Solid Forms of Nitrogen-Containing Heterocyclic Compounds, Pharmaceutical Compositions Containing the Same, and Uses Thereof

Abstract

The present invention provides a solid form of a compound of formula (I) or a solvate thereof having autotaxin (ATX) inhibitory activity, wherein the solid form comprises a crystalline form and / or an amorphous form. The crystalline form comprises two non-solvate crystalline forms: crystalline form A and crystalline form L; six hydrate crystalline forms: crystalline form B (dihydrate), crystalline form D (trihydrate), crystalline form G (tetrahydrate), crystalline form H (monohydrate), crystalline form K (dihydrate) and crystalline form M-1 (monohydrate); and seven solvate crystalline forms: crystalline form C (hemitoluene solvate), crystalline form E (chloroform solvate), crystalline form N (dichloromethane solvate), crystalline form P (isopropanol solvate), crystalline form J-1 (hemisec-butyltetrahydrofuran solvate), crystalline form J-2 (methyl isobutyl ketone solvate) and crystalline form M-2 (acetonitrile solvate). The solid form can be used for treating and / or preventing diseases related to autotaxin (ATX).

Description

[0001] This application claims the priority of a prior application filed by the applicant with the Chinese National Intellectual Property Administration on July 28, 2020, with the patent application number 202010742864.6 and the invention title "Solid Forms of Nitrogen-Containing Heterocyclic Compounds, Their Pharmaceutical Compositions and Uses". The full text of the prior application is incorporated into this application by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a solid form of a nitrogen-containing heterocyclic compound, its pharmaceutical composition and uses. Background Art

[0003] Autotaxin (ATX) is a secreted glycoprotein with phosphodiesterase (PDE) activity and is a member of the ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family, so it is also called ENPP2. It also has lysophospholipase D (LysoPLD) activity and can hydrolyze lysophosphatidylcholine (LPC) into bioactive lysophosphatidic acid (LPA). LPA is an intracellular lipid mediator that affects many biological and biochemical processes. Studies have shown that under pathological conditions, inhibiting ATX can reduce LPA levels, thereby providing therapeutic benefits for unmet clinical needs, including cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrosis, thrombosis, cholestatic pruritus, or fibrotic diseases induced, mediated, and / or propagated by elevated LPA levels and / or ATX activation. Therefore, ATX inhibitors are expected to be used in the treatment of diseases associated with elevated LPA levels, including cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrosis, thrombosis, cholestatic pruritus, fibrotic diseases such as idiopathic pulmonary fibrosis (IPF).

[0004] Chinese Patent Application No. 202010074393.6 describes a compound of formula (I) with ATX inhibitory activity.

[0005]

[0006] The chemical name of the compound of formula (I) is (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one. Based on the good biological activity of this compound, finding and obtaining more stable solid forms, such as crystal forms and amorphous substances, is of great significance for improving the drugability, hygroscopicity, stability, storage, weighing, etc. of this compound. Summary of the Invention

[0007] To improve the above technical problems, the present invention provides a solid form of a compound of formula (I) or a solvate thereof:

[0008]

[0009] Wherein, the solid form includes a crystal form and / or an amorphous substance.

[0010] According to an embodiment of the present invention, the solvent in the solvate can be selected from water and / or non-aqueous solvents. The non-aqueous solvents include, but are not limited to, ethanol, acetonitrile, toluene, chloroform, dichloromethane, isopropanol, propylene glycol, isobutanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, methyl isobutyl ketone, etc.

[0011] According to an embodiment of the present invention, the solid form of the compound of formula (I) may or may not contain adsorbed solvent, such as may or may not contain water of crystallization.

[0012] The present invention provides crystal forms of the compound of formula (I) or a solvate thereof, including: two non-solvate crystal forms: crystal form A and crystal form L; six hydrate crystal forms: crystal form B (dihydrate), crystal form D (trihydrate), crystal form G (tetrahydrate), crystal form H (monohydrate), crystal form K (dihydrate), and crystal form M-1 (monohydrate); seven organic solventate crystal forms: crystal form C (semi-toluene solvate), crystal form E (mono-chloroform solvate), crystal form N (mono-dichloromethane solvate), crystal form P (mono-isopropanol solvate), crystal form J-1 (semi-2-methyltetrahydrofuran solvate), crystal form J-2 (mono-methyl isobutyl ketone solvate), and crystal form M-2 (mono-acetonitrile solvate).

[0013] In the context of the present invention, unless otherwise specified, the error range of the 2θ angle value in the X-ray powder diffraction (XRPD) data is ±0.2°.

[0014] The present invention provides crystal form A of the compound of formula (I), and the X-ray powder diffraction pattern obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 8.05 ± 0.20°, 8.30 ± 0.20°, 14.11 ± 0.20°, 16.18 ± 0.20°, 22.73 ± 0.20°, 25.16 ± 0.20°.

[0015] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at the following 2θ angles: 8.05 ± 0.20°, 8.30 ± 0.20°, 14.11 ± 0.20°, 16.18 ± 0.20°, 16.65 ± 0.20°, 21.85 ± 0.20°, 22.73 ± 0.20°, 25.16 ± 0.20°, 26.23 ± 0.20°.

[0016] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph A has characteristic peaks at the following 2θ angles: 8.05 ± 0.20°, 8.30 ± 0.20°, 14.11 ± 0.20°, 16.18 ± 0.20°, 16.65 ± 0.20°, 19.19 ± 0.20°, 21.85 ± 0.20°, 22.73 ± 0.20°, 25.16 ± 0.20°, 26.23 ± 0.20°, 29.91 ± 0.20°.

[0017] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph A has characteristic peaks at the following 2θ angles: 8.05 ± 0.20°, 8.30 ± 0.20°, 14.11 ± 0.20°, 16.18 ± 0.20°, 16.65 ± 0.20°, 18.19 ± 0.20°, 18.91 ± 0.20°, 19.19 ± 0.20°, 21.85 ± 0.20°, 22.73 ± 0.20°, 25.16 ± 0.20°, 26.23 ± 0.20°, 29.91 ± 0.20°.

[0018] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph A has characteristic peaks at the following 2θ angles: 8.05 ± 0.20°, 8.30 ± 0.20°, 10.77 ± 0.20°, 12.95 ± 0.20°, 14.11 ± 0.20°, 16.18 ± 0.20°, 16.65 ± 0.20°, 17.35 ± 0.20°, 18.19 ± 0.20°, 18.91 ± 0.20°, 19.19 ± 0.20°, 20.93 ± 0.20°, 21.53 ± 0.20°, 21.85 ± 0.20°, 22.31 ± 0.20°, 22.73 ± 0.20°, 24.38 ± 0.20°, 25.16 ± 0.20°, 26.23 ± 0.20°, 27.39 ± 0.20°, 28.44 ± 0.20°, 28.99 ± 0.20°, 29.20 ± 0.20°, 29.91 ± 0.20°, 32.77 ± 0.20°, 36.68 ± 0.20°.

[0019] According to an embodiment of the present invention, the 2θ diffraction angles, D values and / or relative intensities of the X-ray powder diffraction pattern of polymorph A obtained using Cu-Kα radiation are shown in Table 1 below:

[0020] Table 1 XRPD diffraction peak data of polymorph A

[0021]

[0022]

[0023] According to an embodiment of the present invention, the crystalline form A has substantially as Figure 1 the X-ray powder diffraction pattern shown.

[0024] According to an embodiment of the present invention, the crystalline form A has one, two, three or four of the following characteristics:

[0025] (1) The TGA curve of crystalline form A has a weight loss of about 2.59% at 150.0 ± 3 °C;

[0026] (2) The DSC curve of crystalline form A has a starting point of an endothermic peak at 152.4 ± 3 °C;

[0027] (3) The DSC curve of crystalline form A has an endothermic peak at 155.3 ± 3 °C;

[0028] (4) The DVS curve of crystalline form A has a moisture adsorption of less than about 1.2%, such as less than about 1.1%, particularly less than about 1.05% under the conditions of 0% RH to 80% RH.

[0029] According to an embodiment of the present invention, the crystalline form A has one, two or three of the following characteristics:

[0030] (1) Crystalline form A has substantially as Figure 17 the TGA curve shown;

[0031] (2) Crystalline form A has substantially as Figure 17 the DSC curve shown;

[0032] (3) Crystalline form A has substantially as Figure 30 the DVS curve shown.

[0033] The present invention also provides crystalline form B of the dihydrate of the compound of formula (I), and its X-ray powder diffraction pattern obtained by using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 4.93 ± 0.2 °, 5.30 ± 0.2 °, 7.37 ± 0.2 °, 7.93 ± 0.2 °, 15.95 ± 0.2 °.

[0034] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at the following 2θ angles: 4.93 ± 0.2 °, 5.30 ± 0.2 °, 7.37 ± 0.2 °, 7.93 ± 0.2 °, 8.59 ± 0.2 °, 14.04 ± 0.2 °, 15.95 ± 0.2 °, 24.15 ± 0.2 °.

[0035] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at the following 2θ angles: 4.93 ± 0.2°, 5.30 ± 0.2°, 7.37 ± 0.2°, 7.93 ± 0.2°, 8.59 ± 0.2°, 14.04 ± 0.2°, 15.95 ± 0.2°, 17.24 ± 0.2°, 23.33 ± 0.2°, 24.15 ± 0.2°.

[0036] According to an embodiment of the present invention, the 2θ diffraction angles, D values and / or relative intensities of the X-ray powder pattern of the crystalline form B obtained using Cu-Kα radiation are shown in Table 2 below:

[0037] Table 2 XRPD diffraction peak data of crystalline form B

[0038]

[0039]

[0040] According to an embodiment of the present invention, the crystalline form B has substantially as Figure 2 shown in the X-ray powder diffraction pattern.

[0041] According to an embodiment of the present invention, the crystalline form B has one, two or three of the following characteristics:

[0042] (1) The TGA curve of the crystalline form B shows a weight loss of about 9.72% at 150.0 ± 3 °C;

[0043] (2) The DSC curve of the crystalline form B has a starting point of an endothermic peak at 96.8 ± 3 °C;

[0044] (3) The DSC curve of the crystalline form B has an endothermic peak at 111.1 ± 10 °C; in particular, the DSC curve of the crystalline form B has an endothermic peak at 111.1 ± 5 °C.

[0045] According to an embodiment of the present invention, the crystalline form B has one or two of the following characteristics:

[0046] (1) The crystalline form B has substantially as Figure 18 shown in the TGA curve;

[0047] (2) The crystalline form B has substantially as Figure 18 shown in the DSC curve.

[0048] The present invention also provides a crystalline form C of the semi-toluene solvate of the compound of formula (I), the X-ray powder diffraction pattern of which obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 6.80 ± 0.2°, 13.65 ± 0.2°, 16.27 ± 0.2°, 24.69 ± 0.2°, 25.65 ± 0.2°.

[0049] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at the following 2θ angles: 6.80 ± 0.2°, 13.65 ± 0.2°, 16.27 ± 0.2°, 18.92 ± 0.2°, 19.32 ± 0.2°, 21.49 ± 0.2°, 24.69 ± 0.2°, 25.65 ± 0.2°.

[0050] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at the following 2θ angles: 6.80 ± 0.2°, 7.58 ± 0.2°, 12.55 ± 0.2°, 13.65 ± 0.2°, 16.27 ± 0.2°, 18.92 ± 0.2°, 19.32 ± 0.2°, 20.39 ± 0.2°, 21.49 ± 0.2°, 24.69 ± 0.2°, 25.65 ± 0.2°.

[0051] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at the following 2θ angles: 6.80 ± 0.2°, 7.58 ± 0.2°, 8.32 ± 0.2°, 12.55 ± 0.2°, 13.65 ± 0.2°, 16.27 ± 0.2°, 17.73 ± 0.2°, 18.92 ± 0.2°, 19.32 ± 0.2°, 20.39 ± 0.2°, 21.49 ± 0.2°, 23.44 ± 0.2°, 24.69 ± 0.2°, 25.65 ± 0.2°, 28.27 ± 0.2°, 30.25 ± 0.2°.

[0052] According to an embodiment of the present invention, the 2θ diffraction angle, D value and / or relative intensity of the X-ray powder pattern of the crystalline form C obtained by Cu-Kα radiation are as shown in Table 3 below:

[0053] Table 3 XRPD diffraction peak data of crystalline form C

[0054]

[0055] According to an embodiment of the present invention, the crystalline form C has substantially as Figure 3 shown in the X-ray powder diffraction pattern.

[0056] According to an embodiment of the present invention, the crystalline form C has one, two or three of the following characteristics:

[0057] (1) The TGA curve of the crystalline form C has a weight loss of about 12.89% at 150.0 ± 3°C;

[0058] (2) The DSC curve of polymorph C has two endothermic peaks at 80.7 ± 10 °C and 160.6 ± 10 °C; in particular, the DSC curve of polymorph C has two endothermic peaks at 80.7 ± 5 °C and 160.6 ± 5 °C;

[0059] (3) Polymorph C 1 has characteristic hydrogen signals of toluene in its 1H NMR spectrum.

[0060] More specifically, the DSC curve of polymorph C has two endothermic peaks at 119.8 ± 10 °C and 155.5 ± 10 °C, and more particularly at 119.8 ± 5 °C and 155.5 ± 5 °C.

[0061] According to an embodiment of the present invention, polymorph C has one, two, or three of the following characteristics:

[0062] (1) Polymorph C has a TGA curve substantially as Figure 19 shown;

[0063] (2) Polymorph C has a DSC curve substantially as Figure 19 shown;

[0064] (3) Polymorph C has a 1H NMR spectrum substantially as Figure 32 shown 1 for 1H NMR.

[0065] The present invention also provides polymorph D of the trihydrate of the compound of formula (I), which has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern obtained using Cu-Kα radiation: 7.57 ± 0.2 °, 14.31 ± 0.2 °.

[0066] According to an embodiment of the present invention, the 2θ diffraction angle, d-value, and / or relative intensity of the X-ray powder pattern of polymorph D obtained using Cu-Kα radiation are as shown in Table 4 below:

[0067] Table 4 XRPD diffraction peak data of polymorph D

[0068]

[0069] According to an embodiment of the present invention, polymorph D has a X-ray powder diffraction pattern substantially as Figure 4 shown.

[0070] According to an embodiment of the present invention, polymorph D has one or two of the following characteristics:

[0071] (1) The TGA curve of polymorph D shows a weight loss of about 12.93% at 150.0 ± 3 °C;

[0072] (2) The DSC curve of polymorph D has two endothermic peaks at 133.3 ± 10 °C and 159.2 ± 10 °C; in particular, the DSC curve of polymorph D has two endothermic peaks at 133.3 ± 5 °C and 159.2 ± 5 °C.

[0073] More specifically, the DSC curve of polymorph D also has two endothermic peaks at 113.0 ± 10 °C and 155.3 ± 10 °C; in particular, the DSC curve of polymorph D also has two endothermic peaks at 113.0 ± 5 °C and 155.3 ± 5 °C.

[0074] According to an embodiment of the present invention, polymorph D has one or both of the following characteristics:

[0075] (1) Polymorph D has a TGA curve substantially as Figure 20 shown;

[0076] (2) Polymorph D has a DSC curve substantially as Figure 20 shown.

[0077] The present invention also provides polymorph E of the chloroform solvate of the compound of formula (I), whose X-ray powder diffraction pattern obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 7.32 ± 0.2 °, 19.44 ± 0.2 °, 22.06 ± 0.2 °, 25.25 ± 0.2 °, 29.54 ± 0.2 °.

[0078] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph E has characteristic peaks at the following 2θ angles: 7.32 ± 0.2 °, 11.72 ± 0.2 °, 14.66 ± 0.2 °, 16.53 ± 0.2 °, 19.44 ± 0.2 °.

[0079] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph E has characteristic peaks at the following 2θ angles: 7.32 ± 0.2 °, 11.72 ± 0.2 °, 14.66 ± 0.2 °, 16.09 ± 0.2 °, 16.53 ± 0.2 °, 19.44 ± 0.2 °, 20.54 ± 0.2 °, 20.81 ± 0.2 °, 22.06 ± 0.2 °, 25.25 ± 0.2 °, 29.54 ± 0.2 °.

[0080] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph E has characteristic peaks at the following 2θ angles: 7.32 ± 0.2°, 10.25 ± 0.2°, 11.72 ± 0.2°, 14.33 ± 0.2°, 14.66 ± 0.2°, 16.09 ± 0.2°, 16.53 ± 0.2°, 17.57 ± 0.2°, 18.14 ± 0.2°, 18.77 ± 0.2°, 19.44 ± 0.2°, 19.75 ± 0.2°, 20.54 ± 0.2°, 20.81 ± 0.2°, 22.06 ± 0.2°, 22.77 ± 0.2°, 23.19 ± 0.2°, 25.25 ± 0.2°, 26.04 ± 0.2°, 27.06 ± 0.2°, 27.35 ± 0.2°, 29.54 ± 0.2°, 30.41 ± 0.2°, 32.99 ± 0.2°.

[0081] According to an embodiment of the present invention, the 2θ diffraction angles, d-values and / or relative intensities of the X-ray powder pattern of polymorph E obtained using Cu-Kα radiation are as shown in Table 5 below:

[0082] Table 5 XRPD diffraction peak data of polymorph E

[0083]

[0084]

[0085] According to an embodiment of the present invention, polymorph E has an X-ray powder diffraction pattern substantially as Figure 5 shown.

[0086] According to an embodiment of the present invention, polymorph E has one, two or three of the following characteristics:

[0087] (1) The TGA curve of polymorph E shows a weight loss of approximately 3.42% at 90.0 ± 3 °C and a weight loss of approximately 19.74% at 200.0 ± 3 °C;

[0088] (2) The DSC curve of polymorph E has two endothermic peaks at 70.0 ± 10 °C and 127.2 ± 10 °C; in particular, the DSC curve of polymorph E has two endothermic peaks at 70.0 ± 5 °C and 127.2 ± 5 °C;

[0089] (3) The 1 1H NMR spectrum of polymorph E has characteristic hydrogen signals of chloroform.

[0090] According to an embodiment of the present invention, polymorph E has one, two or three of the following characteristics:

[0091] (1) Polymorph E has a TGA curve substantially as Figure 21 shown;

[0092] (2) Polymorph E has a DSC curve substantially as Figure 21 shown;

[0093] (3) Polymorph E has an Figure 33 H NMR spectrum substantially as 1 shown.

[0094] The present invention also provides polymorph G of the tetrahydrate of the compound of formula (I), which has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern obtained using Cu-Kα radiation: 7.08 ± 0.2°, 7.54 ± 0.2°, 14.15 ± 0.2°, 15.10 ± 0.2°, 18.85 ± 0.2°, 25.49 ± 0.2°, 26.06 ± 0.2°.

[0095] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the polymorph G has characteristic peaks at the following 2θ angles: 7.08 ± 0.2°, 7.54 ± 0.2°, 13.54 ± 0.2°, 14.15 ± 0.2°, 15.10 ± 0.2°, 18.85 ± 0.2°, 21.34 ± 0.2°, 22.12 ± 0.2°, 25.49 ± 0.2°, 26.06 ± 0.2°.

[0096] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the polymorph G has characteristic peaks at the following 2θ angles: 7.08 ± 0.2°, 7.54 ± 0.2°, 8.62 ± 0.2°, 11.82 ± 0.2°, 13.54 ± 0.2°, 14.15 ± 0.2°, 15.10 ± 0.2°, 16.36 ± 0.2°, 18.05 ± 0.2°, 18.85 ± 0.2°, 19.49 ± 0.2°, 20.32 ± 0.2°, 21.34 ± 0.2°, 22.12 ± 0.2°, 22.74 ± 0.2°, 25.49 ± 0.2°, 26.06 ± 0.2°, 26.93 ± 0.2°, 28.57 ± 0.2°, 31.82 ± 0.2°.

[0097] According to an embodiment of the present invention, the 2θ diffraction angle, D value and / or relative intensity of the X-ray powder pattern of the polymorph G obtained using Cu-Kα radiation are as shown in Table 6 below:

[0098] Table 6 XRPD diffraction peak data of polymorph G

[0099]

[0100]

[0101] According to an embodiment of the present invention, the crystalline form G has substantially as Figure 6 shown in the X-ray powder diffraction pattern.

[0102] According to an embodiment of the present invention, the crystalline form G shown has one, two or three of the following characteristics:

[0103] (1) The TGA curve of crystalline form G has a weight loss of about 15.06% at 150.0 ± 3 °C;

[0104] (2) The DSC curve of crystalline form G has two endothermic peaks at 74.6 ± 10 °C and 90.1 ± 10 °C; in particular, the DSC curve of crystalline form G has two endothermic peaks at 74.6 ± 5 °C and 90.1 ± 5 °C;

[0105] (3) The DVS curve of crystalline form G has a moisture adsorption of less than about 8.5%, such as less than about 8.44%, under the conditions of 0% RH to 80% RH.

[0106] According to an embodiment of the present invention, the crystalline form G has one, two or three of the following characteristics:

[0107] (1) Crystalline form G has substantially as Figure 22 shown in the TGA curve;

[0108] (2) Crystalline form G has substantially as Figure 22 shown in the DSC curve;

[0109] (3) Crystalline form G has substantially as Figure 31 shown in the DVS curve.

[0110] The present invention also provides a crystalline form H of the monohydrate of the compound of formula (I), the X-ray powder diffraction pattern of which obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.76 ± 0.2 °, 6.81 ± 0.2 °, 11.54 ± 0.2 °, 18.68 ± 0.2 °.

[0111] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at the following 2θ angles: 5.76 ± 0.2 °, 6.81 ± 0.2 °, 7.95 ± 0.2 °, 8.74 ± 0.2 °, 11.54 ± 0.2 °, 13.86 ± 0.2 °, 18.68 ± 0.2 °, 19.90 ± 0.2 °.

[0112] According to an embodiment of the present invention, the 2θ diffraction angle, d-value and / or relative intensity of the X-ray powder pattern of the crystalline form H obtained using Cu-Kα radiation are as shown in Table 7 below:

[0113] Table 7 XRPD diffraction peak data of crystalline form H

[0114]

[0115] According to an embodiment of the present invention, the crystalline form H has an X-ray powder diffraction pattern substantially as Figure 7 shown.

[0116] According to an embodiment of the present invention, the crystalline form H has one or both of the following characteristics:

[0117] (1) The TGA curve of the crystalline form H shows a weight loss of about 3.62% at 150.0 ± 3 °C;

[0118] (2) The DSC curve of the crystalline form H has two endothermic peaks at 72.5 ± 10 °C and 112.8 ± 10 °C; in particular, the DSC curve of the crystalline form H has two endothermic peaks at 72.5 ± 5 °C and 112.8 ± 5 °C.

[0119] According to an embodiment of the present invention, the crystalline form H has one or both of the following characteristics:

[0120] (1) The crystalline form H has a TGA curve substantially as Figure 23 shown;

[0121] (2) The crystalline form H has a DSC curve substantially as Figure 23 shown.

[0122] The present invention also provides a crystalline form J-1 of a hemi-2-methyltetrahydrofuran complex of the compound of formula (I), the X-ray powder diffraction pattern of which obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 4.43 ± 0.2 °, 8.73 ± 0.2 °, 11.53 ± 0.2 °, 15.72 ± 0.2 °.

[0123] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form J-1 has characteristic peaks at the following 2θ angles: 4.43 ± 0.2 °, 8.73 ± 0.2 °, 11.53 ± 0.2 °, 15.72 ± 0.2 °, 20.13 ± 0.2 °, 21.93 ± 0.2 °, 23.99 ± 0.2 °.

[0124] According to an embodiment of the present invention, the 2θ diffraction angle, D value and / or relative intensity of the X-ray powder pattern of the crystalline form J-1 obtained using Cu-Kα radiation are as shown in Table 8-1 below:

[0125] Table 8-1 XRPD diffraction peak data of crystalline form J-1

[0126]

[0127] According to an embodiment of the present invention, the crystalline form J-1 has a substantially as Figure 8-1The X-ray powder diffraction pattern shown

[0128] According to an embodiment of the present invention, the crystalline form J-1 has one or both of the following characteristics:

[0129] (1) The TGA curve of crystalline form J-1 has a weight loss of about 7.91% at 150.0 ± 3 °C;

[0130] (2) The DSC curve of crystalline form J-1 has two endothermic peaks at 96.6 ± 3 °C and 157.6 ± 3 °C.

[0131] More specifically, the DSC curve of crystalline form J-1 also has an endothermic peak at 151.3 ± 3 °C.

[0132] According to an embodiment of the present invention, the crystalline form J-1 has one or both of the following characteristics:

[0133] (1) Crystalline form J-1 has a TGA curve substantially as Figure 24-1 shown;

[0134] (2) Crystalline form J-1 has a DSC curve substantially as Figure 24-1 shown.

[0135] The present invention also provides crystalline form J-2 of the monomethyl isobutyl ketone complex of the compound of formula (I), the X-ray powder diffraction pattern of which obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 4.31 ± 0.2 °, 8.56 ± 0.2 °, 11.32 ± 0.2 °, 15.44 ± 0.2 °, 19.64 ± 0.2 °.

[0136] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form J-2 has characteristic peaks at the following 2θ angles: 4.31 ± 0.2 °, 8.56 ± 0.2 °, 11.32 ± 0.2 °, 15.44 ± 0.2 °, 19.64 ± 0.2 °, 21.80 ± 0.2 °, 23.90 ± 0.2 °.

[0137] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form J-2 has characteristic peaks at the following 2θ angles: 4.31 ± 0.2 °, 8.56 ± 0.2 °, 11.32 ± 0.2 °, 14.84 ± 0.2 °, 15.44 ± 0.2 °, 16.46 ± 0.2 °, 17.15 ± 0.2 °, 19.64 ± 0.2 °, 21.80 ± 0.2, 23.42 ± 0.2 °, 23.90 ± 0.2 °, 24.24 ± 0.2 °.

[0138] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph J-2 obtained using Cu-Kα radiation has 2θ diffraction angles, d-values, and / or relative intensities as shown in Table 8-2 below:

[0139] Table 8-2 XRPD Diffraction Peak Data of Polymorph J-2

[0140]

[0141]

[0142] According to an embodiment of the present invention, polymorph J-2 has an X-ray powder diffraction pattern substantially as Figure 8-2 shown.

[0143] According to an embodiment of the present invention, polymorph J-2 has one or both of the following characteristics:

[0144] (1) The TGA curve of polymorph J-2 shows a weight loss of approximately 19.07% at 150.0 ± 3 °C;

[0145] (2) The DSC curve of polymorph J-2 has an endothermic peak at 94.3 ± 3 °C.

[0146] According to an embodiment of the present invention, polymorph J-2 has one or both of the following characteristics:

[0147] (1) Polymorph J-2 has a TGA curve substantially as Figure 24-2 shown;

[0148] (2) Polymorph J-2 has a DSC curve substantially as Figure 24-2 shown.

[0149] The present invention provides polymorph K of the dihydrate of the compound of formula (I), the X-ray powder diffraction pattern of which obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 6.93 ± 0.2 °, 13.89 ± 0.2 °, 14.81 ± 0.2 °, 20.91 ± 0.2 °, 25.00 ± 0.2 °, 25.72 ± 0.2 °.

[0150] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph K has characteristic peaks at the following 2θ angles: 6.93 ± 0.2 °, 13.89 ± 0.2 °, 14.81 ± 0.2 °, 18.77 ± 0.2 °, 20.91 ± 0.2 °, 25.00 ± 0.2 °, 25.72 ± 0.2 °, 28.04 ± 0.2 °.

[0151] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph K has characteristic peaks at the following 2θ angles: 6.93±0.2°, 11.49±0.2°, 13.89±0.2°, 14.81±0.2°, 18.77±0.2°, 20.05±0.2°, 20.91±0.2°, 21.87±0.2°, 25.00±0.2°, 25.72±0.2°, 28.04±0.2°.

[0152] According to an embodiment of the present invention, the 2θ diffraction angles, d-values and / or relative intensities of the X-ray powder pattern of polymorph K obtained using Cu-Kα radiation are as shown in Table 9 below:

[0153] Table 9 XRPD diffraction peak data of polymorph K

[0154]

[0155] According to an embodiment of the present invention, polymorph K has an X-ray powder diffraction pattern substantially as Figure 9 shown.

[0156] According to an embodiment of the present invention, polymorph K has one, two or three of the following characteristics:

[0157] (1) The TGA curve of polymorph K shows a weight loss of about 10.13% at 150.0±3°C;

[0158] (2) The DSC curve of polymorph K has a starting point of an endothermic peak at 104.5±3°C;

[0159] (3) The DSC curve of polymorph K has an endothermic peak at 110.7±3°C.

[0160] According to an embodiment of the present invention, polymorph K has one or two of the following characteristics:

[0161] (1) Polymorph K has a TGA curve substantially as Figure 25 shown;

[0162] (2) Polymorph K has a DSC curve substantially as Figure 25 shown.

[0163] The present invention also provides polymorph L of the compound of formula (I), the X-ray powder diffraction pattern of which obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 6.07±0.2°, 7.01±0.2°, 7.48±0.2°, 14.05±0.2°, 19.44±0.2°, 21.73±0.2°.

[0164] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form L has characteristic peaks at the following 2θ angles: 6.07±0.2°, 7.01±0.2°, 7.48±0.2°, 9.16±0.2°, 12.13±0.2°, 14.05±0.2°, 14.44±0.2°, 16.49±0.2°, 19.44±0.2°, 21.73±0.2°.

[0165] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form L has characteristic peaks at the following 2θ angles: 6.07±0.2°, 7.01±0.2°, 7.48±0.2°, 9.16±0.2°, 10.22±0.2°, 11.41±0.2°, 12.13±0.2°, 14.05±0.2°, 14.44±0.2°, 16.49±0.2°, 18.32±0.2°, 19.44±0.2°, 21.73±0.2°.

[0166] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form L has characteristic peaks at the following 2θ angles: 6.07±0.2°, 7.01±0.2°, 7.48±0.2°, 8.19±0.2°, 9.16±0.2°, 10.22±0.2°, 11.41±0.2°, 12.13±0.2°, 14.05±0.2°, 14.44±0.2°, 16.49±0.2°, 18.32±0.2°, 19.44±0.2°, 20.55±0.2°, 21.73±0.2°, 24.21±0.2°, 25.54±0.2°.

[0167] According to an embodiment of the present invention, the 2θ diffraction angle, D value and / or relative intensity of the X-ray powder pattern of the crystalline form L obtained using Cu-Kα radiation are as shown in Table 10 below:

[0168] Table 10 XRPD diffraction peak data of crystalline form L

[0169]

[0170] According to an embodiment of the present invention, the crystalline form L has substantially as Figure 10 shown in the X-ray powder diffraction pattern.

[0171] According to an embodiment of the present invention, the crystalline form L has one, two or three of the following characteristics:

[0172] (1) The TGA curve of the crystalline form L shows a weight loss of about 3.00% at 150.0±3°C;

[0173] (2) The DSC curve of polymorph L has an endothermic peak at 114.6 ± 10 °C; in particular, the DSC curve of polymorph L has an endothermic peak at 114.6 ± 5 °C;

[0174] (3) The DSC curve of polymorph L has endothermic peaks at 62.3 ± 10 °C, in particular at 62.3 ± 5 °C.

[0175] According to an embodiment of the present invention, polymorph L has one or two of the following characteristics:

[0176] (1) Polymorph L has a TGA curve substantially as Figure 26 shown;

[0177] (2) Polymorph L has a DSC curve substantially as Figure 26 shown.

[0178] The present invention also provides polymorph M-1 of the monohydrate of the compound of formula (I), which has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern obtained using Cu-Kα radiation: 5.02 ± 0.2 °, 7.45 ± 0.2 °, 7.96 ± 0.2 °, 8.63 ± 0.2 °, 10.05 ± 0.2 °, 15.97 ± 0.2 °.

[0179] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph M-1 has characteristic peaks at the following 2θ angles: 5.02 ± 0.2 °, 7.45 ± 0.2 °, 7.96 ± 0.2 °, 8.63 ± 0.2 °, 9.42 ± 0.2 °, 10.05 ± 0.2 °, 12.25 ± 0.2 °, 15.97 ± 0.2 °, 21.60 ± 0.2 °.

[0180] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph M-1 has characteristic peaks at the following 2θ angles: 5.02 ± 0.2 °, 7.45 ± 0.2 °, 7.96 ± 0.2 °, 8.63 ± 0.2 °, 9.42 ± 0.2 °, 10.05 ± 0.2 °, 12.25 ± 0.2 °, 13.31 ± 0.2 °, 14.16 ± 0.2 °, 15.97 ± 0.2 °, 18.96 ± 0.2 °, 20.02 ± 0.2 °, 21.60 ± 0.2 °.

[0181] According to an embodiment of the present invention, the 2θ diffraction angle, D value and / or relative intensity of the X-ray powder pattern of polymorph M-1 obtained using Cu-Kα radiation are as shown in Table 11-1 below:

[0182] Table 11-1 XRPD diffraction peak data of polymorph M-1

[0183]

[0184]

[0185] According to an embodiment of the present invention, the crystalline form M-1 has an X-ray powder diffraction pattern substantially as Figure 11-1 shown.

[0186] According to an embodiment of the present invention, the crystalline form M-1 has one or both of the following characteristics:

[0187] (1) The TGA curve of the crystalline form M-1 shows a weight loss of about 4.31% at 150.0 ± 3 °C;

[0188] (2) The DSC curve of the crystalline form M-1 has two endothermic peaks at 77.7 ± 3 °C and 96.5 ± 3 °C.

[0189] According to an embodiment of the present invention, the crystalline form M-1 has one or both of the following characteristics:

[0190] (1) The crystalline form M-1 has a TGA curve substantially as Figure 27-1 shown;

[0191] (2) The crystalline form M-1 has a DSC curve substantially as Figure 27-1 shown.

[0192] The present invention also provides a crystalline form M-2 of the monoacetonitrile complex of the compound of formula (I), the X-ray powder diffraction pattern of which obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.01 ± 0.2 °, 7.10 ± 0.2 °, 7.45 ± 0.2 °, 7.96 ± 0.2 °, 8.63 ± 0.2 °, 9.41 ± 0.2 °, 15.94 ± 0.2 °, 21.57 ± 0.2 °, 23.51 ± 0.2 °.

[0193] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form M-2 has characteristic peaks at the following 2θ angles: 5.01 ± 0.2 °, 7.10 ± 0.2 °, 7.45 ± 0.2 °, 7.96 ± 0.2 °, 8.63 ± 0.2 °, 9.41 ± 0.2 °, 15.94 ± 0.2 °, 19.66 ± 0.2 °, 21.57 ± 0.2 °, 23.51 ± 0.2 °, 24.30 ± 0.2 °, 25.22 ± 0.2 °.

[0194] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form M-2 has characteristic peaks at the following 2θ angles: 5.01 ± 0.2°, 7.10 ± 0.2°, 7.45 ± 0.2°, 7.96 ± 0.2°, 8.63 ± 0.2°, 9.41 ± 0.2°, 9.99 ± 0.2°, 15.94 ± 0.2°, 17.29 ± 0.2°, 19.66 ± 0.2°, 21.57 ± 0.2°, 22.48 ± 0.2°, 23.51 ± 0.2°, 24.30 ± 0.2°, 25.22 ± 0.2°, 27.14 ± 0.2°.

[0195] According to an embodiment of the present invention, the 2θ diffraction angle, D value, and / or relative intensity of the X-ray powder pattern of the crystalline form M-2 obtained using Cu-Kα radiation are as shown in Table 11-2 below:

[0196] Table 11-2 XRPD diffraction peak data of crystalline form M-2

[0197]

[0198]

[0199] According to an embodiment of the present invention, the crystalline form M-2 has substantially as Figure 11-2 shown in the X-ray powder diffraction pattern.

[0200] According to an embodiment of the present invention, the crystalline form M-2 has one or both of the following characteristics:

[0201] (1) The TGA curve of the crystalline form M-2 shows a weight loss of approximately 8.36% at 150.0 ± 3°C;

[0202] (2) The DSC curve of the crystalline form M-2 has an endothermic peak at 124.6 ± 10°C; in particular, the DSC curve of the crystalline form M-2 has an endothermic peak at 124.6 ± 5°C.

[0203] According to an embodiment of the present invention, the crystalline form M-2 has one or both of the following characteristics:

[0204] (1) The crystalline form M-2 has substantially as Figure 27-2 shown in the TGA curve;

[0205] (2) The crystalline form M-2 has substantially as Figure 27-2 shown in the DSC curve.

[0206] The present invention also provides a crystalline form N of a dichloromethane solvate of a compound of formula (I), and its X-ray powder diffraction pattern obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 7.07 ± 0.2°, 7.21 ± 0.2°, 14.41 ± 0.2°, 19.46 ± 0.2°, 21.30 ± 0.2°, 21.93 ± 0.2°, 25.37 ± 0.2°.

[0207] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form N has characteristic peaks at the following 2θ angles: 7.07 ± 0.2°, 7.21 ± 0.2°, 14.41 ± 0.2°, 19.46 ± 0.2°, 20.28 ± 0.2°, 21.30 ± 0.2°, 21.93 ± 0.2°, 25.37 ± 0.2°, 26.04 ± 0.2°.

[0208] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form N has characteristic peaks at the following 2θ angles: 7.07 ± 0.2°, 7.21 ± 0.2°, 14.41 ± 0.2°, 16.33 ± 0.2°, 19.46 ± 0.2°, 19.73 ± 0.2°, 20.28 ± 0.2°, 20.82 ± 0.2°, 21.30 ± 0.2°, 21.93 ± 0.2°, 25.37 ± 0.2°, 26.04 ± 0.2°.

[0209] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form N has characteristic peaks at the following 2θ angles: 7.07 ± 0.2°, 7.21 ± 0.2°, 10.08 ± 0.2°, 13.75 ± 0.2°, 14.41 ± 0.2°, 14.41 ± 0.2°, 15.06 ± 0.2°, 16.33 ± 0.2°, 19.46 ± 0.2°, 19.73 ± 0.2°, 20.28 ± 0.2°, 20.82 ± 0.2°, 21.30 ± 0.2°, 21.93 ± 0.2°, 25.37 ± 0.2°, 26.04 ± 0.2°, 27.33 ± 0.2°, 28.53 ± 0.2°, 29.39 ± 0.2°.

[0210] According to an embodiment of the present invention, the 2θ diffraction angles, d values, and / or relative intensities of the X-ray powder pattern of the crystalline form N obtained using Cu-Kα radiation are as shown in Table 12 below:

[0211] Table 12 XRPD diffraction peak data of crystalline form N

[0212]

[0213]

[0214] According to an embodiment of the present invention, the crystalline form N has substantially as Figure 12 shown in the X-ray powder diffraction pattern.

[0215] According to an embodiment of the present invention, the crystalline form N has one, two, three or four of the following characteristics:

[0216] (1) The TGA curve of the crystalline form N shows a weight loss of about 2.98% at 90.0 ± 3 °C and a weight loss of about 13.10% at 150.0 ± 3 °C;

[0217] (2) The DSC curve of the crystalline form N has a starting point of an endothermic peak at 107.5 ± 3 °C;

[0218] (3) The DSC curve of the crystalline form N has an endothermic peak at 118.9 ± 10 °C; In particular, the DSC curve of the crystalline form N has an endothermic peak at 118.9 ± 5 °C;

[0219] (4) The 1 1H NMR spectrum of the crystalline form N has characteristic hydrogen signals of dichloromethane.

[0220] More specifically, the DSC curve of the crystalline form N also has an endothermic peak at 69.9 ± 10 °C, especially at 69.9 ± 5 °C.

[0221] According to an embodiment of the present invention, the crystalline form N has one, two or three of the following characteristics:

[0222] (1) The crystalline form N has a TGA curve substantially as Figure 28 shown;

[0223] (2) The crystalline form N has a DSC curve substantially as Figure 28 shown;

[0224] (3) The crystalline form N has a Figure 34 1H NMR spectrum substantially as 1 shown.

[0225] The present invention also provides a crystalline form P of an isopropanol solvate of the compound of formula (I), and its X-ray powder diffraction pattern obtained by using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 7.13 ± 0.2 °, 9.63 ± 0.2 °, 14.43 ± 0.2 °, 19.12 ± 0.2 °, 21.03 ± 0.2 °, 21.53 ± 0.2 °, 25.46 ± 0.2 °, 25.91 ± 0.2 °.

[0226] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph P has characteristic peaks at the following 2θ angles: 7.13±0.2°, 9.63±0.2°, 11.69±0.2°, 13.59±0.2°, 14.43±0.2°, 19.12±0.2°, 20.55±0.2°, 21.03±0.2°, 21.53±0.2°, 25.46±0.2°, 25.91±0.2°, 27.03±0.2°.

[0227] According to an embodiment of the present invention, the X-ray powder diffraction pattern of polymorph P has characteristic peaks at the following 2θ angles: 7.13±0.2°, 9.63±0.2°, 11.69±0.2°, 13.59±0.2°, 14.43±0.2°, 15.18±0.2°, 16.35±0.2°, 17.75±0.2°, 19.12±0.2°, 20.55±0.2°, 21.03±0.2°, 21.53±0.2°, 23.46±0.2°, 25.46±0.2°, 25.91±0.2°, 27.03±0.2°, 28.89±0.2°.

[0228] According to an embodiment of the present invention, the 2θ diffraction angles, D values, and relative intensities of the X-ray powder pattern of polymorph P obtained using Cu-Kα radiation are shown in Table 13 below:

[0229] Table 13 XRPD diffraction peak data of polymorph P

[0230]

[0231]

[0232] According to an embodiment of the present invention, polymorph P has an X-ray powder diffraction pattern substantially as Figure 13 shown.

[0233] According to an embodiment of the present invention, polymorph P has one, two, or three of the following characteristics:

[0234] (1) The TGA curve of polymorph P shows a weight loss of approximately 10.85% at 150.0±3°C;

[0235] (2) The DSC curve of polymorph P has two endothermic peaks at 66.4±10°C and 103.1±10°C; in particular, the DSC curve of polymorph P has two endothermic peaks at 66.4±5°C and 103.1±5°C;

[0236] (3) The 1 1H NMR spectrum of polymorph P has characteristic hydrogen signals of isopropanol.

[0237] More specifically, the DSC curve of crystalline form P has another endothermic peak at 100.0 ± 10 °C, especially at 100.0 ± 5 °C.

[0238] According to an embodiment of the present invention, crystalline form P has one, two or three of the following characteristics:

[0239] (1) Crystalline form P has a TGA curve substantially as Figure 29 shown;

[0240] (2) Crystalline form P has a DSC curve substantially as Figure 29 shown;

[0241] (3) Crystalline form P has an Figure 35 H NMR spectrum substantially as 1 shown.

[0242] The present invention also provides an amorphous form of the compound of formula (I), which has an X-ray powder diffraction pattern substantially as Figure 14 shown.

[0243] The present invention also provides a pharmaceutical composition, which comprises a solid form of the compound of formula (I) or its solvate, or a mixture of any two or more thereof.

[0244] According to an embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient, such as a carrier or an excipient.

[0245] According to an embodiment of the present invention, in the pharmaceutical composition, a solid form of the compound of formula (I) or its solvate, or a mixture of any two or more thereof is present in a therapeutically effective amount.

[0246] The present invention also provides the use of a solid form of the compound of formula (I) or its solvate, or a mixture of any two or more thereof for the preparation of a drug, wherein the drug is used for the treatment and / or prevention of diseases related to autotaxin ATX.

[0247] The present invention also provides a method for the treatment and / or prevention of diseases related to autotaxin ATX, comprising administering to a patient in need a therapeutically effective amount of a solid form of the compound of formula (I) or its solvate, or a mixture of any two or more thereof, or the pharmaceutical composition.

[0248] The present invention also provides a solid form of the compound of formula (I) or its solvate, or a mixture of any two or more thereof, which is used for the treatment and / or prevention of diseases related to autotaxin ATX.

[0249] According to an embodiment of the present invention, the ATX-related diseases include at least one selected from the following: cancer, metabolic diseases, kidney diseases, liver diseases, fibrotic diseases, interstitial lung diseases, proliferative diseases, inflammatory diseases, pain, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and / or abnormal angiogenesis-related diseases.

[0250] According to an embodiment of the present invention, the ATX-related diseases include at least one selected from the following: interstitial lung diseases, pulmonary fibrosis, liver fibrosis, and kidney fibrosis.

[0251] According to an embodiment of the present invention, the ATX-related diseases include idiopathic pulmonary fibrosis.

[0252] According to an embodiment of the present invention, the ATX-related diseases include type II diabetes and non-alcoholic steatohepatitis.

[0253] According to an embodiment of the present invention, the ATX-related diseases include neuropathic pain and inflammatory pain.

[0254] According to an embodiment of the present invention, the ATX-related diseases include pain associated with osteoarthritis.

[0255] When used as a drug, the solid form of the present invention can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by various routes, depending on whether local or systemic treatment is required and the area being treated. They can be administered locally (e.g., transdermal, cutaneous, ocular, and mucosal including intranasal, vaginal, and rectal delivery), by the pulmonary route (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), orally, or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial administration such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single large dose, or can be administered, for example, by a continuous perfusion pump. Medicinal compositions and preparations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, water, powder or oily matrices, thickening agents, etc. may be necessary or required.

[0256] In preparing the compositions of the present invention, the active ingredient (i.e., the solid form of the present invention) is usually admixed with excipients and diluted or enclosed within such carriers as capsules, cachets, papers, or other containers. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid substance, serving as a solvent, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, cachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid solvent); ointments containing, for example, up to 10% by weight of the active ingredient, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0257] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations may also contain: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweetening and flavoring agents. The compositions of the present invention can be formulated by methods known in the art so as to provide a rapid, sustained or delayed release of the active ingredient upon administration to a patient.

[0258] The compositions can be formulated in unit dosage form, each dosage containing about 5 to 1200 mg, more usually about 50 to 800 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as a single dosage for human patients and other mammals, each unit containing a predetermined quantity of the active ingredient calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0259] The effective dosage range of the active ingredient can be relatively wide and is usually administered in a pharmaceutically effective amount. However, it is understood that the actual amount administered will generally be determined by the physician in view of the relevant circumstances, which include the condition being treated and / or prevented, the route of administration selected, the actual active ingredient being administered; the age, weight and response of the individual patient; the severity of the patient's symptoms, etc.

[0260] For preparing solid compositions such as tablets, the principal active ingredient is admixed with the pharmaceutical excipients to form a solid preformulation composition which is a homogeneous mixture containing the active ingredient of the present invention. When these preformulation compositions are said to be homogeneous, it means that the active ingredient is generally uniformly distributed throughout the composition so that the composition can be readily divided into equally effective unit dosage forms such as tablets, pills and capsules. Then the solid preformulation is divided into unit dosage forms of the above type containing, for example, about 0.1 to 1000 mg of the active ingredient of the present invention.

[0261] The tablets or pills of the present invention can be coated or compounded to obtain a dosage form with the advantage of long-acting effect. For example, the tablets or pills contain an inner dose and an outer dose component, and the latter is in the form of a coating for the former. The two components can be separated by an enteric layer, which is used to prevent disintegration in the stomach so that the inner component can pass through the duodenum intact or be released in a delayed manner. A variety of substances can be used for such enteric layers or coating agents, and such substances include a variety of high molecular acids and mixtures of high molecular acids with such substances as shellac, cetyl alcohol, and cellulose acetate.

[0262] The solid forms and compositions of the present invention can be incorporated therein. The liquid forms for oral or injectable administration include aqueous solutions, properly flavored syrups, aqueous or oily suspensions; and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil; as well as elixirs and similar pharmaceutical solvents.

[0263] The compositions for inhalation or insufflation include solutions and suspensions, powders dissolved in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the compositions are administered by the oral or nasal inhalation route to achieve local or systemic effects. The compositions can be atomized by using an inert gas. The atomized solution can be directly inhaled by an atomizing device, or the atomizing device can be connected to a face mask or an intermittent positive pressure ventilator. The solution, suspension, or powder composition can be administered orally or nasally by a device that delivers the preparation in an appropriate manner.

[0264] The amount of the solid form or composition administered to a patient is not fixed and depends on the drug administered, the purpose of administration such as prevention or treatment; the condition of the patient, the mode of administration, etc. In therapeutic applications, a patient suffering from a disease can be administered an amount of the composition sufficient to cure or at least partially inhibit the symptoms of the disease and its complications. The effective dose should depend on the disease state being treated and the judgment of the attending clinician, which depends on factors such as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0265] The composition administered to a patient can be in the form of the above-mentioned pharmaceutical compositions. These compositions can be sterilized by conventional sterilization techniques or can be filter-sterilized. The aqueous solutions can be packaged and used as such, or lyophilized, and before administration, the lyophilized preparation is mixed with a sterile aqueous carrier. The pH of the compound preparation is generally 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It can be understood that the use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of drug salts.

[0266] The therapeutic dose of the solid forms of the present invention can depend on, for example, the specific use of the treatment, the way of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the solid forms of the present invention in the pharmaceutical composition may not be fixed and depends on various factors, including the dose, chemical properties (such as hydrophobicity), and the route of administration. For example, the compounds of the present invention can be provided for parenteral administration through a physiological buffer aqueous solution containing about 0.1 - 10% w / v of the compound. Some typical dose ranges are about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg body weight per day. The dose is likely to depend on such variables as the type and progression of the disease or disorder, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and its route of administration. The effective dose can be extrapolated from the dose - response curve derived from in vitro or animal model test systems.

[0267] Term Definitions and Explanations

[0268] Unless otherwise specified, the definitions of the groups and terms recited in the specification and claims of this application, including their definitions by way of example, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination should fall within the scope described in the specification of this application.

[0269] Unless otherwise specified, the numerical ranges recited in this specification and claims are equivalent to at least recording each specific integer value therein. For example, two or more represent 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. When certain numerical ranges are defined or understood as "numbers", it should be understood that the two endpoints of the range, each integer within the range, and each decimal within the range are recorded. For example, "numbers from 0 to 10" should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least recording the sum of each integer respectively with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.

[0270] When this specification and claims record "about" a certain numerical value, it includes the numerical value itself, as well as the numerical values within the range before and after the numerical value acceptable in the art. For example, the numerical values within the range of ±15% of the numerical value, the numerical values within the range of ±10% of the numerical value, the numerical values within the range of ±5% of the numerical value, etc. For example, about 10 represents including: the numerical values within the range of 10 ± 1.5, that is, within the range of 8.5 - 11.5; the numerical values within the range of 10 ± 1.0, that is, within the range of 9.0 - 11.0; and the numerical values within the range of 10 ± 0.5, that is, within the range of 9.5 - 10.5.

[0271] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0272] The term "therapeutically effective amount" refers to the amount of an active compound or drug that a researcher, veterinarian, physician or other clinician is seeking in an organization, system, animal, individual or human to elicit a biological or medical response, and it includes one or more of the following: (1) preventing a disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or exhibited the pathology or symptoms of the disease; (2) inhibiting a disease: for example, inhibiting a disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition (i.e., preventing the further development of the pathology and / or symptoms); (3) alleviating a disease: for example, alleviating a disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms).

[0273] The term "pharmaceutically acceptable" means that the prescription component or active ingredient does not have an excessive harmful effect on the health of the general therapeutic target.

[0274] The term "pharmaceutically acceptable excipient or carrier" means one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the pharmacological efficacy of the compounds. Some examples of pharmaceutically acceptable excipients or carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers, wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0275] Beneficial effects

[0276] The solid form of the compound of formula (I) or its solvate of the present invention has good solubility, stability and hygroscopicity, and thus has good storage, weighing and drug-forming properties. Moreover, the solid form also has excellent pharmacological activity. Brief description of the drawings

[0277] Figure 1 Shows the XRPD pattern of crystalline form A (instrument 1);

[0278] Figure 2Shows the XRPD pattern of Polymorph B (Instrument 2);

[0279] Figure 3 Shows the XRPD pattern of Polymorph C (Instrument 3);

[0280] Figure 4 Shows the XRPD pattern of Polymorph D (Instrument 2);

[0281] Figure 5 Shows the XRPD pattern of Polymorph E (Instrument 3);

[0282] Figure 6 Shows the XRPD pattern of Polymorph G (Instrument 2);

[0283] Figure 7 Shows the XRPD pattern of Polymorph H (Instrument 2);

[0284] Figure 8-1 Shows the XRPD pattern of Polymorph J-1 (Instrument 2);

[0285] Figure 8-2 Shows the XRPD pattern of Polymorph J-2 (Instrument 2);

[0286] Figure 9 Shows the XRPD pattern of Polymorph K (Instrument 1);

[0287] Figure 10 Shows the XRPD pattern of Polymorph L (Instrument 3);

[0288] Figure 11-1 Shows the XRPD pattern of Polymorph M-1 (Instrument 2);

[0289] Figure 11-2 Shows the XRPD pattern of Polymorph M-2 (Instrument 2);

[0290] Figure 12 Shows the XRPD pattern of Polymorph N (Instrument 3);

[0291] Figure 13 Shows the XRPD pattern of Polymorph P (Instrument 2);

[0292] Figure 14 Shows the XRPD pattern of the amorphous form (Instrument 2);

[0293] Figure 15 Shows the diagram of the interconversion relationship of polymorphs;

[0294] Figure 16 Shows the XRPD overlay of the stability evaluation sample of Polymorph A (Instrument 2);

[0295] Figure 17Shows the TGA and DSC spectra of polymorph A;

[0296] Figure 18 Shows the TGA and DSC spectra of polymorph B;

[0297] Figure 19 Shows the TGA and DSC spectra of polymorph C;

[0298] Figure 20 Shows the TGA and DSC spectra of polymorph D;

[0299] Figure 21 Shows the TGA and DSC spectra of polymorph E;

[0300] Figure 22 Shows the TGA and DSC spectra of polymorph G;

[0301] Figure 23 Shows the TGA and DSC spectra of polymorph H;

[0302] Figure 24-1 Shows the TGA and DSC spectra of polymorph J-1;

[0303] Figure 24-2 Shows the TGA and DSC spectra of polymorph J-2;

[0304] Figure 25 Shows the TGA and DSC spectra of polymorph L;

[0305] Figure 26 Shows the TGA and DSC spectra of polymorph K;

[0306] Figure 27-1 Shows the TGA and DSC spectra of polymorph M-1;

[0307] Figure 27-2 Shows the TGA and DSC spectra of polymorph M-2;

[0308] Figure 28 Shows the TGA and DSC spectra of polymorph N;

[0309] Figure 29 Shows the TGA and DSC spectra of polymorph P;

[0310] Figure 30 Shows the DVS spectrum of polymorph A;

[0311] Figure 31 Shows the DVS spectrum of polymorph G;

[0312] Figure 32 Shows the NMR spectrum of polymorph C;

[0313] Figure 33The NMR spectrum of crystalline form E is shown;

[0314] Figure 34 The NMR spectrum of crystalline form N is shown;

[0315] Figure 35 The NMR spectrum of crystalline form P is shown;

[0316] Figure 36 The weight change curve of the animal after administration in Test Example 7 according to the present invention is shown;

[0317] Figure 37 The content change diagram of TGF-β1 in lung tissue and bronchoalveolar lavage fluid after administration in Test Example 7 according to the present invention is shown. Detailed Description of the Invention

[0318] The crystalline forms of the present invention, their preparation methods and applications will be further described in detail below with reference to specific examples. The following examples are only illustrative of and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0319] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

[0320] Detection Instruments and Methods for Crystalline Forms

[0321] 1. X-ray Powder Diffraction (XRPD)

[0322] The XRPD pattern was collected on an X-ray powder diffractometer produced by PANalytacal, and the scanning parameters are shown in Table 14-1 below:

[0323] Table 14-1

[0324]

[0325] 2. Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC)

[0326] The TGA and DSC patterns were collected on a TA Q5000 / 5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter respectively, and the test parameters are listed in Table 14-2 below.

[0327] Table 14-2

[0328]

[0329] 3. Solution Nuclear Magnetic Resonance (Solution NMR):

[0330] The liquid nuclear magnetic spectrum was collected on a Bruker 400M nuclear magnetic resonance instrument, with DMSO-d6 as the solvent.

[0331] 4. High Performance Liquid Chromatography (HPLC):

[0332] In the experiment, purity test, solubility and stability test were performed using an Agilent 1260 high performance liquid chromatograph, and the analysis conditions are shown in Table 14-3 below:

[0333] Table 14-3

[0334]

[0335] 5. Dynamic Vapor Sorption (DVS):

[0336] The dynamic vapor sorption (DVS) curve was collected on a DVSIntrinsic of SMS (Surface Measurement Systems). The relative humidity at 25 °C was calibrated using the deliquescence points of LiCl, Mg(NO 3 ) 2 and KCl. The DVS test parameters are listed in Table 14-4 below:

[0337] Table 14-4

[0338]

[0339] 6. Polarizing Microscope (PLM)

[0340] The polarizing microscopy data was collected at room temperature using an Axio Lab.A1 upright microscope.

[0341] 7. High Performance Liquid Chromatography / Ion Chromatography (HPLC / IC):

[0342] In the experiment, purity test, dynamic solubility and stability test were performed using an Agilent 1260 high performance liquid chromatograph, and the molar ratio of ion salt formation was tested using ion chromatography. The analysis conditions are shown in Table 14-5 and Table 14-6 below:

[0343] Table 14-5 HPLC Test Conditions

[0344]

[0345] Table 14-6 Ion Chromatography Test Conditions

[0346]

[0347] Example 1: Preparation of the Compound of Formula (I)

[0348] (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl))ethan-1-one (Target Compound I)

[0349]

[0350] Step 1: Synthesis of (R)-5-(trimethylsilyl)pent-4-yn-2-ol (5A)

[0351]

[0352] Add trimethylsilylacetylene (51.7 g) and diethyl ether (600 mL) into a three-necked flask. Under nitrogen protection, cool to -78 °C, and slowly add n-butyllithium (2.5 M, 217 mL). After the addition, keep the temperature at -78 °C and react for 1 hour. Then add boron trifluoride tetrahydrofuran (50%, 30 mL) solution, and slowly add (R)-propylene oxide (30 g). After the addition, stir at the same temperature for 1 hour, and then add saturated sodium bicarbonate aqueous solution (300 mL) to quench the reaction. After warming to room temperature, separate the layers. The organic layer is dried, mixed with silica gel, and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain the light yellow liquid compound (R)-5-(trimethylsilyl)pent-4-yn-2-ol (5A) with a yield of 42.1% (34 g).

[0353] Step 2: Synthesis of tert-butyl (R)-2-((5-(trimethylsilyl)pent-4-yn-2-yl)oxy)acetate (5B)

[0354]

[0355] Add the raw material (R)-5-(trimethylsilyl)pent-4-yn-2-ol (34 g, 218 mmol) into 340 mL of dry tetrahydrofuran. Cool to 0 °C, add 60% NaH (10.44 g, 261 mmol), and stir for 30 minutes. Then add the raw material tert-butyl 2-bromoacetate (46.7 g, 239 mmol) at 0 °C, and let it warm to room temperature naturally and stir for 16 hours. Add methanol (20 mL) to the reaction solution at 0 °C, mix with silica gel, concentrate, and purify by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain the light yellow liquid compound tert-butyl (R)-2-((5-(trimethylsilyl)pent-4-yn-2-yl)oxy)acetate (5B) with a yield of 85% (50 g).

[0356] Step 3: Synthesis of tert-butyl (R)-2-(pent-4-yn-2-yloxy)acetate (5C)

[0357]

[0358] At room temperature, the raw material tert-butyl (R)-2-((5-(trimethylsilyl)pent-4-yn-2-yl)oxy)acetate (50 g, 185 mmol) was added to 500 mL of tetrahydrofuran, and then tetrabutylammonium fluoride (53.2 g, 203 mmol) was added. The reaction was carried out at room temperature for 15 hours. The mixture was stirred with silica gel, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain the title yellow liquid compound tert-butyl (R)-2-(pent-4-yn-2-yloxy)acetate (27 g, 73.7%).

[0359] Step 4: Synthesis of tert-butyl (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)acetate (5D)

[0360]

[0361] At room temperature, the raw material tert-butyl (R)-2-(pent-4-yn-2-yloxy)acetate (27 g, 136 mmol) was added to 150 mL of DMF and 20 mL of methanol. Under nitrogen protection, trimethylsilyl azide (23.53 g, 204 mmol) and copper(I) iodide (2.08 g, 10.89 mmol) were added respectively. The reaction solution was heated to 90 °C and stirred for 15 hours. The reaction solution was cooled to 40 °C, concentrated to dryness, diluted with dichloromethane and stirred with silica gel, and then concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the yellow oily compound tert-butyl (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)acetate (14 g, 42.6%).

[0362] Step 5: Synthesis of (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)acetic acid (5E)

[0363]

[0364] At room temperature, the raw material tert-butyl (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)acetate (14 g, 58 mmol) was added to a hydrochloric acid solution in 1,4-dioxane (4 mol / L, 70 mL). The mixture was stirred at room temperature for 16 hours, filtered, and the solid was washed with methyl tert-butyl ether and dried to obtain the white solid (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)acetic acid (9.2 g, 86%).

[0365] Step 6: Synthesis of (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Target Compound I)

[0366]

[0367] At room temperature, the raw materials (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)acetic acid (9.41 g, 42.5 mmol) and N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine (9.2 g, 28.3 mmol) were added to 1000 mL of DMF. At 0 °C, T3P (50% DMF solution) (27 g, 42.5 mmol) and diisopropylethylamine (21.95 g, 170 mmol) were added. The mixture was allowed to warm to room temperature naturally and stirred for 16 hours. The reaction solution was filtered, and water (3 mL) was added to the filtrate. The mixture was concentrated to dryness, and the residue was separated and purified by silica gel column chromatography (methylene chloride:methanol (V / V) = 10:1) to obtain 12 g of crude product. The crude product was slurried in 120 mL of isopropyl acetate for 10 hours, filtered, and dried to obtain (R)-2-((1-(-1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (7.8 g, HPLC purity: 98.63%, ee value > 99%, yield 65.7%).

[0368] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, 1H), 7.64 (b, 1H), 7.57 (t, 1H), 7.22 - 7.20 (m, 2H), 7.16 - 7.12 (m, 2H), 4.65 - 4.59 (m, 3H), 4.52 (s, 1H), 4.42 (s, 1H), 4.25 - 4.17 (m, 2H), 3.87 - 3.81 (m, 1H), 3.27 - 3.21 (m, 2H), 2.90 - 2.85 (m, 4H), 1.19 (t, 3H).

[0369] LC-MS, M / Z (ESI): 420.4 (M+1).

[0370] Example 2: Preparation of the Solid Form of the Compound of Formula (I) or Its Solvate

[0371] 2.1 Preparation of Crystal Form A

[0372] Dissolve the compound of formula (I) (15 mg) in acetone (2 mL), slowly add toluene (13 mL) dropwise under stirring at room temperature, slowly volatilize overnight at room temperature, and centrifuge the precipitated solid to obtain polymorph A.

[0373] Dissolve the compound of formula (I) (15 mg) in acetone (2 mL), slowly add water (10 mL) dropwise under stirring at room temperature, slowly volatilize overnight at room temperature, and centrifuge the precipitated solid to obtain polymorph A.

[0374] Dissolve the compound of formula (I) (15 mg) in 1,4-dioxane (2 mL), slowly add methyl tert-butyl ether (13 mL) dropwise under stirring at room temperature, slowly volatilize overnight at room temperature, and centrifuge the precipitated solid to obtain polymorph A.

[0375] Dissolve the compound of formula (I) (15 mg) in 1,4-dioxane (2 mL), slowly add water (10 mL) dropwise under stirring at room temperature, cool to 5 °C and stir slowly for 1 h, and centrifuge the precipitated solid to obtain polymorph A.

[0376] Dissolve the compound of formula (I) (15 mg) in dimethyl sulfoxide (0.2 mL), slowly add water (5 mL) dropwise under stirring at room temperature, cool to 5 °C and stir slowly for 1 h, and centrifuge the precipitated solid to obtain polymorph A.

[0377] Add ethyl acetate (0.5 mL) to the compound of formula (I) (15 mg), stir the suspension at room temperature for 3 days, and centrifuge to collect the solid to obtain polymorph A.

[0378] Add methyl tert-butyl ether (0.5 mL) to the compound of formula (I) (15 mg), stir the suspension at room temperature for 3 days, and centrifuge to collect the solid to obtain polymorph A.

[0379] Add 2-methyltetrahydrofuran (0.5 mL) to the compound of formula (I) (15 mg), stir the suspension at room temperature for 3 days, and centrifuge to collect the solid to obtain polymorph A.

[0380] Add toluene (0.5 mL) to the compound of formula (I) (15 mg), stir the suspension at room temperature for 3 days, and centrifuge to collect the solid to obtain polymorph A.

[0381] Add n-heptane (0.5 mL) to the compound of formula (I) (15 mg), stir the suspension at room temperature for 3 days, and centrifuge to collect the solid to obtain polymorph A.

[0382] Add water (0.5 mL) to the compound of formula (I) (15 mg), stir the suspension at room temperature for 3 days, and centrifuge to collect the solid to obtain polymorph A.

[0383] To the compound of formula (I) (15 mg), water (0.4 mL) and dimethyl sulfoxide (0.1 mL) were added. The suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation to obtain Crystal Form A.

[0384] 2.2 Preparation of Crystal Form B

[0385] The compound of formula (I) (15 mg) was dissolved in acetone (2 mL). Methyl tert-butyl ether (10 mL) was slowly added dropwise with stirring at room temperature. The mixture was cooled to -20 °C and slowly stirred for 1 h. The precipitated solid was separated by centrifugation to obtain Crystal Form B.

[0386] The compound of formula (I) (15 mg) was dissolved in tetrahydrofuran (2.4 mL). The mouth of the bottle was sealed with a sealing film and 4 pinholes were pricked on it. It was placed at room temperature and slowly volatilized for 7 days. The solid was collected by centrifugation to obtain Crystal Form B.

[0387] To the compound of formula (I) (15 mg), a mixed solvent of tetrahydrofuran and water (volume ratio 1:1, 0.5 mL) was added. The suspension was cycled up and down in temperature between 50 °C and 5 °C (0.1 °C / min) with stirring, and the solid was collected by centrifugation to obtain Crystal Form B.

[0388] In a 3 mL vial, the compound of formula (I) (15 mg) was dissolved in acetone (2 mL). The vial containing the clear sample was placed open in a 20 mL large bottle containing 3 mL of isopropyl acetate. The 20 mL large bottle was sealed and placed at room temperature for 3 days. The precipitated solid was collected by centrifugation to obtain Crystal Form B.

[0389] In a 3 mL vial, the compound of formula (I) (15 mg) was dissolved in tetrahydrofuran (2 mL). The vial containing the clear sample was placed open in a 20 mL large bottle containing 3 mL of n-heptane. The 20 mL large bottle was sealed and placed at room temperature for 3 days. The precipitated solid was collected by centrifugation to obtain Crystal Form B.

[0390] In a 3 mL vial, the compound of formula (I) (15 mg) was dissolved in tetrahydrofuran (2 mL). The vial containing the clear sample was placed open in a 20 mL large bottle containing 3 mL of water. The 20 mL large bottle was sealed and placed at room temperature for 3 days. The precipitated solid was collected by centrifugation to obtain Crystal Form B.

[0391] 2.3 Preparation of Crystal Form C

[0392] The compound of formula (I) (15 mg) was dissolved in tetrahydrofuran (2 mL). Toluene (13 mL) was slowly added dropwise with stirring at room temperature. The mixture was cooled to -20 °C and slowly stirred for 1 h. The precipitated solid was separated by centrifugation to obtain Crystal Form C.

[0393] 2.4 Preparation of Crystal Form D

[0394] Dissolve the compound of formula (I) (15 mg) in 1,4-dioxane (2 mL), slowly add n-heptane (13 mL) dropwise with stirring at room temperature, cool to 5 °C and stir slowly for 1 h, and precipitate a solid, which is separated by centrifugation to obtain Polymorph D.

[0395] In a 3 mL vial, dissolve the compound of formula (I) (15 mg) in dimethyl sulfoxide (0.2 mL). Place the vial containing the clear solution open in a 20 mL large vial containing 3 mL of water. Seal the 20 mL large vial and let it stand at room temperature for 3 days. Precipitate a solid and collect it by centrifugation to obtain Polymorph B.

[0396] 2.5 Preparation of Polymorph E

[0397] Dissolve the compound of formula (I) (15 mg) in chloroform (1 mL), slowly add n-heptane (13 mL) dropwise with stirring at room temperature, cool to 5 °C and stir slowly for 1 h, and precipitate a solid, which is separated by centrifugation to obtain Polymorph E.

[0398] Dissolve the compound of formula (I) (15 mg) in chloroform (1 mL). Seal the vial mouth with a sealing film and pierce 4 pinholes in it. Place it at room temperature and let it slowly volatilize for 7 days. Collect the solid by centrifugation to obtain Polymorph E.

[0399] In a 3 mL vial, dissolve the compound of formula (I) (15 mg) in chloroform (1 mL). Place the vial containing the clear solution open in a 20 mL large vial containing 3 mL of isopropyl acetate. Seal the 20 mL large vial and let it stand at room temperature for 3 days. Precipitate a solid and collect it by centrifugation to obtain Polymorph E.

[0400] In a 3 mL vial, dissolve the compound of formula (I) (15 mg) in chloroform (1 mL). Place the vial containing the clear solution open in a 20 mL large vial containing 3 mL of n-heptane. Seal the 20 mL large vial and let it stand at room temperature for 3 days. Precipitate a solid and collect it by centrifugation to obtain Polymorph E.

[0401] 2.6 Preparation of Polymorph G

[0402] In a 3 mL vial, dissolve the compound of formula (I) (15 mg) in 1,4-dioxane (2 mL). Place the vial containing the clear solution open in a 20 mL large vial containing 3 mL of water. Seal the 20 mL large vial and let it stand at room temperature for 3 days. Precipitate a solid and collect it by centrifugation to obtain Polymorph G.

[0403] 2.7 Preparation of Polymorph H

[0404] Add ethanol (0.5 mL) to the compound of formula (I) (15 mg), stir the suspension at room temperature for 3 days, and collect the solid by centrifugation to obtain Polymorph H.

[0405] Acetone (0.5 mL) was added to the compound of formula (I) (15 mg), and the suspension was stirred at room temperature for 3 days. The solid was collected by centrifugation to obtain polymorph H.

[0406] Acetonitrile (0.5 mL) was added to the compound of formula (I) (15 mg), and the suspension was stirred at room temperature for 3 days. The solid was collected by centrifugation to obtain polymorph H.

[0407] A mixed solvent of tetrahydrofuran and isopropyl acetate (volume ratio 1:1, 0.5 mL) was added to the compound of formula (I) (15 mg), and the suspension was stirred at room temperature for 3 days. The solid was collected by centrifugation to obtain polymorph H.

[0408] A mixed solvent of acetone and water (volume ratio 1:1, 0.5 mL) was added to the compound of formula (I) (15 mg), and the suspension was heated to 50 °C and stirred for 3 days. The solid was collected by centrifugation to obtain polymorph H.

[0409] 2.8 Preparation of Polymorph J-1

[0410] 2-Methyltetrahydrofuran (1 mL) was added to the compound of formula (I) (15 mg), and the mixture was heated to 50 °C and stirred for 3 h. It was then filtered while hot, and the clear solution was slowly cooled to 5 °C (0.1 °C / minute) and kept at a constant temperature at 5 °C for overnight evaporation. The solid was collected by centrifugation to obtain polymorph J-1.

[0411] 2.9 Preparation of Polymorph J-2

[0412] Methyl tert-butyl ether (1 mL) was added to the compound of formula (I) (15 mg), and the mixture was heated to 50 °C and stirred for 3 h. It was then filtered while hot, and the clear solution was slowly cooled to 5 °C (0.1 °C / minute) and kept at a constant temperature at 5 °C for overnight evaporation. The solid was collected by centrifugation to obtain polymorph J-2.

[0413] 2.10 Preparation of Polymorph K

[0414] In a 3 mL vial, the compound of formula (I) (15 mg) was dissolved in 1,4-dioxane (2 mL). The vial containing the clear solution was placed open in a 20 mL large vial containing 3 mL of water. The 20 mL large vial was sealed and left at room temperature for 3 days. The solid was collected by centrifugation and heated to 100 °C and then cooled to room temperature to obtain polymorph K.

[0415] 2.11 Preparation of Polymorph L

[0416] Ethanol (0.5 mL) was added to the compound of formula (I) (15 mg), and the suspension was stirred at room temperature for 3 days. The solid was collected by centrifugation and heated to 90 °C under a nitrogen atmosphere and then cooled to 30 °C to obtain polymorph L.

[0417] 2.12 Preparation of Polymorph M-1

[0418] Ethanol (0.5 mL) was added to the compound of formula (I) (15 mg). The suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation and dried to obtain polymorph M-1.

[0419] 2.13 Preparation of Polymorph M-2

[0420] Acetonitrile (0.5 mL) was added to the compound of formula (I) (15 mg). The suspension was stirred at room temperature for 7 days, and the solid was collected by centrifugation and dried to obtain polymorph M-2.

[0421] 2.14 Preparation of Polymorph N

[0422] The compound of formula (I) (15 mg) was weighed in a 3 mL vial and placed open in a 20 mL large vial containing 2 mL of dichloromethane. The 20 mL large vial was sealed and left at room temperature for 8 days. The solid was collected by centrifugation to obtain polymorph N.

[0423] 2.15 Preparation of Polymorph P

[0424] A mixed solvent of isopropanol and water (volume ratio 0.98:0.02, 1.0 mL) was added to the compound of formula (I) (15 mg). The suspension was stirred at room temperature for 1 h, filtered using a PTFE membrane, and the filtrate was transferred to a vial containing various polymorphs (polymorphs A, B, G, K, and L). The suspension was stirred at room temperature for 20 days, and the solid was collected by centrifugation to obtain polymorph P.

[0425] 2.16 Preparation of Amorphous

[0426] The compound of formula (I) (15 mg) was dissolved in acetone (2 mL), and isopropyl acetate (10 mL) was slowly added dropwise under stirring at room temperature. The solution was slowly evaporated overnight at room temperature, and the precipitated solid was separated by centrifugation to obtain the amorphous form of the compound of formula (I).

[0427] The compound of formula (I) (15 mg) was dissolved in acetone (2 mL), and n-heptane (10 mL) was slowly added dropwise under stirring at room temperature. The precipitated solid was separated by centrifugation to obtain the amorphous form of the compound of formula (I).

[0428] The compound of formula (I) (15 mg) was dissolved in tetrahydrofuran (2.4 mL), and water (10 mL) was slowly added dropwise under stirring at room temperature. The solution was cooled to 5 °C and stirred for 1 h, and the precipitated solid was separated by centrifugation to obtain the amorphous form of the compound of formula (I).

[0429] The compound of formula (I) (15 mg) was dissolved in chloroform (1 mL), and ethyl acetate (10 mL) was slowly added dropwise under stirring at room temperature. The precipitated solid was separated by centrifugation to obtain the amorphous form of the compound of formula (I).

[0430] Dissolve the compound of formula (I) (15 mg) in chloroform (1 mL), and slowly add methyl tert-butyl ether (10 mL) dropwise with stirring at room temperature. The precipitated solid is separated by centrifugation to obtain the amorphous form of the compound of formula (I).

[0431] Dissolve the compound of formula (I) (15 mg) in acetone (2 mL), seal the bottle mouth with a sealing film, and pierce 4 pinholes on it. Place it at room temperature and slowly volatilize for 7 days. Centrifuge to collect the solid to obtain the amorphous form of the compound of formula (I).

[0432] Add ethyl acetate (1 mL) to the compound of formula (I) (15 mg), heat to 50 °C and stir for 3 h, then perform hot filtration. Slowly cool the clear liquid to 5 °C (0.1 °C / minute), and keep it at 5 °C for 1 h. Centrifuge to collect the solid to obtain the amorphous form of the compound of formula (I).

[0433] Add a mixed solvent of acetone and water (volume ratio 4:1, 1 mL) to the compound of formula (I) (15 mg), heat to 50 °C and stir for 3 h, then perform hot filtration. Slowly cool the clear liquid to 5 °C (0.1 °C / minute), and keep it at a constant temperature and volatilize overnight at 5 °C. Centrifuge to collect the solid to obtain the amorphous form of the compound of formula (I).

[0434] In a 3 mL vial, dissolve the compound of formula (I) (15 mg) in acetone (2 mL). Place the vial containing the clear solution open in a 20 mL large bottle containing 3 mL of methyl tert-butyl ether. Seal the 20 mL large bottle and place it at room temperature for 3 days. The precipitated solid is centrifuged and collected to obtain polymorph E.

[0435] Example 3: Polymorph evaluation

[0436] 3.1 Transformation between polymorphs of the compound of formula (I) or its solvate

[0437] Through the suspension competition test in the MeOH / H 2 O solvent system with different water activities at room temperature, the mutual transformation relationship between the anhydrous crystal form and the hydrate crystal form was studied. The results showed that crystal form A was obtained in all suspension tests. The mutual transformation relationship diagrams of each crystal form are listed in Figure 15 , and the transformation methods are summarized in Table 15-1.

[0438] Table 15-1 Summary of polymorph transformation methods

[0439]

[0440] 3.2 Polymorph evaluation of the compound of formula (I) or its solvate

[0441] Based on the results of suspension competition, crystal form A without crystal water was selected for the evaluation of physicochemical stability under the conditions of 60 °C / 60% RH for 24 hours. The results are summarized in Table 15-2 below, and the XRPD results are shown in Figure 16 . The results showed that no obvious decrease in purity or crystal form transformation was found after crystal form A was placed at 60 °C for 24 hours.

[0442] Table 15-2 Stability data of crystal form A under the conditions of 60 °C / 60% RH

[0443]

[0444] In addition, the stability data of crystal form A under the two conditions of 25 °C / 60% RH and 40 °C / 75% RH are shown in Table 15-3.

[0445] Table 15-3 Stability data of crystal form A under the conditions of 25 °C / 60% RH and 40 °C / 75% RH

[0446]

[0447] The results showed that crystal form A had good stability after being stored for 1 week under the two conditions of 25 °C / 60% RH and 40 °C / 75% RH, and there was no change in crystal form and HPLC purity.

[0448] Example 4: Performance evaluation of the compound of formula (I)

[0449] 4.1 Weigh 20 mg of the crystal form A sample of the compound of formula (I) into a 5 mL vial, add 4 mL of the following solvents respectively, mix by rotation (25 rpm) at 37 °C for 1 hour, 4 hours, and 24 hours. Take about 1 mL for centrifugation and filtration respectively, detect the crystal form by XRPD for the solid, and detect the HPLC concentration and pH value for the liquid. The results are shown in Table 15-4.

[0450] Table 15-4 Dynamic solubility evaluation of crystal form A

[0451]

[0452] Note: "S" represents solubility (mg / mL), "SGF" represents simulated gastric fluid, "FaSSIF" represents simulated fasting state intestinal fluid, and "FeSSIF" represents simulated fed state intestinal fluid.

[0453] 4.2 The dynamic vapor sorption (DVS) evaluation was carried out on crystal form A of the compound of formula (I), and the results are as Figure 30 shown in and Table 15-5.

[0454] Table 15-5 DVS evaluation of crystal form A

[0455]

[0456] Figure 30 The DVS spectrum of crystalline form A is shown. The results indicate that the water adsorption of crystalline form A is approximately 1.03% under the conditions of 25 °C / 80% RH, showing good hygroscopicity.

[0457] 4.3 The approximate solubility of crystalline form A of the compound of formula (I) in some solvents was tested at room temperature, and the results are shown in Table 15-6.

[0458] Table 15-6 Approximate solubility of crystalline form A in some solvents

[0459] Solvent Solubility (mg / mL) Solvent Solubility (mg / mL) Methanol 2.1<S<5.3 1,4-Dioxane 20.0<S<40.0 Ethanol 2.1<S<5.3 Acetonitrile 2.0<S<5.0 Isopropanol 1.0<S<2.0 Chloroform 22.0<S<44.0 Acetone 5.0<S<10.0 Dichloromethane 11.5<S<23.0 Methyl isobutyl ketone 1.1<S<2.2 n-Heptane S<1.0 Ethyl acetate 1.1<S<2.2 Toluene S<1.1 Isopropyl acetate S<1.1 Dimethylacetamide S>42.0 Methyl tert-butyl ether S<1.1 Dimethyl sulfoxide S>40.0 Tetrahydrofuran 10.0<S<20.0 N-Methylpyrrolidone S>42.0 2-Methyltetrahydrofuran 2.2<S<5.5 Water S<1.0

[0460] In the following test examples, the compound of formula (I) used was the compound of formula (I) prepared in Example 1 above, and the structure of the control compound used was as follows:

[0461]

[0462] This control compound was synthesized with reference to Patent Application WO2014110000A1, HPLC purity: 99.88%.

[0463] Test Example 1: Autotaxin (ATX) enzyme activity inhibition test

[0464] The inhibitory activity of the compound against Autotaxin enzyme was detected using the Autotaxin Inhibitor Screening Assay Kit (Cayman, 700580). First, the compound to be tested was prepared into a 10 mM stock solution in DMSO solvent, and then 8 concentration points were diluted with DMSO in a gradient manner. Subsequently, the 8 concentration points were diluted into a 19× compound working solution (the content of DMSO was 1.9%) using the Autotaxin Assay buffer (1×) provided in the kit. Take out the Autotaxin Assay Reagent (10×) and dilute it 10 times with the Autotaxin Assay Buffer (1×). Take out the Autotaxin Substrate, add 1.2 mL of the Autotaxin Assay Buffer (1×) to dissolve it, mix well and let it stand at room temperature. In a 96-well plate, in each well where each concentration point is located, add 150 μL of the Autotaxin Assay Buffer (1×), 10 μL of the diluted 19× compound working solution, 10 μL of the Autotaxin Assay Reagent (1×), and 20 μL of the dissolved Autotaxin Substrate, mix well, incubate in a constant temperature shaking incubator at 37 °C in the dark for 30 min; take out the 96-well plate and read the OD405 on an enzyme-linked immunosorbent assay (ELISA) reader; the experimental results were input into GraphPad Prism software, and the IC 50 .

[0465] Table 16-1 Results of the inhibitory activity of the test compounds against ATX enzyme activity

[0466] Test compound <![CDATA[IC 50 (nM)]]> Control compound 2.60 Compound of formula (I) 1.59

[0467] The experimental results showed that the compound of formula (I) of the present invention had good inhibitory activity against ATX enzyme; it could effectively inhibit the activity of ATX enzyme.

[0468] Test Example 2: Human liver microsome stability test

[0469] The human liver microsome stability test was performed by in vitro co-incubation of the compound with human liver microsomes. First, the test compound was formulated into a 10 mM stock solution in DMSO solvent, and then the compound was diluted to 0.5 mM using acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and this solution was used to dilute the 0.5 mM compound to form a working solution with a compound concentration of 1.5 μM and a human liver microsome concentration of 0.75 mg / ml in the working solution. Take a deep well plate, add 30 μL of the working solution to each well, and then add 15 μL of pre-warmed 6 mM NADPH solution to initiate the reaction, and incubate at 37 °C. At 0, 5, 15, 30, and 45 minutes of incubation, add 135 μL of acetonitrile to the corresponding wells to terminate the reaction. After terminating the reaction with acetonitrile at the last 45-minute time point, the deep well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, take the supernatant, add purified water in a 1:1 ratio and then perform LC-MS / MS detection to obtain the ratio of the compound peak area to the internal standard peak area at each time point. Compare the peak area ratios of the compound at 5, 15, 30, and 45 minutes with the peak area ratio at 0 minute, calculate the remaining percentage of the compound at each time point, and use Excel to calculate T 1 / 2 。

[0470] Table 16-2 Results of human liver microsome stability test

[0471]

[0472] Compared with the control compound, the compound of formula (I) of the present invention exhibits better liver metabolic stability, slower metabolism in the human body, and higher exposure. The T of the liver microsome stability of the compound of formula (I) of the present invention 1 / 2 is better than that of the control compound, and can even reach more than twice that of the control compound, which can reduce the clinical dosage and dosing frequency, reduce the toxic and side effects of clinical administration, and improve clinical compliance.

[0473] Test Example 3: Detection of the inhibitory effect of the compound on hERG by the fully automated electrophysiological patch clamp QPatch

[0474] The inhibitory effect of compounds on hERG was detected using the fully automated electrophysiological patch clamp QPatch. The cells used in this experiment were CHO cell lines transfected with hERG cDNA and stably expressing hERG channels (provided by Sophion Bioscience, Denmark), and the cell passage number was P24. The cells were cultured in a medium containing the following components (all from Invitrogen): Ham’s F12 medium, 10% (v / v) heat-inactivated fetal bovine serum, 100 μg / ml hygromycin B, and 100 μg / ml Geneticin. The CHO hERG cells were grown in culture dishes containing the above-mentioned culture medium and cultured in an incubator at 37°C with 5% CO 2 2.

[0475] Prepare extracellular solution (2 mM CaCl 2 2, 1 mM MgCl 2 2, 4 mM KCl, 145 mM NaCl, 10 mM Glucose, 10 mM HEPES, pH about 7.4, osmotic pressure about 305 mOsm) and intracellular solution (5.374 mM CaCl 2 2, 1.75 mM MgCl 2 2, 120 mM KCl, 10 mM HEPES, 5 mM EGTA, 4 mM Na-ATP, pH about 7.25, osmotic pressure about 295 mOsm).

[0476] Prepare a 10 mM stock solution of the compound to be tested in DMSO solvent, and dilute the compound with DMSO to 3, 1, 0.3, 0.1 mM, and then dilute the compound with extracellular solution to 30, 10, 3, 1, 0.3, and 0.1 μM. Except for the final concentration of DMSO in the 30 μM compound solution being 0.3%, the final concentration of DMSO in the compound solutions of other concentrations is 0.1%.

[0477] After digesting and resuspending the CHO hERG cells, add them to the fully automated QPatch system (Sophion, Denmark) and conduct the experiment according to the following preset procedures.

[0478] After achieving the whole-cell configuration state with membrane rupture in the initial stage, at room temperature (about 25 °C), whole-cell currents were recorded. The cells were recorded for at least 120 seconds to reach stability, and stable cells were selected for the experiment. During the whole experiment, the cells were clamped at a voltage of -80 mV, and the cell-clamping voltage was depolarized to +20 mV to activate the hERG potassium channel. After 2.5 seconds, it was clamped to -50 mV to eliminate inactivation and generate an outward tail current. The peak value of the tail current was used as the value of the hERG current magnitude. The above voltage pattern was applied to the cells every 15 seconds for electrophysiological experiments. An external solution containing 0.1% dimethyl sulfoxide (solvent) was added to the cells to establish a baseline, and then the current was allowed to stabilize for 3 minutes. After the compound solution was added, the cells were maintained in the test environment until the effect of the compound reached a stable state or within a limit of 4 minutes. In the test experiments with different concentration gradients of the compound, the compound was added to the clamped cells from low to high concentrations. After the compound test was completed, the cells were washed with the external solution until the current returned to a stable state.

[0479] The experimental data were analyzed by Qpatch analysis software provided by Sophion, Excel, Graphpad Prism, etc.

[0480] Table 16-3 Results of the inhibitory effect of the compound on hERG

[0481] Compound <![CDATA[hERG IC 50 (μM)]]> <![CDATA[hERG IC 50 / ATX IC 50 > Control compound 6.69 6.69 / 2.60＝2.6 Compound of formula (I) 9.48 9.48 / 1.59＝6.0

[0482] Compared with the control compound, the compound of formula (I) of the present invention exhibited weaker hERG inhibitory activity. Considering the IC 50 value of the inhibitory effect of the compound on ATX enzyme activity, the compound of formula (I) showed a better safety window for hERG inhibition and had obvious cardiac safety advantages.

[0483] Test Example 4: Thermodynamic solubility test

[0484] Prepare phosphate buffer solution (PBS) at pH 7.4, FeSSIF solution at pH 5.8 (containing 10 mM sodium taurocholate, 2 mM lecithin, 81.65 mM sodium hydroxide, 125.5 mM sodium chloride, 0.8 mM sodium oleate, 5 mM glycerol monoleate, 55.02 mM maleic acid), and FaSSGF solution at pH 1.6 (1 L solution contains 80 μM sodium taurocholate, 20 μM lecithin, 0.1 g pepsin, 34.2 mM sodium chloride).

[0485] Accurately weigh the compound, add the prepared phosphate buffer solution with pH 7.4, FeSSIF solution with pH 5.8, and FaSSGF solution with pH 1.6 to prepare a solution with a concentration of 4 mg / mL. Shake it at a speed of 1000 rpm for 1 hour, and then incubate it overnight at room temperature. Centrifuge the incubated solution at a speed of 12000 rpm for 10 minutes to remove undissolved particles, and transfer the supernatant to a new centrifuge tube. After appropriately diluting the supernatant, add an acetonitrile solution containing an internal standard, and perform quantification using a calibration curve prepared with the same matrix.

[0486] Table 16-4 Results of Thermodynamic Solubility Test

[0487]

[0488] The experimental results show that the solubility of the control compound is relatively poor, and it is expected that the gastrointestinal absorption will be relatively poor, which is not conducive to the development into an oral drug. Compared with the control compound, the thermodynamic solubility of the compound of formula (I) of the present invention is significantly improved under simulated gastric juice, simulated intestinal juice, and neutral conditions. Therefore, it is expected that the intestinal absorption degree in the human body will be greatly improved, the oral exposure is relatively high, the clinical dosage can be reduced, and the clinical compliance can be improved.

[0489] Test Example 5: Pharmacokinetic Test

[0490] For the pharmacokinetic test in rats, 6 male SD rats weighing 180 - 240 g were used and fasted overnight. Take 3 rats and administer the drug orally by gavage at a dose of 10 mg / kg. Blood samples were collected before dosing and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing. Take another 3 rats and administer the drug intravenously at a dose of 1 mg / kg. Blood samples were collected before dosing and at 5, 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing. Centrifuge the blood samples at 8000 rpm at 4°C for 6 minutes, collect the plasma, and store it at -20°C. Take the plasma at each time point, add 3 - 5 times the volume of an acetonitrile solution containing an internal standard and mix well by vortexing for 1 minute. Centrifuge at 13000 rpm at 4°C for 10 minutes, take the supernatant, add 3 times the volume of water and mix well. Take an appropriate amount of the mixed solution for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed using the non-compartmental model with WinNonlin 7.0 software.

[0491] For the pharmacokinetic test in mice, 18 male ICR mice weighing 20 - 25 g were used and fasted overnight. Take 9 mice and administer the drug orally by gavage at a dose of 10 mg / kg. 3 mice were used at each blood sampling time point, and a total of 9 mice were sampled alternately; take another 9 mice and administer the drug intravenously at a dose of 1 mg / kg. 3 mice were used at each blood sampling time point, and a total of 9 mice were sampled alternately. The remaining operations were the same as those in the rat pharmacokinetic test.

[0492] Table 16-5 Results of Pharmacokinetic Test in Mice

[0493]

[0494] Table 16-6 Results of Pharmacokinetic Experiments in Rats

[0495]

[0496] The experimental results show that, compared with the control compound, the compound of formula (I) of the present invention exhibits more excellent pharmacokinetic properties. Especially in rats, the clearance rate (CL) of the compound of formula (I) of the present invention is lower, about 1 / 6 of that of the control compound, indicating that the compound of formula (I) is relatively stable in vivo, and its oral C max and AUC 0-t can reach 6.1 times and 4.2 times that of the control compound, respectively.

[0497] Test Example 6: Inhibitory Test of ATX Enzyme Activity in Human Plasma

[0498] Collect whole blood from healthy volunteers, anticoagulate it with heparin, centrifuge the blood collection tube at 3000 rpm for 10 minutes, take the plasma and store it at -80 °C for later use.

[0499] The compound is serially diluted with DMSO according to the conventional concentration requirements, then 3 μL is taken and added to a 96-well plate. 147 μL of PBS is taken and added to the wells containing 3 μL of the compound respectively. After mixing, 50 μL is taken from it and added to a new 96-well plate. Take out the human plasma from the -80 °C refrigerator and quickly thaw it in a 37 °C water bath. Take 50 μL of human plasma and add it to the 96-well plate containing 50 μL of the diluted compound (the final system is 1% DMSO). Set the group without the compound as the positive group. Shake and mix the 96-well plate evenly and incubate it at 37 °C for 3 hours; another blank group is set, and the plasma of the blank group is stored at -80 °C. The role of the blank group is to measure the baseline concentration of endogenous LPA.

[0500] After the incubation is completed, thaw the blank group on ice and transfer it to an incubation plate. Add an excessive amount of acetonitrile containing the internal standard LPA17:0 to precipitate plasma proteins in the incubation plate. After vortex centrifugation, take the supernatant and dilute it, and use LC-MSMS mass spectrometry to detect the peak areas of LPA18:2 and the internal standard LPA17:0.

[0501] Calculate the peak area ratio of LPA18:2 to the internal standard LPA17:0, and calculate the inhibition rate of LPA18:2 generation according to the following formula:

[0502] Inhibition rate (%) = 100 - (compound group at different concentrations - blank group) / (positive group - blank group) * 100

[0503] According to the inhibition rates of different concentrations of the compound, calculate the inhibitory IC 50 value of the compound on the activity of ATX enzyme in human plasma.

[0504] Table 16-7 Results of the inhibitory activity of the test compounds on the activity of ATX enzyme in human plasma

[0505] Test compound <![CDATA[IC 50 (nM)]]> Control compound 13.0 Compound of formula (I) 4.7

[0506] The experimental results show that the compound of formula (I) of the present invention has good inhibitory activity on the ATX enzyme in human plasma, can effectively inhibit the activity of the ATX enzyme, and is significantly superior to the control compound.

[0507] Test Example 7: Bleomycin-induced IPF model in rats

[0508] Male BN rats, 180-240 g, were used to induce an IPF model (idiopathic pulmonary fibrosis model) with a dose of 5 U / kg of bleomycin. After modeling, the animals were randomly grouped into a vehicle control group, a GLPG-1690 group (a compound in clinical phase III of Galapagos), a control compound group, and a compound of formula (I). Oral gavage was administered twice a day starting from the second day after modeling. The administration dose for each administration group was 30 mg / kg, and the vehicle control group was given the blank vehicle. Administration was continued for 21 days.

[0509] During the administration period, the body weight was weighed every three days. On the 21st day of administration, alveolar lavage was performed 2 h after the first administration. The inflammatory cells in the lavage fluid were counted, and the relevant biomarkers in the supernatant of the lavage fluid were detected. After lavage, the left lung of the rat was fixed, and Masson trichrome staining was used for fibrosis pathological scoring, and the remaining lung lobes were frozen. The supernatant of the alveolar lavage fluid and the freshly frozen lung tissue of the three compound groups were taken, and the TGF-β1 protein content and total protein content were detected by ELISA method, and the amount of TGF-β1 per milligram of total protein was calculated.

[0510] The experimental results showed that the decrease in the body weight of the animals in the compound of formula (I) was significantly less than that in the control compound group, and the safety of the compound of formula (1) was better (the results are as Figure 36 shown); the content of TGF-β1 in the supernatant of the alveolar lavage fluid and the freshly frozen lung tissue of the compound of formula (I) was significantly lower than that in the vehicle control group, and the compound of formula (I) had a significant anti-fibrosis formation effect (the results are as Figure 37 shown).

[0511] The above describes the exemplary embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A solid form of the compound of formula (I), wherein the solid form is crystalline form A: The X-ray powder diffraction pattern of the crystalline form A obtained with Cu-Kα radiation has characteristic peaks at the following 2θ angles: 8.05 ± 0.20°, 8.30 ± 0.20°, 14.11 ± 0.20°, 16.18 ± 0.20°, 22.73 ± 0.20°, 25.16 ± 0.20°.

2. The solid form according to claim 1, wherein, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at the following 2θ angles: 8.05 ± 0.20°, 8.30 ± 0.20°, 14.11 ± 0.20°, 16.18 ± 0.20°, 16.65 ± 0.20°, 21.85 ± 0.20°, 22.73 ± 0.20°, 25.16 ± 0.20°, 26.23 ± 0.20°.

3. The solid form according to claim 1, wherein, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at the following 2θ angles: 8.05 ± 0.20°, 8.30 ± 0.20°, 14.11 ± 0.20°, 16.18 ± 0.20°, 16.65 ± 0.20°, 19.19 ± 0.20°, 21.85 ± 0.20°, 22.73 ± 0.20°, 25.16 ± 0.20°, 26.23 ± 0.20°, 29.91 ± 0.20°.

4. The solid form according to claim 1, wherein, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at the following 2θ angles: 8.05 ± 0.20°, 8.30 ± 0.20°, 14.11 ± 0.20°, 16.18 ± 0.20°, 16.65 ± 0.20°, 18.19 ± 0.20°, 18.91 ± 0.20°, 19.19 ± 0.20°, 21.85 ± 0.20°, 22.73 ± 0.20°, 25.16 ± 0.20°, 26.23 ± 0.20°, 29.91 ± 0.20°.

5. The solid form according to claim 1, wherein, The X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at the following 2θ angles: 8.05 ± 0.20°, 8.30 ± 0.20°, 10.77 ± 0.20°, 12.95 ± 0.20°, 14.11 ± 0.20°, 16.18 ± 0.20°, 16.65 ± 0.20°, 17.35 ± 0.20°, 18.19 ± 0.20°, 18.91 ± 0.20°, 19.19 ± 0.20°, 20.93 ± 0.20°, 21.53 ± 0.20°, 21.85 ± 0.20°, 22.31 ± 0.20°, 22.73 ± 0.20°, 24.38 ± 0.20°, 25.16 ± 0.20°, 26.23 ± 0.20°, 27.39 ± 0.20°, 28.44 ± 0.20°, 28.99 ± 0.20°, 29.20 ± 0.20°, 29.91 ± 0.20°, 32.77 ± 0.20°, 36.68 ± 0.20°.

6. The solid form according to claim 1, wherein, the 2θ diffraction angle, D value and / or relative intensity of the X-ray powder diffraction pattern of the crystalline form A obtained using Cu-Kα radiation are as follows:

7. The solid form according to claim 1, wherein, the crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 1.

8. The solid form according to claim 1, wherein, the crystalline form A has one, two, three or four of the following characteristics: (1) The TGA curve of the crystalline form A shows a weight loss of about 2.59% at 150.0 ± 3°C; (2) The DSC curve of the crystalline form A has a starting point of an endothermic peak at 152.4 ± 3°C; (3) The DSC curve of the crystalline form A has an endothermic peak at 155.3 ± 3°C; (4) The DVS curve of the crystalline form A shows a moisture adsorption of less than about 1.2% under the conditions of 0% RH to 80% RH.

9. The solid form according to claim 8, wherein, the DVS curve of the crystalline form A shows a moisture adsorption of less than about 1.1% under the conditions of 0% RH to 80% RH.

10. The solid form according to claim 8, wherein, the DVS curve of the crystalline form A shows a moisture adsorption of less than about 1.05% under the conditions of 0% RH to 80% RH.

11. The solid form of the compound of formula (I), wherein the solid form is crystalline form B: The X-ray powder diffraction pattern of the crystalline form B obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 4.93 ± 0.2°, 5.30 ± 0.2°, 7.37 ± 0.2°, 7.93 ± 0.2°, 15.95 ± 0.2°.

12. The solid form according to claim 11, wherein, The X-ray powder diffraction pattern of polymorph B has characteristic peaks at the following 2θ angles: 4.93 ± 0.2°, 5.30 ± 0.2°, 7.37 ± 0.2°, 7.93 ± 0.2°, 8.59 ± 0.2°, 14.04 ± 0.2°, 15.95 ± 0.2°, 24.15 ± 0.2°.

13. The solid form according to claim 11, wherein, the X-ray powder diffraction pattern of polymorph B has characteristic peaks at the following 2θ angles: 4.93 ± 0.2°, 5.30 ± 0.2°, 7.37 ± 0.2°, 7.93 ± 0.2°, 8.59 ± 0.2°, 14.04 ± 0.2°, 15.95 ± 0.2°, 17.24 ± 0.2°, 23.33 ± 0.2°, 24.15 ± 0.2°.

14. The solid form according to claim 11, wherein, the 2θ diffraction angles, D values and / or relative intensities of the X-ray powder pattern of polymorph B obtained with Cu-Kα radiation are as follows:

15. The solid form according to claim 11, wherein, polymorph B has an X-ray powder diffraction pattern substantially as shown in Figure 2.

16. The solid form according to claim 16, wherein, polymorph B has one, two or three of the following characteristics: (1) The TGA curve of polymorph B shows a weight loss of about 9.72% at 150.0 ± 3°C; (2) The DSC curve of polymorph B has a starting point of an endothermic peak at 96.8 ± 3°C; (3) The DSC curve of polymorph B has an endothermic peak at 111.1 ± 10°C.

17. The solid form according to claim 16, wherein, the DSC curve of polymorph B has an endothermic peak at 111.1 ± 5°C.

18. The solid form of the compound of formula (I), wherein the solid form is polymorph C: The X-ray powder diffraction pattern of polymorph C obtained with Cu-Kα radiation has characteristic peaks at the following 2θ angles: 6.80 ± 0.2°, 13.65 ± 0.2°, 16.27 ± 0.2°, 24.69 ± 0.2°, 25.65 ± 0.2°.

19. The solid form according to claim 18, wherein, the X-ray powder diffraction pattern of polymorph C has characteristic peaks at the following 2θ angles: 6.80 ± 0.2°, 13.65 ± 0.2°, 16.27 ± 0.2°, 18.92 ± 0.2°, 19.32 ± 0.2°, 21.49 ± 0.2°, 24.69 ± 0.2°, 25.65 ± 0.2°.

20. The solid form according to claim 18, wherein, The X-ray powder diffraction pattern of crystalline form C has characteristic peaks at the following 2θ angles: 6.80 ± 0.2°, 7.58 ± 0.2°, 12.55 ± 0.2°, 13.65 ± 0.2°, 16.27 ± 0.2°, 18.92 ± 0.2°, 19.32 ± 0.2°, 20.39 ± 0.2°, 21.49 ± 0.2°, 24.69 ± 0.2°, 25.65 ± 0.2°.

21. The solid form according to claim 18, wherein, the X-ray powder diffraction pattern of crystalline form C has characteristic peaks at the following 2θ angles: 6.80 ± 0.2°, 7.58 ± 0.2°, 8.32 ± 0.2°, 12.55 ± 0.2°, 13.65 ± 0.2°, 16.27 ± 0.2°, 17.73 ± 0.2°, 18.92 ± 0.2°, 19.32 ± 0.2°, 20.39 ± 0.2°, 21.49 ± 0.2°, 23.44 ± 0.2°, 24.69 ± 0.2°, 25.65 ± 0.2°, 28.27 ± 0.2°, 30.25 ± 0.2°.

22. The solid form according to claim 18, wherein, the 2θ diffraction angles, D values and / or relative intensities of the X-ray powder pattern of crystalline form C obtained using Cu-Kα radiation are as follows:

23. The solid form according to claim 18, wherein, crystalline form C has an X-ray powder diffraction pattern substantially as shown in Figure 3.

24. The solid form according to claim 18, wherein, crystalline form C has one, two or three of the following characteristics: (1) The TGA curve of crystalline form C shows a weight loss of about 12.89% at 150.0 ± 3°C; (2) The DSC curve of crystalline form C has two endothermic peaks at 80.7 ± 10°C and 160.6 ± 10°C; (3) For polymorph C 1 The characteristic hydrogen signals of toluene appear in the 1H NMR spectrum.

25. The solid form according to claim 24, wherein, the DSC curve of crystalline form C has two endothermic peaks at 80.7 ± 5°C and 160.6 ± 5°C.

26. The solid form of the compound of formula (I), wherein the solid form is crystalline form D: The 2θ diffraction angles, D values and / or relative intensities of the X-ray powder pattern of crystalline form D obtained using Cu-Kα radiation are as follows:

27. The solid form according to claim 26, wherein, crystalline form D has an X-ray powder diffraction pattern substantially as shown in Figure 4.

28. The solid form according to claim 26, wherein, crystalline form D has one or two of the following characteristics: (1) The TGA curve of crystalline form D shows a weight loss of about 12.93% at 150.0 ± 3°C; (2) The DSC curve of crystalline form D has two endothermic peaks at 133.3 ± 10°C and 159.2 ± 10°C.

29. The solid form according to claim 28, wherein, the DSC curve of crystalline form D has two endothermic peaks at 133.3 ± 5°C and 159.2 ± 5°C.

30. The solid form of the compound of formula (I), wherein the solid form is crystalline form E: The X-ray powder diffraction pattern of the crystalline form E obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 7.32 ± 0.2°, 19.44 ± 0.2°, 22.06 ± 0.2°, 25.25 ± 0.2°, 29.54 ± 0.2°.

31. The solid form according to claim 30, wherein, the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at the following 2θ angles: 7.32 ± 0.2°, 11.72 ± 0.2°, 14.66 ± 0.2°, 16.53 ± 0.2°, 19.44 ± 0.2°, 20.54 ± 0.2°, 22.06 ± 0.2°, 25.25 ± 0.2°, 29.54 ± 0.2°.

32. The solid form according to claim 30, wherein, the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at the following 2θ angles: 7.32 ± 0.2°, 11.72 ± 0.2°, 14.66 ± 0.2°, 16.09 ± 0.2°, 16.53 ± 0.2°, 19.44 ± 0.2°, 20.54 ± 0.2°, 20.81 ± 0.2°, 22.06 ± 0.2°, 25.25 ± 0.2°, 29.54 ± 0.2°.

33. The solid form according to claim 30, wherein, the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at the following 2θ angles: 7.32 ± 0.2°, 10.25 ± 0.2°, 11.72 ± 0.2°, 14.33 ± 0.2°, 14.66 ± 0.2°, 16.09 ± 0.2°, 16.53 ± 0.2°, 17.57 ± 0.2°, 18.14 ± 0.2°, 18.77 ± 0.2°, 19.44 ± 0.2°, 19.75 ± 0.2°, 20.54 ± 0.2°, 20.81 ± 0.2°, 22.06 ± 0.2°, 22.77 ± 0.2°, 23.19 ± 0.2°, 25.25 ± 0.2°, 26.04 ± 0.2°, 27.06 ± 0.2°, 27.35 ± 0.2°, 29.54 ± 0.2°, 30.41 ± 0.2°, 32.99 ± 0.2°.

34. The solid form according to claim 30, wherein, the 2θ diffraction angles, D values and / or relative intensities of the X-ray powder pattern of the crystalline form E obtained using Cu-Kα radiation are as follows:

35. The solid form according to claim 30, wherein, the crystalline form E has an X-ray powder diffraction pattern substantially as shown in Figure 5.

36. The solid form according to claim 30, wherein, the crystalline form E has one, two or three of the following characteristics: (1) The TGA curve of the crystalline form E shows a weight loss of approximately 3.42% at 90.0 ± 3°C and a weight loss of approximately 19.74% at 200.0 ± 3°C; (2) The DSC curve of the crystalline form E has two endothermic peaks at 70.0 ± 10°C and 127.2 ± 10°C; (3) Of crystalline form E 1 The characteristic hydrogen signals of chloroform are present in the 1H NMR spectrum.

37. The solid form according to claim 36, wherein, the DSC curve of crystalline form E has two endothermic peaks at 70.0 ± 5 °C and 127.2 ± 5 °C.

38. The solid form of the compound of formula (I), wherein the solid form is crystalline form G: The X-ray powder diffraction pattern of the crystalline form G obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 7.08 ± 0.2 °, 7.54 ± 0.2 °, 14.15 ± 0.2 °, 15.10 ± 0.2 °, 18.85 ± 0.2 °, 25.49 ± 0.2 °, 26.06 ± 0.2 °.

39. The solid form according to claim 38, wherein, the X-ray powder diffraction pattern of the crystalline form G has characteristic peaks at the following 2θ angles: 7.08 ± 0.2 °, 7.54 ± 0.2 °, 13.54 ± 0.2 °, 14.15 ± 0.2 °, 15.10 ± 0.2 °, 18.85 ± 0.2 °, 21.34 ± 0.2 °, 22.12 ± 0.2 °, 25.49 ± 0.2 °, 26.06 ± 0.2 °.

40. The solid form according to claim 38, wherein, the X-ray powder diffraction pattern of the crystalline form G has characteristic peaks at the following 2θ angles: 7.08 ± 0.2 °, 7.54 ± 0.2 °, 8.62 ± 0.2 °, 11.82 ± 0.2 °, 13.54 ± 0.2 °, 14.15 ± 0.2 °, 15.10 ± 0.2 °, 16.36 ± 0.2 °, 18.05 ± 0.2 °, 18.85 ± 0.2 °, 19.49 ± 0.2 °, 20.32 ± 0.2 °, 21.34 ± 0.2 °, 22.12 ± 0.2 °, 22.74 ± 0.2 °, 25.49 ± 0.2 °, 26.06 ± 0.2 °, 26.93 ± 0.2 °, 28.57 ± 0.2 °, 31.82 ± 0.2 °.

41. The solid form according to claim 38, wherein, the 2θ diffraction angle, D value and / or relative intensity of the X-ray powder pattern of the crystalline form G obtained using Cu-Kα radiation are as follows:

42. The solid form according to claim 38, wherein, the crystalline form G has an X-ray powder diffraction pattern substantially as shown in Figure 6.

43. The solid form according to claim 38, wherein, the crystalline form G shown has one, two or three of the following characteristics: (1) The TGA curve of the crystalline form G shows a weight loss of about 15.06% at 150.0 ± 3 °C; (2) The DSC curve of the crystalline form G has two endothermic peaks at 74.6 ± 10 °C and 90.1 ± 10 °C; (3) The DVS curve of the crystalline form G shows a water adsorption of less than about 8.5% under conditions of 0% RH to 80% RH.

44. The solid form according to claim 43, wherein, the DSC curve of the crystalline form G has two endothermic peaks at 74.6 ± 5 °C and 90.1 ± 5 °C.

45. The solid form according to claim 43, wherein, The DVS curve of crystalline form G adsorbs about 8.44% water under the condition of 0% RH to 80% RH.

46. A solid form of the compound of formula (I), wherein the solid form is crystalline form H: The X-ray powder diffraction pattern of the crystalline form H obtained with Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.76 ± 0.2°, 6.81 ± 0.2°, 11.54 ± 0.2°, 18.68 ± 0.2°.

47. The solid form according to claim 46, wherein, The X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at the following 2θ angles: 5.76 ± 0.2°, 6.81 ± 0.2°, 7.95 ± 0.2°, 8.74 ± 0.2°, 11.54 ± 0.2°, 13.86 ± 0.2°, 18.68 ± 0.2°, 19.90 ± 0.2°.

48. The solid form according to claim 46, wherein, The 2θ diffraction angles, d values and / or relative intensities of the X-ray powder pattern of the crystalline form H obtained with Cu-Kα radiation are as follows:

49. The solid form according to claim 46, wherein, The crystalline form H has an X-ray powder diffraction pattern substantially as shown in Figure 7.

50. The solid form according to claim 46, wherein, The crystalline form H has one or both of the following characteristics: (1) The TGA curve of the crystalline form H loses about 3.62% weight at 150.0 ± 3 °C; (2) The DSC curve of the crystalline form H has two endothermic peaks at 72.5 ± 10 °C and 112.8 ± 10 °C.

51. The solid form according to claim 50, wherein, The DSC curve of the crystalline form H has two endothermic peaks at 72.5 ± 5 °C and 112.8 ± 5 °C.

52. A solid form of the compound of formula (I), wherein the solid form is crystalline form J-1 of the hemi-2-methyltetrahydrofuran complex: The X-ray powder diffraction pattern of the crystalline form J-1 obtained with Cu-Kα radiation has characteristic peaks at the following 2θ angles: 4.43 ± 0.2°, 8.73 ± 0.2°, 11.53 ± 0.2°, 15.72 ± 0.2°.

53. The solid form according to claim 52, wherein, The X-ray powder diffraction pattern of the crystalline form J-1 has characteristic peaks at the following 2θ angles: 4.43 ± 0.2°, 8.73 ± 0.2°, 11.53 ± 0.2°, 15.72 ± 0.2°, 20.13 ± 0.2°, 21.93 ± 0.2°, 23.99 ± 0.2°.

54. The solid form according to claim 52, wherein, The 2θ diffraction angles, d values and / or relative intensities of the X-ray powder pattern of the crystalline form J-1 obtained with Cu-Kα radiation are as follows:

55. The solid form according to claim 53, wherein, The crystalline form J-1 has an X-ray powder diffraction pattern substantially as shown in Figure 8-1.

56. The solid form according to claim 54, wherein, The crystalline form J-1 has one or both of the following characteristics: (1) The TGA curve of crystalline form J-1 has a weight loss of about 7.91% at 150.0 ± 3 °C; (2) The DSC curve of crystalline form J-1 has two endothermic peaks at 96.6 ± 3 °C and 157.6 ± 3 °C.

57. A solid form of the compound of formula (I), wherein the solid form is crystalline form J-2 of methyl isobutyl ketone complex: The X-ray powder diffraction pattern of the crystalline form J-2 obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 4.31 ± 0.2°, 8.56 ± 0.2°, 11.32 ± 0.2°, 15.44 ± 0.2°, 19.64 ± 0.2°.

58. The solid form according to claim 57, wherein, The X-ray powder diffraction pattern of the crystalline form J-2 has characteristic peaks at the following 2θ angles: 4.31 ± 0.2°, 8.56 ± 0.2°, 11.32 ± 0.2°, 15.44 ± 0.2°, 19.64 ± 0.2°, 21.80 ± 0.2°, 23.90 ± 0.2°.

59. The solid form according to claim 57, wherein, The X-ray powder diffraction pattern of the crystalline form J-2 has characteristic peaks at the following 2θ angles: 4.31 ± 0.2°, 8.56 ± 0.2°, 11.32 ± 0.2°, 14.84 ± 0.2°, 15.44 ± 0.2°, 16.46 ± 0.2°, 17.15 ± 0.2°, 19.64 ± 0.2°, 21.80 ± 0.2, 23.42 ± 0.2°, 23.90 ± 0.2°, 24.24 ± 0.2°.

60. The solid form according to claim 57, wherein, The 2θ diffraction angle, D value and / or relative intensity of the X-ray powder pattern of the crystalline form J-2 obtained using Cu-Kα radiation are as follows:

61. The solid form according to claim 57, wherein, The crystalline form J-2 has an X-ray powder diffraction pattern substantially as shown in Figure 8-2.

62. The solid form according to claim 57, wherein, The crystalline form J-2 has one or both of the following characteristics: (1) The TGA curve of crystalline form J-2 has a weight loss of about 19.07% at 150.0 ± 3 °C; (2) The DSC curve of crystalline form J-2 has an endothermic peak at 94.3 ± 3 °C.

63. A solid form of the compound of formula (I), wherein the solid form is crystalline form K: The X-ray powder diffraction pattern of the crystalline form K obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 6.93 ± 0.2°, 13.89 ± 0.2°, 14.81 ± 0.2°, 20.91 ± 0.2°, 25.00 ± 0.2°, 25.72 ± 0.2°.

64. The solid form according to claim 63, wherein, The X-ray powder diffraction pattern of crystalline form K has characteristic peaks at the following 2θ angles: 6.93±0.2°, 13.89±0.2°, 14.81±0.2°, 18.77±0.2°, 20.91±0.2°, 25.00±0.2°, 25.72±0.2°, 28.04±0.2°.

65. The solid form according to claim 63, wherein, the X-ray powder diffraction pattern of crystalline form K has characteristic peaks at the following 2θ angles: 6.93±0.2°, 11.49±0.2°, 13.89±0.2°, 14.81±0.2°, 18.77±0.2°, 20.05±0.2°, 20.91±0.2°, 21.87±0.2°, 25.00±0.2°, 25.72±0.2°, 28.04±0.2°.

66. The solid form according to claim 63, wherein, the 2θ diffraction angles, D values and / or relative intensities of the X-ray powder pattern of crystalline form K obtained using Cu-Kα radiation are as follows:

67. The solid form according to claim 63, wherein, crystalline form K has an X-ray powder diffraction pattern substantially as shown in Figure 9.

68. The solid form according to claim 63, wherein, crystalline form K has one, two or three of the following characteristics: (1) The TGA curve of crystalline form K shows a weight loss of about 10.13% at 150.0±3°C; (2) The DSC curve of crystalline form K has a starting point of an endothermic peak at 104.5±3°C; (3) The DSC curve of crystalline form K has an endothermic peak at 110.7±3°C.

69. A solid form of the compound of formula (I), said solid form being crystalline form L: The X-ray powder diffraction pattern of crystalline form L obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 6.07±0.2°, 7.01±0.2°, 7.48±0.2°, 14.05±0.2°, 19.44±0.2°, 21.73±0.2°.

70. The solid form according to claim 69, wherein, the X-ray powder diffraction pattern of crystalline form L has characteristic peaks at the following 2θ angles: 6.07±0.2°, 7.01±0.2°, 7.48±0.2°, 9.16±0.2°, 12.13±0.2°, 14.05±0.2°, 14.44±0.2°, 16.49±0.2°, 19.44±0.2°, 21.73±0.2°.

71. The solid form according to claim 69, wherein, The X-ray powder diffraction pattern of polymorph L has characteristic peaks at the following 2θ angles: 6.07±0.2°, 7.01±0.2°, 7.48±0.2°, 9.16±0.2°, 10.22±0.2°, 11.41±0.2°, 12.13±0.2°, 14.05±0.2°, 14.44±0.2°, 16.49±0.2°, 18.32±0.2°, 19.44±0.2°, 21.73±0.2°.

72. The solid form according to claim 69, wherein, the X-ray powder diffraction pattern of polymorph L has characteristic peaks at the following 2θ angles: 6.07±0.2°, 7.01±0.2°, 7.48±0.2°, 8.19±0.2°, 9.16±0.2°, 10.22±0.2°, 11.41±0.2°, 12.13±0.2°, 14.05±0.2°, 14.44±0.2°, 16.49±0.2°, 18.32±0.2°, 19.44±0.2°, 20.55±0.2°, 21.73±0.2°, 24.21±0.2°, 25.54±0.2°.

73. The solid form according to claim 69, wherein, the 2θ diffraction angles, d-values and / or relative intensities of the X-ray powder pattern of polymorph L obtained using Cu-Kα radiation are as follows:

74. The solid form according to claim 69, wherein, polymorph L has an X-ray powder diffraction pattern substantially as shown in Figure 10.

75. The solid form according to claim 69, wherein, polymorph L has one, two or three of the following characteristics: (1) The TGA curve of polymorph L shows a weight loss of about 3.00% at 150.0±3°C; (2) The DSC curve of polymorph L has an endothermic peak at 114.6±10°C; (3) The DSC curve of polymorph L has an endothermic peak at 62.3±10°C.

76. The solid form according to claim 75, wherein, the DSC curve of polymorph L has an endothermic peak at 114.6±5°C.

77. The solid form according to claim 75, wherein, the DSC curve of polymorph L has an endothermic peak at 62.3±5°C.

78. A solid form of the compound of formula (I), said solid form being polymorph M-1 of the monohydrate: The X-ray powder diffraction pattern of polymorph M-1 obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.02±0.2°, 7.45±0.2°, 7.96±0.2°, 8.63±0.2°, 10.05±0.2°, 15.97±0.2°.

79. The solid form according to claim 78, wherein, The X-ray powder diffraction pattern of the crystalline form M-1 has characteristic peaks at the following 2θ angles: 5.02 ± 0.2°, 7.45 ± 0.2°, 7.96 ± 0.2°, 8.63 ± 0.2°, 9.42 ± 0.2°, 10.05 ± 0.2°, 12.25 ± 0.2°, 15.97 ± 0.2°, 21.60 ± 0.2°.

80. The solid form according to claim 78, wherein, the X-ray powder diffraction pattern of the crystalline form M-1 has characteristic peaks at the following 2θ angles: 5.02 ± 0.2°, 7.45 ± 0.2°, 7.96 ± 0.2°, 8.63 ± 0.2°, 9.42 ± 0.2°, 10.05 ± 0.2°, 12.25 ± 0.2°, 13.31 ± 0.2°, 14.16 ± 0.2°, 15.97 ± 0.2°, 18.96 ± 0.2°, 20.02 ± 0.2°, 21.60 ± 0.2°.

81. The solid form according to claim 78, wherein, the 2θ diffraction angles, d values and / or relative intensities of the X-ray powder pattern of the crystalline form M-1 obtained using Cu-Kα radiation are as follows:

82. The solid form according to claim 78, wherein, the crystalline form M-1 has an X-ray powder diffraction pattern substantially as shown in Figure 11-1.

83. The solid form according to claim 78, wherein, the crystalline form M-1 has one or both of the following characteristics: (1) The TGA curve of the crystalline form M-1 shows a weight loss of approximately 4.31% at 150.0 ± 3°C; (2) The DSC curve of the crystalline form M-1 has two endothermic peaks at 77.7 ± 3°C and 96.5 ± 3°C.

84. The solid form of the compound of formula (I) is the crystalline form M-2 of a mono-acetonitrile complex: The X-ray powder diffraction pattern of the crystalline form M-2 obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.01 ± 0.2°, 7.10 ± 0.2°, 7.45 ± 0.2°, 7.96 ± 0.2°, 8.63 ± 0.2°, 9.41 ± 0.2°, 15.94 ± 0.2°, 21.57 ± 0.2°, 23.51 ± 0.2°.

85. The solid form according to claim 84, wherein, the X-ray powder diffraction pattern of the crystalline form M-2 has characteristic peaks at the following 2θ angles: 5.01 ± 0.2°, 7.10 ± 0.2°, 7.45 ± 0.2°, 7.96 ± 0.2°, 8.63 ± 0.2°, 9.41 ± 0.2°, 15.94 ± 0.2°, 19.66 ± 0.2°, 21.57 ± 0.2°, 23.51 ± 0.2°, 24.30 ± 0.2°, 25.22 ± 0.2°.

86. The solid form according to claim 84, wherein, The X-ray powder diffraction pattern of the crystal form M-2 has characteristic peaks at the following 2θ angles: 5.01 ± 0.2°, 7.10 ± 0.2°, 7.45 ± 0.2°, 7.96 ± 0.2°, 8.63 ± 0.2°, 9.41 ± 0.2°, 9.99 ± 0.2°, 15.94 ± 0.2°, 17.29 ± 0.2°, 19.66 ± 0.2°, 21.57 ± 0.2°, 22.48 ± 0.2°, 23.51 ± 0.2°, 24.30 ± 0.2°, 25.22 ± 0.2°, 27.14 ± 0.2°.

87. The solid form according to claim 84, wherein, the 2θ diffraction angle, D value, and / or relative intensity of the X-ray powder pattern of the crystal form M-2 obtained using Cu-Kα radiation are as follows:

88. The solid form according to claim 84, wherein, the crystal form M-2 has an X-ray powder diffraction pattern substantially as shown in Figure 11-2.

89. The solid form according to claim 84, wherein, the crystal form M-2 has one or both of the following characteristics: (1) The TGA curve of the crystal form M-2 shows a weight loss of approximately 8.36% at 150.0 ± 3°C; and (2) The DSC curve of the crystal form M-2 has an endothermic peak at 124.6 ± 10°C.

90. The solid form according to claim 89, wherein, the DSC curve of the crystal form M-2 has an endothermic peak at 124.6 ± 5°C.

91. A solid form of the compound of formula (I), wherein the solid form is crystal form N: The X-ray powder diffraction pattern of the crystal form N obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 7.07 ± 0.2°, 7.21 ± 0.2°, 14.41 ± 0.2°, 19.46 ± 0.2°, 21.30 ± 0.2°, 21.93 ± 0.2°, 25.37 ± 0.2°.

92. The solid form according to claim 91, wherein, the X-ray powder diffraction pattern of the crystal form N has characteristic peaks at the following 2θ angles: 7.07 ± 0.2°, 7.21 ± 0.2°, 14.41 ± 0.2°, 19.46 ± 0.2°, 20.28 ± 0.2°, 21.30 ± 0.2°, 21.93 ± 0.2°, 25.37 ± 0.2°, 26.04 ± 0.2°.

93. The solid form according to claim 91, wherein, the X-ray powder diffraction pattern of the crystal form N has characteristic peaks at the following 2θ angles: 7.07 ± 0.2°, 7.21 ± 0.2°, 14.41 ± 0.2°, 16.33 ± 0.2°, 19.46 ± 0.2°, 19.73 ± 0.2°, 20.28 ± 0.2°, 20.82 ± 0.2°, 21.30 ± 0.2°, 21.93 ± 0.2°, 25.37 ± 0.2°, 26.04 ± 0.2°.

94. The solid form according to claim 91, wherein, The X-ray powder diffraction pattern of polymorph N has characteristic peaks at the following 2θ angles: 7.07±0.2°, 7.21±0.2°, 10.08±0.2°, 13.75±0.2°, 14.41±0.2°, 14.41±0.2°, 15.06±0.2°, 16.33±0.2°, 19.46±0.2°, 19.73±0.2°, 20.28±0.2°, 20.82±0.2°, 21.30±0.2°, 21.93±0.2°, 25.37±0.2°, 26.04±0.2°, 27.33±0.2°, 28.53±0.2°, 29.39±0.2°.

95. The solid form according to claim 91, wherein, the 2θ diffraction angles, D values and / or relative intensities of the X-ray powder pattern of polymorph N obtained using Cu-Kα radiation are as follows:

96. The solid form according to claim 91, wherein, polymorph N has an X-ray powder diffraction pattern substantially as shown in Figure 12.

97. The solid form according to claim 91, wherein, polymorph N has one, two, three or four of the following characteristics: (1) The TGA curve of polymorph N shows a weight loss of about 2.98% at 90.0±3°C and a weight loss of about 13.10% at 150.0±3°C; (2) The DSC curve of polymorph N has a starting point of an endothermic peak at 107.5±3°C; (3) The DSC curve of polymorph N has an endothermic peak at 118.9±10°C; (4) of Polymorph N 1 The 1H NMR spectrum has characteristic hydrogen signals of dichloromethane.

98. The solid form according to claim 97, wherein, the DSC curve of polymorph N has an endothermic peak at 118.9±5°C.

99. The solid form of the compound of formula (I), wherein the solid form is polymorph P: The X-ray powder diffraction pattern of polymorph P obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 7.13±0.2°, 9.63±0.2°, 14.43±0.2°, 19.12±0.2°, 21.03±0.2°, 21.53±0.2°, 25.46±0.2°, 25.91±0.2°.

100. The solid form according to claim 99, wherein, the X-ray powder diffraction pattern of polymorph P has characteristic peaks at the following 2θ angles: 7.13±0.2°, 9.63±0.2°, 11.69±0.2°, 13.59±0.2°, 14.43±0.2°, 19.12±0.2°, 20.55±0.2°, 21.03±0.2°, 21.53±0.2°, 25.46±0.2°, 25.91±0.2°, 27.03±0.2°.

101. The solid form according to claim 99, wherein, The X-ray powder diffraction pattern of the crystalline form P has characteristic peaks at the following 2θ angles: 7.13±0.2°, 9.63±0.2°, 11.69±0.2°, 13.59±0.2°, 14.43±0.2°, 15.18±0.2°, 16.35±0.2°, 17.75±0.2°, 19.12±0.2°, 20.55±0.2°, 21.03±0.2°, 21.53±0.2°, 23.46±0.2°, 25.46±0.2°, 25.91±0.2°, 27.03±0.2°, 28.89±0.2°.

102. The solid form according to claim 99, wherein, the 2θ diffraction angles, D values and relative intensities of the X-ray powder pattern of the crystalline form P obtained using Cu-Kα radiation are as follows:

103. The solid form according to claim 99, wherein, the crystalline form P has an X-ray powder diffraction pattern substantially as shown in Figure 13.

104. The solid form according to claim 99, wherein, the crystalline form P has one, two or three of the following characteristics: (1) The TGA curve of the crystalline form P shows a weight loss of about 10.85% at 150.0±3°C; (2) The DSC curve of the crystalline form P has two endothermic peaks at 66.4±10°C and 103.1±10°C; (3) The 1 1H NMR spectrum of polymorph P has characteristic hydrogen signals of isopropanol.

105. The solid form according to claim 104, wherein, the DSC curve of the crystalline form P has two endothermic peaks at 66.4±5°C and 103.1±5°C.

106. The solid form of the compound of formula (I), which is an amorphous form, and has an X-ray powder diffraction pattern substantially as shown in Figure 14.

107. A pharmaceutical composition comprising the solid form according to any one of claims 1-106, or a mixture of any two or more thereof.

108. Use of the solid form according to any one of claims 1-106, or a mixture of any two or more thereof, or the pharmaceutical composition according to claim 107 for the preparation of a medicament for the treatment and / or prevention of diseases related to autotaxin ATX.

109. The use according to claim 108, wherein, the ATX-related diseases are selected from at least one of the following: cancer, metabolic diseases, kidney diseases, liver diseases, fibrotic diseases, interstitial lung diseases, proliferative diseases, inflammatory diseases, pain, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders and / or diseases related to abnormal angiogenesis.

110. The use according to claim 108, wherein, the ATX-related diseases are selected from at least one of the following: interstitial lung disease, pulmonary fibrosis, liver fibrosis, renal fibrosis.

111. The use according to claim 108, wherein, the ATX-related diseases are selected from idiopathic pulmonary fibrosis, type II diabetes, non-alcoholic steatohepatitis, neuropathic pain, inflammatory pain.

112. The use according to claim 108, wherein, the ATX-related disease is selected from pain related to osteoarthritis.

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