Salts of nitrogen-containing heterocyclic compounds, solid forms of such salts, pharmaceutical compositions and uses thereof

Abstract

The present invention provides salts of the compound of formula (I) having ATX inhibitory activity, including inorganic acid salts or organic acid salts, as well as solid forms of the salts, such as crystalline forms. The salts of the compound of formula (I) of the present invention and their crystalline forms have good solubility, stability and hygroscopicity, and are more suitable for pharmaceutical use; moreover, their preparation methods are simple and easy to implement, and are suitable for large-scale production.

Description

[0001] This application claims the priority of a prior application filed by the applicant with the China National Intellectual Property Administration on July 28, 2020, with the patent application number 202010727300.5 and the invention title "Salt of a nitrogen-containing heterocyclic compound and its solid form, pharmaceutical composition and use". 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 medicinal chemistry, and specifically relates to a salt of a nitrogen-containing heterocyclic compound, its solid form, pharmaceutical composition and use. 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. ATX also has lysophospholipase D (LysoPLD) activity and can hydrolyze lysophosphatidylcholine (LPC) into biologically active 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. It has now been found that ATX inhibitors can be used to treat 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, it is necessary to develop suitable salt forms and their solid forms to obtain improved drug properties or other characteristics. Summary of the Invention

[0007] To solve the above technical problems, the present invention provides a salt of a compound of formula (I) or a solid form of such a salt:

[0008]

[0009] Wherein, the salt is selected from inorganic acid salts or organic acid salts; the solid form may be a crystal form or an amorphous substance.

[0010] According to an embodiment of the present invention, the inorganic acid salt is a salt formed by a compound of formula (I) and an inorganic acid. Preferably, the inorganic acid is selected from one or more of the following: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid.

[0011] According to an embodiment of the present invention, the inorganic acid salt includes but is not limited to one or more salts selected from the salts of the following compounds of formula (I): hydrochloride, sulfate, phosphate, hydrobromide, etc.

[0012] According to an embodiment of the present invention, the organic acid salt is a salt formed by a compound of formula (I) and an organic acid. Preferably, the organic acid is selected from one or more of the following: aspartic acid, maleic acid, glutamic acid, mucic acid, tartaric acid, fumaric acid, citric acid, glycolic acid, malic acid, hippuric acid, lactic acid, ascorbic acid, succinic acid, adipic acid, sebacic acid, lauric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, nicotinic acid.

[0013] According to an embodiment of the present invention, the organic acid salt includes but is not limited to one or more salts selected from the salts of the following compounds of formula (I): aspartate, maleate, glutamate, mucate, tartrate, fumarate, citrate, glycolate, malate, hippurate, lactate, ascorbate, succinate, adipate, sebacate, laurate, p-toluenesulfonate, methanesulfonate, benzenesulfonate, benzoate, nicotinate, etc.

[0014] According to an exemplary embodiment of the present invention, the salt is selected from the hydrochloride, fumarate or benzenesulfonate of the compound of formula (I).

[0015] According to an embodiment of the present invention, in the salt, the molar ratio of the compound of formula (I) to the acid forming the salt (such as an inorganic acid or an organic acid) can be 1:(0.5 - 2), for example 1:(0.5 - 1).

[0016] According to an embodiment of the present invention, the crystalline form may be selected from solid forms of the following salts of the compound of formula (I): hydrochloride (1:1), sulfate (1:1), maleate (1:1), phosphate (1:1), tartrate (1:1), fumarate (1:1), citrate (1:1), glycolate (1:0.5), succinate (1:(0.5 - 1)), adipate (1:1), sebacate (1:1), p-toluenesulfonate (1:1), benzenesulfonate (1:1), and hydrobromide (1:1), such as their crystalline forms or amorphous forms. Among them, the ratios given in parentheses after each salt are the molar ratios of the compound of formula (I) to the corresponding acid in the salt. In the context of the present invention, when referring to the salts, they all have the molar ratios described in the parentheses.

[0017] According to an embodiment of the present invention, the crystalline form may be selected from crystalline forms of the following salts of the compound of formula (I): hydrochloride crystalline form A, sulfate crystalline form A, maleate crystalline form A, phosphate crystalline form A, tartrate crystalline form A, tartrate crystalline form B, tartrate crystalline form C, fumarate crystalline form A, citrate crystalline form A, glycolate crystalline form A, succinate crystalline form A, succinate crystalline form B, adipate crystalline form B, sebacate crystalline form A, p-toluenesulfonate crystalline form A, benzenesulfonate crystalline form A, hydrobromide crystalline form A, or hydrobromide crystalline form B, such as being selected from hydrochloride crystalline form A, fumarate crystalline form A, or benzenesulfonate crystalline form A of the compound of formula (I).

[0018] In the context of the present invention, unless otherwise specified, the error range of the 2θ angle values in the X-ray powder diffraction (XRPD) data is ±0.2°.

[0019] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 7.48 ± 0.20°, 13.13 ± 0.20°, 16.47 ± 0.20°, 23.94 ± 0.20°.

[0020] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form A has characteristic peaks at the following 2θ angles: 7.48 ± 0.20°, 13.13 ± 0.20°, 16.47 ± 0.20°, 18.29 ± 0.20°, 19.89 ± 0.20°, 23.94 ± 0.20°.

[0021] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystal form A has characteristic peaks at the following 2θ angles: 7.48 ± 0.20°, 13.13 ± 0.20°, 14.86 ± 0.20°, 16.47 ± 0.20°, 18.29 ± 0.20°, 19.89 ± 0.20°, 23.94 ± 0.20°, 26.92 ± 0.20°.

[0022] According to an embodiment of the present invention, the 2θ diffraction angle, D value and / or relative intensity of the X-ray powder diffraction pattern of the hydrochloride crystal form A obtained using Cu-Kα radiation are shown in Table 1 below:

[0023] Table 1 XRPD diffraction peak data of hydrochloride crystal form A

[0024]

[0025] According to an embodiment of the present invention, the hydrochloride crystal form A has an X-ray powder diffraction pattern substantially as Figure 1 shown.

[0026] According to an embodiment of the present invention, the hydrochloride crystal form A has one, two, three or four of the following characteristics:

[0027] (1) The TGA curve of the hydrochloride crystal form A shows a weight loss of about 2.83% at 150.0 ± 3°C;

[0028] (2) The DSC curve of the hydrochloride crystal form A has a starting point of an endothermic peak at 163.5 ± 3°C;

[0029] (3) The DSC curve of the hydrochloride crystal form A has an endothermic peak at 170.9 ± 10°C; in particular, the DSC curve of the hydrochloride crystal form A has an endothermic peak at 170.9 ± 5°C;

[0030] (4) The DVS curve of the hydrochloride crystal form A shows less than about 10% water adsorption, such as less than about 5%, in particular less than about 3.85%, under conditions of 0% RH to 80% RH.

[0031] According to an embodiment of the present invention, the hydrochloride crystal form A has one, two or three of the following characteristics:

[0032] (1) The hydrochloride crystal form A has a TGA curve substantially as Figure 20 shown;

[0033] (2) The hydrochloride crystal form A has a DSC curve substantially as Figure 20 shown;

[0034] (3) The hydrochloride crystal form A has a DVS curve substantially as Figure 37The DVS curve shown

[0035] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the sulfate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.49 ± 0.20°, 15.88 ± 0.20°, 17.48 ± 0.20°, 22.40 ± 0.20°.

[0036] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the sulfate crystal form A has characteristic peaks at the following 2θ angles: 5.49 ± 0.20°, 6.93 ± 0.20°, 11.08 ± 0.20°, 15.88 ± 0.20°, 17.48 ± 0.20°, 20.82 ± 0.20°, 22.40 ± 0.20°.

[0037] According to an embodiment of the present invention, the 2θ diffraction angle, D value, and / or relative intensity of the X-ray powder diffraction pattern of the sulfate crystal form A obtained using Cu-Kα radiation are as shown in Table 2 below:

[0038] Table 2 XRPD diffraction peak data of sulfate crystal form A

[0039]

[0040] According to an embodiment of the present invention, the sulfate crystal form A has an X-ray powder diffraction pattern substantially as Figure 2 shown

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

[0042] (1) The TGA curve of the sulfate crystal form A shows a weight loss of approximately 3.53% at 150.0 ± 3°C;

[0043] (2) The DSC curve of the sulfate crystal form A has a starting point of an endothermic peak at 131.8 ± 3°C;

[0044] (3) The DSC curve of the sulfate crystal form A has an endothermic peak at 141.9 ± 10°C; in particular, the DSC curve of the sulfate crystal form A has an endothermic peak at 141.9 ± 5°C.

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

[0046] (1) The sulfate crystal form A has a TGA curve substantially as Figure 21 shown

[0047] (2) The sulfate crystal form A has a DSC curve substantially as Figure 21 shown

[0048] According to an embodiment of the present invention, the maleate crystal form A has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern obtained using Cu-Kα radiation: 4.43 ± 0.20°, 13.86 ± 0.20°, 14.41 ± 0.20°, 15.00 ± 0.20°, 22.07 ± 0.20°, 22.65 ± 0.20°, 25.58 ± 0.20°, 27.34 ± 0.20°.

[0049] According to an embodiment of the present invention, the maleate crystal form A has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern: 4.43 ± 0.20°, 9.92 ± 0.20°, 13.86 ± 0.20°, 14.41 ± 0.20°, 15.00 ± 0.20°, 17.82 ± 0.20°, 22.07 ± 0.20°, 22.65 ± 0.20°, 25.58 ± 0.20°, 27.34 ± 0.20°.

[0050] According to an embodiment of the present invention, the maleate crystal form A has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern: 4.43 ± 0.20°, 9.92 ± 0.20°, 13.86 ± 0.20°, 14.41 ± 0.20°, 15.00 ± 0.20°, 17.82 ± 0.20°, 22.07 ± 0.20°, 22.65 ± 0.20°, 24.20 ± 0.20°, 24.53 ± 0.20°, 25.58 ± 0.20°, 25.84 ± 0.20°, 27.34 ± 0.20°.

[0051] According to an embodiment of the present invention, the 2θ diffraction angle, D value, and / or relative intensity of the X-ray powder diffraction pattern of the maleate crystal form A obtained using Cu-Kα radiation are as shown in Table 3 below:

[0052] Table 3 XRPD diffraction peak data of maleate crystal form A

[0053]

[0054]

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

[0056] According to an embodiment of the present invention, the maleate crystal form A has one or both of the following characteristics:

[0057] (1) The TGA curve of the maleate crystal form A shows a weight loss of approximately 10.48% at 150.0 ± 3°C;

[0058] (2) The DSC curve of maleate polymorph A has two endothermic peaks at 103.0 ± 10 °C and 132.8 ± 10 °C; in particular, the DSC curve of maleate polymorph A has two endothermic peaks at 103.0 ± 5 °C and 132.8 ± 5 °C.

[0059] According to an embodiment of the present invention, the maleate polymorph A has one or both of the following characteristics:

[0060] (1) Maleate polymorph A has a TGA curve substantially as Figure 22 shown;

[0061] (2) Maleate polymorph A has a DSC curve substantially as Figure 22 shown.

[0062] According to an embodiment of the present invention, the phosphate polymorph A has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern obtained using Cu-Kα radiation: 5.08 ± 0.20 °, 15.93 ± 0.20 °, 24.37 ± 0.20 °, 25.19 ± 0.20 °.

[0063] According to an embodiment of the present invention, the 2θ diffraction angle, d-value, and / or relative intensity of the X-ray powder diffraction pattern of the phosphate polymorph A obtained using Cu-Kα radiation are as shown in Table 4 below:

[0064] Table 4 XRPD diffraction peak data of phosphate polymorph A

[0065]

[0066] According to an embodiment of the present invention, the phosphate polymorph A has an X-ray powder diffraction pattern substantially as Figure 4 shown.

[0067] According to an embodiment of the present invention, the phosphate polymorph A has one or both of the following characteristics:

[0068] (1) The TGA curve of the phosphate polymorph A shows a weight loss of approximately 12.68% at 150.0 ± 3 °C;

[0069] (2) The DSC curve of the phosphate polymorph A has two endothermic peaks at 89.4 ± 3 °C and 94.3 ± 3 °C.

[0070] According to an embodiment of the present invention, the phosphate polymorph A has one or both of the following characteristics:

[0071] (1) The phosphate polymorph A has a TGA curve substantially as Figure 23 shown;

[0072] (2) The phosphate crystal form A has a DSC curve substantially as Figure 23 shown.

[0073] According to an embodiment of the present invention, the tartrate crystal form A has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern obtained using Cu-Kα radiation: 5.00 ± 0.20°, 15.88 ± 0.20°.

[0074] According to an embodiment of the present invention, the tartrate crystal form A has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern: 5.00 ± 0.20°, 7.34 ± 0.20°, 8.59 ± 0.20°, 15.88, 19.54 ± 0.20°, 21.46 ± 0.20°, 23.43 ± 0.20°, 25.08 ± 0.20°.

[0075] According to an embodiment of the present invention, the 2θ diffraction angle, D value, and / or relative intensity of the X-ray powder diffraction pattern of the tartrate crystal form A obtained using Cu-Kα radiation are as shown in Table 5 below:

[0076] Table 5 XRPD diffraction peak data of tartrate crystal form A

[0077]

[0078] According to an embodiment of the present invention, the tartrate crystal form A has a X-ray powder diffraction pattern substantially as Figure 5 shown.

[0079] According to an embodiment of the present invention, the tartrate crystal form A has one or both of the following characteristics:

[0080] (1) The TGA curve of the tartrate crystal form A shows a weight loss of about 14.67% at 150.0 ± 3°C;

[0081] (2) The DSC curve of the tartrate crystal form A has an endothermic peak at 96.8 ± 10°C; in particular, the DSC curve of the tartrate crystal form A has an endothermic peak at 96.8 ± 5°C.

[0082] According to an embodiment of the present invention, the tartrate crystal form A has one or both of the following characteristics:

[0083] (1) The tartrate crystal form A has a TGA curve substantially as Figure 24 shown;

[0084] (2) The tartrate crystal form A has a DSC curve substantially as Figure 24 shown.

[0085] According to an embodiment of the present invention, the tartrate crystal form B has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern obtained using Cu-Kα radiation: 5.24 ± 0.20°, 23.94 ± 0.20°.

[0086] According to an embodiment of the present invention, the 2θ diffraction angle, d-value and / or relative intensity in the X-ray powder diffraction pattern of the tartrate crystal form B obtained using Cu-Kα radiation are as shown in Table 6 below:

[0087] Table 6 XRPD diffraction peak data of tartrate crystal form B

[0088]

[0089] According to an embodiment of the present invention, the tartrate crystal form B has substantially the Figure 6 as shown X-ray powder diffraction pattern.

[0090] According to an embodiment of the present invention, the tartrate crystal form B has one, two or three of the following characteristics:

[0091] (1) The TGA curve of the tartrate crystal form B shows a weight loss of about 4.87% at 150.0 ± 3 °C;

[0092] (2) The DSC curve of the tartrate crystal form B has a starting point of an endothermic peak at 173.9 ± 3 °C;

[0093] (3) The DSC curve of the tartrate crystal form B has an endothermic peak at 175.3 ± 3 °C.

[0094] According to an embodiment of the present invention, the tartrate crystal form B has one or two of the following characteristics:

[0095] (1) The tartrate crystal form B has substantially the Figure 25 as shown TGA curve;

[0096] (2) The tartrate crystal form B has substantially the Figure 25 as shown DSC curve.

[0097] According to an embodiment of the present invention, the tartrate crystal form C has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern obtained using Cu-Kα radiation: 4.60 ± 0.20°, 16.15 ± 0.20°, 18.13 ± 0.20°.

[0098] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the tartrate crystal form C has characteristic peaks at the following 2θ angles: 4.60 ± 0.20°, 7.58 ± 0.20°, 14.39 ± 0.20°, 16.15 ± 0.20°, 18.13 ± 0.20°, 22.32 ± 0.20°, 24.44 ± 0.20°, 26.69 ± 0.20°.

[0099] According to an embodiment of the present invention, the 2θ diffraction angle, D value, and / or relative intensity in the X-ray powder diffraction pattern of the tartrate crystal form C using Cu-Kα radiation are as shown in Table 7 below:

[0100] Table 7 XRPD diffraction peak data of tartrate crystal form C

[0101]

[0102] According to an embodiment of the present invention, the tartrate crystal form C has an X-ray powder diffraction pattern substantially as Figure 7 shown.

[0103] According to an embodiment of the present invention, the fumarate crystal form A has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern obtained using Cu-Kα radiation: 9.52 ± 0.20°, 13.29 ± 0.20°, 14.92 ± 0.20°, 25.23 ± 0.20°.

[0104] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the fumarate crystal form A has characteristic peaks at the following 2θ angles: 9.52 ± 0.20°, 13.29 ± 0.20°, 14.92 ± 0.20°, 19.02 ± 0.20°, 21.39 ± 0.20°, 25.23 ± 0.20°, 28.07 ± 0.20°.

[0105] According to an embodiment of the present invention, the 2θ diffraction angle, D value, and / or relative intensity in the X-ray powder diffraction pattern of the fumarate crystal form A obtained using Cu-Kα radiation are as shown in Table 8 below:

[0106] Table 8 XRPD diffraction peak data of fumarate crystal form A

[0107]

[0108]

[0109] According to an embodiment of the present invention, the fumarate crystal form A has an X-ray powder diffraction pattern substantially as Figure 8 shown.

[0110] According to an embodiment of the present invention, the fumarate polymorph A has one, two, three or four of the following characteristics:

[0111] (1) The TGA curve of the fumarate polymorph A shows a weight loss of about 3.86% at 150.0 ± 3 °C;

[0112] (2) The DSC curve of the fumarate polymorph A has a starting point of an endothermic peak at 208.6 ± 3 °C;

[0113] (3) The DSC curve of the fumarate polymorph A has an endothermic peak at 210.2 ± 3 °C;

[0114] (4) The DVS curve of the fumarate polymorph A shows a water adsorption of less than about 1%, such as less than about 0.8%, particularly less than about 0.60% under the conditions of 0% RH to 80% RH.

[0115] According to an embodiment of the present invention, the fumarate polymorph A has one, two or three of the following characteristics:

[0116] (1) The fumarate polymorph A has a TGA curve substantially as Figure 26 shown;

[0117] (2) The fumarate polymorph A has a DSC curve substantially as Figure 26 shown;

[0118] (3) The fumarate polymorph A has a DVS curve substantially as Figure 38 shown.

[0119] According to an embodiment of the present invention, the citrate polymorph A has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern obtained using Cu-Kα radiation: 4.96 ± 0.20 °, 15.76 ± 0.20 °.

[0120] According to an embodiment of the present invention, the 2θ diffraction angle, d-value and / or relative intensity in the X-ray powder diffraction pattern of the citrate polymorph A obtained using Cu-Kα radiation are as shown in Table 9 below:

[0121] Table 9 XRPD diffraction peak data of citrate polymorph A

[0122]

[0123] According to an embodiment of the present invention, the citrate polymorph A has an X-ray diffraction powder pattern substantially as Figure 9 shown.

[0124] According to an embodiment of the present invention, the citrate polymorph A has one or two of the following characteristics:

[0125] (1) The TGA curve of citrate crystal form A shows a weight loss of approximately 10.24% at 150.0 ± 3 °C;

[0126] (2) The DSC curve of citrate crystal form A has an endothermic peak at 91.2 ± 5 °C; in particular, the DSC curve of citrate crystal form A has an endothermic peak at 91.2 ± 3 °C.

[0127] According to an embodiment of the present invention, the citrate crystal form A has one or both of the following characteristics:

[0128] (1) Citrate crystal form A has a TGA curve substantially as Figure 27 shown;

[0129] (2) Citrate crystal form A has a DSC curve substantially as Figure 27 shown.

[0130] According to an embodiment of the present invention, the glycolate crystal form A obtained by Cu-Kα radiation has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern: 5.26 ± 0.20 °, 7.27 ± 0.20 °, 14.12 ± 0.20 °, 16.02 ± 0.20 °, 24.11 ± 0.20 °.

[0131] According to an embodiment of the present invention, the 2θ diffraction angle, D value, and / or relative intensity in the X-ray powder diffraction pattern of the glycolate crystal form A obtained by Cu-Kα radiation are as shown in Table 10 below:

[0132] Table 10 XRPD diffraction peak data of glycolate crystal form A

[0133]

[0134] According to an embodiment of the present invention, the glycolate crystal form A has a X-ray powder diffraction pattern substantially as Figure 10 shown.

[0135] According to an embodiment of the present invention, the glycolate crystal form A has one or both of the following characteristics:

[0136] (1) The TGA curve of glycolate crystal form A shows a weight loss of approximately 7.72% at 150.0 ± 3 °C;

[0137] (2) The DSC curve of glycolate crystal form A has an endothermic peak at 103.1 ± 15 °C; in particular, the DSC curve of glycolate crystal form A has an endothermic peak at 103.1 ± 10 °C.

[0138] According to an embodiment of the present invention, the glycolate crystal form A has one or both of the following characteristics:

[0139] (1) The glycollate crystal form A has a TGA curve substantially as Figure 28 shown;

[0140] (2) The glycollate crystal form A has a DSC curve substantially as Figure 28 shown.

[0141] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the succinate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.26 ± 0.20°, 14.00 ± 0.20°, 15.76 ± 0.20°, 21.07 ± 0.20°, 22.00 ± 0.20°, 27.08 ± 0.20°.

[0142] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the succinate crystal form A has characteristic peaks at the following 2θ angles: 5.26 ± 0.20°, 6.99 ± 0.20°, 7.35 ± 0.20°, 14.00 ± 0.20°, 15.76 ± 0.20°, 21.07 ± 0.20°, 22.00 ± 0.20°, 27.08 ± 0.20°.

[0143] According to an embodiment of the present invention, the 2θ diffraction angles, d values, and / or relative intensities in the X-ray powder diffraction pattern of the succinate crystal form A obtained using Cu-Kα radiation are as shown in Table 11 below:

[0144] Table 11 XRPD diffraction peak data of succinate crystal form A

[0145]

[0146] According to an embodiment of the present invention, the succinate crystal form A has an X-ray powder diffraction pattern substantially as Figure 11 shown.

[0147] According to an embodiment of the present invention, the succinate crystal form A has one or both of the following characteristics:

[0148] (1) The TGA curve of the succinate crystal form A loses weight by about 3.74% at 150.0 ± 3°C;

[0149] (2) The DSC curve of the succinate crystal form A has four endothermic peaks at 73.3 ± 10°C, at 102.2 ± 10°C, at 136.6 ± 10°C, and at 173.6 ± 10°C; in particular, the DSC curve of the succinate crystal form A has four endothermic peaks at 73.3 ± 5°C, at 102.2 ± 5°C, at 136.6 ± 5°C, and at 173.6 ± 5°C.

[0150] According to an embodiment of the present invention, the succinate crystal form A has one or both of the following characteristics:

[0151] (1) The succinate crystal form A has a TGA curve substantially as Figure 29 shown;

[0152] (2) The succinate crystal form A has a DSC curve substantially as Figure 29 shown.

[0153] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the succinate crystal form B obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 9.54 ± 0.20°, 12.60 ± 0.20°, 14.91 ± 0.20°, 19.17 ± 0.20°, 21.02 ± 0.20°, 24.88 ± 0.20°.

[0154] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the succinate crystal form B has characteristic peaks at the following 2θ angles: 9.54 ± 0.20°, 12.60 ± 0.20°, 13.28 ± 0.20°, 14.91 ± 0.20°, 15.20 ± 0.20°, 19.17 ± 0.20°, 21.02 ± 0.20°, 24.88 ± 0.20°, 28.15 ± 0.20°.

[0155] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the succinate crystal form B has characteristic peaks at the following 2θ angles: 9.54 ± 0.20°, 12.60 ± 0.20°, 13.28 ± 0.20°, 14.91 ± 0.20°, 15.20 ± 0.20°, 19.17 ± 0.20°, 19.77 ± 0.20°, 21.02 ± 0.20°, 21.44 ± 0.20°, 24.88 ± 0.20°, 25.22 ± 0.20°, 28.15 ± 0.20°.

[0156] According to an embodiment of the present invention, the 2θ diffraction angle, D value, and / or relative intensity in the X-ray powder diffraction pattern of the succinate crystal form B obtained using Cu-Kα radiation are as shown in Table 12 below:

[0157] Table 12 XRPD diffraction peak data of succinate crystal form B

[0158]

[0159] According to an embodiment of the present invention, the succinate crystal form B has an X-ray powder diffraction pattern substantially as Figure 12 shown.

[0160] According to an embodiment of the present invention, the succinate crystal form B has one, two or three of the following characteristics:

[0161] (1) The TGA curve of the succinate crystal form B shows a weight loss of about 0.83% at 150.0 ± 3 °C;

[0162] (2) The DSC curve of the succinate crystal form B has a starting point of an endothermic peak at 128.8 ± 3 °C;

[0163] (3) The DSC curve of the succinate crystal form B has an endothermic peak at 129.9 ± 3 °C.

[0164] According to an embodiment of the present invention, the succinate crystal form B has one or two of the following characteristics:

[0165] (1) The succinate crystal form B has a TGA curve substantially as Figure 30 shown;

[0166] (2) The succinate crystal form B has a DSC curve substantially as Figure 30 shown.

[0167] According to an embodiment of the present invention, the adipate crystal form B has characteristic peaks at the following 2θ angles in the X-ray powder diffraction pattern obtained using Cu-Kα radiation: 4.98 ± 0.20 °, 10.69 ± 0.20 °, 13.88 ± 0.20 °, 21.41 ± 0.20 °, 24.97 ± 0.20 °, 26.15 ± 0.20 °.

[0168] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the adipate crystal form B has characteristic peaks at the following 2θ angles: 4.98 ± 0.20 °, 10.69 ± 0.20 °, 13.88 ± 0.20 °, 14.28 ± 0.20 °, 20.72 ± 0.20 °, 21.41 ± 0.20 °, 24.97 ± 0.20 °, 26.15 ± 0.20 °.

[0169] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the adipate crystal form B has characteristic peaks at the following 2θ angles: 4.98 ± 0.20 °, 9.23 ± 0.20 °, 10.69 ± 0.20 °, 13.88 ± 0.20 °, 14.28 ± 0.20 °, 19.35 ± 0.20 °, 20.72 ± 0.20 °, 21.41 ± 0.20 °, 24.97 ± 0.20 °, 26.15 ± 0.20 °.

[0170] According to an embodiment of the present invention, the 2θ diffraction angle, D value and / or relative intensity in the X-ray powder diffraction pattern of the adipate crystal form B obtained using Cu-Kα radiation are as shown in Table 13 below:

[0171] XRPD diffraction peak data of adipate crystal form B in Table 13

[0172]

[0173]

[0174] According to an embodiment of the present invention, the adipate crystal form B has an X-ray powder diffraction pattern substantially as Figure 13 shown.

[0175] According to an embodiment of the present invention, the adipate crystal form B has one, two or three of the following characteristics:

[0176] (1) The TGA curve of adipate crystal form B shows a weight loss of about 1.23% at 150.0 ± 3 °C;

[0177] (2) The DSC curve of adipate crystal form B has a starting point of an endothermic peak at 112.8 ± 3 °C;

[0178] (3) The DSC curve of adipate crystal form B has an endothermic peak at 115.6 ± 3 °C.

[0179] According to an embodiment of the present invention, the adipate crystal form B has one or two of the following characteristics:

[0180] (1) The adipate crystal form B has a TGA curve substantially as Figure 31 shown;

[0181] (2) The adipate crystal form B has a DSC curve substantially as Figure 31 shown.

[0182] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the sebacate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 4.57 ± 0.20 °, 9.27 ± 0.20 °, 11.20 ± 0.20 °, 14.40 ± 0.20 °, 20.16 ± 0.20 °, 24.63 ± 0.20 °, 26.73 ± 0.20 °.

[0183] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the sebacate crystal form A has characteristic peaks at the following 2θ angles: 4.57 ± 0.20 °, 9.27 ± 0.20 °, 11.20 ± 0.20 °, 14.40 ± 0.20 °, 14.95 ± 0.20 °, 20.16 ± 0.20 °, 20.55 ± 0.20 °, 22.95 ± 0.20 °, 23.91 ± 0.20 °, 24.63 ± 0.20 °, 26.73 ± 0.20 °.

[0184] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the sebacate crystal form A has characteristic peaks at the following 2θ angles: 4.57 ± 0.20°, 9.27 ± 0.20°, 11.20 ± 0.20°, 14.40 ± 0.20°, 14.95 ± 0.20°, 15.26 ± 0.20°, 18.25 ± 0.20°, 20.16 ± 0.20°, 20.95 ± 0.20°, 22.95 ± 0.20°, 23.91 ± 0.20°, 24.63 ± 0.20°, 26.73 ± 0.20°.

[0185] According to an embodiment of the present invention, the 2θ diffraction angle, D value, and / or relative intensity in the X-ray powder diffraction pattern of the sebacate crystal form A obtained using Cu-Kα radiation are as shown in Table 14 below:

[0186] Table 14 XRPD diffraction peak data of sebacate crystal form A

[0187]

[0188]

[0189] According to an embodiment of the present invention, the sebacic acid crystal form A has an X-ray powder diffraction pattern substantially as Figure 14 shown.

[0190] According to an embodiment of the present invention, the sebacate crystal form A has one or both of the following characteristics:

[0191] (1) The TGA curve of the sebacate crystal form A shows a weight loss of approximately 0.45% at 150.0 ± 3°C;

[0192] (2) The DSC curve of the sebacate crystal form A has two endothermic peaks at 80.9 ± 10°C and 142.1 ± 10°C.

[0193] According to an embodiment of the present invention, the sebacate crystal form A has one or both of the following characteristics:

[0194] (1) The sebacate crystal form A has a TGA curve substantially as Figure 32 shown;

[0195] (2) The sebacate crystal form A has a DSC curve substantially as Figure 32 shown.

[0196] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 6.04 ± 0.20°, 8.59 ± 0.20°, 14.27 ± 0.20°, 17.14 ± 0.20°, 25.29 ± 0.20°.

[0197] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A has characteristic peaks at the following 2θ angles: 6.04 ± 0.20°, 8.59 ± 0.20°, 14.27 ± 0.20°, 17.14 ± 0.20°, 20.41 ± 0.20°, 23.68 ± 0.20°, 25.29 ± 0.20°, 27.65 ± 0.20°.

[0198] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A has characteristic peaks at the following 2θ angles: 6.04 ± 0.20°, 8.59 ± 0.20°, 12.28 ± 0.20°, 14.27 ± 0.20°, 16.02 ± 0.20°, 17.14 ± 0.20°, 20.41 ± 0.20°, 22.01 ± 0.20°, 23.68 ± 0.20°, 25.29 ± 0.20°, 27.65 ± 0.20°.

[0199] According to an embodiment of the present invention, the 2θ diffraction angle, D value, and / or relative intensity in the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A are as shown in Table 15 below:

[0200] Table 15 XRPD diffraction peak data of p-toluenesulfonate crystal form A

[0201]

[0202] According to an embodiment of the present invention, the p-toluenesulfonate crystal form A has substantially as Figure 15 the X-ray diffraction pattern shown.

[0203] According to an embodiment of the present invention, the p-toluenesulfonate crystal form A has one or both of the following characteristics:

[0204] (1) The TGA curve of the p-toluenesulfonate crystal form A shows a weight loss of approximately 3.29% at 150.0 ± 3°C;

[0205] (2) The DSC curve of the p-toluenesulfonate crystal form A has an endothermic peak at 210.8 ± 10°C; in particular, the DSC curve of the p-toluenesulfonate crystal form A has an endothermic peak at 210.8 ± 5°C.

[0206] More specifically, the DSC curve of p-toluenesulfonate crystal form A has an endothermic peak at 72.7 ± 10 °C, especially at 72.7 ± 5 °C.

[0207] According to an embodiment of the present invention, the p-toluenesulfonate crystal form A has one or both of the following characteristics:

[0208] (1) The p-toluenesulfonate crystal form A has a TGA curve substantially as Figure 33 shown;

[0209] (2) The p-toluenesulfonate crystal form A has a DSC curve substantially as Figure 33 shown.

[0210] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the benzenesulfonate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 6.16 ± 0.20°, 8.98 ± 0.20°, 14.22 ± 0.20°, 16.90 ± 0.20°, 18.31 ± 0.20°, 20.92 ± 0.20°, 25.11 ± 0.20°, 26.29 ± 0.20°.

[0211] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the benzenesulfonate crystal form A has characteristic peaks at the following 2θ angles: 6.16 ± 0.20°, 8.98 ± 0.20°, 14.22 ± 0.20°, 15.67 ± 0.20°, 16.90 ± 0.20°, 17.55 ± 0.20°, 18.31 ± 0.20°, 20.34 ± 0.20°, 20.92 ± 0.20°, 25.11 ± 0.20°, 26.29 ± 0.20°, 29.24 ± 0.20°.

[0212] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the benzenesulfonate crystal form A has characteristic peaks at the following 2θ angles: 6.16 ± 0.20°, 8.98 ± 0.20°, 14.22 ± 0.20°, 15.67 ± 0.20°, 16.90 ± 0.20°, 17.55 ± 0.20°, 18.31 ± 0.20°, 20.34 ± 0.20°, 20.92 ± 0.20°, 23.54 ± 0.20°, 24.65 ± 0.20°, 25.11 ± 0.20°, 26.29 ± 0.20°, 29.24 ± 0.20°.

[0213] According to an embodiment of the present invention, the 2θ diffraction angle, D value and / or relative intensity in the X-ray powder diffraction pattern of the benzenesulfonate crystal form A obtained using Cu-Kα radiation are as shown in Table 16 below:

[0214] XRPD Diffraction Peak Data of Benzenesulfonate Crystal Form A in Table 16

[0215]

[0216]

[0217] According to an embodiment of the present invention, the benzenesulfonate crystal form A has substantially as Figure 16 shown in the X-ray powder diffraction pattern.

[0218] According to an embodiment of the present invention, the benzenesulfonate crystal form A has one, two, three or four of the following characteristics:

[0219] (1) The TGA curve of benzenesulfonate crystal form A shows a weight loss of about 1.87% at 150.0 ± 3 °C;

[0220] (2) The DSC curve of benzenesulfonate crystal form A has a starting point of an endothermic peak at 184.7 ± 3 °C;

[0221] (3) The DSC curve of benzenesulfonate crystal form A has an endothermic peak at 187.0 ± 3 °C;

[0222] (4) The DVS curve of benzenesulfonate crystal form A shows a moisture adsorption of less than about 2%, such as less than about 1.8%, particularly less than about 1.46% under the conditions of 0% RH to 80% RH.

[0223] According to an embodiment of the present invention, the benzenesulfonate crystal form A has one, two or three of the following characteristics:

[0224] (1) Benzenesulfonate crystal form A has substantially as Figure 34 shown in the TGA curve;

[0225] (2) Benzenesulfonate crystal form A has substantially as Figure 34 shown in the DSC curve:

[0226] (3) Benzenesulfonate crystal form A has substantially as Figure 39 shown in the DVS curve.

[0227] According to an embodiment of the present invention, the X-ray powder diffraction pattern of hydrobromide crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 9.54 ± 0.20 °, 24.63 ± 0.20 °.

[0228] According to an embodiment of the present invention, the 2θ diffraction angle, D value and / or relative intensity in the X-ray powder diffraction pattern of hydrobromide crystal form A obtained using Cu-Kα radiation are as shown in Table 17 below:

[0229] Table 17 XRPD diffraction peak data of hydrobromide crystal form A

[0230]

[0231]

[0232] According to an embodiment of the present invention, the hydrobromide crystal acid form A has substantially as Figure 17 shown X-ray powder diffraction pattern.

[0233] According to an embodiment of the present invention, the hydrobromide crystal form A has one or both of the following characteristics:

[0234] (1) The TGA curve of the hydrobromide crystal form A loses about 7.86% of its weight at 150.0 ± 3 °C;

[0235] (2) The DSC curve of the hydrobromide crystal form A has three endothermic peaks at 96.5 ± 5 °C, at 107.3 ± 5 °C, and at 141.8 ± 5 °C.

[0236] According to an embodiment of the present invention, the hydrobromide crystal form A has one or both of the following characteristics:

[0237] (1) The hydrobromide crystal form A has substantially as Figure 35 shown TGA curve;

[0238] (2) The hydrobromide crystal form A has substantially as Figure 35 shown DSC curve.

[0239] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the hydrobromide crystal form B obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 9.48 ± 0.20 °, 15.89 ± 0.20 °, 23.98 ± 0.20 °.

[0240] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the hydrobromide crystal form B has characteristic peaks at the following 2θ angles: 9.48 ± 0.20 °, 15.89 ± 0.20 °, 19.40 ± 0.20 °, 23.98 ± 0.20 °, 26.55 ± 0.20 °, 28.02 ± 0.20 °.

[0241] According to an embodiment of the present invention, the 2θ diffraction angle, D value, and / or relative intensity in the X-ray powder diffraction pattern of the hydrobromide crystal form B obtained using Cu-Kα radiation are as shown in Table 18 below:

[0242] Table 18 XRPD diffraction peak data of hydrobromide crystal form B

[0243]

[0244] According to an embodiment of the present invention, the hydrobromide polymorph B has an X-ray powder diffraction pattern substantially as Figure 18 shown.

[0245] According to an embodiment of the present invention, the hydrobromide polymorph B has one or both of the following characteristics:

[0246] (1) The TGA curve of the hydrobromide polymorph B shows a weight loss of about 4.95% at 150.0 ± 3 °C;

[0247] (2) The DSC curve of the hydrobromide polymorph B has three endothermic peaks at 81.6 ± 10 °C, at 128.9 ± 10 °C, and at 163.6 ± 10 °C; in particular, the DSC curve of the hydrobromide polymorph B has three endothermic peaks at 81.6 ± 5 °C, at 128.9 ± 5 °C, and at 163.6 ± 5 °C.

[0248] According to an embodiment of the present invention, the hydrobromide polymorph B has one or both of the following characteristics:

[0249] (1) The hydrobromide polymorph B has a TGA curve substantially as Figure 36 shown;

[0250] (2) The hydrobromide polymorph B has a DSC curve substantially as Figure 36 shown.

[0251] The present invention also provides a method for preparing a salt of a compound of formula (I), comprising the step of contacting a compound of formula (I) with an inorganic acid or an organic acid:

[0252]

[0253] According to an embodiment of the present invention, the inorganic acid or the organic acid is independently selected from the definitions described above.

[0254] According to an embodiment of the present invention, the molar ratio of the compound of formula (I) to the inorganic acid or the organic acid can be 1:(0.5 - 5), for example 1:(0.5 - 2), and exemplarily 1:0.5 or 1:1.

[0255] The present invention also provides a method for preparing a crystal form of a salt of a compound of formula (I), comprising the following steps: stirring a compound of formula (I) with a corresponding inorganic acid or organic acid in a solvent at room temperature, transferring the clarified sample to stir at 5 °C to -20 °C, and transferring the clarified sample to room temperature to evaporate the solvent.

[0256] According to an embodiment of the present invention, the inorganic acid or the organic acid is independently selected from the definitions described above.

[0257] According to an embodiment of the present invention, the molar ratio of the compound of formula (I) to an inorganic acid or an organic acid may be 1: (0.5 to 5), for example 1: (0.5 to 2), and exemplarily 1:0.5 or 1:1.

[0258] The present invention also provides a pharmaceutical composition comprising a salt of the compound of formula (I), for example in its solid form, such as its crystal form or amorphous form.

[0259] 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.

[0260] According to an embodiment of the present invention, in the pharmaceutical composition, the salt of the compound of formula (I) is present in a therapeutically effective amount.

[0261] The present invention also provides the use of the salt of the compound of formula (I), for example in its solid form, such as its crystal form or amorphous form, in the preparation of a drug. Preferably, the drug is used for the treatment and / or prevention of ATX-related diseases.

[0262] The present invention also provides a method for preventing and / or treating autotaxin (ATX)-related diseases, comprising administering to a patient in need a therapeutically effective amount of the salt of the above-mentioned compound of formula (I), for example in its solid form, such as its crystal form or amorphous form, or the pharmaceutical composition.

[0263] The present invention also provides the salt of the compound of formula (I), for example in its solid form, such as its crystal form or amorphous form, or the pharmaceutical composition, which is used for the treatment and / or prevention of autotaxin (ATX)-related diseases.

[0264] 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 diseases related to abnormal angiogenesis.

[0265] According to an embodiment of the present invention, the ATX-related diseases include at least one selected from the following: interstitial lung disease, pulmonary fibrosis, liver fibrosis, renal fibrosis.

[0266] According to an embodiment of the present invention, the ATX-related disease includes idiopathic pulmonary fibrosis.

[0267] According to an embodiment of the present invention, the ATX-related diseases include type II diabetes, non-alcoholic steatohepatitis.

[0268] According to an embodiment of the present invention, the ATX-related diseases include neuropathic pain, inflammatory pain.

[0269] According to an embodiment of the present invention, the ATX-related diseases include pain related to osteoarthritis.

[0270] When used as a medicine, the salt of the present invention or its solid form 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 a variety of routes, depending on whether local or systemic treatment is required and the area being treated. They can be administered locally (e.g., transdermally, dermally, ophthalmically and mucosally including intranasally, vaginally and rectally), by the pulmonary route (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheally, intranasally), orally or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranially such as intrathecally or intraventricularly. Parenteral administration can be in the form of a single large dose, or can be administered, for example, by means of a continuous perfusion pump. Medicinal compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, water, powder or oily bases, thickening agents, etc. may be necessary or desirable.

[0271] In preparing the compositions of the present invention, the active ingredient (i.e., the salt of the present invention or its solid form) is usually admixed with an excipient, diluted by the excipient or enclosed within a carrier such as in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid substance serving as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid vehicle); ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders containing, for example, up to 10% by weight of the active ingredient.

[0272] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The formulations can also contain: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl p-hydroxybenzoate; sweetening and flavoring agents. The compositions of the present invention can be formulated by using methods known in the art so as to provide a rapid, sustained or delayed release action of the active ingredient after administration to a patient.

[0273] The composition can be formulated in unit dosage forms, 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 unit for human patients and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect in admixture with a suitable pharmaceutical excipient.

[0274] The effective dosage range of the active compound can be very wide and is usually administered in a pharmaceutically effective amount. However, it is understood that the amount of the compound actually administered will generally be determined by the physician in view of the relevant circumstances, which include the disorder being treated, the route of administration selected, the actual compound being administered; the age, weight and response of the individual patient; the severity of the patient's symptoms, etc.

[0275] For the preparation of 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 salt of the invention or its solid form. When these preformulation compositions are said to be homogeneous, it is meant that the active ingredient is generally uniformly distributed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preformulation is then subdivided into unit dosage forms of the above type containing, for example, about 0.1 to 1000 mg of the active ingredient of the invention.

[0276] The tablets or pills of the invention can be coated or compounded to provide dosage forms affording the advantage of prolonged action. For example, the tablets or pills contain an inner dosage and an outer dosage component, the latter being in the form of a coating for the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach so that the inner component passes intact through the duodenum or is released in a delayed manner. A variety of substances can be used for such enteric layers or coatings, including a variety of high molecular weight acids and mixtures of high molecular weight acids with such substances as shellac, cetyl alcohol and cellulose acetate.

[0277] Liquid forms in which the salt of the invention or its solid form and the composition can be incorporated for oral or parenteral 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; and elixirs and similar pharmaceutical vehicles.

[0278] Compositions for inhalation or insufflation include solutions, suspensions, and powders dissolved in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the compositions are administered by the oral or nasal breathing route to achieve local or systemic effects. The compositions can be atomized by using an inert gas. The atomized solution can be inhaled directly by an atomization device, or the atomization device can be connected to a face mask or an intermittent positive pressure ventilator. Solutions, suspensions, or powder compositions can be administered orally or nasally by a device that delivers the formulation in an appropriate manner.

[0279] The amount of the salt or its solid form or composition administered to a patient is not fixed and depends on the drug administered, the purpose of administration such as prophylaxis 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 disease and the symptoms of 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.

[0280] 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. 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 from 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8. It is understood that the use of certain of the foregoing excipients, carriers, or stabilizers can result in the formation of drug salts.

[0281] The therapeutic dose of the salt or its solid form of the present invention can depend on, for example: the specific use for treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present invention in the pharmaceutical composition is not fixed and depends on various factors, which include the dose, chemical properties (such as hydrophobicity), and route of administration. For example, the compound of the present invention can be provided in a physiological buffer aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg / kg to about 1 g / kg body weight per day. In certain embodiments, the dose range is from 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 compound selected, the excipient formulation, and its route of administration. The effective dose can be extrapolated from a dose-response curve derived from in vitro or animal model test systems.

[0282] Term Definitions and Explanations

[0283] Unless otherwise specified, the definitions of 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 definitions and compound structures after such combination and combination shall fall within the scope recited in the specification of this application.

[0284] 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 to not only record each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least record the sum of each integer and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 respectively.

[0285] When this specification and claims recite "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, such as 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 to 11.5; the numerical values within the range of 10 ± 1.0, that is, within the range of 9.0 to 11.0; and the numerical values within the range of 10 ± 0.5, that is, within the range of 9.5 to 10.5.

[0286] 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.

[0287] 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 organism, system, animal, individual or human that causes 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 presented the disease pathology or symptoms; (2) Inhibiting a disease: For example, inhibiting a disease, disorder or condition in an individual who is experiencing or presenting 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 presenting the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms).

[0288] The term "pharmaceutically acceptable" means that the prescription components or active ingredients do not have an excessive harmful effect on the health of the general therapeutic target.

[0289] 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 blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically 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.

[0290] Beneficial effects

[0291] The salts and crystal forms of the compound of formula (I) of the present invention have good solubility, stability and hygroscopicity. For example, the benzenesulfonate crystal form A of the compound of formula (I) has the following advantages: (1) weak hygroscopicity, no crystal transformation occurs after DVS testing, which is convenient for controlling the drug-like CMC and provides a material basis for formulation research and development; (2) uniform particle size, the particle size is less than 50um under PLM, and impurities in the reaction process can be effectively removed during the crystallization process, improving production efficiency and reducing production costs; (3) significantly improved solubility, suitable for drug development and giving play to clinical advantages; (4) better solid-state stability.

[0292] Therefore, the salts and crystal forms provided by the present invention are more suitable for medicinal use. Moreover, their preparation methods are simple and easy to implement, and are suitable for large-scale production. Description of the drawings

[0293] Figure 1 XRPD diagram of the hydrochloride crystal form A of the compound of formula (I) (instrument 2);

[0294] Figure 2 XRPD diagram of the sulfate crystal form A of the compound of formula (I) (instrument 2);

[0295] Figure 3 XRPD diagram of the maleate crystal form A of the compound of formula (I) (instrument 3);

[0296] Figure 4 XRPD diagram of the phosphate crystal form A of the compound of formula (I) (instrument 2);

[0297] Figure 5XRPD pattern (Instrument 2) of tartrate polymorph A of the compound of formula (I);

[0298] Figure 6 XRPD pattern (Instrument 2) of tartrate polymorph B of the compound of formula (I);

[0299] Figure 7 XRPD pattern (Instrument 3) of tartrate polymorph C of the compound of formula (I);

[0300] Figure 8 XRPD pattern (Instrument 2) of fumarate polymorph A of the compound of formula (I);

[0301] Figure 9 XRPD pattern (Instrument 2) of citrate polymorph A of the compound of formula (I);

[0302] Figure 10 XRPD pattern (Instrument 2) of glycolate polymorph A of the compound of formula (I);

[0303] Figure 11 XRPD pattern (Instrument 3) of succinate polymorph A of the compound of formula (I);

[0304] Figure 12 XRPD pattern (Instrument 1) of succinate polymorph B of the compound of formula (I);

[0305] Figure 13 XRPD pattern (Instrument 2) of adipate polymorph B of the compound of formula (I);

[0306] Figure 14 XRPD pattern (Instrument 1) of sebacate polymorph A of the compound of formula (I);

[0307] Figure 15 XRPD pattern (Instrument 2) of p-toluenesulfonate polymorph A of the compound of formula (I);

[0308] Figure 16 XRPD pattern (Instrument 1) of benzenesulfonate polymorph A of the compound of formula (I);

[0309] Figure 17 XRPD pattern (Instrument 2) of hydrobromide polymorph A of the compound of formula (I);

[0310] Figure 18 XRPD pattern (Instrument 1) of hydrobromide polymorph B of the compound of formula (I);

[0311] Figure 19 XRPD overlay pattern (Instrument 2) of the stability evaluation sample of benzenesulfonate polymorph A of the compound of formula (I);

[0312] Figure 20 TGA / DSC diagram of hydrochloride salt crystal form A of compound (I);

[0313] Figure 21 TGA / DSC diagram of sulfate salt crystal form A of compound (I);

[0314] Figure 22 TGA / DSC diagram of maleate salt crystal form A of compound (I);

[0315] Figure 23 TGA / DSC diagram of phosphate salt crystal form A of compound (I);

[0316] Figure 24 TGA / DSC diagram of tartrate salt crystal form A of compound (I);

[0317] Figure 25 TGA / DSC diagram of tartrate salt crystal form B of compound (I);

[0318] Figure 26 TGA / DSC diagram of fumarate salt crystal form A of compound (I);

[0319] Figure 27 TGA / DSC diagram of citrate salt crystal form A of compound (I);

[0320] Figure 28 TGA / DSC diagram of glycolate salt crystal form A of compound (I);

[0321] Figure 29 TGA / DSC diagram of succinate salt crystal form A of compound (I);

[0322] Figure 30 TGA / DSC diagram of succinate salt crystal form B of compound (I);

[0323] Figure 31 TGA / DSC diagram of adipate salt crystal form B of compound (I);

[0324] Figure 32 TGA / DSC diagram of sebacate salt crystal form A of compound (I);

[0325] Figure 33 TGA / DSC diagram of p-toluenesulfonate salt crystal form A of compound (I);

[0326] Figure 34 TGA / DSC diagram of benzenesulfonate salt crystal form A of compound (I);

[0327] Figure 35 TGA / DSC diagram of hydrobromide salt crystal form A of compound (I);

[0328] Figure 36 It is the TGA / DSC diagram of crystalline form B of the hydrobromide salt of compound (I);

[0329] Figure 37 It is the DVS diagram of crystalline form A of the hydrochloride salt of compound (I);

[0330] Figure 38 It is the DVS diagram of crystalline form A of the fumarate salt of compound (I);

[0331] Figure 39 It is the DVS diagram of crystalline form A of the benzenesulfonate salt of compound (I);

[0332] Figure 40 It is the XRPD diagram (instrument 1) of crystalline form A of the free base of compound (I);

[0333] Figure 41 It is the TGA / DSC diagram of crystalline form A of the free base of compound (I);

[0334] Figure 42 It is the DVS diagram of crystalline form A of the free base of compound (I);

[0335] Figure 43 It is the body weight change curve of the animal after administration in Test Example 7 according to the present invention;

[0336] Figure 44 It is 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. Detailed implementation manners

[0337] The salt forms and crystalline forms of the compound of formula (I) of the present invention, their preparation methods and applications will be further described in detail below in conjunction with 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.

[0338] 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.

[0339] Detection instruments and methods for crystalline forms

[0340] 1. X-ray powder diffraction (XRPD)

[0341] The XRPD diagram was collected on an X-ray powder diffractometer produced by PANalytacal, and the scanning parameters are shown in Table 19-1 below:

[0342] Table 19-1

[0343]

[0344] 2. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0345] The TGA and DSC graphs were collected on a TA Q5000 / 5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter respectively. The test parameters are listed in Table 19-2 below.

[0346] Table 19-2

[0347]

[0348] 3. Solution Nuclear Magnetic Resonance (Solution NMR):

[0349] The solution NMR spectra were collected on a Bruker 400M nuclear magnetic resonance spectrometer with DMSO-d6 as the solvent.

[0350] 4. High Performance Liquid Chromatography (HPLC):

[0351] In the experiment, purity test, solubility and stability tests were performed using an Agilent 1260 high performance liquid chromatograph. The analysis conditions are as shown in Table 19-3 below:

[0352] Table 19-3

[0353]

[0354] 5. Dynamic Vapor Sorption (DVS):

[0355] The Dynamic Vapor Sorption (DVS) curves were collected on a DVSIntrinsic from 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 19-4 below:

[0356] Table 19-4

[0357]

[0358] 6. Polarizing Light Microscopy (PLM)

[0359] The polarizing microscopy data were collected at room temperature using an Axio Lab.A1 upright microscope.

[0360] 7. High Performance Liquid Chromatography / Ion Chromatography (HPLC / IC):

[0361] In the experiment, purity test, dynamic solubility and stability test were carried out by Agilent 1260 high performance liquid chromatograph, and the molar ratio test of ion salt formation was carried out by ion chromatography. The analysis conditions are shown in Table 19-5 and Table 19-6 as follows:

[0362] Table 19-5 High performance liquid chromatography test conditions

[0363]

[0364] Table 19-6 Ion chromatography test conditions

[0365]

[0366] Example 1: Preparation of the compound of formula (I)

[0367] (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)

[0368]

[0369] The first step: Synthesis of (R)-5-(trimethylsilyl)pentyl-4-yn-2-ol (5A)

[0370]

[0371] Trimethylsilylacetylene (51.7 g) and diethyl ether (600 mL) were added to a three-necked flask. Under nitrogen protection, it was cooled to -78 °C, and n-butyllithium (2.5 M, 217 mL) was slowly added dropwise. After the addition was complete, the reaction was carried out at -78 °C for 1 hour. Boron trifluoride tetrahydrofuran (50%, 30 mL) solution was added, and (R)-propylene oxide (30 g) was slowly added dropwise. After the addition was complete, the temperature was maintained and stirred for 1 hour, and the reaction was quenched with saturated aqueous sodium bicarbonate solution (300 mL). After rising to room temperature, liquid separation was carried out. The organic phase was dried, mixed with silica gel, and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=10:1) to obtain a pale yellow liquid compound (R)-5-(trimethylsilyl)pentyl-4-yn-2-ol (5A) to obtain the product (34 g, yield 42.1%).

[0372] The second step: Synthesis of tert-butyl (R)-2-((5-(trimethylsilyl)pent-4-yn-2-yl)oxy)acetate (5B)

[0373]

[0374] The raw material (R)-5-(trimethylsilyl)pentyl-4-yn-2-ol (34 g, 218 mmol) was added to 340 mL of dry tetrahydrofuran, cooled to 0 °C, 60% NaH (10.44 g, 261 mmol) was added, and the mixture was stirred for 30 minutes. At 0 °C, the raw material tert-butyl 2-bromoacetate (46.7 g, 239 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 16 hours. At 0 °C, methanol (20 mL) was added to the reaction solution, mixed with silica gel, concentrated, and purified 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)pentyl-4-yn-2-yl)oxy)acetate (5B) (50 g, yield 85%).

[0375] Step 3: Synthesis of tert-butyl (R)-2-(pent-4-yn-2-yloxy)acetate (5C)

[0376]

[0377] At room temperature, the raw material tert-butyl (R)-2-((5-(trimethylsilyl)pentyl-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. Mixed with silica gel, concentrated, and the residue was 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%).

[0378] Step 4: Synthesis of tert-butyl (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)acetate (5D)

[0379]

[0380] 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 mixed with silica gel, concentrated, and the residue was 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%).

[0381] Step 5: Synthesis of (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)acetic acid (5E)

[0382]

[0383] At room temperature, 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 hydrogen chloride 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 white solid (R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)acetic acid (9.2 g, 86%).

[0384] 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)

[0385]

[0386] At room temperature, (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 and stirred for 16 hours. The reaction mixture was filtered, water (3 mL) was added to the filtrate, and the mixture was concentrated to dryness. The residue was 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%).

[0387] 11H 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).

[0388] LC-MS, M / Z (ESI): 420.4 (M+1).

[0389] Example 2: Preparation of Salts and Crystal Forms of the Compound of Formula (I)

[0390] Approximately 15 mg of the free base of the compound of formula (I) was stirred with an equimolar ratio of the corresponding inorganic or organic acid in 0.5 mL of solvent at room temperature for 3 days. The clear sample was transferred to be stirred at 5 °C; if no solid precipitated, it was suspended and stirred at -20 °C; the clear sample was transferred to room temperature to volatilize. The sample was centrifuged to obtain the salt of the compound of formula (I), wherein the salt existed in crystalline form.

[0391] The inorganic or organic acids, solvents used, and the 14 salts and 18 crystal forms obtained are shown in Table 20 below.

[0392] Table 20 Inorganic or Organic Acids, Solvents Used, and Salts of the Compound of Formula (I) and Crystal Forms of the Salts

[0393]

[0394]

[0395] Example 3: Evaluation of Crystal Forms of Salts of the Compound of Formula (I)

[0396] Based on the characterization results of each salt form (higher crystallinity, smaller TGA weight loss, fewer and sharper DSC endothermic peaks) and the commonness and safety level of the acid, hydrochloride crystal form A, fumarate crystal form A, and benzenesulfonate crystal form A were selected for the next evaluation. The prepared samples were characterized by XRPD, TGA, DSC, NMR, or HPLC / IC, and the results are summarized in Table 21-1 below:

[0397] Table 21-1 Summary of Characterization of Crystal Forms of Salts of the Compound of Formula (I)

[0398]

[0399] The salt form evaluation was carried out using 3 repetitively prepared salt forms, and the non-salt and non-solvate crystal form A of the compound of formula (I) (also known as free base crystal form A) was selected as a comparison. The evaluation items included hygroscopicity, polarized light microscopy (PLM), dynamic solubility, and solid stability.

[0400] Among them, the 2θ diffraction angle, D value, and / or relative intensity of the X-ray powder diffraction pattern of the free base crystal form A obtained using Cu-Kα radiation are as shown in Table 21-2 below:

[0401] Table 21-2 XRPD diffraction peak data of free base crystal form A

[0402]

[0403]

[0404] The free base crystal form A has an X-ray powder diffraction pattern substantially as Figure 40 shown, a TGA and DSC curve substantially as Figure 41 shown, and a DVS curve substantially as Figure 42 shown.

[0405] 3.1 Hygroscopicity

[0406] The hygroscopicity of repetitively prepared hydrochloride crystal form A, fumarate crystal form A, benzenesulfonate crystal form A, and free base crystal form A was evaluated by a dynamic vapor sorption (DVS) instrument. Starting from 0% relative humidity (0% RH), the percentage change in the mass of the samples was measured at a constant temperature of 25 °C as the humidity changed (0% RH - 95% RH - 0% RH). The DVS evaluation results are summarized in Table 21-3 below. The results show that hydrochloride crystal form A is hygroscopic and the crystal form changes after the DVS test, while the other samples are slightly hygroscopic and no crystal form transformation occurs after the DVS test.

[0407] Table 21-3 Hygroscopicity evaluation results

[0408]

[0409] *: Transformed into a new crystal form

[0410] 3.2 Polarized light microscopy (PLM)

[0411] The repetitively prepared hydrochloride crystal form A, fumarate crystal form A, benzenesulfonate crystal form A, and free base crystal form A were characterized by polarized light microscopy (PLM). The particle size of each sample was less than 50 μm.

[0412] 3.3 Dynamic solubility

[0413] The dynamic solubility of repeatedly prepared hydrochloride crystal form A, fumarate crystal form A, benzenesulfonate crystal form A, and free base crystal form A in water and three biological solvents was evaluated. Using a feeding concentration of 5 mg / mL (20 mg of the material was put into 4 mL of the solvent), the dynamic solubility (at 1, 4, and 24 hours) of each sample in four solvent systems of water, SGF, FaSSIF, and FeSSIF 1 was measured at 37 °C by means of rotary mixing (25 rpm). After centrifugal filtration (0.45 μm PTFE filter head) of the samples at each time point, the HPLC concentration and pH value of the filtrate were measured, and the solid samples after centrifugation were tested by XRPD. The results of the solubility test are summarized in Table 21-4 below, and the results show that the solubility of hydrochloride crystal form A and benzenesulfonate crystal form A in each system is significantly improved compared to that of free base crystal form A.

[0414] Summary of the Results of Dynamic Solubility Tests

[0415]

[0416]

[0417] 3.4 Solid Stability

[0418] After placing the repeatedly prepared hydrochloride crystal form A, fumarate crystal form A, benzenesulfonate crystal form A, and free base crystal form A at 25 °C / 60% RH and 40 °C / 75% RH for 1 week respectively, the physical and chemical stability of the samples was detected by XRPD and HPLC. The results of the stability evaluation are summarized in Table 21-5 below, and the results show that the HPLC purity of hydrochloride crystal form A decreased after being placed at 40 °C / 75% RH for 1 week, and the crystallinity detected by XRPD also decreased. No obvious decrease in purity or crystal form transformation occurred in other samples after being placed under the two conditions for 1 week.

[0419] Summary of Solid Stability Evaluation

[0420]

[0421] *: Decrease in crystallinity

[0422] Further tests showed that benzenesulfonate crystal form A had excellent stability when stored under the following conditions for 6 months, and no crystal form change occurred:

[0423] Condition 1: Packaging: Polyethylene bag + Aluminum foil bag. Investigation conditions: 40 °C ± 2 °C / 75% RH ± 5% RH (the aluminum foil bag is a light-impermeable material and can avoid light; both the polyethylene bag and the aluminum foil bag are sealed when packaged);

[0424] Condition 2: Packaging: Polyethylene bag + aluminum foil bag, with a desiccant placed between the outer and inner packages. Investigation conditions: 25°C ± 2°C / 60% RH ± 10% RH (the aluminum foil bag is an opaque material and can block light; both the polyethylene bag and the aluminum foil bag are sealed during packaging).

[0425] Condition 3: Packaging: Polyethylene bag + aluminum foil bag, with a desiccant placed between the outer and inner packages. Investigation conditions: 2°C to 8°C (the aluminum foil bag is an opaque material and can block light; both the polyethylene bag and the aluminum foil bag are sealed during packaging).

[0426] 3.5 Conclusion

[0427] Three salt forms and the free base crystalline form A were selected for salt form evaluation. The DVS results showed that crystalline form A of the hydrochloride salt was hygroscopic and the crystal form changed after the DVS test. The other samples were slightly hygroscopic and did not undergo crystal form transformation after the DVS test. The PLM results showed that the particle sizes of all samples were less than 50 μm. The dynamic solubility results showed that the solubilities of crystalline form A of the hydrochloride salt and the benzenesulfonate salt in each system were significantly improved compared to the free base crystalline form A. The solid state stability evaluation showed that the HPLC purity of crystalline form A of the hydrochloride salt decreased after being placed at 40°C / 75% RH for 1 week, and the crystallinity of the sample also decreased. No significant decrease in purity or crystal form transformation occurred for the other samples after being placed under the two conditions for 1 week. Moreover, crystalline form A of the benzenesulfonate salt remained crystal form stable for 6 months under the above conditions.

[0428] Example 4: Polymorph evaluation of the benzenesulfonate salt of the compound of formula (I)

[0429] Using crystalline form A of the benzenesulfonate salt of the compound of formula (I) as the starting sample, a total of 100 polymorph screening tests under different conditions were set up. The screening methods included: anti-solvent addition, slow evaporation, slow cooling, suspension stirring (room temperature and 50°C), cyclic temperature rise and fall, gas-solid penetration, gas-liquid diffusion, polymer induction, and grinding. According to the X-ray powder diffraction (XRPD) results of the separated solids, only one benzenesulfonate polymorph, namely the starting crystalline form A, was found. Some evaluations had been completed during the salt form screening stage, so only its solid state stability evaluation at 60°C for 24 hours was carried out. The results are summarized in Table 22-1, and the XRPD results are listed in Figure 19 , showing that no significant decrease in purity or crystal form transformation was found for crystalline form A of the benzenesulfonate salt of compound A after being placed at 60°C for 24 hours.

[0430] Table 22-1 Summary of the solid state stability evaluation of crystalline form A of the benzenesulfonate salt of the compound of formula (I)

[0431]

[0432] The compound of formula (I) used in the following test examples is the compound of formula (I) prepared in Example 1 above. The structures of the control compounds used are as follows:

[0433]

[0434] This control compound was synthesized with reference to patent application WO2014110000A1, HPLC purity: 99.88%.

[0435] Test Example 1: Autotaxin (ATX) enzyme activity inhibition test

[0436] The inhibitory activity of the compound against the Autotaxin enzyme was detected using the Autotaxin Inhibitor Screening Assay Kit (Cayman, 700580). First, the test compound was prepared into a 10 mM stock solution in DMSO solvent, and then 8 concentration points were diluted with DMSO gradient. Subsequently, the 8 concentration points were diluted into a 19× compound working solution (the content of DMSO was 1.9%) with the Autotaxin Assay buffer (1×) provided by 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 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 Autotaxin Assay Buffer (1×), 10 μL of the diluted 19× compound working solution, 10 μL of 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-labeled instrument; the experimental results were input into GraphPad Prism software, and the IC 50 .

[0437] Table 16-1 Results of the inhibitory activity of the test compound against the ATX enzyme activity

[0438] Test compound <![CDATA[IC 50 (nM)]]> Control compound 2.60 Compound of formula (I) 1.59

[0439] The experimental results show that the compound of formula (I) of the present invention has good inhibitory activity against the ATX enzyme; it can effectively inhibit the activity of the ATX enzyme.

[0440] Test Example 2: Human liver microsome stability test

[0441] The human liver microsome stability test was performed by co-incubating the compound with human liver microsomes in vitro. 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 。

[0442] Table 16-2 Results of human liver microsome stability test

[0443]

[0444] 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.

[0445] Test Example 3: Detection of the inhibitory effect of the compound on hERG by the fully automated electrophysiological patch clamp QPatch

[0446] 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 the hERG channel (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 a culture dish containing the above-mentioned culture medium and cultured in an incubator at 37 °C with 5% CO 2 in the incubator.

[0447] Prepare the extracellular solution (2 mM CaCl 2 、1 mM MgCl 2 、4 mM KCl, 145 mM NaCl, 10 mM Glucose, 10 mM HEPES, pH about 7.4, osmotic pressure about 305 mOsm) and the intracellular solution (5.374 mM CaCl 2 、1.75 mM MgCl 2 、120 mM KCl, 10 mM HEPES, 5 mM EGTA, 4 mM Na-ATP, pH about 7.25, osmotic pressure about 295 mOsm).

[0448] Prepare a 10 mM stock solution of the compound to be tested in DMSO solvent, and dilute the compound to 3, 1, 0.3, 0.1 mM with DMSO, and then dilute the compound to 30, 10, 3, 1, 0.3 and 0.1 μM with the extracellular solution. Except that the final concentration of DMSO for the 30 μM compound is 0.3%, the final concentration of DMSO in the compound solutions at other concentrations is 0.1%.

[0449] After digesting and resuspending the CHO hERG cells, add them to the fully automated QPatch system (Sophion, Denmark) and perform the experiment according to the following preset program.

[0450] 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. Throughout the 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 again 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.

[0451] The experimental data were analyzed by Qpatch analysis software provided by Sophion, Excel, Graphpad Prism, etc.

[0452] Table 16-3 Results of the inhibitory effect of the compound on hERG

[0453] 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

[0454] 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.

[0455] Test Example 4: Thermodynamic solubility test

[0456] 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 glyceryl monooleate, 55.02 mM maleic acid), and FaSSGF solution at pH 1.6 (1 L of the solution contains 80 μM sodium taurocholate, 20 μM lecithin, 0.1 g pepsin, 34.2 mM sodium chloride).

[0457] 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. The incubated solution is centrifuged at 12000 rpm for 10 minutes to remove undissolved particles, and the supernatant is transferred to a new centrifuge tube. After appropriate dilution of the supernatant, add an acetonitrile solution containing an internal standard, and perform quantification using a calibration curve prepared with the same matrix.

[0458] Table 16-4 Results of Thermodynamic Solubility Test

[0459]

[0460] The experimental results show that the solubility of the control compound is relatively poor, and it is expected that the absorption in the gastrointestinal tract will be relatively poor, which is not conducive to the development of 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 exposure of oral administration is relatively high, the clinical dosage can be reduced, and the clinical compliance can be improved.

[0461] Test Example 5: Pharmacokinetic Test

[0462] For the pharmacokinetic test in rats, 6 male SD rats weighing 180 - 240 g are used and fasted overnight. Take 3 rats and administer the drug orally by gavage at a dose of 10 mg / kg. Blood samples are 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 are collected before dosing and at 5, 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing. The blood samples are centrifuged at 8000 rpm at 4°C for 6 minutes, the plasma is collected and stored 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, vortex 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, and take an appropriate amount of the mixed solution for LC-MS / MS analysis. The main pharmacokinetic parameters are analyzed using the non-compartmental model of WinNonlin 7.0 software.

[0463] For the pharmacokinetic test in mice, 18 male ICR mice weighing 20 - 25 g are used and fasted overnight. Take 9 mice and administer the drug orally by gavage at a dose of 10 mg / kg. At each blood sampling time point, 3 mice are used, and a total of 9 mice are sampled alternately; take another 9 mice and administer the drug intravenously at a dose of 1 mg / kg. At each blood sampling time point, 3 mice are used, and a total of 9 mice are sampled alternately. The remaining operations are the same as those in the rat pharmacokinetic test.

[0464] Table 16-5 Results of Pharmacokinetic Test in Mice

[0465]

[0466] Table 16-6 Results of Pharmacokinetic Experiments in Rats

[0467]

[0468] 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.

[0469] Test Example 6: Inhibition Test of ATX Enzyme Activity in Human Plasma

[0470] 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.

[0471] 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 out 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 with rapid oscillation. 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 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.

[0472] After the incubation is completed, thaw the blank group on ice and transfer it to the 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.

[0473] 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:

[0474] Inhibition rate (%) = 100 - (compound group at different concentrations - blank group) / (positive group - blank group) * 100

[0475] According to the inhibition rates of different concentrations of the compound, calculate the inhibition IC 50 value of the compound on the activity of ATX enzyme in human plasma.

[0476] Table 16-7 Results of the inhibitory activity of the test compounds on the activity of ATX enzyme in human plasma

[0477] Test compound <![CDATA[IC 50 (nM)]]> Control compound 13.0 Compound of formula (I) 4.7

[0478] 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.

[0479] Test Example 7: Bleomycin-induced IPF model in rats

[0480] 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 divided into groups: 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). Starting from the second day after modeling, oral gavage was administered twice a day. The single-dose administration of the dosing group was 30 mg / kg, and the vehicle control group was given the blank vehicle. The administration was continued for 21 days.

[0481] 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 cell count in the lavage fluid was performed, 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 fibrotic 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 amount were detected by ELISA method, and the amount of TGF-β1 per milligram of total protein was calculated.

[0482] The experimental results showed that the decrease in the body weight of the animals in the compound of formula (I) group was significantly less than that in the control compound group, and the compound of formula (1) had better safety (the results are as Figure 43 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-fibrotic formation effect (the results are as Figure 44 shown).

[0483] Test Example 8: Pharmacokinetic experiment (crystal form)

[0484] In the in vivo pharmacokinetic study in mice, 9 male ICR mice weighing 20 - 25 g were fasted overnight and administered orally by gavage at a dose of 10 mg / kg. Three mice were used at each blood sampling time point, and the 9 mice were alternated. Blood samples were collected before dosing and at 15, 30 minutes, and 1, 2, 4, 8, 12, 24 hours after dosing. The blood samples were centrifuged at 8000 rpm for 6 minutes at 4°C, and the plasma was collected and stored at -20°C. Plasma samples at each time point were mixed with 3 - 5 volumes of acetonitrile solution containing internal standard, vortexed for 1 minute, centrifuged at 13000 rpm for 10 minutes at 4°C, and the supernatant was mixed with 3 volumes of water. An appropriate amount of the mixed solution was subjected to LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed using the non-compartmental model with WinNonlin 7.0 software.

[0485] Table 16 - 8 Results of the in vivo pharmacokinetic study in mice

[0486]

[0487] The experimental results showed that compared with the control compound, the benzenesulfonate crystal form A of the compound of formula (I) of the present invention exhibited more excellent pharmacokinetic properties.

[0488] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, 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), which solid form is hydrochloride crystal form A: The X-ray powder diffraction pattern of the hydrochloride crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 7.48 ± 0.20°, 13.13 ± 0.20°, 16.47 ± 0.20°, 23.94 ± 0.20°.

2. The solid form according to claim 1, wherein, the X-ray powder diffraction pattern of the hydrochloride crystal form A has characteristic peaks at the following 2θ angles: 7.48 ± 0.20°, 13.13 ± 0.20°, 16.47 ± 0.20°, 18.29 ± 0.20°, 19.89 ± 0.20°, 23.94 ± 0.20°.

3. The solid form according to claim 1, wherein, the X-ray powder diffraction pattern of the hydrochloride crystal form A has characteristic peaks at the following 2θ angles: 7.48 ± 0.20°, 13.13 ± 0.20°, 14.86 ± 0.20°, 16.47 ± 0.20°, 18.29 ± 0.20°, 19.89 ± 0.20°, 23.94 ± 0.20°, 26.92 ± 0.20°.

4. The solid form according to claim 1, wherein, the 2θ diffraction angles, D values and / or relative intensities of the X-ray powder diffraction pattern of the hydrochloride crystal form A obtained using Cu-Kα radiation are as follows:

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

6. The solid form according to claim 1, wherein, the hydrochloride crystal form A has one, two, three or four of the following characteristics: (1) The TGA curve of the hydrochloride crystal form A shows a weight loss of about 2.83% at 150.0 ± 3 °C; (2) The DSC curve of the hydrochloride crystal form A has a starting point of an endothermic peak at 163.5 ± 3 °C; (3) The DSC curve of the hydrochloride crystal form A has an endothermic peak at 170.9 ± 10 °C; (4) The DVS curve of the hydrochloride crystal form A shows a water adsorption of less than about 10% under the conditions of 0% RH to 80% RH.

7. The solid form according to claim 6, wherein, the DSC curve of the hydrochloride crystal form A has an endothermic peak at 170.9 ± 5 °C.

8. The solid form according to claim 6, wherein, the DVS curve of the hydrochloride crystal form A shows a water adsorption of less than about 5% under the conditions of 0% RH to 80% RH.

9. The solid form according to claim 6, wherein, the DVS curve of the hydrochloride crystal form A shows a water adsorption of less than about 3.85% under the conditions of 0% RH to 80% RH.

10. A solid form of the compound of formula (I), which solid form is sulfate crystal form A: The X-ray powder diffraction pattern of the sulfate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.49 ± 0.20°, 15.88 ± 0.20°, 17.48 ± 0.20°, 22.40 ± 0.20°.

11. The solid form according to claim 10, wherein, the X-ray powder diffraction pattern of the sulfate crystal form A has characteristic peaks at the following 2θ angles: 5.49 ± 0.20°, 6.93 ± 0.20°, 11.08 ± 0.20°, 15.88 ± 0.20°, 17.48 ± 0.20°, 20.82 ± 0.20°, 22.40 ± 0.20°.

12. The solid form according to claim 10, wherein, the 2θ diffraction angles, D values and / or relative intensities of the X-ray powder diffraction pattern of the sulfate crystal form A obtained using Cu-Kα radiation are as follows:

13. The solid form according to claim 10, wherein, the sulfate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 2.

14. The solid form according to claim 10, wherein, the sulfate crystal form A has one, two or three of the following characteristics: (1) The TGA curve of the sulfate crystal form A has a weight loss of about 3.53% at 150.0 ± 3 °C; (2) The DSC curve of the sulfate crystal form A has a starting point of an endothermic peak at 131.8 ± 3 °C; (3) The DSC curve of the sulfate crystal form A has an endothermic peak at 141.9 ± 10 °C.

15. The solid form according to claim 14, wherein, the DSC curve of the sulfate crystal form A has an endothermic peak at 141.9 ± 5 °C.

16. The solid form of the compound of formula (I), wherein the solid form is maleate crystal form A: The X-ray powder diffraction pattern of the maleate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 4.43 ± 0.20°, 13.86 ± 0.20°, 14.41 ± 0.20°, 15.00 ± 0.20°, 22.07 ± 0.20°, 22.65 ± 0.20°, 25.58 ± 0.20°, 27.34 ± 0.20°.

17. The solid form according to claim 16, wherein, the X-ray powder diffraction pattern of the maleate crystal form A has characteristic peaks at the following 2θ angles: 4.43 ± 0.20°, 9.92 ± 0.20°, 13.86 ± 0.20°, 14.41 ± 0.20°, 15.00 ± 0.20°, 17.82 ± 0.20°, 22.07 ± 0.20°, 22.65 ± 0.20°, 25.58 ± 0.20°, 27.34 ± 0.20°.

18. The solid form according to claim 16, wherein, The X-ray powder diffraction pattern of the maleate polymorph A has characteristic peaks at the following 2θ angles: 4.43 ± 0.20°, 9.92 ± 0.20°, 13.86 ± 0.20°, 14.41 ± 0.20°, 15.00 ± 0.20°, 17.82 ± 0.20°, 22.07 ± 0.20°, 22.65 ± 0.20°, 24.20 ± 0.20°, 24.53 ± 0.20°, 25.58 ± 0.20°, 25.84 ± 0.20°, 27.34 ± 0.20°.

19. The solid form according to claim 16, wherein, the X-ray powder diffraction pattern of the maleate polymorph A obtained using Cu-Kα radiation has 2θ diffraction angles, d values, and / or relative intensities as follows:

20. The solid form according to claim 16, wherein, the maleate polymorph A has an X-ray powder diffraction pattern substantially as shown in Figure 3.

21. The solid form according to claim 16, wherein, the maleate polymorph A has one or both of the following characteristics: (1) The TGA curve of the maleate polymorph A shows a weight loss of about 10.48% at 150.0 ± 3 °C; (2) The DSC curve of the maleate polymorph A has two endothermic peaks at 103.0 ± 10 °C and 132.8 ± 10 °C.

22. The solid form according to claim 21, wherein, the DSC curve of the maleate polymorph A has two endothermic peaks at 103.0 ± 5 °C and 132.8 ± 5 °C.

23. A solid form of the compound of formula (I), the solid form being phosphate polymorph A: The X-ray powder diffraction pattern of the phosphate polymorph A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.08 ± 0.20°, 15.93 ± 0.20°, 24.37 ± 0.20°, 25.19 ± 0.20°.

24. The solid form according to claim 23, wherein, the X-ray powder diffraction pattern of the phosphate polymorph A obtained using Cu-Kα radiation has 2θ diffraction angles, d values, and / or relative intensities as follows:

25. The solid form according to claim 23, wherein, the phosphate polymorph A has an X-ray powder diffraction pattern substantially as shown in Figure 4.

26. The solid form according to claim 23, wherein, the phosphate polymorph A has one or both of the following characteristics: (1) The TGA curve of the phosphate polymorph A shows a weight loss of about 12.68% at 150.0 ± 3 °C; (2) The DSC curve of the phosphate polymorph A has two endothermic peaks at 89.4 ± 3 °C and 94.3 ± 3 °C.

27. A solid form of the compound of formula (I), the solid form being tartrate polymorph A: The X-ray powder diffraction pattern of the tartrate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.00 ± 0.20°, 7.34 ± 0.20°, 8.59 ± 0.20°, 15.88, 19.54 ± 0.20°, 21.46 ± 0.20°, 23.43 ± 0.20°, 25.08 ± 0.20°.

28. The solid form according to claim 27, wherein, the 2θ diffraction angle, D value and / or relative intensity of the X-ray powder diffraction pattern of the tartrate crystal form A obtained using Cu-Kα radiation are as follows:

29. The solid form according to claim 27, wherein, the tartrate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 5.

30. The solid form according to claim 27, wherein, the tartrate crystal form A has one or both of the following characteristics: (1) The TGA curve of the tartrate crystal form A shows a weight loss of about 14.67% at 150.0 ± 3 °C; (2) The DSC curve of the tartrate crystal form A has an endothermic peak at 96.8 ± 10 °C.

31. The solid form according to claim 30, wherein, the DSC curve of the tartrate crystal form A has an endothermic peak at 96.8 ± 5 °C.

32. The solid form of the compound of formula (I), wherein the solid form is tartrate crystal form B: the 2θ diffraction angle, D value and / or relative intensity in the X-ray powder diffraction pattern of the tartrate crystal form B obtained using Cu-Kα radiation are as follows:

33. The solid form according to claim 32, wherein, the tartrate crystal form B has an X-ray powder diffraction pattern substantially as shown in Figure 6.

34. The solid form according to claim 32, wherein, the tartrate crystal form B has one, two or three of the following characteristics: (1) The TGA curve of the tartrate crystal form B shows a weight loss of about 4.87% at 150.0 ± 3 °C; (2) The DSC curve of the tartrate crystal form B has a starting point of an endothermic peak at 173.9 ± 3 °C; (3) The DSC curve of the tartrate crystal form B has an endothermic peak at 175.3 ± 3 °C.

35. The solid form of the compound of formula (I), wherein the solid form is tartrate crystal form C: The X-ray powder diffraction pattern of the tartrate crystal form C obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 4.60 ± 0.20°, 16.15 ± 0.20°, 18.13 ± 0.20°.

36. The solid form according to claim 35, wherein, the X-ray powder diffraction pattern of the tartrate crystal form C has characteristic peaks at the following 2θ angles: 4.60 ± 0.20°, 7.58 ± 0.20°, 14.39 ± 0.20°, 16.15 ± 0.20°, 18.13 ± 0.20°, 22.32 ± 0.20°, 24.44 ± 0.20°, 26.69 ± 0.20°.

37. The solid form according to claim 35, wherein, the tartrate crystal form C has the following 2θ diffraction angles, D values and / or relative intensities in the X-ray powder diffraction pattern using Cu-Kα radiation:

38. The solid form according to claim 35, wherein, the tartrate crystal form C has an X-ray powder diffraction pattern substantially as shown in Figure 7.

39. A solid form of the compound of formula (I), the solid form being fumarate crystal form A: The X-ray powder diffraction pattern of the fumarate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 9.52 ± 0.20°, 13.29 ± 0.20°, 14.92 ± 0.20°, 25.23 ± 0.20°.

40. The solid form according to claim 39, wherein, the X-ray powder diffraction pattern of the fumarate crystal form A has characteristic peaks at the following 2θ angles: 9.52 ± 0.20°, 13.29 ± 0.20°, 14.92 ± 0.20°, 19.02 ± 0.20°, 21.39 ± 0.20°, 25.23 ± 0.20°, 28.07 ± 0.20°.

41. The solid form according to claim 39, wherein, the 2θ diffraction angles, D values and / or relative intensities in the X-ray powder diffraction pattern of the fumarate crystal form A obtained using Cu-Kα radiation are as follows:

42. The solid form according to claim 39, wherein, the fumarate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 8.

43. The solid form according to claim 39, wherein, the fumarate crystal form A has one, two, three or four of the following characteristics: (1) The TGA curve of the fumarate crystal form A shows a weight loss of about 3.86% at 150.0 ± 3 °C; (2) The DSC curve of the fumarate crystal form A has a starting point of an endothermic peak at 208.6 ± 3 °C; (3) The DSC curve of the fumarate crystal form A has an endothermic peak at 210.2 ± 3 °C; (4) The DVS curve of the fumarate crystal form A shows a moisture adsorption of less than about 1% under the conditions of 0% RH to 85% RH.

44. The solid form according to claim 43, wherein, the DVS curve of the fumarate crystal form A shows a moisture adsorption of less than about 0.8% under the conditions of 0% RH to 85% RH.

45. The solid form according to claim 43, wherein, the DVS curve of the fumarate crystal form A shows a moisture adsorption of less than about 0.60% under the conditions of 0% RH to 85% RH.

46. A solid form of the compound of formula (I), the solid form being citrate crystal form A: The 2θ diffraction angles, D values and / or relative intensities in the X-ray powder diffraction pattern of the citrate crystal form A obtained using Cu-Kα radiation are as follows:

47. The solid form according to claim 46, wherein, the citrate crystal form A has an X-ray diffraction powder pattern substantially as shown in Figure 9.

48. The solid form according to claim 46, wherein, the citrate crystal form A has one or both of the following characteristics: (1) The TGA curve of the citrate crystal form A shows a weight loss of about 10.24% at 150.0 ± 3 °C; (2) The DSC curve of the citrate crystal form A has an endothermic peak at 91.2 ± 5 °C.

49. The solid form according to claim 48, wherein, the DSC curve of the citrate crystal form A has an endothermic peak at 91.2 ± 3 °C.

50. The solid form of the compound of formula (I), wherein the solid form is glycolate crystal form A: The X-ray powder diffraction pattern of the glycolate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.26 ± 0.20 °, 7.27 ± 0.20 °, 14.12 ± 0.20 °, 16.02 ± 0.20 °, 24.11 ± 0.20 °.

51. The solid form according to claim 50, wherein, the 2θ diffraction angles, D values and / or relative intensities in the X-ray powder diffraction pattern of the glycolate crystal form A obtained using Cu-Kα radiation are as follows:

52. The solid form according to claim 50, wherein, the glycolate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 10.

53. The solid form according to claim 50, wherein, the glycolate crystal form A has one or both of the following characteristics: (1) The TGA curve of the glycolate crystal form A shows a weight loss of about 7.72% at 150.0 ± 3 °C; (2) The DSC curve of the glycolate crystal form A has an endothermic peak at 103.1 ± 15 °C.

54. The solid form according to claim 53, wherein, the DSC curve of the glycolate crystal form A has an endothermic peak at 103.1 ± 10 °C.

55. The solid form of the compound of formula (I), wherein the solid form is succinate crystal form A: The X-ray powder diffraction pattern of the succinate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 5.26 ± 0.20 °, 14.00 ± 0.20 °, 15.76 ± 0.20 °, 21.07 ± 0.20 °, 22.00 ± 0.20 °, 27.08 ± 0.20 °.

56. The solid form according to claim 55, wherein, the X-ray powder diffraction pattern of the succinate crystal form A has characteristic peaks at the following 2θ angles: 5.26 ± 0.20 °, 6.99 ± 0.20 °, 7.35 ± 0.20 °, 14.00 ± 0.20 °, 15.76 ± 0.20 °, 21.07 ± 0.20 °, 22.00 ± 0.20 °, 27.08 ± 0.20 °.

57. The solid form according to claim 55, wherein, the 2θ diffraction angles, D values and / or relative intensities in the X-ray powder diffraction pattern of the succinate crystal form A obtained using Cu-Kα radiation are as follows:

58. The solid form according to claim 55, wherein, the succinate polymorph A has an X-ray powder diffraction pattern substantially as shown in Figure 11.

59. The solid form according to claim 55, wherein, the succinate polymorph A has one or both of the following characteristics: (1) The TGA curve of the succinate polymorph A shows a weight loss of about 3.74% at 150.0 ± 3 °C; (2) The DSC curve of the succinate polymorph A has four endothermic peaks at 73.3 ± 10 °C, at 102.2 ± 10 °C, at 136.6 ± 10 °C, and at 173.6 ± 10 °C.

60. The solid form according to claim 59, wherein, the DSC curve of the succinate polymorph A has four endothermic peaks at 73.3 ± 5 °C, at 102.2 ± 5 °C, at 136.6 ± 5 °C, and at 173.6 ± 5 °C.

61. The solid form of the compound of formula (I), which is the succinate polymorph B: The X-ray powder diffraction pattern of the succinate polymorph B obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 9.54 ± 0.20 °, 12.60 ± 0.20 °, 14.91 ± 0.20 °, 19.17 ± 0.20 °, 21.02 ± 0.20 °, 24.88 ± 0.20 °.

62. The solid form according to claim 61, wherein, the X-ray powder diffraction pattern of the succinate polymorph B has characteristic peaks at the following 2θ angles: 9.54 ± 0.20 °, 12.60 ± 0.20 °, 13.28 ± 0.20 °, 14.91 ± 0.20 °, 15.20 ± 0.20 °, 19.17 ± 0.20 °, 21.02 ± 0.20 °, 24.88 ± 0.20 °, 28.15 ± 0.20 °.

63. The solid form according to claim 61, wherein, the X-ray powder diffraction pattern of the succinate polymorph B has characteristic peaks at the following 2θ angles: 9.54 ± 0.20 °, 12.60 ± 0.20 °, 13.28 ± 0.20 °, 14.91 ± 0.20 °, 15.20 ± 0.20 °, 19.17 ± 0.20 °, 19.77 ± 0.20 °, 21.02 ± 0.20 °, 21.44 ± 0.20 °, 24.88 ± 0.20 °, 25.22 ± 0.20 °, 28.15 ± 0.20 °.

64. The solid form according to claim 61, wherein, the 2θ diffraction angles, D values, and / or relative intensities in the X-ray powder diffraction pattern of the succinate polymorph B obtained using Cu-Kα radiation are as follows:

65. The solid form according to claim 61, wherein, the succinate polymorph B has an X-ray powder diffraction pattern substantially as shown in Figure 12.

66. The solid form according to claim 61, wherein, the succinate polymorph B has one, two, or three of the following characteristics: (1) The TGA curve of succinate polymorph B shows a weight loss of about 0.83% at 150.0 ± 3 °C; (2) The DSC curve of succinate polymorph B has a starting point of an endothermic peak at 128.8 ± 3 °C; (3) The DSC curve of succinate polymorph B has an endothermic peak at 129.9 ± 3 °C.

67. A solid form of the compound of formula (I), wherein the solid form is adipate polymorph B: The X-ray powder diffraction pattern of the adipate polymorph B obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 4.98 ± 0.20°, 10.69 ± 0.20°, 13.88 ± 0.20°, 21.41 ± 0.20°, 24.97 ± 0.20°, 26.15 ± 0.20°.

68. The solid form according to claim 67, wherein, the X-ray powder diffraction pattern of the adipate polymorph B has characteristic peaks at the following 2θ angles: 4.98 ± 0.20°, 10.69 ± 0.20°, 13.88 ± 0.20°, 14.28 ± 0.20°, 20.72 ± 0.20°, 21.41 ± 0.20°, 24.97 ± 0.20°, 26.15 ± 0.20°.

69. The solid form according to claim 67, wherein, the X-ray powder diffraction pattern of the adipate polymorph B has characteristic peaks at the following 2θ angles: 4.98 ± 0.20°, 9.23 ± 0.20°, 10.69 ± 0.20°, 13.88 ± 0.20°, 14.28 ± 0.20°, 19.35 ± 0.20°, 20.72 ± 0.20°, 21.41 ± 0.20°, 24.97 ± 0.20°, 26.15 ± 0.20°.

70. The solid form according to claim 67, wherein, the 2θ diffraction angles, D values and / or relative intensities in the X-ray powder diffraction pattern of the adipate polymorph B obtained using Cu-Kα radiation are as follows:

71. The solid form according to claim 67, wherein, the adipate polymorph B has an X-ray powder diffraction pattern substantially as shown in Figure 13.

72. The solid form according to claim 67, wherein, the adipate polymorph B has one, two or three of the following characteristics: (1) The TGA curve of adipate polymorph B shows a weight loss of about 1.23% at 150.0 ± 3 °C; (2) The DSC curve of adipate polymorph B has a starting point of an endothermic peak at 112.8 ± 3 °C; (3) The DSC curve of adipate polymorph B has an endothermic peak at 115.6 ± 3 °C.

73. A solid form of the compound of formula (I), wherein the solid form is sebacate polymorph A: The X-ray powder diffraction pattern of the sebacate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 4.57 ± 0.20°, 9.27 ± 0.20°, 11.20 ± 0.20°, 14.40 ± 0.20°, 20.16 ± 0.20°, 24.63 ± 0.20°, 26.73 ± 0.20°.

74. The solid form according to claim 73, wherein, the X-ray powder diffraction pattern of the sebacate crystal form A has characteristic peaks at the following 2θ angles: 4.57 ± 0.20°, 9.27 ± 0.20°, 11.20 ± 0.20°, 14.40 ± 0.20°, 14.95 ± 0.20°, 20.16 ± 0.20°, 20.55 ± 0.20°, 22.95 ± 0.20°, 23.91 ± 0.20°, 24.63 ± 0.20°, 26.73 ± 0.20°.

75. The solid form according to claim 73, wherein, the X-ray powder diffraction pattern of the sebacate crystal form A has characteristic peaks at the following 2θ angles: 4.57 ± 0.20°, 9.27 ± 0.20°, 11.20 ± 0.20°, 14.40 ± 0.20°, 14.95 ± 0.20°, 15.26 ± 0.20°, 18.25 ± 0.20°, 20.16 ± 0.20°, 20.95 ± 0.20°, 22.95 ± 0.20°, 23.91 ± 0.20°, 24.63 ± 0.20°, 26.73 ± 0.20°.

76. The solid form according to claim 73, wherein, the 2θ diffraction angles, D values and / or relative intensities in the X-ray powder diffraction pattern of the sebacate crystal form A obtained using Cu-Kα radiation are as follows:

77. The solid form according to claim 73, wherein, the sebacate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 14.

78. The solid form according to claim 73, wherein, the sebacate crystal form A has one or both of the following characteristics: (1) The TGA curve of the sebacate crystal form A shows a weight loss of about 0.45% at 150.0 ± 3°C; (2) The DSC curve of the sebacate crystal form A has two endothermic peaks at 80.9 ± 10°C and 142.1 ± 10°C.

79. The solid form of the compound of formula (I), wherein the solid form is p-toluenesulfonate crystal form A: The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 6.04 ± 0.20°, 8.59 ± 0.20°, 14.27 ± 0.20°, 17.14 ± 0.20°, 25.29 ± 0.20°.

80. The solid form according to claim 79, wherein, The X-ray powder diffraction pattern of the p-toluenesulfonate polymorph A has characteristic peaks at the following 2θ angles: 6.04±0.20°, 8.59±0.20°, 14.27±0.20°, 17.14±0.20°, 20.41±0.20°, 23.68±0.20°, 25.29±0.20°, 27.65±0.20°.

81. The solid form according to claim 79, wherein, the X-ray powder diffraction pattern of the p-toluenesulfonate polymorph A has characteristic peaks at the following 2θ angles: 6.04±0.20°, 8.59±0.20°, 12.28±0.20°, 14.27±0.20°, 16.02±0.20°, 17.14±0.20°, 20.41±0.20°, 22.01±0.20°, 23.68±0.20°, 25.29±0.20°, 27.65±0.20°.

82. The solid form according to claim 79, wherein, the 2θ diffraction angles, D values and / or relative intensities in the X-ray powder diffraction pattern of the p-toluenesulfonate polymorph A obtained using Cu-Kα radiation are as follows:

83. The solid form according to claim 79, wherein, the p-toluenesulfonate polymorph A has an X-ray diffraction pattern substantially as shown in Figure 15.

84. The solid form according to claim 79, wherein, the p-toluenesulfonate polymorph A has one or both of the following characteristics: (1) The TGA curve of the p-toluenesulfonate polymorph A shows a weight loss of about 3.29% at 150.0±3°C; (2) The DSC curve of the p-toluenesulfonate polymorph A has an endothermic peak at 210.8±10°C.

85. The solid form according to claim 84, wherein, the DSC curve of the p-toluenesulfonate polymorph A has an endothermic peak at 210.8±5°C.

86. The solid form of the compound of formula (I), wherein the solid form is benzenesulfonate polymorph A: The X-ray powder diffraction pattern of the benzenesulfonate polymorph A obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 6.16±0.20°, 8.98±0.20°, 14.22±0.20°, 16.90±0.20°, 18.31±0.20°, 20.92±0.20°, 25.11±0.20°, 26.29±0.20°.

87. The solid form according to claim 86, wherein, The X-ray powder diffraction pattern of the benzenesulfonate crystal form A has characteristic peaks at the following 2θ angles: 6.16 ± 0.20°, 8.98 ± 0.20°, 14.22 ± 0.20°, 15.67 ± 0.20°, 16.90 ± 0.20°, 17.55 ± 0.20°, 18.31 ± 0.20°, 20.34 ± 0.20°, 20.92 ± 0.20°, 25.11 ± 0.20°, 26.29 ± 0.20°, 29.24 ± 0.20°.

88. The solid form according to claim 86, wherein, the X-ray powder diffraction pattern of the benzenesulfonate crystal form A has characteristic peaks at the following 2θ angles: 6.16 ± 0.20°, 8.98 ± 0.20°, 14.22 ± 0.20°, 15.67 ± 0.20°, 16.90 ± 0.20°, 17.55 ± 0.20°, 18.31 ± 0.20°, 20.34 ± 0.20°, 20.92 ± 0.20°, 23.54 ± 0.20°, 24.65 ± 0.20°, 25.11 ± 0.20°, 26.29 ± 0.20°, 29.24 ± 0.20°.

89. The solid form according to claim 86, wherein, the 2θ diffraction angles, D values and / or relative intensities in the X-ray powder diffraction pattern of the benzenesulfonate crystal form A obtained using Cu-Kα radiation are as follows:

90. The solid form according to claim 86, wherein, the benzenesulfonate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 16.

91. The solid form according to claim 86, wherein, the benzenesulfonate crystal form A has one, two, three or four of the following characteristics: (1) The TGA curve of the benzenesulfonate crystal form A shows a weight loss of about 1.87% at 150.0 ± 3 °C; (2) The DSC curve of the benzenesulfonate crystal form A has a starting point of an endothermic peak at 184.7 ± 3 °C; (3) The DSC curve of the benzenesulfonate crystal form A has an endothermic peak at 187.0 ± 3 °C; (4) The DVS curve of the benzenesulfonate crystal form A shows a water adsorption of less than about 2% under the conditions of 0% RH to 85% RH.

92. The solid form according to claim 91, wherein, the DVS curve of the benzenesulfonate crystal form A shows a water adsorption of less than about 1.8% under the conditions of 0% RH to 85% RH.

93. The solid form according to claim 91, wherein, the DVS curve of the benzenesulfonate crystal form A shows a water adsorption of less than about 1.46% under the conditions of 0% RH to 85% RH.

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

95. The solid form according to claim 94, wherein, the hydrobromide crystal acid form A has an X-ray powder diffraction pattern substantially as shown in Figure 17.

96. The solid form according to claim 94, wherein, the hydrobromide crystal form A has one or both of the following characteristics: (1) The TGA curve of the hydrobromide crystal form A shows a weight loss of about 7.86% at 150.0 ± 3 °C; (2) The DSC curve of the hydrobromide crystal form A has three endothermic peaks at 96.5 ± 5 °C, at 107.3 ± 5 °C, and at 141.8 ± 5 °C.

97. A solid form of the compound of formula (I), wherein the solid form is hydrobromide crystal form B: The X-ray powder diffraction pattern of the hydrobromide crystal form B obtained using Cu-Kα radiation has characteristic peaks at the following 2θ angles: 9.48 ± 0.20 °, 15.89 ± 0.20 °, 23.98 ± 0.20 °.

98. The solid form according to claim 97, wherein, the X-ray powder diffraction pattern of the hydrobromide crystal form B has characteristic peaks at the following 2θ angles: 9.48 ± 0.20 °, 15.89 ± 0.20 °, 19.40 ± 0.20 °, 23.98 ± 0.20 °, 26.55 ± 0.20 °, 28.02 ± 0.20 °.

99. The solid form according to claim 97, wherein, the 2θ diffraction angle, D value, and / or relative intensity in the X-ray powder diffraction pattern of the hydrobromide crystal form B obtained using Cu-Kα radiation are as follows:

100. The solid form according to claim 97, wherein, the hydrobromide crystal form B has an X-ray powder diffraction pattern substantially as shown in Figure 18.

101. The solid form according to claim 97, wherein, the hydrobromide crystal form B has one or both of the following characteristics: (1) The TGA curve of the hydrobromide crystal form B shows a weight loss of about 4.95% at 150.0 ± 3 °C; (2) The DSC curve of the hydrobromide crystal form B has three endothermic peaks at 81.6 ± 10 °C, at 128.9 ± 10 °C, and at 163.6 ± 10 °C.

102. The solid form according to claim 101, wherein, the DSC curve of the hydrobromide crystal form B has three endothermic peaks at 81.6 ± 5 °C, at 128.9 ± 5 °C, and at 163.6 ± 5 °C.

103. A pharmaceutical composition comprising the solid form according to any one of claims 1-102, or a mixture of any two or more thereof.

104. Use of the solid form according to any one of claims 1-102, or a mixture of any two or more thereof, or the pharmaceutical composition according to claim 103 for the preparation of a drug, wherein the drug is used for the treatment and / or prevention of diseases related to autotaxin ATX.

105. The use according to claim 104, 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.

106. The use according to claim 104, wherein, the ATX-related diseases are selected from at least one of the following: interstitial lung diseases, pulmonary fibrosis, liver fibrosis, and renal fibrosis.

107. The use according to claim 104, wherein, the ATX-related diseases include idiopathic pulmonary fibrosis, type II diabetes, non-alcoholic steatohepatitis, neuropathic pain, and inflammatory pain.

108. The use according to claim 104, wherein, the ATX-related diseases include pain related to osteoarthritis.

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