented by formula (I), comprising: a) mixing the compound represented by formula I with N-methylpyrrolidone and dissolving the mixture; b) adding isopropyl acetate and crystallizing the mixture.

[0050] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0051] In certain embodiments, the method for preparing the E crystal form of the compound represented by formula (I) described in the present disclosure further comprises steps such as filtering, washing or drying.

[0052] The present disclosure provides Form F of the compound represented by formula (I), which has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.6, 11.1, 13.6, 15.0, 22.3, 24.2 and 26.1.

[0053] In certain embodiments, the crystalline form F of the compound represented by formula (I) has characteristic peaks at 6.6, 11.1, 13.6, 15.0, 16.1, 18.6, 22.3, 24.2, 26.1 and 28.2.

[0054] In certain embodiments, the crystalline form F of the compound represented by formula (I) has characteristic peaks at 6.6, 8.8, 11.1, 12.9, 13.6, 15.0, 16.1, 17.7, 18.6, 22.3, 24.2, 26.1 and 28.2.

[0055] In certain embodiments, the X-ray powder diffraction pattern of Form F of the compound represented by Formula (I) expressed in terms of a diffraction angle 2θ is shown in FIG7 .

[0056] The present disclosure further provides a method for preparing the crystalline form F of compound represented by formula (I), comprising:

[0057] Method 1: a) mixing the compound represented by formula I with N-methylpyrrolidone and dissolving the mixture; b) stirring and crystallizing the mixture;

[0058] Alternatively, method 2: a) mixing the compound represented by formula I with N-methylpyrrolidone and dissolving the mixture; b) adding methyl tert-butyl ether or n-heptane for crystallization.

[0059] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0060] In certain embodiments, the method for preparing the F crystal form of the compound represented by formula (I) described in the present disclosure further comprises the steps of filtering, washing or drying.

[0061] The present disclosure provides a G crystal form of the compound represented by formula (I), which has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.1, 12.3, 14.2, 16.9, 19.2, 21.4 and 24.0.

[0062] In certain embodiments, the crystalline form G of the compound represented by formula (I) has characteristic peaks at 6.1, 12.3, 13.1, 14.2, 15.2, 16.1, 16.9, 19.2, 21.4 and 24.0.

[0063] In certain embodiments, the crystalline form G of the compound represented by formula (I) has characteristic peaks at 6.1, 11.3, 12.3, 13.1, 14.2, 15.2, 16.1, 16.9, 19.2, 21.4, 24.0, 26.6 and 28.8.

[0064] In certain embodiments, the X-ray powder diffraction pattern of Form G of the compound represented by Formula (I) expressed in terms of a diffraction angle 2θ is shown in FIG8 .

[0065] The present disclosure further provides a method for preparing a crystalline form of compound G represented by formula (I), comprising: a) mixing the compound represented by formula I with dichloromethane and dissolving the mixture; b) adding isopropyl acetate or methyl tert-butyl ether and crystallizing the mixture.

[0066] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0067] In certain embodiments, the method for preparing Form G of the compound of formula (I) described in the present disclosure further comprises steps such as filtration, washing or drying.

[0068] The present disclosure provides a H-type crystalline compound represented by formula (I), which has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.8, 7.5, 9.7, 13.0, 14.0, 15.1 and 16.1.

[0069] In certain embodiments, the H crystalline form of the compound represented by formula (I) has characteristic peaks at 6.8, 7.5, 9.7, 10.2, 10.9, 13.0, 14.0, 15.1, 16.1 and 26.5.

[0070] In certain embodiments, the H crystalline form of the compound represented by formula (I) has characteristic peaks at 6.8, 7.5, 9.7, 10.2, 10.9, 13.0, 14.0, 15.1, 16.1, 22.1, 23.1, 25.8 and 26.5.

[0071] In certain embodiments, the X-ray powder diffraction pattern of Form H of the compound represented by Formula (I) expressed in terms of a diffraction angle of 2θ is shown in FIG9 .

[0072] The present disclosure further provides a method for preparing the crystalline form H of the compound represented by formula (I), comprising:

[0073] Method 1: a) mixing Form A of the compound of Formula I with methanol and heating; b) cooling and crystallizing;

[0074] Method 2: a) mixing the compound represented by formula I with an acetonitrile / methanol mixture and dissolving it; b) adding methyl tert-butyl ether for crystallization.

[0075] In certain embodiments, the volume (μl) of the solvent used in the present disclosure may be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the method for preparing the H crystal form of the compound of Formula (I) described in the present disclosure further comprises the steps of filtration, washing or drying.

[0076] The present disclosure provides Form I of the compound represented by formula (I), which has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.2, 7.2, 9.6, 10.2, 12.0, 13.3 and 22.1.

[0077] In certain embodiments, Form I of the compound of Formula (I) has characteristic peaks at 5.2, 7.2, 9.6, 10.2, 12.0, 13.3, 14.5, 15.0, 19.5, and 22.1.

[0078] In certain embodiments, Form I of the compound of Formula (I) has characteristic peaks at 5.2, 7.2, 7.9, 9.6, 10.2, 12.0, 13.3, 14.5, 15.0, 19.5, 21.2, 22.1 and 23.6.

[0079] In certain embodiments, the X-ray powder diffraction pattern of Form I of the compound represented by Formula (I) expressed in terms of a diffraction angle of 2θ is shown in FIG10 .

[0080] The present disclosure further provides a method for preparing a crystalline form of compound I represented by formula (I), comprising: a) mixing the compound represented by formula I with ethanol, dissolving, and heating; and b) cooling and crystallizing.

[0081] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0082] In certain embodiments, the method for preparing Form I of the compound of formula (I) described in the present disclosure further comprises steps such as filtering, washing or drying.

[0083] The present disclosure provides Form J of the compound represented by formula (I), which has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.7, 11.7, 13.5, 14.0, 18.6, 21.6 and 24.3.

[0084] In certain embodiments, Form J of the compound of Formula (I) has characteristic peaks at 7.7, 10.1, 11.7, 13.5, 14.0, 18.6, 20.2, 21.6, 23.3, and 24.3.

[0085] In certain embodiments, Form J of the compound of Formula (I) has characteristic peaks at 7.7, 10.1, 10.7, 11.7, 13.5, 14.0, 16.0, 17.3, 18.6, 20.2, 21.6, 23.3, and 24.3.

[0086] In certain embodiments, the X-ray powder diffraction pattern of Form J of the compound represented by Formula (I) expressed in terms of a diffraction angle of 2θ is shown in FIG11 .

[0087] The present disclosure further provides a method for preparing the crystal form J of the compound represented by formula (I), comprising: a) mixing the crystal form A of the compound represented by formula I with isopropyl alcohol, heating, and b) cooling and crystallizing.

[0088] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0089] In certain embodiments, the method for preparing Form J of the compound of formula (I) described in the present disclosure further comprises steps such as filtration, washing or drying.

[0090] The present disclosure provides a K-type crystal of a compound represented by formula (I), which has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.8, 7.4, 13.8, 15.0, 15.8, 20.7 and 22.1.

[0091] In certain embodiments, the K crystal form of the compound represented by formula (I) has characteristic peaks at 6.8, 7.4, 9.5, 13.8, 14.2, 15.0, 15.8, 20.7, 22.1 and 27.6.

[0092] In certain embodiments, the K crystal form of the compound represented by formula (I) has characteristic peaks at 6.8, 7.4, 9.5, 13.8, 14.2, 15.0, 15.8, 17.9, 18.4, 20.7, 22.1, 26.5 and 27.6.

[0093] In certain embodiments, the X-ray powder diffraction pattern of Form K of the compound represented by Formula (I) expressed in terms of a diffraction angle of 2θ is shown in FIG12 .

[0094] The present disclosure further provides a method for preparing the crystal form K of the compound represented by formula (I), comprising: a) mixing the crystal form A of the compound represented by formula I with acetonitrile, heating, and b) cooling and crystallizing.

[0095] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0096] In certain embodiments, the method for preparing the K crystal form of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.

[0097] The present disclosure provides an L-type crystalline compound represented by formula (I), which has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.1, 7.6, 12.8, 13.6, 19.5, 21.1 and 25.8.

[0098] In certain embodiments, the L-form of the compound represented by formula (I) has characteristic peaks at 7.1, 7.6, 9.2, 12.8, 13.6, 16.1, 19.5, 21.1, 24.6 and 25.8.

[0099] In certain embodiments, the L-form of the compound represented by formula (I) has characteristic peaks at 7.1, 7.6, 9.2, 12.8, 13.6, 16.1, 19.5, 21.1, 24.6 and 25.8.

[0100] In certain embodiments, the X-ray powder diffraction pattern of the L-type crystalline compound represented by the formula (I) expressed in terms of a diffraction angle of 2θ is shown in FIG13 .

[0101] The present disclosure further provides a method for preparing the L-form of the compound represented by formula (I), comprising: a) mixing the compound represented by formula I with dichloromethane and dissolving the mixture; and b) adding methyl tert-butyl ether for crystallization.

[0102] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0103] In certain embodiments, the method for preparing the L-form of the compound of formula (I) described in the present disclosure further comprises steps such as filtration, washing or drying.

[0104] The present disclosure provides a crystalline form M of a compound represented by formula (I), which has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.6, 12.8, 14.8, 19.9, 25.3, 28.1 and 29.9.

[0105] In certain embodiments, the M crystalline form of the compound represented by formula (I) has characteristic peaks at 6.6, 12.8, 14.8, 15.3, 19.9, 24.9, 25.3, 25.9, 28.1 and 29.9.

[0106] In certain embodiments, the M crystalline form of the compound represented by formula (I) has characteristic peaks at 6.6, 10.9, 12.8, 14.8, 15.3, 18.0, 19.9, 24.9, 25.3, 25.9, 27.0, 28.1 and 29.9.

[0107] In certain embodiments, the X-ray powder diffraction pattern of Form M of the compound represented by Formula (I) expressed in terms of a diffraction angle of 2θ is shown in FIG14 .

[0108] The present disclosure further provides a method for preparing the crystalline form M of the compound represented by formula (I), comprising: a) mixing the compound represented by formula I with dimethyl sulfoxide, dissolving the mixture, and b) volatilizing and crystallizing the mixture.

[0109] In certain embodiments, the volume (μl) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.

[0110] In certain embodiments, the method for preparing the M crystal form of the compound represented by formula (I) described in the present disclosure further comprises steps such as filtering, washing or drying.

[0111] The present disclosure provides an N-type crystal of a compound represented by formula (I), which has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.8, 7.6, 16.0, 16.2, 18.6, 22.0 and 22.3.

[0112] In certain embodiments, the N crystalline form of the compound represented by formula (I) has characteristic peaks at 5.8, 7.6, 13.5, 16.0, 16.2, 17.9, 18.6, 22.0, 22.3 and 24.0.

[0113] In certain embodiments, the N crystalline form of the compound represented by formula (I) has characteristic peaks at 5.8, 7.6, 11.0, 13.5, 16.0, 16.2, 17.9, 18.6, 20.3, 21.2, 22.0, 22.3 and 24.0.

[0114] In certain embodiments, the X-ray powder diffraction pattern of Form N of the compound represented by Formula (I) expressed at a diffraction angle of 2θ is shown in FIG15 .

[0115] The present disclosure further provides a method for preparing the N-type crystal of the compound represented by formula (I), comprising: a) mixing the compound represented by formula I with a phosphoric acid solution and a solvent II, heating to dissolve, wherein the solvent II is selected from at least one of isopropanol, tetrahydrofuran, and ethanol; and b) cooling to crystallize.

[0116] In certain embodiments, the volume (μl) of the solvent used in the present disclosure may be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the method for preparing Form N described in the present disclosure further comprises the steps of filtration, washing or drying.

[0117] The present disclosure also provides a pharmaceutical composition prepared from the crystal form of the compound represented by the aforementioned formula (I).

[0118] The present disclosure also provides a pharmaceutical composition comprising the aforementioned crystal form and optionally a pharmaceutically acceptable carrier, diluent or excipient.

[0119] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned crystal form with a pharmaceutically acceptable carrier, diluent or excipient.

[0120] The present disclosure also provides use of the aforementioned crystal form, or the aforementioned composition, or the composition prepared by the aforementioned method in preparing a medicament for preventing and / or treating PDE-related disorders.

[0121] The present disclosure also provides the use of the aforementioned crystal form, or the aforementioned composition, or the composition prepared by the aforementioned method in preparing a medicament for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis or rheumatism.

[0122] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number exceeding 1 decimal place is rounded off), which can be -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0123] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "9103 Guiding Principles for Hygroscopicity of Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia,

[0124] Deliquescent: Absorbs sufficient water to form a liquid;

[0125] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0126] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0127] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0128] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0129] The "differential scanning calorimetry or DSC" described in this disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0130] The drying temperature in the present disclosure is generally 25° C. to 150° C., preferably 40° C. to 80° C., and the drying can be performed at normal pressure or under reduced pressure.

[0131] A "pharmaceutical composition" refers to a mixture containing one or more compounds of Formula (I) or pharmaceutically acceptable salts thereof, as described herein, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating the absorption of the active ingredient and thereby exerting its biological activity.

[0132] The crystalline forms disclosed herein include, but are not limited to, solvates of the compound represented by formula (I), wherein the solvents include, but are not limited to, n-heptane, cyclohexane, petroleum ether, dichloromethane, acetonitrile, methanol, propylene glycol methyl ether, 1,2-dichloroethane, ethyl acetate, ethanol, n-propanol, tetrahydrofuran, chloroform, N,N-dimethylformamide, acetone, isopropyl acetate, methyl tert-butyl ether, N-methylpyrrolidone, water, 2-butanone, 1,4-dioxane, isopentanol, o-xylene, isopropyl ether, toluene, isopropyl alcohol, dimethyl sulfoxide, and benzyl alcohol.

[0133] The "solvate" described in the present disclosure includes, but is not limited to, a complex formed by the combination of the compound of formula (I) and a solvent. BRIEF DESCRIPTION OF THE DRAWINGS

[0134] Figure 1: XRPD pattern of the amorphous form of the compound represented by formula (I).

[0135] Figure 2: XRPD pattern of the crystalline form of compound A represented by formula (I).

[0136] Figure 3: XRPD pattern of the crystalline form of compound B represented by formula (I).

[0137] Figure 4: XRPD pattern of the crystalline form of compound C represented by formula (I).

[0138] Figure 5: XRPD pattern of the crystalline form D of compound represented by formula (I).

[0139] Figure 6: XRPD pattern of the crystalline form E of compound represented by formula (I).

[0140] Figure 7: XRPD pattern of the crystalline form F of compound represented by formula (I).

[0141] Figure 8: XRPD pattern of the crystalline form G of compound represented by formula (I).

[0142] Figure 9: XRPD pattern of Form H of the compound represented by formula (I).

[0143] Figure 10: XRPD pattern of the crystalline form of compound I represented by formula (I).

[0144] Figure 11: XRPD pattern of Form J of the compound represented by formula (I).

[0145] Figure 12: XRPD pattern of the crystal form K of the compound represented by formula (I).

[0146] Figure 13: XRPD pattern of the crystalline form L of the compound represented by formula (I).

[0147] Figure 14: XRPD pattern of the crystalline form M of the compound represented by formula (I).

[0148] Figure 15: XRPD pattern of Form N of the compound represented by formula (I). DETAILED DESCRIPTION

[0149] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure, and are not intended to limit the essence and scope of the present disclosure.

[0150] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0151] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0152] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer / mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0153] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs.

[0154] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0155] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0156] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0157] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0158] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0159] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0160] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0161] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0162] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0163] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0164] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0165] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0166] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0167] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0168] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0169] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0170] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0171] Test conditions of the instruments used in the experiments in this disclosure:

[0172] 1. Differential Scanning Calorimeter (DSC)

[0173] Instrument model: Mettler Toledo DSC 3+STARe System

[0174] Purge gas: nitrogen; nitrogen purge rate: 50mL / min

[0175] Heating rate: 10.0℃ / min

[0176] Temperature range: 25-350℃ (or 25-300℃)

[0177] 2. X-ray Powder Diffraction (XRPD)

[0178] Instrument model: BRUKER D8 Discover X-ray powder diffractometer

[0179] Rays: Monochromatic Cu-Kα rays

[0180] Scanning mode: θ / 2θ, scanning range (2θ range): 3 to 45°

[0181] Voltage: 40kV, Current: 40mA

[0182] 3. Thermogravimetric Analysis (TGA)

[0183] Instrument model: Mettler Toledo TGA2

[0184] Purge gas: nitrogen; nitrogen purge rate: 50mL / min

[0185] Heating rate: 10.0℃ / min

[0186] Temperature range: 30-350℃

[0187] Example 1: Preparation of the compound represented by formula (I)

[0188] Preparation of 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]isoquinolin-4-one (Compound 1)

[0189] Intermediate 1a: Preparation of 1-(2-chloroethyl)imidazolidinone

[0190] To 1-(2-hydroxyethyl)imidazolidinone (3.5 g, 26.9 mmol) was slowly added thionyl chloride (5 ml) at 0°C, and the temperature was raised to 45°C and stirred until the reaction was complete. The reaction was quenched by adding saturated sodium chloride solution, and the pH was adjusted to 7 with 10% NaOH solution. The product was extracted with dichloromethane, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give intermediate 1a (3.5 g, yield 88.4%). MS (ESI) m / z 149.1 [M+H] + .

[0191] Intermediate 1b: Preparation of 1-(3,4-dimethoxyphenethyl)urea

[0192] At room temperature, 2-(3,4-dimethoxyphenyl)ethylamine hydrochloride (4.3 g, 19.8 mmol) was dissolved in water (25 ml), and the temperature was raised to 50°C. Potassium cyanate (1.8 g, 21.8 mmol) was added portionwise and stirred until the reaction was complete. The temperature was then lowered to 0°C and filtered. The filter cake was washed with ice water and dried to obtain intermediate 1b (4.1 g, yield 93.8%). MS (ESI) m / z 225.1 [M+H] + .

[0193] Intermediate 1c: Preparation of 1-[2-(3,4-dimethoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione

[0194] Under ice-bath conditions, sodium ethoxide (3.8 g, 55.8 mmol) was added portionwise to anhydrous ethanol (50 ml). After the addition, the temperature was raised to reflux, and diethyl malonate (5.9 g, 36.6 mmol) was added dropwise. After stirring for 0.25 to 0.5 h, a solution of intermediate 1b (4.1 g, 18.3 mmol) in ethanol (30 ml) was added dropwise. The reaction was stirred until the reaction was complete, and the temperature was lowered to 0°C. 5% HCl solution was added dropwise until the pH was 6. 300 ml of water was added, and the mixture was filtered. The filter cake was washed with ice water and dried to give intermediate 1c (3.9 g, yield 77.1%). MS (ESI) m / z 293.1 [M+H] + .

[0195] Intermediate 1d: Preparation of 2-chloro-9,10-dimethoxy-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one

[0196] At room temperature, intermediate B2 (3.9 g, 13.4 mmol) was added to phosphorus oxychloride (120 ml), and the temperature was raised to 110°C and stirred until the reaction was completed. The temperature was then lowered and concentrated. The solid was poured into ice water, and saturated NaOH solution was added dropwise until the pH was 10. The mixture was filtered, and the filter cake was washed with ice water and dried to obtain intermediate 1d (2.4 g, yield 62.4%). MS (ESI) m / z 293.1 [M+H] + .

[0197] Intermediate 1e: Preparation of 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-2,3,6,7-tetrahydropyrimido[6,1-a]isoquinolin-4-one

[0198] At room temperature, intermediate 1d (2.4 g, 8.2 mmol) was suspended in isopropanol (30 ml), and 2,4,6-trimethylaniline (4.5 g, 24.6 mmol) was added. The system was heated to 90°C and stirred until the reaction was complete. The temperature was then lowered and the mixture was filtered. The filter cake was washed with ice water and dried to obtain intermediate 1e (3.0 g, yield 92.1%). MS (ESI) m / z 392.2 [M+H] + .

[0199] Compound 1: Preparation of 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]isoquinolin-4-one

[0200] At room temperature, intermediate 1e (0.72 g, 1.8 mmol) was dissolved in tetrahydrofuran (20 ml), and potassium tert-butoxide (0.42 g, 3.6 mmol) was added under nitrogen atmosphere. After the addition, the temperature was raised to 65°C and stirring was continued for 48 h. The temperature was then lowered to 25°C and intermediate 1a (0.82 g, 5.5 mmol) was added. After the addition, the temperature was raised to 80°C and stirring was continued until the reaction was completed. A saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with dichloromethane, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The target compound 1 (0.21 g, yield 46.5%) was obtained by chromatography on a silica gel column (n-heptane / ethyl acetate).

[0201] 1H NMR (400MHz, CDCl3) δ6.99(s,2H),6.69(s,1H),6.64(s,1H),5.39(s,1H),4.61(s,1H),4.22-4.15(m,2H),4.08-3.99(m,2H),3.93 (s,3H),3.77-3.69(m,5H),3.55-3.46(m,2H),3.38-3.42(t,J=6.8Hz,2H),2.88-2.92(t,J=6.4Hz,2H),2.34(s,3H),2.18(s,6H).

[0202] MS (ESI) m / z 504.4 [M+H] + .

[0203] Comparative Example 1

[0204] Intermediate 3d was prepared by referring to the method of Example 1 using 2-(3-ethoxy-4-methoxyphenyl)ethylamine hydrochloride as the starting material.

[0205] At room temperature, intermediate 3d (1 g) was dissolved in 1,2-dichloroethane (20 ml), and 4-methylbenzenesulfonic acid 2-(2-oxazolidinone-3-yl)ethyl ester (844 mg), potassium carbonate (612 mg), and sodium iodide (443 mg) were added in sequence. The mixture was heated to 80°C and stirred until the reaction was complete. The mixture was cooled, filtered, concentrated, diluted with water, and extracted with ethyl acetate. The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography to obtain WX001. MS (ESI) m / z 519.0 [M+H] + .

[0206] Biological evaluation

[0207] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0208] Test Example 1 In vitro PDE4B enzyme activity detection experiment: IMAP FP-based analysis method detection

[0209] 1. Experimental Materials

[0210] 2. Experimental steps

[0211] The compound was serially diluted 5-fold with DMSO to obtain different concentrations (10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.005 nM). 200 μL of compound at different concentrations was added to a 384-well plate (n=2), and two 200 μL DMSOs were added to the 384-well plate (n=2) as blank controls. 10 μL of 0.025 μg / mL PDE4B1 enzyme solution (prepared with 1 mM 5*IMAP reaction buffer and 1 mM DTT) was then added to the 384-well plate, and 10 μL of blank buffer without PDE4B1 enzyme was added to one of the blank controls. The plates were incubated with shaking at room temperature for 15 minutes. 10 μL of 0.1 μM FAM-cAMP solution (prepared with 1 mM 5*IMAP reaction buffer r and 1 mM DTT) was then added. The plates were incubated with shaking at room temperature for 30 minutes, and then 60 μL of detection solution (prepared with 0.5625 mM 5*IMAP progressive binding buffer A) was added. A), 0.1875mM 5*IMAP binding buffer B and 0.75mM binding beads (beads), incubated at room temperature with shaking for 60 minutes and data collected. The inhibition rate is calculated as follows: Inhibition rate = M / (MM 对照 )*100; IC was calculated based on the concentration and inhibition rate fitting curve 50 In this experiment, RPL554 was used as a positive control.

[0212] The examples disclosed herein were used to determine the inhibition of PDE4B1 enzyme activity in vitro using the above assays. The IC 50 The values ​​are shown in Tables I and II.

[0213] Test Example 2 In vitro PDE3A enzyme activity detection experiment: IMAP FP-based analysis method detection

[0214] 1. Experimental Materials

[0215] 2. Experimental steps

[0216] Compounds were serially diluted 5-fold with DMSO to obtain different concentrations (10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.005 nM). 200 μL of compound at different concentrations was added to a 384-well plate (n=2), and 2 200 μL DMSO was added to 384-well plates (n=2) as blank controls. 10 μL of 0.025 μg / mL PDE4B1 enzyme solution (prepared with 1 mM 5*IMAP reaction buffer and 1 mM DTT) was then added to the 384-well plate. 10 μL of blank buffer without PDE3A enzyme was added to one of the blank controls. The plates were incubated with shaking at room temperature for 15 minutes. Then, 10 μL of 0.1 μM FAM-cAMP solution (prepared with 1mM 5*IMAP reaction buffer and 1mM DTT) was incubated at room temperature with shaking for 30 minutes, after which 60μL of detection solution (prepared with 0.5625mM 5*IMAP progress binding buffer, 0.1875mM 5*IMAP progress binding buffer B and 0.75mM binding beads) was added and incubated at room temperature with shaking for 60 minutes before data collection. The inhibition rate was calculated as follows: Inhibition rate = M / (MM 对照 )*100; IC was calculated based on the concentration and inhibition rate fitting curve 50 In this experiment, RPL554 was used as a positive control.

[0217] The examples disclosed herein were used to determine the inhibition of PDE3A enzyme activity in vitro using the above assays. The IC 50 The values ​​are shown in Tables I and II.

[0218] Table I

[0219] Table II Note: N / A Not tested

[0220] Conclusion: Compared with the positive compound RPL554, compound 1 showed good biological activity in the in vitro enzyme experiment, and compared with compound WX001, compound 1 had a 7-fold increase in PDE3A enzyme inhibitory activity, and has good development prospects.

[0221] Test Example 3: PK experiment of intratracheal administration

[0222] 1. Purpose of the experiment

[0223] To evaluate the pharmacokinetic characteristics and lung tissue distribution of the test article in SD rats after intratracheal administration

[0224] 2. Experimental Plan

[0225] 2.1 Investigational Drugs

[0226] Compound 1 and RPL-554

[0227] 2.2 Experimental animals

[0228] ICR mice (Shanghai Slake Laboratory Animal Co., Ltd.), 198, half male and half female.

[0229] 2.3 Drug preparation

[0230] 1) Full solution:

[0231] Weigh 0.5 g of Tween 80 and dissolve it in 50 ml of pH 2.5 citric acid / disodium hydrogen phosphate buffer solution for later use.

[0232] Weigh 1.0 mg of the test drug and dissolve it in an appropriate amount of Tween solution to prepare a 0.03 mg / ml solution for later use.

[0233] 2) Suspension:

[0234] Weigh 0.5 g of CMC-Na and 0.5 g of Tween 20, add 50 ml of 0.9% saline solution and stir evenly to obtain a 1% CMC-Na and Tween 20 solution for later use.

[0235] Weigh 1.0 mg of the test drug and add it to 10 ml of the above solution, disperse it by ultrasonic and stir it evenly to obtain a suspension for later use.

[0236] 2.4 Dosage regimen

[0237] 3. Experimental Operation / Process

[0238] 3.1 Intratracheal administration of mice

[0239] Mice were anesthetized with isoflurane gas and administered intratracheally. Plasma was collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours. 200 μL of whole blood was collected, anticoagulated with EDTA-K2, and centrifuged at approximately 6800 g for 6 minutes at 2-8°C. The resulting plasma was transferred to appropriately labeled tubes within 1 hour of blood collection / centrifugation and stored frozen at -80°C. Lung tissue was collected at 0.5, 2, 8, and 24 hours. Tissue samples were transferred to appropriately labeled tubes and stored frozen at -80°C.

[0240] 3.2 Plasma processing and LC-MS / MS analysis

[0241] Take 30.0 μL of plasma sample to a 1.5 mL centrifuge tube, add 150 μL of internal standard working solution, vortex mix for 1 min, centrifuge for 5 min (13000 rpm, 4 ° C), take 70.0 μL of supernatant to a 96-well plate, add 70.0 μL of deionized water, shake well, and inject 2.00 μL for LC-MS / MS analysis.

[0242] 3.3 Lung tissue processing

[0243] Accurately weigh an appropriate amount of lung tissue sample and place it in a homogenizer tube. Add acetonitrile equal to 5 times its weight and mix the mixture. Sonicate for 5 minutes. Take 20.0 μL of lung tissue homogenate sample, add 30.0 μL of internal standard working solution and 200 μL of acetonitrile, vortex for 1 minute, and centrifuge for 10 minutes (4000 rpm, 4°C). Transfer 100 μL of the supernatant to a 96-well plate, add 100 μL of deionized water, shake the plate to mix (1000 rpm, RT), and inject 1.00 μL for LC-MS / MS analysis.

[0244] 4. Pharmacokinetic parameter results

[0245] Compared to RPL-554, Compound 1 showed higher in vivo exposure and a longer duration of exposure in the lungs. Related data are shown in Tables III and IV.

[0246] Table III: PK and tissue distribution test results of suspension solution formulation

[0247] Table IV: PK and tissue distribution results of full solution formulations

[0248] Example 2: Preparation of amorphous compound represented by formula (I)

[0249] About 8 mg of the compound of formula (I) was added with 0.04 mL of benzyl alcohol, stirred at room temperature for dissolution, and evaporated at room temperature for crystallization to obtain the product. X-ray powder diffractometer analysis showed that the product was amorphous.

[0250] Example 3: Preparation of the crystalline form of compound A represented by formula (I)

[0251] The product was prepared according to Example 1. X-ray powder diffractometer analysis identified the product as Form A. The XRPD pattern is shown in Figure 2, and the positions of its characteristic peaks are shown in Table 1. The DSC spectrum showed endothermic peaks at 135.93°C and 263.19°C. The TGA spectrum showed a weight loss of 3.97% from 30°C to 275°C.

[0252] Table 1

[0253] Example 4: Preparation of the Crystalline Form of Compound B Represented by Formula (I)

[0254] Approximately 8 mg of the compound of formula (I) was added to 0.16 mL of dichloromethane, stirred and dissolved at room temperature, and evaporated to crystallize to obtain the product. X-ray powder diffraction analysis identified the product as Form B. The XRPD spectrum is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 2. The DSC spectrum showed endothermic peaks at 139.31°C and 263.02°C, and an exothermic peak at 153.33°C. The TGA spectrum showed a weight loss of 7.14% from 30°C to 290°C.

[0255] Table 2

[0256] Example 5: Preparation of the Crystalline Form of Compound C Represented by Formula (I)

[0257] Approximately 8 mg of the compound of formula (I) was added to 0.28 mL of acetonitrile / methanol (1:1), stirred and dissolved at room temperature, and evaporated and crystallized at room temperature to obtain the product. X-ray powder diffraction analysis identified the product as Form C. The XRPD spectrum is shown in Figure 4, and the positions of its characteristic peaks are shown in Table 3. The DSC spectrum showed endothermic peaks at 148.77°C and 262.90°C. The TGA spectrum showed a weight loss of 4.36% from 30°C to 195°C.

[0258] Table 3

[0259] Example 6: Preparation of the crystal form D of the compound represented by formula (I)

[0260] Approximately 8 mg of the compound of formula (I) was added to 0.8 mL of propylene glycol methyl ether, heated, dissolved, and evaporated at room temperature to obtain the product. X-ray powder diffraction analysis identified the product as Form D. The XRPD spectrum is shown in Figure 5, and the positions of its characteristic peaks are shown in Table 4. The DSC spectrum showed endothermic peaks at 163.12°C and 263.24°C, and an exothermic peak at 166.84°C. The TGA spectrum showed a weight loss of 3.02% from 30°C to 165°C.

[0261] Table 4

[0262] Example 7: Preparation of the crystal form D of the compound represented by formula (I)

[0263] About 8 mg of the compound of formula (I) was added to 0.44 mL of ethyl acetate / ethanol (1:1), stirred at room temperature for dissolution, and evaporated at room temperature for crystallization to obtain the product, which was confirmed to be Form D by X-ray powder diffraction.

[0264] Example 8: Preparation of the crystal form D of the compound represented by formula (I)

[0265] About 8 mg of the compound of formula (I) was added to 0.3 mL of ethanol and dissolved by stirring at room temperature. 1 mL of water was added to precipitate a solid, which was centrifuged and dried in vacuo to obtain the product. X-ray powder diffraction analysis confirmed the product to be Form D.

[0266] Example 9: Preparation of the crystal form D of the compound represented by formula (I)

[0267] About 8 mg of Form A of the compound of formula (I) was added to 0.8 mL of water, stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain the product, which was confirmed to be Form D by X-ray powder diffraction.

[0268] Example 10: Preparation of the crystal form D of compound represented by formula (I)

[0269] About 8 mg of Form A of the compound of formula (I) was added to 0.8 ml of acetone, stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain the product, which was confirmed to be Form D by X-ray powder diffraction.

[0270] Example 11: Preparation of the crystalline form of compound E represented by formula (I)

[0271] Approximately 8 mg of the compound of formula (I) was dissolved in 0.3 mL of N-methylpyrrolidone with stirring. 1 mL of isopropyl acetate was added, and a solid precipitated. The mixture was centrifuged and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as Form E. The XRPD spectrum is shown in Figure 6, and the positions of its characteristic peaks are shown in Table 5. The DSC spectrum showed an endothermic peak at 265.03°C. The TGA spectrum showed a weight loss of 0.33% from 30°C to 170°C.

[0272] Table 5

[0273] Example 12: Preparation of the crystalline form of compound F represented by formula (I)

[0274] Approximately 8 mg of the compound of formula (I) was dissolved in 0.12 ml of N-methylpyrrolidone with stirring, crystallized by stirring, centrifuged, and the solid dried in vacuo to obtain the product. X-ray powder diffraction analysis identified the product as Form F. The XRPD spectrum is shown in Figure 7, and the positions of its characteristic peaks are shown in Table 6. The DSC spectrum showed endothermic peaks at 96.91°C, 141.88°C, and 263.70°C. The TGA spectrum showed a weight loss of 25.77% from 30°C to 220°C.

[0275] Table 6

[0276] Example 13: Preparation of the crystalline form F of compound represented by formula (I)

[0277] About 8 mg of the compound of formula (I) was added to 0.3 mL of N-methylpyrrolidone and dissolved by stirring. 1 mL of methyl tert-butyl ether was added to precipitate a solid. The solid was centrifuged and vacuum dried to obtain the product. X-ray powder diffraction analysis showed that the product was Form F.

[0278] Example 14: Preparation of the Crystalline Form of Compound G Represented by Formula (I)

[0279] Approximately 8 mg of the compound of formula (I) was dissolved in 0.2 mL of dichloromethane with stirring. 1.2 mL of isopropyl acetate was added, and a solid precipitated. The mixture was centrifuged and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as Form G. The XRPD spectrum is shown in Figure 8, and the positions of its characteristic peaks are shown in Table 7. The DSC spectrum showed an endothermic peak at 264.37°C. The TGA spectrum showed a weight loss of 0.24% from 30°C to 205°C.

[0280] Table 7

[0281] Example 15: Preparation of Crystalline Form H of Compound Represented by Formula (I)

[0282] Approximately 8 mg of Form A of the compound of formula (I) was added to 0.8 ml of methanol and stirred at room temperature until insoluble. The mixture was heated to 50°C, slowly cooled to precipitate, centrifuged, and the solid dried in vacuo to obtain the product. X-ray powder diffraction analysis identified the product as Form H. The XRPD spectrum is shown in Figure 9, and the positions of its characteristic peaks are shown in Table 8. The DSC spectrum showed endothermic peaks at 149.99°C and 264.92°C, and an exothermic peak at 158.39°C. The TGA spectrum showed a weight loss of 2.53% between 30°C and 160°C.

[0283] Table 8

[0284] Example 16: Preparation of Crystalline Form H of Compound Represented by Formula (I)

[0285] About 8 mg of the compound of formula (I) was added to 0.25 mL of acetonitrile / methanol (1:1) and stirred to dissolve. 1.2 mL of methyl tert-butyl ether was added, and a solid precipitated. The solid was centrifuged and vacuum dried to obtain the product. X-ray powder diffraction analysis showed that the product was Form H.

[0286] Example 17: Preparation of the Crystalline Form of Compound I Represented by Formula (I)

[0287] Approximately 8 mg of the compound of formula (I) was dissolved in 0.4 ml of ethanol with stirring, heated to 50°C, slowly cooled to crystallize, centrifuged, and the solid dried in vacuo to obtain the product. X-ray powder diffraction analysis identified the product as Form I. The XRPD spectrum is shown in Figure 10, and the positions of its characteristic peaks are shown in Table 9. The DSC spectrum showed endothermic peaks at 140.16°C and 264.78°C, and an exothermic peak at 159.54°C. The TGA spectrum showed a weight loss of 6.27% between 30°C and 170°C.

[0288] Table 9

[0289] Example 18: Preparation of Crystalline Form J of Compound Represented by Formula (I)

[0290] Approximately 8 mg of Form A of the compound of formula (I) was added to 0.8 ml of isopropanol, heated to 50°C, slowly cooled to crystallize, centrifuged, and the solid dried in vacuo to obtain the product. X-ray powder diffraction analysis identified the product as Form J. The XRPD spectrum is shown in Figure 11, and the positions of its characteristic peaks are shown in Table 10. The DSC spectrum showed endothermic peaks at 153.46°C and 264.58°C. The TGA spectrum showed a weight loss of 9.46% between 30°C and 160°C.

[0291] Table 10

[0292] Example 19: Preparation of Crystalline Form K of Compound Represented by Formula (I)

[0293] Approximately 8 mg of Form A of the compound of formula (I) was added to 0.8 mL of acetonitrile, heated to 50°C, slowly cooled to crystallize, centrifuged, and the solid dried in vacuo to obtain the product. X-ray powder diffraction analysis identified the product as Form K. The XRPD spectrum is shown in Figure 12, and the positions of its characteristic peaks are shown in Table 11. The DSC spectrum showed endothermic peaks at 153.65°C, 160.48°C, and 265.14°C, and an exothermic peak at 158.85°C. The TGA spectrum showed a weight loss of 5.27% from 30°C to 195°C.

[0294] Table 11

[0295] Example 20: Preparation of Crystal Form L of Compound Represented by Formula (I)

[0296] Approximately 200 mg of the compound of formula (I) was dissolved in 5 mL of dichloromethane with stirring. 30 mL of methyl tert-butyl ether was added, and a solid precipitated. The mixture was centrifuged and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as Form L. The XRPD spectrum is shown in Figure 13, and the positions of its characteristic peaks are shown in Table 12. The DSC spectrum showed endothermic peaks at 137.47°C and 264.18°C, and an exothermic peak at 159.83°C. The TGA spectrum showed a weight loss of 9.46% between 30°C and 195°C.

[0297] Table 12

[0298] Example 21: Preparation of Crystalline Form M of Compound Represented by Formula (I)

[0299] Approximately 8 mg of the compound of formula (I) was added to 0.48 ml of dimethyl sulfoxide, stirred and dissolved, and evaporated at room temperature to crystallize to obtain the product. X-ray powder diffraction analysis identified the product as Form M. The XRPD spectrum is shown in Figure 14, and the positions of its characteristic peaks are shown in Table 13. The DSC spectrum showed endothermic peaks at 161.65°C and 264.86°C. The TGA spectrum showed a weight loss of 13.41% from 30°C to 235°C.

[0300] Table 13

[0301] Example 22: Preparation of Form N of the Compound Represented by Formula (I)

[0302] To 10 mg of the compound represented by formula (I), 0.5 ml of isopropanol was added and stirred at 50°C to dissolve the mixture. 11 μl of 2M aqueous phosphoric acid was added, the mixture was cooled to allow crystallization, centrifuged, and the solid dried under vacuum to obtain the product. X-ray powder diffractometer analysis confirmed that the product was Form N. The XRPD spectrum is shown in Figure 15, and the positions of its characteristic peaks are shown in Table 14. The DSC spectrum revealed an endothermic peak at 226.58°C. The TGA spectrum showed a weight loss of 4.51% from 30°C to 235°C.

[0303] Table 14

[0304] Example 23: Hygroscopicity Study of Form D of the Compound of Formula (I)

[0305] Using Surface Measurement Systems advantage 2, at 25°C and humidity starting from 50%, the humidity range was examined from 0% to 95% in 10% increments. The judgment criterion was that the mass change dM / dT for each gradient was less than 0.002%. The running time TMAX of each humidity gradient was 360 minutes, and the cycle was repeated twice.

[0306] Table 15

[0307] Example 24: Experiment on factors affecting the crystal form of the compound of formula (I)

[0308] The crystal forms D, E, G, H and N of the compound of formula (I) were laid out in an open container and their stability was investigated under high temperature (40°C, 60°C) and high humidity (RH 75%, RH 92.5%) conditions for 30 days.

[0309] Table 16

[0310] Conclusion: The influencing factor experiment showed that Form D of the compound of formula (I) had good physical and chemical stability under high temperature conditions of 40°C and 60°C and high humidity conditions of 75% and 92.5% for 30 days; Forms E, G and H had poor physical stability but good chemical stability under high humidity conditions of 75% and 92.5% for 30 days.

[0311] Example 25: Long-term / accelerated stability of the crystalline form of the compound of formula (I)

[0312] The stability of the compound of formula (I) in form D, form E, form G and form H was investigated at -20°C, 4°C, 25°C / 60% RH and 40°C / 75% RH, respectively.

[0313] Conclusion: Long-term accelerated tests showed that at 25°C / 60RH and 40°C / 75RH for 6 months, Form D had good physical and chemical stability, while Forms E, G, and H had good chemical stability but slightly poor physical stability.

Claims

1. Crystal Form B of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.6, 11.0, 12.7, 15.5, 19.1, 23.7 and 25.8, preferably has characteristic peaks at 6.6, 10.0, 11.0, 11.7, 12.7, 15.5, 19.1, 23.7, 24.6 and 25.8, more preferably has characteristic peaks at 6.6, 8.6, 10.0, 11.0, 11.7, 12.7, 15.5, 17.8, 19.1, 23.7, 24.6, 25.8 and 26.9, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, is shown in Figure 3.

2. Crystal Form C of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.6, 7.5, 10.1, 10.9, 15.6, 23.8 and 24.3, preferably has characteristic peaks at 6.6, 7.5, 10.1, 10.9, 13.8, 15.6, 20.7, 23.8, 24.3 and 24.7, more preferably has characteristic peaks at 6.6, 7.5, 10.1, 10.9, 13.8, 15.6, 17.5, 19.3, 20.7, 23.8, 24.3, 24.7 and 27.0, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, is shown in Figure 4.

3. Crystal form D of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5 and 24.2, preferably has characteristic peaks at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5, 20.3, 24.2, 25.8 and 26.9, more preferably has characteristic peaks at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5, 20.3, 23.3, 24.2, 24.7, 25.1, 25.8 and 26.9, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, is shown in Figure 5.

4. Crystal form E of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.3, 11.1, 12.8, 14.3, 17.9, 22.9 and 25.6, preferably has characteristic peaks at 6.3, 11.1, 12.8, 14.3, 17.0, 17.9, 18.7, 22.9, 23.8 and 25.6, more preferably has characteristic peaks at 6.3, 11.1, 12.8, 14.3, 15.9, 17.0, 17.9, 18.7, 20.1, 22.9, 23.8 and 25.6, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, is shown in Figure 6.

5. Crystal Form F of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.6, 11.1, 13.6, 15.0, 22.3, 24.2 and 26.1, preferably has characteristic peaks at 6.6, 11.1, 13.6, 15.0, 16.1, 18.6, 22.3, 24.2, 26.1 and 28.1, more preferably has characteristic peaks at 6.6, 8.8, 11.1, 12.9, 13.6, 15.0, 16.1, 17.7, 18.6, 22.3, 24.2, 26.1 and 28.2, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, is shown in Figure 7.

6. Form G of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.1, 12.3, 14.2, 16.9, 19.2, 21.4 and 24.0, preferably has characteristic peaks at 6.1, 12.3, 13.1, 14.2, 15.2, 16.1, 16.9, 19.2, 21.4 and 24.0, more preferably has characteristic peaks at 6.1, 11.3, 12.3, 13.1, 14.2, 15.2, 16.1, 16.9, 19.2, 21.4, 24.0, 26.6 and 28.8, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, is shown in Figure 8.

7. H crystal form of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.8, 7.5, 9.7, 13.0, 14.0, 15.1 and 16.1, preferably has characteristic peaks at 6.8, 7.5, 9.7, 10.2, 10.9, 13.0, 14.0, 15.1, 16.1 and 26.5, more preferably has characteristic peaks at 6.8, 7.5, 9.7, 10.2, 10.9, 13.0, 14.0, 15.1, 16.1, 22.1, 23.1, 25.8 and 26.5, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, is shown in Figure 9.

8. Crystal Form I of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.2, 7.2, 9.6, 10.2, 12.0, 13.3 and 22.1, preferably has characteristic peaks at 5.2, 7.2, 9.6, 10.2, 12.0, 13.3, 14.5, 15.0, 19.5 and 22.1, more preferably has characteristic peaks at 5.2, 7.2, 7.9, 9.6, 10.2, 12.0, 13.3, 14.5, 15.0, 19.5, 21.2, 22.1 and 23.6, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, is shown in Figure 10.

9. Crystal Form J of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 7.7, 11.7, 13.5, 14.0, 18.6, 21.6 and 24.3, preferably has characteristic peaks at 7.7, 10.1, 11.7, 13.5, 14.0, 18.6, 20.2, 21.6, 23.3 and 24.3, more preferably has characteristic peaks at 7.7, 10.1, 10.7, 11.7, 13.5, 14.0, 16.0, 17.3, 18.6, 20.2, 21.6, 23.3 and 24.3, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, is shown in Figure 11.

10. K crystal form of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.8, 7.4, 13.8, 15.0, 15.8, 20.7 and 22.1, preferably has characteristic peaks at 6.8, 7.4, 9.5, 13.8, 14.2, 15.0, 15.8, 20.7, 22.1 and 27.6, more preferably has characteristic peaks at 6.8, 7.4, 9.5, 13.8, 14.2, 15.0, 15.8, 17.9, 18.4, 20.7, 22.1, 26.5 and 27.6, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, is shown in Figure 12.

11. L crystal form of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ has characteristic peaks at 7.1, 7.6, 12.8, 13.6, 19.5, 21.1 and 25.8, preferably has characteristic peaks at 7.1, 7.6, 9.2, 12.8, 13.6, 16.1, 19.5, 21.1, 24.6 and 25.8, more preferably has characteristic peaks at 7.1, 7.6, 9.2, 12.8, 13.6, 16.1, 19.5, 21.1, 24.6 and 25.8, and most preferably the X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ is shown in FIG13 .

12. Crystal form M of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.6, 12.8, 14.8, 19.9, 25.3, 28.1 and 29.9, preferably has characteristic peaks at 6.6, 12.8, 14.8, 15.3, 19.9, 24.9, 25.3, 25.9, 28.1 and 29.9, more preferably has characteristic peaks at 6.6, 10.9, 12.8, 14.8, 15.3, 18.0, 19.9, 24.9, 25.3, 25.9, 27.0, 28.1 and 29.9, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, is shown in Figure 14.

13. N crystal form of the compound represented by formula (I), It is characterized by: The X-ray powder diffraction pattern, expressed as a diffraction angle of 2θ, has characteristic peaks at 5.8, 7.6, 16.0, 16.2, 18.6, 22.0 and 22.3, preferably has characteristic peaks at 5.8, 7.6, 13.5, 16.0, 16.2, 17.9, 18.6, 22.0, 22.3 and 24.0, more preferably has characteristic peaks at 5.8, 7.6, 11.0, 13.5, 16.0, 16.2, 17.9, 18.6, 20.3, 21.2, 22.0, 22.3 and 24.0, and most preferably the X-ray powder diffraction pattern, expressed as a diffraction angle of 2θ, is shown in Figure 15.

14. The crystal form according to any one of claims 1 to 13, characterized in that The 2θ angle error range is ±0.

2.

15. A pharmaceutical composition prepared from the crystal form according to any one of claims 1 to 14.

16. A pharmaceutical composition comprising the crystal form according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier, diluent or excipient.

17. A method for preparing a pharmaceutical composition, comprising the step of mixing the crystal form described in any one of 1-14 with a pharmaceutically acceptable carrier, diluent or excipient.

18. Use of the crystalline form according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15 or 16, or the pharmaceutical composition prepared by the method according to claim 17 in the preparation of a medicament for preventing and / or treating a PDE-related disorder.

19. Use of the crystalline form according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15 or 16, or the pharmaceutical composition prepared by the method according to claim 17 in the preparation of a medicament for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism.

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