CN113999235A

CN113999235A - Solid forms of nitrogen-containing heterocyclic compounds, pharmaceutical compositions and uses thereof

Info

Publication number: CN113999235A
Application number: CN202110857967.1A
Authority: CN
Inventors: 张学军; 乐洋; 雷四军; 夏庆丰; 李园; 杨琼峰; 刘民安; 杨少侠; 刘明; 胡斌; 张守波; 丁肖华; 刘哲
Original assignee: Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Current assignee: Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Priority date: 2020-07-28
Filing date: 2021-07-28
Publication date: 2022-02-01
Also published as: TW202214644A; WO2022022569A1

Abstract

The present invention provides solid forms of a compound of formula (I) or a solvate thereof, having ATX inhibitory activity, wherein said solid forms comprise crystalline and/or amorphous forms. The crystalline forms include two non-solvate crystalline forms: form a and form L; six hydrate crystal forms: form B (dihydrate), form D (trihydrate), form G (tetrahydrate), form H (monohydrate), form K (dihydrate), and form M-1 (monohydrate); seven solvate crystalline forms: form C (hemi-toluate), form E (mono-chloroform), form N (dichloromethane), form P (mono-isopropanol), form J-1 (hemi-2-methyltetrahydrofuran), form J-2 (mono-methyl isobutyl ketone), and form M-2 (mono-acetonitrile). The solid forms are useful for the treatment and/or prevention of autotaxin ATX-related diseases.

Description

Solid forms of nitrogen-containing heterocyclic compounds, pharmaceutical compositions and uses thereof

The present application claims priority to a prior application entitled "solid forms of nitrogen-containing heterocyclic compounds and pharmaceutical compositions and uses thereof" filed by the applicant on 28.7.2020 to the chinese intellectual property office under patent application No. 202010742864.6. The entire content of this prior application is incorporated by reference into this application.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a solid form of a nitrogen-containing heterocyclic compound, a pharmaceutical composition and application thereof.

Background

Autotaxin (ATX) is a secreted glycoprotein with Phosphodiesterase (PDE) activity, a member of the extracellular pyrophosphatase/phosphodiesterase (ENPP) family, and therefore also known as ENPP2, which also has lysophospholipase d (lysopld) activity and is capable of hydrolyzing Lysophosphatidylcholine (LPC) to bioactive lysophosphatidic acid (LPA). LPA is an intracellular lipid mediator that affects many biological and biochemical processes. Studies have shown that inhibition of ATX can reduce LPA levels in pathological conditions, thereby providing therapeutic benefit to 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 activation of ATX. Accordingly, ATX inhibitors are expected to be useful in the treatment of diseases associated with elevated LPA levels, including cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrosis, thrombosis, cholestatic pruritus, fibrotic diseases, such as Idiopathic Pulmonary Fibrosis (IPF).

The chinese patent application No. 202010074393.6 describes compounds of formula (I) having ATX inhibitory activity.

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. On the basis of good biological activity of the compound, more stable solid forms such as crystal forms and amorphous substances are searched and obtained, and the method has important significance for improving the drug forming property, hygroscopicity, stability, storage or weighing and the like of the compound.

Disclosure of Invention

To ameliorate the above technical problem, the present invention provides a solid form of a compound of formula (I):

wherein the solid form comprises a crystalline and/or amorphous form.

According to an embodiment of the invention, the solvent in the solvate may be selected from aqueous and/or non-aqueous solvents. The non-aqueous solvent includes, but is not limited to, ethanol, acetonitrile, toluene, chloroform, dichloromethane, isopropanol, propylene glycol, isobutanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, methyl isobutyl ketone, and the like.

According to an embodiment of the invention, the solid form of the compound of formula (I) may or may not comprise an adsorption solvent, for example comprising or not comprising water of crystallization.

The present invention provides a crystalline form of a compound of formula (I) or a solvate thereof, comprising: two non-solvate crystalline forms: form a and form L; six hydrate crystal forms: form B (dihydrate), form D (trihydrate), form G (tetrahydrate), form H (monohydrate), form K (dihydrate), and form M-1 (monohydrate); seven organic solvate crystal forms: form C (hemitoluate), form E (monochloro-chloroform), form N (monochloro-methane), form P (monoisopropanol), form J-1 (hemi2-methyltetrahydrofuran), form J-2 (monomethyl isobutyl ketone) and form M-2 (acetonitrile).

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

The invention provides a crystal form A of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern obtained by Cu-K alpha rays has characteristic peaks at the following 2 theta angles: 8.05 +/-0.20 degrees, 8.30 +/-0.20 degrees, 14.11 +/-0.20 degrees, 16.18 +/-0.20 degrees, 22.73 +/-0.20 degrees and 25.16 +/-0.20 degrees.

According to an embodiment of the present invention, the form a has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 8.05 +/-0.20 degrees, 8.30 +/-0.20 degrees, 14.11 +/-0.20 degrees, 16.18 +/-0.20 degrees, 16.65 +/-0.20 degrees, 21.85 +/-0.20 degrees, 22.73 +/-0.20 degrees, 25.16 +/-0.20 degrees and 26.23 +/-0.20 degrees.

According to an embodiment of the present invention, the form a has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 8.05 +/-0.20 degrees, 8.30 +/-0.20 degrees, 14.11 +/-0.20 degrees, 16.18 +/-0.20 degrees, 16.65 +/-0.20 degrees, 19.19 +/-0.20 degrees, 21.85 +/-0.20 degrees, 22.73 +/-0.20 degrees, 25.16 +/-0.20 degrees, 26.23 +/-0.20 degrees and 29.91 +/-0.20 degrees.

According to an embodiment of the present invention, the form a has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 8.05 +/-0.20 degrees, 8.30 +/-0.20 degrees, 14.11 +/-0.20 degrees, 16.18 +/-0.20 degrees, 16.65 +/-0.20 degrees, 18.19 +/-0.20 degrees, 18.91 +/-0.20 degrees, 19.19 +/-0.20 degrees, 21.85 +/-0.20 degrees, 22.73 +/-0.20 degrees, 25.16 +/-0.20 degrees, 26.23 +/-0.20 degrees and 29.91 +/-0.20 degrees.

According to an embodiment of the present invention, the form a has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 8.05 +/-0.20 degrees, 8.30 +/-0.20 degrees, 10.77 +/-0.20 degrees, 12.95 +/-0.20 degrees, 14.11 +/-0.20 degrees, 16.18 +/-0.20 degrees, 16.65 +/-0.20 degrees, 17.35 +/-0.20 degrees, 18.19 +/-0.20 degrees, 18.91 +/-0.20 degrees, 19.19 +/-0.20 degrees, 20.93 +/-0.20 degrees, 21.53 +/-0.20 degrees, 21.85 +/-0.20 degrees, 22.31 +/-0.20 degrees, 22.73 +/-0.20 degrees, 24.38 +/-0.20 degrees, 25.16 +/-0.20 degrees, 26.23 +/-0.20 degrees, 27.39 +/-0.20 degrees, 28.44 +/-0.20 degrees, 28.99 +/-0.20 degrees, 29.20 +/-0.20 degrees, 29.91 +/-0.20 degrees, 32.77 +/-0.20 degrees and 36.68 +/-0.20 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angle, D value and/or relative intensity of the X-ray powder diffraction pattern obtained by using Cu — K α rays for the form a are shown in table 1 below:

table 1 XRPD diffraction peak data for form a

According to an embodiment of the invention, said form a has an X-ray powder diffraction pattern substantially as shown in figure 1.

According to an embodiment of the invention, the form a has one, two, three or four of the following features:

(1) the TGA curve for form a lost about 2.59% weight at 150.0 ± 3 ℃;

(2) the DSC curve of the crystal form A has an initial point of an endothermic peak at the temperature of 152.4 +/-3 ℃;

(3) the DSC curve of the crystal form A has an endothermic peak at 155.3 +/-3 ℃;

(4) the DVS curve for form a has a moisture sorption of less than about 1.2%, such as less than about 1.1%, specifically less than about 1.05% at 0% RH to 80% RH.

According to an embodiment of the invention, the form a has one, two or three of the following features:

(1) form a has a TGA profile substantially as shown in figure 17;

(2) form a has a DSC profile substantially as shown in figure 17;

(3) form a has a DVS profile substantially as shown in figure 30.

The present invention also provides crystalline form B of the dihydrate of the compound of formula (I) having characteristic peaks at the following 2 Θ angles in its X-ray powder diffraction pattern obtained with Cu-K α radiation: 4.93 plus or minus 0.2 degrees, 5.30 plus or minus 0.2 degrees, 7.37 plus or minus 0.2 degrees, 7.93 plus or minus 0.2 degrees and 15.95 plus or minus 0.2 degrees.

According to an embodiment of the invention, the form B has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 4.93 plus or minus 0.2 degrees, 5.30 plus or minus 0.2 degrees, 7.37 plus or minus 0.2 degrees, 7.93 plus or minus 0.2 degrees, 8.59 plus or minus 0.2 degrees, 14.04 plus or minus 0.2 degrees, 15.95 plus or minus 0.2 degrees and 24.15 plus or minus 0.2 degrees.

According to an embodiment of the invention, the form B has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 4.93 plus or minus 0.2 degrees, 5.30 plus or minus 0.2 degrees, 7.37 plus or minus 0.2 degrees, 7.93 plus or minus 0.2 degrees, 8.59 plus or minus 0.2 degrees, 14.04 plus or minus 0.2 degrees, 15.95 plus or minus 0.2 degrees, 17.24 plus or minus 0.2 degrees, 23.33 plus or minus 0.2 degrees and 24.15 plus or minus 0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — ka ray for the form B are shown in table 2 below:

table 2 XRPD diffraction peak data for form B

According to an embodiment of the invention, said form B has an X-ray powder diffraction pattern substantially as shown in figure 2.

According to an embodiment of the invention, said form B has one, two or three of the following features:

(1) the TGA curve of form B lost about 9.72% weight at 150.0 ± 3 ℃;

(2) the DSC curve of the crystal form B has an initial point of an endothermic peak at 96.8 +/-3 ℃;

(3) the DSC curve of the crystal form B has an endothermic peak at 111.1 +/-10 ℃; in particular, the DSC curve of form B has an endothermic peak at 111.1 ± 5 ℃.

According to an embodiment of the invention, said form B has one or both of the following characteristics:

(1) form B has a TGA profile substantially as shown in figure 18;

(2) form B has a DSC profile substantially as shown in figure 18.

The present invention also provides crystalline form C of the hemi-toluene solvate of compound of formula (I) having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-K α radiation: 6.80 +/-0.2 degrees, 13.65 +/-0.2 degrees, 16.27 +/-0.2 degrees, 24.69 +/-0.2 degrees and 25.65 +/-0.2 degrees.

According to an embodiment of the invention, the form C has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 6.80 +/-0.2 degrees, 13.65 +/-0.2 degrees, 16.27 +/-0.2 degrees, 18.92 +/-0.2 degrees, 19.32 +/-0.2 degrees, 21.49 +/-0.2 degrees, 24.69 +/-0.2 degrees and 25.65 +/-0.2 degrees.

According to an embodiment of the invention, the form C has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 6.80 +/-0.2 degrees, 7.58 +/-0.2 degrees, 12.55 +/-0.2 degrees, 13.65 +/-0.2 degrees, 16.27 +/-0.2 degrees, 18.92 +/-0.2 degrees, 19.32 +/-0.2 degrees, 20.39 +/-0.2 degrees, 21.49 +/-0.2 degrees, 24.69 +/-0.2 degrees and 25.65 +/-0.2 degrees.

According to an embodiment of the invention, the form C has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 6.80 +/-0.2 degrees, 7.58 +/-0.2 degrees, 8.32 +/-0.2 degrees, 12.55 +/-0.2 degrees, 13.65 +/-0.2 degrees, 16.27 +/-0.2 degrees, 17.73 +/-0.2 degrees, 18.92 +/-0.2 degrees, 19.32 +/-0.2 degrees, 20.39 +/-0.2 degrees, 21.49 +/-0.2 degrees, 23.44 +/-0.2 degrees, 24.69 +/-0.2 degrees, 25.65 +/-0.2 degrees, 28.27 +/-0.2 degrees and 30.25 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — ka rays for the form C are shown in table 3 below:

table 3 XRPD diffraction peak data for form C

According to an embodiment of the invention, said form C has an X-ray powder diffraction pattern substantially as shown in figure 3.

According to an embodiment of the invention, the form C has one, two or three of the following features:

(1) the TGA curve for form C lost about 12.89% weight at 150.0 ± 3 ℃;

(2) the DSC curve of the crystal form C has two endothermic peaks at 80.7 +/-10 ℃ and 160.6 +/-10 ℃; in particular, the DSC curve of form C has two endothermic peaks at 80.7 ± 5 ℃ and 160.6 ± 5 ℃;

(3) of form C¹The H NMR spectrum has the characteristic hydrogen signal of toluene.

More specifically, the DSC curve of form C also has two endothermic peaks at 119.8 + -10 deg.C and 155.5 + -10 deg.C, more specifically at 119.8 + -5 deg.C, 155.5 + -5 deg.C.

(1) form C has a TGA profile substantially as shown in figure 19;

(2) form C has a DSC profile substantially as shown in figure 19;

(3) form C has a structure substantially as shown in figure 32¹H NAn MR atlas.

The present invention also provides crystalline form D of the trihydrate of the compound of formula (I) having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-K α radiation: 7.57 +/-0.2 degrees and 14.31 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — ka rays for the form D are shown in table 4 below:

table 4 XRPD diffraction peak data for form D

According to an embodiment of the invention, the crystalline form D has an X-ray powder diffraction pattern substantially as shown in figure 4.

According to an embodiment of the invention, said form D has one or both of the following characteristics:

(1) the TGA curve of form D lost about 12.93% weight at 150.0 ± 3 ℃;

(2) the DSC curve of the crystal form D has two endothermic peaks at 133.3 +/-10 ℃ and 159.2 +/-10 ℃; in particular, the DSC curve of form D has two endothermic peaks at 133.3 ± 5 ℃ and 159.2 ± 5 ℃.

More specifically, the DSC curve of form D also has two endothermic peaks at 113.0 ± 10 ℃ and 155.3 ± 10 ℃; in particular, the DSC curve of form D also has two endothermic peaks at 113.0 ± 5 ℃ and 155.3 ± 5 ℃.

(1) form D has a TGA profile substantially as shown in figure 20;

(2) form D has a DSC profile substantially as shown in figure 20.

The present invention also provides crystalline form E of the monochloroform solvate of the compound of formula (I) having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-K α radiation: 7.32 +/-0.2 degrees, 19.44 +/-0.2 degrees, 22.06 +/-0.2 degrees, 25.25 +/-0.2 degrees and 29.54 +/-0.2 degrees.

According to an embodiment of the invention, the form E has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 7.32 +/-0.2 degrees, 11.72 +/-0.2 degrees, 14.66 +/-0.2 degrees, 16.53 +/-0.2 degrees, 19.44 +/-0.2 degrees, 20.54 +/-0.2 degrees, 22.06 +/-0.2 degrees, 25.25 +/-0.2 degrees and 29.54 +/-0.2 degrees.

According to an embodiment of the invention, the form E has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 7.32 +/-0.2 degrees, 11.72 +/-0.2 degrees, 14.66 +/-0.2 degrees, 16.09 +/-0.2 degrees, 16.53 +/-0.2 degrees, 19.44 +/-0.2 degrees, 20.54 +/-0.2 degrees, 20.81 +/-0.2 degrees, 22.06 +/-0.2 degrees, 25.25 +/-0.2 degrees and 29.54 +/-0.2 degrees.

According to an embodiment of the invention, the form E has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 7.32 +/-0.2 degrees, 10.25 +/-0.2 degrees, 11.72 +/-0.2 degrees, 14.33 +/-0.2 degrees, 14.66 +/-0.2 degrees, 16.09 +/-0.2 degrees, 16.53 +/-0.2 degrees, 17.57 +/-0.2 degrees, 18.14 +/-0.2 degrees, 18.77 +/-0.2 degrees, 19.44 +/-0.2 degrees, 19.75 +/-0.2 degrees, 20.54 +/-0.2 degrees, 20.81 +/-0.2 degrees, 22.06 +/-0.2 degrees, 22.77 +/-0.2 degrees, 23.19 +/-0.2 degrees, 25.25 +/-0.2 degrees, 26.04 +/-0.2 degrees, 27.06 +/-0.2 degrees, 27.35 +/-0.2 degrees, 29.54 +/-0.2 degrees, 30.41 +/-0.2 degrees and 32.99 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — ka rays for the form E are shown in table 5 below:

table 5 XRPD diffraction peak data for form E

According to an embodiment of the invention, the crystalline form E has an X-ray powder diffraction pattern substantially as shown in figure 5.

According to an embodiment of the invention, the crystalline form E has one, two or three of the following characteristics:

(1) the TGA curve of form E loses about 3.42% weight at 90.0 + -3 deg.C and about 19.74% weight at 200.0 + -3 deg.C;

(2) the DSC curve of the crystal form E has two endothermic peaks at 70.0 +/-10 ℃ and 127.2 +/-10 ℃; in particular, the DSC curve of form E has two endothermic peaks at 70.0 ± 5 ℃ and 127.2 ± 5 ℃;

(3) of the crystalline form E¹The H NMR spectrum has the characteristic hydrogen signal of chloroform.

(1) form E has a TGA profile substantially as shown in figure 21;

(2) form E has a DSC profile substantially as shown in figure 21;

(3) form E has a crystalline form substantially as shown in FIG. 33¹H NMR spectrum.

The present invention also provides crystalline form G of the tetrahydrate of the compound of formula (I) having the characteristic peaks at the following 2 Θ angles in its X-ray powder diffraction pattern, obtained with Cu-K α radiation: 7.08 +/-0.2 degrees, 7.54 +/-0.2 degrees, 14.15 +/-0.2 degrees, 15.10 +/-0.2 degrees, 18.85 +/-0.2 degrees, 25.49 +/-0.2 degrees and 26.06 +/-0.2 degrees.

According to an embodiment of the invention, the form G has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 7.08 +/-0.2 degrees, 7.54 +/-0.2 degrees, 13.54 +/-0.2 degrees, 14.15 +/-0.2 degrees, 15.10 +/-0.2 degrees, 18.85 +/-0.2 degrees, 21.34 +/-0.2 degrees, 22.12 +/-0.2 degrees, 25.49 +/-0.2 degrees and 26.06 +/-0.2 degrees.

According to an embodiment of the invention, the form G has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 7.08 +/-0.2 degrees, 7.54 +/-0.2 degrees, 8.62 +/-0.2 degrees, 11.82 +/-0.2 degrees, 13.54 +/-0.2 degrees, 14.15 +/-0.2 degrees, 15.10 +/-0.2 degrees, 16.36 +/-0.2 degrees, 18.05 +/-0.2 degrees, 18.85 +/-0.2 degrees, 19.49 +/-0.2 degrees, 20.32 +/-0.2 degrees, 21.34 +/-0.2 degrees, 22.12 +/-0.2 degrees, 22.74 +/-0.2 degrees, 25.49 +/-0.2 degrees, 26.06 +/-0.2 degrees, 26.93 +/-0.2 degrees, 28.57 +/-0.2 degrees and 31.82 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — ka rays for said form G are as shown in table 6 below:

table 6 XRPD diffraction peak data for form G

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

According to an embodiment of the invention, the form G shown has one, two or three of the following characteristics:

(1) the TGA curve for form G lost about 15.06% weight at 150.0 ± 3 ℃;

(2) the DSC curve of the crystal form G has two endothermic peaks at 74.6 +/-10 ℃ and 90.1 +/-10 ℃; in particular, the DSC curve of form G has two endothermic peaks at 74.6 ± 5 ℃ and 90.1 ± 5 ℃;

(3) form G has a DVS curve with a moisture sorption of less than about 8.5%, e.g., less than about 8.44%, at 0% RH to 80% RH.

According to an embodiment of the invention, the form G has one, two or three of the following characteristics:

(1) form G has a TGA profile substantially as shown in figure 22;

(2) form G has a DSC profile substantially as shown in figure 22;

(3) form G has a DVS profile substantially as shown in figure 31.

The present invention also provides crystalline form H of the monohydrate of the compound of formula (I) having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-K α radiation: 5.76 +/-0.2 degrees, 6.81 +/-0.2 degrees, 11.54 +/-0.2 degrees and 18.68 +/-0.2 degrees.

According to an embodiment of the invention, the form H has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 5.76 +/-0.2 degrees, 6.81 +/-0.2 degrees, 7.95 +/-0.2 degrees, 8.74 +/-0.2 degrees, 11.54 +/-0.2 degrees, 13.86 +/-0.2 degrees, 18.68 +/-0.2 degrees and 19.90 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — ka rays for the form H are shown in table 7 below:

table 7 XRPD diffraction peak data for form H

According to an embodiment of the invention, the crystalline form H has an X-ray powder diffraction pattern substantially as shown in figure 7.

According to an embodiment of the invention, said form H has one or both of the following characteristics:

(1) the TGA curve of form H lost about 3.62% weight at 150.0 ± 3 ℃;

(2) the DSC curve of the crystal form H has two endothermic peaks at 72.5 +/-10 ℃ and 112.8 +/-10 ℃; in particular, the DSC curve for form H has two endothermic peaks at 72.5 ± 5 ℃ and 112.8 ± 5 ℃.

(1) form H has a TGA profile substantially as shown in figure 23;

(2) form H has a DSC profile substantially as shown in figure 23.

The invention also provides a crystalline form J-1 of the hemi-2-methyltetrahydrofuran compound of the compound of formula (I) having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-ka radiation: 4.43 +/-0.2 degrees, 8.73 +/-0.2 degrees, 11.53 +/-0.2 degrees and 15.72 +/-0.2 degrees.

According to an embodiment of the present invention, the crystalline form J-1 has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 4.43 +/-0.2 degrees, 8.73 +/-0.2 degrees, 11.53 +/-0.2 degrees, 15.72 +/-0.2 degrees, 20.13 +/-0.2 degrees, 21.93 +/-0.2 degrees and 23.99 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — ka rays for the crystalline form J-1 are shown in the following table 8-1:

table 8-1 XRPD diffraction peak data for form J-1

According to an embodiment of the present invention, the crystalline form J-1 has an X-ray powder diffraction pattern substantially as shown in figure 8-1.

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

(1) the TGA curve for form J-1 loses about 7.91% weight at 150.0 + -3 ℃;

(2) the DSC curve of the crystal form J-1 has two endothermic peaks at 96.6 +/-3 ℃ and 157.6 +/-3 ℃.

More specifically, the DSC curve of the crystal form J-1 also has an endothermic peak at 151.3 +/-3 ℃.

(1) form J-1 has a TGA profile substantially as shown in figure 24-1;

(2) form J-1 has a DSC curve substantially as shown in figure 24-1.

The present invention also provides crystalline form J-2 of the monomethyl isobutyl ketone compound of the compound of formula (I) having characteristic peaks at the following 2 θ angles in its X-ray powder diffraction pattern obtained with Cu-ka radiation: 4.31 +/-0.2 degrees, 8.56 +/-0.2 degrees, 11.32 +/-0.2 degrees, 15.44 +/-0.2 degrees and 19.64 +/-0.2 degrees.

According to an embodiment of the present invention, the X-ray powder diffraction pattern of form J-2 has characteristic peaks at the following 2 Θ angles: 4.31 +/-0.2 degrees, 8.56 +/-0.2 degrees, 11.32 +/-0.2 degrees, 15.44 +/-0.2 degrees, 19.64 +/-0.2 degrees, 21.80 +/-0.2 degrees and 23.90 +/-0.2 degrees.

According to an embodiment of the present invention, the X-ray powder diffraction pattern of form J-2 has characteristic peaks at the following 2 Θ angles: 4.31 +/-0.2 degrees, 8.56 +/-0.2 degrees, 11.32 +/-0.2 degrees, 14.84 +/-0.2 degrees, 15.44 +/-0.2 degrees, 16.46 +/-0.2 degrees, 17.15 +/-0.2 degrees, 19.64 +/-0.2 degrees, 21.80 +/-0.2 degrees, 23.42 +/-0.2 degrees, 23.90 +/-0.2 degrees and 24.24 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — ka radiation for the crystalline form J-2 are shown in the following table 8-2:

table 8-2 XRPD diffraction peak data for form J-2

According to an embodiment of the present invention, the crystalline form J-2 has an X-ray powder diffraction pattern substantially as shown in figure 8-2.

According to an embodiment of the invention, said crystalline form J-2 has one or both of the following characteristics:

(1) the TGA curve for form J-2 loses about 19.07% weight at 150.0 ± 3 ℃;

(2) the DSC curve of the crystal form J-2 has an endothermic peak at 94.3 +/-3 ℃.

(1) form J-2 has a TGA profile substantially as shown in figure 24-2;

(2) form J-2 has a DSC curve substantially as shown in figure 24-2.

The present invention provides crystalline form K of the dihydrate of the compound of formula (I) having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-K α radiation: 6.93 plus or minus 0.2 degrees, 13.89 plus or minus 0.2 degrees, 14.81 plus or minus 0.2 degrees, 20.91 plus or minus 0.2 degrees, 25.00 plus or minus 0.2 degrees and 25.72 plus or minus 0.2 degrees.

According to an embodiment of the invention, the form K has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 6.93 plus or minus 0.2 degrees, 13.89 plus or minus 0.2 degrees, 14.81 plus or minus 0.2 degrees, 18.77 plus or minus 0.2 degrees, 20.91 plus or minus 0.2 degrees, 25.00 plus or minus 0.2 degrees, 25.72 plus or minus 0.2 degrees and 28.04 plus or minus 0.2 degrees.

According to an embodiment of the invention, the form K has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 6.93 plus or minus 0.2 degrees, 11.49 plus or minus 0.2 degrees, 13.89 plus or minus 0.2 degrees, 14.81 plus or minus 0.2 degrees, 18.77 plus or minus 0.2 degrees, 20.05 plus or minus 0.2 degrees, 20.91 plus or minus 0.2 degrees, 21.87 plus or minus 0.2 degrees, 25.00 plus or minus 0.2 degrees, 25.72 plus or minus 0.2 degrees and 28.04 plus or minus 0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — ka rays for form K are shown in table 9 below:

table 9 XRPD diffraction peak data for form K

According to an embodiment of the invention, the crystalline form K has an X-ray powder diffraction pattern substantially as shown in figure 9.

According to an embodiment of the invention, said form K has one, two or three of the following features:

(1) the TGA curve of form K loses about 10.13% weight at 150.0 + -3 ℃;

(2) the DSC curve of the crystal form K has an initial point of an endothermic peak at 104.5 +/-3 ℃;

(3) the DSC curve of the crystal form K has an endothermic peak at 110.7 +/-3 ℃.

According to an embodiment of the invention, said form K has one or both of the following characteristics:

(1) form K has a TGA profile substantially as shown in figure 25;

(2) form K has a DSC profile substantially as shown in figure 25.

The present invention also provides a crystalline form L of the compound of formula (I) having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-ka radiation: 6.07 +/-0.2 degrees, 7.01 +/-0.2 degrees, 7.48 +/-0.2 degrees, 14.05 +/-0.2 degrees, 19.44 +/-0.2 degrees and 21.73 +/-0.2 degrees.

According to an embodiment of the invention, the crystalline form L has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 6.07 +/-0.2 degrees, 7.01 +/-0.2 degrees, 7.48 +/-0.2 degrees, 9.16 +/-0.2 degrees, 12.13 +/-0.2 degrees, 14.05 +/-0.2 degrees, 14.44 +/-0.2 degrees, 16.49 +/-0.2 degrees, 19.44 +/-0.2 degrees and 21.73 +/-0.2 degrees.

According to an embodiment of the invention, the crystalline form L has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 6.07 +/-0.2 degrees, 7.01 +/-0.2 degrees, 7.48 +/-0.2 degrees, 9.16 +/-0.2 degrees, 10.22 +/-0.2 degrees, 11.41 +/-0.2 degrees, 12.13 +/-0.2 degrees, 14.05 +/-0.2 degrees, 14.44 +/-0.2 degrees, 16.49 +/-0.2 degrees, 18.32 +/-0.2 degrees, 19.44 +/-0.2 degrees and 21.73 +/-0.2 degrees.

According to an embodiment of the invention, the crystalline form L has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 6.07 +/-0.2 degrees, 7.01 +/-0.2 degrees, 7.48 +/-0.2 degrees, 8.19 +/-0.2 degrees, 9.16 +/-0.2 degrees, 10.22 +/-0.2 degrees, 11.41 +/-0.2 degrees, 12.13 +/-0.2 degrees, 14.05 +/-0.2 degrees, 14.44 +/-0.2 degrees, 16.49 +/-0.2 degrees, 18.32 +/-0.2 degrees, 19.44 +/-0.2 degrees, 20.55 +/-0.2 degrees, 21.73 +/-0.2 degrees, 24.21 +/-0.2 degrees and 25.54 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — ka rays for the crystalline form L are shown in table 10 below:

table 10 XRPD diffraction peak data for form L

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

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

(1) the TGA curve of form L lost about 3.00% weight at 150.0 ± 3 ℃;

(2) the DSC curve of the crystal form L has an endothermic peak at 114.6 +/-10 ℃; in particular, the DSC curve of form L has an endothermic peak at 114.6 ± 5 ℃;

(3) the DSC curve of form L has an endothermic peak at 62.3. + -. 10 ℃ and in particular at 62.3. + -. 5 ℃.

According to an embodiment of the invention, the crystalline form L has one or both of the following characteristics:

(1) form L has a TGA profile substantially as shown in figure 26;

(2) form L has a DSC profile substantially as shown in figure 26.

The present invention also provides crystalline form M-1 of the monohydrate of the compound of formula (I) having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-K α radiation: 5.02 +/-0.2 degrees, 7.45 +/-0.2 degrees, 7.96 +/-0.2 degrees, 8.63 +/-0.2 degrees, 10.05 +/-0.2 degrees and 15.97 +/-0.2 degrees.

According to an embodiment of the present invention, the crystalline form M-1 has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 5.02 +/-0.2 degrees, 7.45 +/-0.2 degrees, 7.96 +/-0.2 degrees, 8.63 +/-0.2 degrees, 9.42 +/-0.2 degrees, 10.05 +/-0.2 degrees, 12.25 +/-0.2 degrees, 15.97 +/-0.2 degrees and 21.60 +/-0.2 degrees.

According to an embodiment of the present invention, the crystalline form M-1 has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 5.02 +/-0.2 degrees, 7.45 +/-0.2 degrees, 7.96 +/-0.2 degrees, 8.63 +/-0.2 degrees, 9.42 +/-0.2 degrees, 10.05 +/-0.2 degrees, 12.25 +/-0.2 degrees, 13.31 +/-0.2 degrees, 14.16 +/-0.2 degrees, 15.97 +/-0.2 degrees, 18.96 +/-0.2 degrees, 20.02 +/-0.2 degrees and 21.60 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — K α rays for the crystalline form M-1 are shown in the following table 11-1:

table 11-1 XRPD diffraction peak data for form M-1

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

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

(1) the TGA curve for form M-1 loses about 4.31% weight at 150.0 + -3 deg.C;

(2) the DSC curve of the crystal form M-1 has two endothermic peaks at 77.7 +/-3 ℃ and 96.5 +/-3 ℃.

(1) form M-1 has a TGA profile substantially as shown in figure 27-1;

(2) form M-1 has a DSC curve substantially as shown in figure 27-1.

The invention also provides a crystalline form M-2 of the mono-acetonitrile compound of the compound of formula (I) having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-ka radiation: 5.01 +/-0.2 degrees, 7.10 +/-0.2 degrees, 7.45 +/-0.2 degrees, 7.96 +/-0.2 degrees, 8.63 +/-0.2 degrees, 9.41 +/-0.2 degrees, 15.94 +/-0.2 degrees, 21.57 +/-0.2 degrees and 23.51 +/-0.2 degrees.

According to an embodiment of the present invention, the X-ray powder diffraction pattern of said crystalline form M-2 has characteristic peaks at the following 2 Θ angles: 5.01 +/-0.2 degrees, 7.10 +/-0.2 degrees, 7.45 +/-0.2 degrees, 7.96 +/-0.2 degrees, 8.63 +/-0.2 degrees, 9.41 +/-0.2 degrees, 15.94 +/-0.2 degrees, 19.66 +/-0.2 degrees, 21.57 +/-0.2 degrees, 23.51 +/-0.2 degrees, 24.30 +/-0.2 degrees and 25.22 +/-0.2 degrees.

According to an embodiment of the present invention, the X-ray powder diffraction pattern of said crystalline form M-2 has characteristic peaks at the following 2 Θ angles: 5.01 +/-0.2 degrees, 7.10 +/-0.2 degrees, 7.45 +/-0.2 degrees, 7.96 +/-0.2 degrees, 8.63 +/-0.2 degrees, 9.41 +/-0.2 degrees, 9.99 +/-0.2 degrees, 15.94 +/-0.2 degrees, 17.29 +/-0.2 degrees, 19.66 +/-0.2 degrees, 21.57 +/-0.2 degrees, 22.48 +/-0.2 degrees, 23.51 +/-0.2 degrees, 24.30 +/-0.2 degrees, 25.22 +/-0.2 degrees and 27.14 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — K α rays for the crystalline form M-2 are shown in the following table 11-2:

table 11-2 XRPD diffraction peak data for form M-2

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

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

(1) the TGA curve for form M-2 loses about 8.36% weight at 150.0 + -3 deg.C;

(2) the DSC curve of the crystal form M-2 has an endothermic peak at the temperature of 124.6 +/-10 ℃; in particular, the DSC curve of form M-2 has an endothermic peak at 124.6. + -. 5 ℃.

(1) form M-2 has a TGA profile substantially as shown in figure 27-2;

(2) form M-2 has a DSC profile substantially as shown in figure 27-2.

The present invention also provides a crystalline form N of a dichloromethane solvate of the compound of formula (I) having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained using Cu-K α radiation: 7.07 +/-0.2 degrees, 7.21 +/-0.2 degrees, 14.41 +/-0.2 degrees, 19.46 +/-0.2 degrees, 21.30 +/-0.2 degrees, 21.93 +/-0.2 degrees and 25.37 +/-0.2 degrees.

According to an embodiment of the invention, the X-ray powder diffraction pattern of form N has characteristic peaks at the following 2 Θ angles: 7.07 +/-0.2 degrees, 7.21 +/-0.2 degrees, 14.41 +/-0.2 degrees, 19.46 +/-0.2 degrees, 20.28 +/-0.2 degrees, 21.30 +/-0.2 degrees, 21.93 +/-0.2 degrees, 25.37 +/-0.2 degrees and 26.04 +/-0.2 degrees.

According to an embodiment of the invention, the X-ray powder diffraction pattern of form N has characteristic peaks at the following 2 Θ angles: 7.07 +/-0.2 degrees, 7.21 +/-0.2 degrees, 14.41 +/-0.2 degrees, 16.33 +/-0.2 degrees, 19.46 +/-0.2 degrees, 19.73 +/-0.2 degrees, 20.28 +/-0.2 degrees, 20.82 +/-0.2 degrees, 21.30 +/-0.2 degrees, 21.93 +/-0.2 degrees, 25.37 +/-0.2 degrees and 26.04 +/-0.2 degrees.

According to an embodiment of the invention, the X-ray powder diffraction pattern of form N has characteristic peaks at the following 2 Θ angles: 7.07 +/-0.2 degrees, 7.21 +/-0.2 degrees, 10.08 +/-0.2 degrees, 13.75 +/-0.2 degrees, 14.41 +/-0.2 degrees, 15.06 +/-0.2 degrees, 16.33 +/-0.2 degrees, 19.46 +/-0.2 degrees, 19.73 +/-0.2 degrees, 20.28 +/-0.2 degrees, 20.82 +/-0.2 degrees, 21.30 +/-0.2 degrees, 21.93 +/-0.2 degrees, 25.37 +/-0.2 degrees, 26.04 +/-0.2 degrees, 27.33 +/-0.2 degrees, 28.53 +/-0.2 degrees and 29.39 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angles, D values and/or relative intensities of the X-ray powder pattern obtained by using Cu — ka ray for the form N are shown in table 12 below:

table 12 XRPD diffraction peak data for form N

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

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

(1) the TGA curve of the crystal form N is about 2.98% lost weight at 90.0 +/-3 ℃ and about 13.10% lost weight at 150.0 +/-3 ℃;

(2) the DSC curve of the crystal form N has an initial point of an endothermic peak at 107.5 +/-3 ℃;

(3) the DSC curve of the crystal form N has an endothermic peak at 118.9 +/-10 ℃; in particular, the DSC curve of the crystal form N has an endothermic peak at 118.9 +/-5 ℃;

(4) of crystal form N¹The H NMR spectrum has the characteristic hydrogen signal of dichloromethane.

More specifically, the DSC curve of form N has an endothermic peak at 69.9 + -10 deg.C, especially 69.9 + -5 deg.C.

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

(1) form N has a TGA profile substantially as shown in figure 28;

(2) form N has a DSC profile substantially as shown in figure 28;

(3) form N has a structure substantially as shown in FIG. 34¹H NMR spectrum.

The present invention also provides crystalline form P of the monoisopropanol solvate of the compound of formula (I) having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-K α radiation: 7.13 +/-0.2 degrees, 9.63 +/-0.2 degrees, 14.43 +/-0.2 degrees, 19.12 +/-0.2 degrees, 21.03 +/-0.2 degrees, 21.53 +/-0.2 degrees, 25.46 +/-0.2 degrees and 25.91 +/-0.2 degrees.

According to an embodiment of the invention, the X-ray powder diffraction pattern of form P has characteristic peaks at the following 2 Θ angles: 7.13 +/-0.2 degrees, 9.63 +/-0.2 degrees, 11.69 +/-0.2 degrees, 13.59 +/-0.2 degrees, 14.43 +/-0.2 degrees, 19.12 +/-0.2 degrees, 20.55 +/-0.2 degrees, 21.03 +/-0.2 degrees, 21.53 +/-0.2 degrees, 25.46 +/-0.2 degrees, 25.91 +/-0.2 degrees and 27.03 +/-0.2 degrees.

According to an embodiment of the invention, the X-ray powder diffraction pattern of form P has characteristic peaks at the following 2 Θ angles: 7.13 +/-0.2 degrees, 9.63 +/-0.2 degrees, 11.69 +/-0.2 degrees, 13.59 +/-0.2 degrees, 14.43 +/-0.2 degrees, 15.18 +/-0.2 degrees, 16.35 +/-0.2 degrees, 17.75 +/-0.2 degrees, 19.12 +/-0.2 degrees, 20.55 +/-0.2 degrees, 21.03 +/-0.2 degrees, 21.53 +/-0.2 degrees, 23.46 +/-0.2 degrees, 25.46 +/-0.2 degrees, 25.91 +/-0.2 degrees, 27.03 +/-0.2 degrees and 28.89 +/-0.2 degrees.

According to an embodiment of the present invention, the 2 θ diffraction angle, D value and relative intensity of the X-ray powder pattern obtained by using Cu — ka ray for the crystalline form P are shown in table 13 below:

table 13 XRPD diffraction peak data for form P

According to an embodiment of the invention, the crystalline form P has an X-ray powder diffraction pattern substantially as shown in figure 13.

According to an embodiment of the invention, said crystalline form P has one, two or three of the following characteristics:

(1) the TGA curve of form P lost about 10.85% weight at 150.0 ± 3 ℃;

(2) the DSC curve of the crystal form P has two endothermic peaks at 66.4 +/-10 ℃ and 103.1 +/-10 ℃; in particular, the DSC curve of form P has two endothermic peaks at 66.4 ± 5 ℃ and 103.1 ± 5 ℃;

(3) of the crystal form P¹The H NMR spectrum has a characteristic hydrogen signal of isopropanol.

More specifically, the DSC curve of form P also has an endothermic peak at 100.0. + -. 10 ℃, especially 100.0. + -. 5 ℃.

(1) form P has a TGA profile substantially as shown in figure 29;

(2) form P has a DSC profile substantially as shown in figure 29;

(3) form P has a structure substantially as shown in FIG. 35¹H NMR spectrum.

The present invention also provides an amorphous form of the compound of formula (I) having an X-ray powder diffraction pattern substantially as shown in figure 14.

The present invention also provides a pharmaceutical composition comprising a solid form of a compound of formula (I) as described above or a solvate thereof, or a mixture of any two or more thereof.

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

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

The present invention also provides the use of a solid form of a compound of formula (I) as described above or a solvate thereof, or a mixture of any two or more thereof, for the manufacture of a medicament for the treatment and/or prevention of an autotaxin ATX-related disease.

The present invention also provides a method for the treatment and/or prophylaxis of autotaxin ATX-related diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of a solid form of a compound of formula (I) as described above or a solvate thereof, or a mixture of any two or more thereof, or a pharmaceutical composition as described.

The present invention also provides a solid form of a compound of formula (I) or a solvate thereof, or a mixture of any two or more thereof, for use in the treatment and/or prevention of an autotaxin ATX related disease.

According to an embodiment of the invention, the ATX-related disease comprises at least one selected from the group consisting of: cancer, metabolic disease, kidney disease, liver disease, fibrotic disease, interstitial lung disease, proliferative disease, inflammatory disease, pain, autoimmune disease, respiratory disease, cardiovascular disease, neurodegenerative disease, dermatological disorder, and/or abnormal angiogenesis-related disease.

According to an embodiment of the invention, the ATX-related disease comprises at least one selected from the group consisting of: interstitial lung disease, pulmonary fibrosis, hepatic fibrosis, and renal fibrosis.

According to an embodiment of the invention, the ATX-related disease comprises idiopathic pulmonary fibrosis.

According to an embodiment of the present invention, the ATX-related diseases include type II diabetes, nonalcoholic steatohepatitis.

According to an embodiment of the invention, the ATX-related diseases comprise neuropathic pain, inflammatory pain.

According to an embodiment of the invention, the ATX-related disease comprises osteoarthritis-related pain.

As a medicament, the solid forms of the present invention may be administered in the form of a pharmaceutical composition. These compositions may be prepared in a manner well known in the pharmaceutical arts and may be administered by a variety of routes depending on whether local or systemic treatment is desired and the area to be treated. Can be administered topically (e.g., transdermal, dermal, ocular, and mucosal including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), orally, or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intracerebroventricular, administration. The administration may be parenteral in a single bolus form, or may be by, for example, a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners and the like may be necessary or desirable.

In preparing the compositions of the present invention, the active ingredient (i.e., the solid form of the invention) is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material that serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may 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.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulation may also contain: lubricants such as talc, magnesium stearate and mineral oil; a humectant; emulsifying and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweetening agents and flavoring agents. The compositions of the present invention may be formulated so as to provide immediate, sustained or delayed release of the active ingredient after administration to the patient by employing methods known in the art.

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

The effective dosage of the active ingredient may vary widely and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amounts actually administered will generally be determined by a physician, in the light of the relevant circumstances, and include the condition to be treated and/or prevented, the chosen route of administration, the actual active ingredient being administered; age, weight and response of the individual patient; severity of patient symptoms, etc.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the active ingredient of the invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is generally uniformly distributed throughout the composition such that the composition may be readily divided into equally effective unit dosage forms such as tablets, pills and capsules. The solid pre-formulations are then divided into unit dosage forms of the type described above containing, for example, from about 0.1 to 1000mg of the active ingredient of the invention.

The tablets or pills of the present invention may be coated or compounded to provide a dosage form affording the advantage of prolonged action. For example, a tablet or pill contains an inner dose and an outer dose component, the latter being in the form of a capsule of the former. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach, leaving the inner component intact through the duodenum or delayed in release. A variety of materials may be used for such enteric layers or coatings, such materials including polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

Solid forms and compositions of the invention may be incorporated therein, and liquid forms for oral or injectable administration include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions; and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil; as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions, suspensions, and powders dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the composition is administered by the oral or nasal respiratory route to achieve a local or systemic effect. The composition may be atomized by the use of an inert gas. The nebulized solution may be inhaled directly from the nebulizing device, or the nebulizing device may be connected to a mask or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered orally or nasally by means of a device that delivers the formulation in a suitable manner.

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

The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques or may be sterilized by filtration. The aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation is usually 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be appreciated that the use of certain of the aforementioned excipients, carriers or stabilizers may result in the formation of a pharmaceutical salt.

The therapeutic dosage of the solid forms of the invention may be determined, for example, by: the particular use of the 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 solid form of the invention in the pharmaceutical composition may not be fixed and depends on a number of factors including the dosage, the chemical nature (e.g. hydrophobicity) and the route of administration. For example, the compounds of the present invention can be provided for parenteral administration by a physiological buffered aqueous solution containing about 0.1-10% w/v of the compound. Some typical dosage ranges are from about 1. mu.g/kg to about 1g/kg body weight/day. In certain embodiments, the dosage range is from about 0.01mg/kg to about 100mg/kg body weight/day. The dosage will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health status of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

Term definition and interpretation

Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.

Unless otherwise indicated, the numerical ranges set forth in the specification and claims are equivalent to at least each and every specific integer numerical value set forth 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 is understood that the two endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, "a number of 0 to 10" should be understood to not only recite each integer of 0, 1,2,3, 4, 5, 6,7, 8, 9, and 10, but also to recite at least 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.

Where the specification and claims recite "about" a value, that value is included by itself, as well as values within a range around the value that is acceptable in the art, such as values within the range of ± 15% of the value, values within the range of ± 10% of the value, values within the range of ± 5% of the value, and the like. For example, about 10, is representative of a composition comprising: a value within a range of 10 + -1.5, i.e., within a range of 8.5-11.5; a value within the range of 10 + -1.0, i.e., within the range of 9.0-11.0; and a value within a range of 10 + -0.5, i.e., within a range of 9.5 to 10.5.

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

The term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual, or human, which includes one or more of the following: (1) prevention of diseases: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or exhibited disease pathology or symptomatology; (2) inhibiting the disease: for example, inhibiting the disease, disorder or condition (i.e., arresting the further development of the pathology and/or condition) in an individual who is experiencing or presenting the pathology or condition of the disease, disorder or condition; (3) and (3) relieving the diseases: for example, relieving the disease, disorder or condition (i.e., reversing the pathology and/or symptomatology) in an individual who is experiencing or presenting with the pathology or symptomatology of the disease, disorder or condition.

The term "pharmaceutically acceptable" means that the prescribed components or active ingredients do not unduly adversely affect the health of the general therapeutic target.

The term "pharmaceutically acceptable excipient or carrier" means one or more compatible solid or liquid fillers or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being blended with the compounds of the present invention and with each other without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifiers, wetting agents (e.g. sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water etc.

Advantageous effects

The solid forms of the compounds of formula (I) or solvates thereof according to the invention have good solubility, stability and hygroscopicity and thus good storage, weighing and pharmaceutical properties. Also, the solid form has excellent pharmacological activity.

Drawings

Figure 1 shows an XRPD pattern of form a (instrument 1);

figure 2 shows an XRPD pattern of form B (instrument 2);

figure 3 shows an XRPD pattern of form C (instrument 3);

figure 4 shows an XRPD pattern of form D (instrument 2);

figure 5 shows an XRPD pattern of form E (instrument 3);

figure 6 shows an XRPD pattern of form G (instrument 2);

figure 7 shows an XRPD pattern of form H (instrument 2);

figure 8-1 shows an XRPD pattern of form J-1 (instrument 2);

figure 8-2 shows an XRPD pattern of form J-2 (instrument 2);

figure 9 shows an XRPD pattern of form K (instrument 1);

figure 10 shows an XRPD pattern of form L (instrument 3);

figure 11-1 shows an XRPD pattern of form M-1 (instrument 2);

figure 11-2 shows an XRPD pattern of form M-2 (instrument 2);

figure 12 shows an XRPD pattern of form N (instrument 3);

figure 13 shows an XRPD pattern of form P (instrument 2);

figure 14 shows an XRPD pattern of an amorphous form (instrument 2);

FIG. 15 shows a polymorphic interconversion profile;

figure 16 shows an XRPD overlay (instrument 2) of form a stability evaluation samples;

figure 17 shows a TGA and DSC profile of form a;

figure 18 shows a TGA and DSC profile of form B;

figure 19 shows a TGA and DSC profile of form C;

figure 20 shows a TGA and DSC profile of form D;

figure 21 shows a TGA and DSC profile of form E;

figure 22 shows a TGA and DSC profile of form G;

figure 23 shows a TGA and DSC profile of form H;

figure 24-1 shows a TGA and DSC profile of form J-1;

figure 24-2 shows a TGA and DSC profile of form J-2;

figure 25 shows a TGA and DSC profile of form L;

figure 26 shows a TGA and DSC profile of form K;

FIG. 27-1 shows a TGA and DSC profile of form M-1;

figure 27-2 shows a TGA and DSC profile of crystalline form M-2;

figure 28 shows a TGA and DSC profile of form N;

figure 29 shows a TGA and DSC profile of form P;

figure 30 shows a DVS profile for form a;

figure 31 shows a DVS profile for form G;

figure 32 shows a nuclear magnetic spectrum of form C;

figure 33 shows a nuclear magnetic spectrum of form E;

figure 34 shows a nuclear magnetic spectrum of form N;

figure 35 shows a nuclear magnetic spectrum of form P;

FIG. 36 is a graph showing the change in body weight of animals after the administration of test example 7 according to the present invention;

FIG. 37 is a graph showing the change in the amount of TGF-. beta.1 in lung tissue and alveolar lavage fluid after administration according to test example 7 of the present invention.

Detailed Description

The crystal forms of the present invention, methods for preparing the same, and uses thereof are described in further detail below with reference to specific examples. The following examples are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

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

Crystal form detection instrument and method

X-ray powder diffraction (XRPD)

The XRPD patterns were collected on an X-ray powder diffraction analyzer manufactured by PANALytacal, and the scanning parameters are shown in the following Table 14-1:

TABLE 14-1

2. Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC)

TGA and DSC plots were taken on a TA Q5000/5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter, respectively, and the test parameters are listed in Table 14-2 below.

TABLE 14-2

3. Liquid nuclear magnetic (Solution NMR):

the liquid NMR spectra were taken on a Bruker 400M NMR spectrometer with DMSO-d6 as solvent.

4. High Performance Liquid Chromatography (HPLC):

in the test, the purity test, the solubility test and the stability test are tested by an Agilent 1260 high performance liquid chromatograph, and the analysis conditions are shown in the following table 14-3:

TABLE 14-3

5. Dynamic moisture sorption (DVS):

dynamic water sorption (DVS) curves were collected on a DVS Intrasic in SMS (surface Measurement systems). At a relative humidity of 25 ℃ with LiCl, Mg (NO)₃)₂And deliquescence point correction of KCl. The DVS test parameters are listed in tables 14-4 below:

tables 14-4

6. Polarizing microscope (PLM)

The polarizing microscopy data were collected by an Axio lab.a1 upright microscope at room temperature.

7. High performance liquid chromatography/ion chromatography (HPLC/IC):

in the test, the purity test, the dynamic solubility test and the stability test are carried out by an Agilent 1260 high performance liquid chromatograph, the salt forming molar ratio test of ions is carried out by an ion chromatograph, and the analysis conditions are shown in the following tables 14-5 and 14-6:

TABLE 14-5 high Performance liquid chromatography test conditions

TABLE 14-6 ion chromatography test conditions

Example 1: preparation of Compounds of formula (I)

(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)

The first step is as follows: synthesis of (R) -5- (trimethylsilyl) pentyl-4-alkynyl-2-ol (5A)

Trisilyl acetylene (51.7g) and diethyl ether (600mL) are added into a three-necked flask, the mixture is cooled to-78 ℃ under the protection of nitrogen, n-butyllithium (2.5M, 217mL) is slowly dropped, after the dropping is finished, the temperature is kept at-78 ℃ for reaction for 1 hour, a boron trifluoride tetrahydrofuran (50 percent, 30mL) solution is added, the (R) -propylene oxide (30g) is slowly dropped, after the dropping is finished, the temperature is kept for stirring for 1 hour, and a saturated sodium bicarbonate aqueous solution (300mL) is added for quenching reaction. After the mixture was warmed to room temperature, the mixture was separated, dried with an organic phase, and purified with silica gel column (petroleum ether: ethyl acetate (V/V) ═ 10:1) to obtain (R) -5- (trimethylsilyl) pentyl-4-alkynyl-2-ol (5A) as a pale yellow liquid compound (34g, yield 42.1%).

The second step is that: synthesis of tert-butyl (R) -2- ((5- (trimethylsilyl) pentyl-4-yn-2-yl) oxy) acetate (5B)

The starting material (R) -5- (trimethylsilyl) pentyl-4-alkynyl-2-ol (34g, 218mmol) was added to 340mL of dry tetrahydrofuran, cooled to 0 deg.C, 60% NaH (10.44g, 261mmol) was added, and stirred for 30 minutes, the starting material tert-butyl 2-bromoacetate (46.7g, 239mmol) was added at 0 deg.C, allowed to warm to room temperature naturally, and stirred for 16 hours. Methanol (20mL) was added to the reaction mixture at 0 ℃, stirred with silica gel, concentrated, and subjected to silica gel column separation and purification (petroleum ether: ethyl acetate (V/V) ═ 10:1) to give tert-butyl (R) -2- ((5- (trimethylsilyl) pentyl-4-yn-2-yl) oxy) acetate (5B) (50g, yield 85%) as a pale yellow liquid.

The third step: synthesis of tert-butyl (R) -2- (pent-4-yn-2-yloxy) acetate (5C)

The starting material tert-butyl (R) -2- ((5- (trimethylsilyl) pentyl-4-yn-2-yl) oxy) acetate (50g,185mmol) was added to 500mL of tetrahydrofuran at room temperature, tetrabutylammonium fluoride (53.2g, 203mmol) was further added, and the reaction was carried out at room temperature for 15 hours. After stirring with silica gel, concentration was performed, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 10:1) to obtain the title compound tert-butyl (R) -2- (pent-4-yn-2-yloxy) acetate (27g, 73.7%) as a yellow liquid.

The fourth step: synthesis of tert-butyl (R) -2- ((1- (1H-1,2, 3-triazol-5-yl) propan-2-yl) oxy) acetate (5D)

The starting material tert-butyl (R) -2- (pent-4-yn-2-yloxy) acetate (27g, 136mmol) was added to 150mL of DMF and 20mL of methanol at room temperature, azidotrimethylsilane (23.53g, 204mmol) and cuprous iodide (2.08g, 10.89mmol) were added under nitrogen protection, respectively, and the reaction mixture was heated to 90 ℃ and stirred for 15 hours. The reaction mixture was cooled to 40 ℃, concentrated to dryness, diluted with dichloromethane and stirred with silica gel, concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 1:1) to give tert-butyl (R) -2- ((1- (1H-1,2, 3-triazol-5-yl) propan-2-yl) oxy) acetate (14g, 42.6%) as a yellow oily compound.

The fifth step: synthesis of (R) -2- ((1- (1H-1,2, 3-triazol-5-yl) propan-2-yl) oxy) acetic acid (5E)

The starting material tert-butyl (R) -2- ((1- (1H-1,2, 3-triazol-5-yl) propan-2-yl) oxy) acetate (14g, 58mmol) was added to a solution of 1, 4-dioxane in hydrogen chloride (4mol/L, 70mL) at room temperature, stirred at room temperature for 16H, filtered, the solid washed with methyl tert-butyl ether and dried to give (R) -2- ((1- (1H-1,2, 3-triazol-5-yl) propan-2-yl) oxy) acetic acid as a white solid (9.2g, 86%).

And a sixth step: 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)

The starting material (R) -2- ((1- (1H-1,2, 3-triazol-5-yl) propan-2-yl) oxy) acetic acid (9.41g, 42.5mmol), N- (2, 3-dihydro-1H-inden-2-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine (9.2g, 28.3mmol) were added to 1000mL of DMF at room temperature, T3P (50% DMF solution) (27g,42.5mmol) and diisopropylethylamine (21.95g, 170mmol) were added at 0 ℃ and allowed to rise to room temperature naturally, the reaction was stirred for 16 hours, the filtrate was filtered, water (3mL) was added to the filtrate, the filtrate was concentrated to dryness, and the residue was purified by silica gel column separation (dichloromethane: methanol (V/V) ═ 10:1) to give 12g of crude product, 120mL of isopropyl acetate is beaten 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 (7.8g, HPLC purity: 98.63%, ee value > 99%, yield 65.7%).

¹H NMR(400MHz,DMSO-d6)δ8.30(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)。

LC-MS,M/Z(ESI):420.4(M+1)。

Example 2: preparation of solid forms of the compound of formula (I) or solvates thereof

2.1 preparation of form A

Dissolving a compound (15mg) shown in the formula (I) in acetone (2mL), slowly dropwise adding toluene (13mL) while stirring at room temperature, slowly volatilizing overnight at room temperature, separating out a solid, and performing centrifugal separation to obtain the crystal form A.

Dissolving the compound (15mg) shown in the formula (I) in acetone (2mL), slowly dripping water (10mL) while stirring at room temperature, slowly volatilizing overnight at room temperature, separating out a solid, and centrifuging to obtain the crystal form A.

Dissolving a compound (15mg) shown in the formula (I) in 1, 4-dioxane (2mL), slowly dropwise adding methyl tert-butyl ether (13mL) under stirring at room temperature, slowly volatilizing overnight at room temperature, separating out a solid, and centrifuging to obtain the crystal form A.

Dissolving a compound (15mg) shown in the formula (I) in 1, 4-dioxane (2mL), slowly dripping water (10mL) while stirring at room temperature, cooling to 5 ℃, slowly stirring for 1h, separating out a solid, and performing centrifugal separation to obtain the crystal form A.

Dissolving a compound (15mg) shown in the formula (I) in dimethyl sulfoxide (0.2mL), slowly dripping water (5mL) while stirring at room temperature, cooling to 5 ℃, slowly stirring for 1h, separating out a solid, and performing centrifugal separation to obtain a crystal form A.

To the compound of formula (I) (15mg) was added ethyl acetate (0.5mL), the suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation to give form A.

To the compound of formula (I) (15mg) was added methyl tert-butyl ether (0.5mL), the suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation to give form A.

To the compound of formula (I) (15mg) was added 2-methyltetrahydrofuran (0.5mL), the suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation to give form A.

To the compound of formula (I) (15mg) was added toluene (0.5mL), the suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation to give form A.

To the compound of formula (I) (15mg) was added n-heptane (0.5mL), the suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation to give form A.

To the compound of formula (I) (15mg) was added water (0.5mL), the suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation to give form A.

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

2.2 preparation of form B

Dissolving the compound (15mg) shown in the formula (I) in acetone (2mL), slowly dropwise adding methyl tert-butyl ether (10mL) under stirring at room temperature, cooling to-20 ℃, slowly stirring for 1h, separating out a solid, and performing centrifugal separation to obtain a crystal form B.

Dissolving the compound (15mg) of the formula (I) in tetrahydrofuran (2.4mL), sealing the bottle mouth with a sealing film, pricking 4 pinholes on the sealing film, standing at room temperature, slowly volatilizing for 7 days, and centrifuging to collect a solid to obtain the crystal form B.

Adding a mixed solvent of tetrahydrofuran and water (volume ratio of 1:1, 0.5mL) into a compound (15mg) of the formula (I), circularly heating and cooling the suspension for 2 times (0.1 ℃/min) at 50-5 ℃ under stirring, and centrifuging to collect a solid to obtain a crystal form B.

Dissolving the compound (15mg) of formula (I) in acetone (2mL) in a 3mL vial, placing the vial of the lysate sample in a 20mL vial of isopropyl acetate in an open state, sealing the 20mL vial, standing at room temperature for 3 days, separating out the solid, centrifuging and collecting the solid to obtain the crystal form B.

In a 3mL vial, the compound of formula (I) (15mg) was dissolved in tetrahydrofuran (2mL), the vial of the lysate sample was placed open in a 20mL large bottle containing 3mL of n-heptane, the 20mL large bottle was sealed, left at room temperature for 3 days, the precipitated solid was collected by centrifugation to give form B.

In a 3mL vial, the compound of formula (I) (15mg) was dissolved in tetrahydrofuran (2mL), the vial of the dissolved clear sample was placed open in a 20mL large bottle containing 3mL of water, the 20mL large bottle was sealed, left at room temperature for 3 days, the precipitated solid was collected by centrifugation to give form B.

2.3 preparation of form C

Dissolving the compound (15mg) shown in the formula (I) in tetrahydrofuran (2mL), slowly dropwise adding toluene (13mL) while stirring at room temperature, cooling to-20 ℃, slowly stirring for 1h, separating out a solid, and performing centrifugal separation to obtain a crystal form C.

2.4 preparation of form D

Dissolving the compound (15mg) shown in the formula (I) in 1, 4-dioxane (2mL), slowly dropwise adding n-heptane (13mL) under stirring at room temperature, cooling to 5 ℃, slowly stirring for 1h, separating out a solid, and performing centrifugal separation to obtain a crystal form D.

Dissolving the compound (15mg) of formula (I) in dimethyl sulfoxide (0.2mL) in a 3mL vial, placing the vial of the dissolved clear sample in a 20mL large bottle containing 3mL of water in an open manner, sealing the 20mL large bottle, placing the bottle at room temperature for 3 days, separating out a solid, centrifuging and collecting the separated solid to obtain the crystal form B.

2.5 preparation of form E

Dissolving the compound (15mg) shown in the formula (I) in chloroform (1mL), slowly dropwise adding n-heptane (13mL) while stirring at room temperature, cooling to 5 ℃, slowly stirring for 1h, separating out a solid, and centrifuging to obtain the crystal form E.

Dissolving the compound (15mg) of the formula (I) in chloroform (1mL), sealing the bottle mouth with a sealing film, pricking 4 pinholes on the sealing film, standing at room temperature, slowly volatilizing for 7 days, and centrifuging to collect a solid to obtain the crystal form E.

In a 3mL vial, the compound of formula (I) (15mg) was dissolved in chloroform (1mL), the vial of the lysate sample was placed open in a 20mL vial containing 3mL isopropyl acetate, the 20mL vial was sealed, left at room temperature for 3 days, the precipitated solid was collected by centrifugation to give form E.

In a 3mL vial, the compound of formula (I) (15mg) was dissolved in chloroform (1mL), the vial of the lysate sample was placed open in a 20mL large bottle containing 3mL of n-heptane, the 20mL large bottle was sealed, left at room temperature for 3 days, the precipitated solid was collected by centrifugation to give form E.

2.6 preparation of form G

Dissolving the compound (15mg) of the formula (I) in 1, 4-dioxane (2mL) in a 3mL vial, placing the vial of the dissolved clear sample in a 20mL large bottle containing 3mL of water in an open manner, sealing the 20mL large bottle, placing the bottle at room temperature for 3 days, separating out a solid, centrifuging and collecting the solid to obtain the crystal form G.

2.7 preparation of form H

To the compound of formula (I) (15mg) was added ethanol (0.5mL), the suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation to give form H.

To the compound of formula (I) (15mg) was added acetone (0.5mL), the suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation to give form H.

To the compound of formula (I) (15mg) was added acetonitrile (0.5mL), the suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation to give form H.

To the compound of formula (I) (15mg) was added a mixed solvent of tetrahydrofuran and isopropyl acetate (volume ratio 1:1, 0.5mL), the suspension was stirred at room temperature for 3 days, and the solid was collected by centrifugation to give form H.

To the compound of formula (I) (15mg) was added a mixed solvent of acetone and water (volume ratio 1:1, 0.5mL), the suspension was warmed to 50 ℃ and stirred for 3 days, and the solid was collected by centrifugation to give form H.

2.8 preparation of crystalline form J-1

To the compound of formula (I) (15mg) was added 2-methyltetrahydrofuran (1mL), warmed to 50 ℃ and stirred for 3h, hot filtered, the clear solution was slowly cooled to 5 ℃ (0.1 ℃/min) and left to volatilize overnight at 5 ℃ at constant temperature, and the solid was collected by centrifugation to give form J-1.

2.9 preparation of crystalline form J-2

To the compound of formula (I) (15mg) was added methyl tert-butyl ether (1mL), warmed to 50 ℃ and stirred for 3h, hot filtered, the supernatant slowly cooled to 5 ℃ (0.1 ℃/min) and evaporated overnight at 5 ℃ at constant temperature, and the solid was collected by centrifugation to give crystalline form J-2.

2.10 preparation of form K

In a 3mL vial, the compound of formula (I) (15mg) was dissolved in 1, 4-dioxane (2mL), the vial of the dissolved clear sample was placed open in a 20mL large bottle containing 3mL of water, the 20mL large bottle was sealed, left at room temperature for 3 days, the solid was collected by centrifugation, heated to 100 ℃ and cooled to room temperature to give form K.

2.11 preparation of form L

To the compound of formula (I) (15mg) was added ethanol (0.5mL), the suspension was stirred at room temperature for 3 days, the solid was collected by centrifugation, heated to 90 ℃ under nitrogen and then cooled to 30 ℃ to give form L.

2.12 preparation of crystalline form M-1

To the compound of formula (I) (15mg) was added ethanol (0.5mL), the suspension was stirred at room temperature for 3 days, the solid was collected by centrifugation and dried to give crystalline form M-1.

2.13 preparation of crystalline form M-2

To the compound of formula (I) (15mg) was added acetonitrile (0.5mL), the suspension was stirred at room temperature for 7 days, the solid was collected by centrifugation and dried to give form M-2.

2.14 preparation of form N

Compound of formula (I) (15mg) was weighed into a 3mL vial, placed open in a 20mL vial with 2mL dichloromethane, the 20mL vial was sealed, placed at room temperature for 8 days, and the solid was collected by centrifugation to give form N.

2.15 preparation of form P

Adding a mixed solvent of isopropanol and water (volume ratio of 0.98:0.02, 1.0mL) into a compound (15mg) of formula (I), stirring for 1h at room temperature in a suspension manner, filtering by using a PTFE filter membrane, transferring filtrate into a small bottle containing each crystal form (crystal forms A, B, G, K and L), stirring the suspension at room temperature for 20 days, and centrifuging to collect solid to obtain the crystal form P.

2.16 preparation of amorphous Material

The compound of formula (I) (15mg) was dissolved in acetone (2mL), isopropyl acetate (10mL) was slowly added dropwise with stirring at room temperature, slowly evaporated overnight at room temperature, and the precipitated solid was centrifuged to give an amorphous form of the compound of formula (I).

The compound of the formula (I) (15mg) was dissolved in acetone (2mL), and n-heptane (10mL) was slowly added dropwise with stirring at room temperature to precipitate a solid, which was then centrifuged to give an amorphous form of the compound of the formula (I).

The compound of formula (I) (15mg) was dissolved in tetrahydrofuran (2.4mL), water (10mL) was added dropwise slowly with stirring at room temperature, and the mixture was cooled to 5 ℃ and stirred for 1 hour to precipitate a solid, which was then centrifuged to give an amorphous form of the compound of formula (I).

The compound of the formula (I) (15mg) was dissolved in chloroform (1mL), ethyl acetate (10mL) was slowly added dropwise with stirring at room temperature, and the precipitated solid was centrifuged to give an amorphous form of the compound of the formula (I).

The compound of the formula (I) (15mg) was dissolved in chloroform (1mL), and methyl t-butyl ether (10mL) was added dropwise slowly with stirring at room temperature to precipitate a solid, which was then centrifuged to give an amorphous form of the compound of the formula (I).

The compound of formula (I) (15mg) was dissolved in acetone (2mL), the bottle mouth was sealed with a sealing film, 4 pinholes were punctured on the top, left to evaporate slowly at room temperature for 7 days, and the solid was collected by centrifugation to give an amorphous form of the compound of formula (I).

Ethyl acetate (1mL) was added to the compound of formula (I) (15mg), the mixture was warmed to 50 ℃ and stirred for 3h, hot filtered, the clear solution was slowly cooled to 5 ℃ (0.1 ℃/min) and kept at 5 ℃ for 1h, and the solid was collected by centrifugation to give an amorphous form of the compound of formula (I).

To the compound of formula (I) (15mg) was added a mixed solvent of acetone and water (volume ratio 4:1, 1mL), warmed to 50 ℃ and stirred for 3h, hot filtered, the clear solution was slowly cooled to 5 ℃ (0.1 ℃/min) and evaporated overnight at 5 ℃ while maintaining constant temperature, and the solid was collected by centrifugation to give an amorphous form of the compound of formula (I).

In a 3mL vial, the compound of formula (I) (15mg) was dissolved in acetone (2mL), the vial of the lysate sample was placed open in a 20mL large vial containing 3mL of methyl tert-butyl ether, the 20mL large vial was sealed, left at room temperature for 3 days, the precipitated solid was collected by centrifugation to give form E.

Example 3: polymorphism evaluation

3.1 polymorphic forms of a compound of formula (I) or a solvate thereof

By MeOH/H at different water activities at room temperature₂Suspension competition tests in an O solvent system study the mutual transformation relationship between the anhydrous crystal form and the hydrate crystal form, and the results show that the crystal form A is obtained in all suspension tests. The interconversion relationship between the forms is shown in FIG. 15, and the transformation method is summarized in Table 15-1.

TABLE 15-1 summary of polymorphic conversion methods

3.2 polymorphic evaluation of a Compound of formula (I) or a solvate thereof

According to the suspension competition result, selecting the anhydrous crystal form A, and carrying out physical and chemical stability evaluation under 60 ℃/60% RH for 24 hours. The results are summarized in Table 15-2 below, and the XRPD results are shown in FIG. 16. The results show that no significant purity reduction or crystal form transformation was observed after 24 hours of standing at 60 ℃.

TABLE 15-2 stability data of form A at 60 deg.C/60% RH

In addition, the stability data for form A at both 25 ℃/60% RH and 40 ℃/75% RH are shown in tables 15-3.

TABLE 15-3 stability data for form A at 25 deg.C/60% RH and 40 deg.C/75% RH

The result shows that the crystal form A has good stability after being stored for 1 week under the conditions of 25 ℃/60% RH and 40 ℃/75% RH, and the crystal form and the HPLC purity are not changed.

Example 4: evaluation of the Properties of the Compounds of formula (I)

4.1 weighing 20mg of the compound of formula (I) in a 5mL vial, adding less than 4mL of solvent, mixing by rotation at 37 deg.C (25rpm) for 1 hr, 4 hr, 24 hr, taking about 1mL of solution, centrifuging, filtering, detecting solid XRPD to determine crystal form, and detecting HPLC concentration and pH value in liquid. The results are shown in Table 15-4.

Table 15-4 dynamic solubility evaluation of form a

Note: "S" represents: solubility (mg/mL) "SGF" represents: simulated gastric fluid "FaSSIF" represents: simulated fasted state intestinal fluid and "FeSSIF" stands for: simulating the feeding state of intestinal juice.

4.2 dynamic moisture sorption (DVS) evaluation of form A of the compound of formula (I) is shown in FIG. 30 and tables 15-5.

Tables 15-5 DVS evaluation of form A

Figure 30 shows a DVS profile for form a. The results show that the crystal form A has moisture adsorption of about 1.03% and good hygroscopicity at the temperature of 25 ℃/80% RH.

4.3 the compound of formula (I) was tested for its crude solubility in a portion of the solvent at room temperature and the results are shown in tables 15-6.

Tables 15-6 crude solubility of form a in partial solvent

Solvent(s)	Solubility (mg/ml)	Solvent(s)	Solubility (mg/ml)
				Methanol	2.1<S<5.3	1, 4-dioxane	20.0<S<40.0
Ethanol	2.1<S<5.3	Acetonitrile	2.0<S<5.0
				Isopropanol (I-propanol)	1.0<S<2.0	Chloroform	22.0<S<44.0
Acetone (II)	5.0<S<10.0	Methylene dichloride	11.5<S<23.0
				Methyl isobutyl ketone	1.1<S<2.2	N-heptane	S<1.0
Ethyl acetate	1.1<S<2.2	Toluene	S<1.1
				Acetic acid isopropyl ester	S<1.1	Dimethylacetamide	S>42.0
Methyl tert-butyl ether	S<1.1	Dimethyl sulfoxide	S>40.0
				Tetrahydrofuran (THF)	10.0<S<20.0	N-methyl pyrrolidone	S>42.0
2-methyltetrahydrofuran	2.2<S<5.5	Water (W)	S<1.0

The compound of formula (I) used in the following test examples is the compound of formula (I) prepared in example 1 above, and the control compound used has the following structure:

this control compound was synthesized according to patent application WO2014110000a1, with HPLC purity: 99.88 percent.

Test example 1: autotaxin (ATX) enzyme activity inhibition assay

The inhibitory activity of the compound on the Autotaxin enzyme is detected by adopting an Autotaxin inhibition Screening Assay Kit (Cayman, 700580). Firstly, a test object is testedCompounds were formulated as 10mM stock solutions in DMSO solvent, then 8 concentration points were diluted using a DMSO gradient, followed by dilution of the 8 concentration points into 19 × compound working solution (DMSO content 1.9%) with an Autotaxin Assay buffer (1 ×) provided in the kit. Autotaxin Assay Reagent (10X) was removed and diluted 10-fold with Autotaxin Assay Buffer (1X). The Autotaxin Substrate was removed, dissolved in 1.2mL Autotaxin Assay Buffer (1X), mixed, and allowed to stand at room temperature. In a 96-well plate, 150 μ L of Autotaxin Assay Buffer (1 ×), 10 μ L of diluted 19 × compound working solution, 10 μ L of Autotaxin Assay Reagent (1 ×), 20 μ L of dissolved Autotaxin Substrate, mixing, shaking at a constant temperature of 37 ℃ for 30min in a light-shielding manner; taking out the 96-well plate, and placing the 96-well plate on an enzyme labeling instrument to read OD 405; inputting the experimental result into GraphPad Prism software, and obtaining the IC of each compound through fitting calculation₅₀。

TABLE 16-1 results of ATX enzyme inhibitory Activity of test Compounds

Test compounds	IC₅₀(nM)
		Control Compounds	2.60
A compound of formula (I)	1.59

The experimental result shows that the compound of the formula (I) has good inhibitory activity to ATX enzyme; can effectively inhibit ATX enzyme activity.

Test example 2: human liver microsome stability test

Human liver microsome stabilizationThe sexual test adopts the compound and human liver microsome in vitro co-incubation for detection. Test compounds were first formulated in DMSO solvent as 10mM stock solutions, followed by dilution of the compounds to 0.5mM using acetonitrile. Human liver microsomes (Corning) were diluted with PBS to a microsome/buffer solution, and 0.5mM compound was diluted with this solution to a working solution at a compound concentration of 1.5. mu.M and a human liver microsome concentration of 0.75 mg/ml. The reaction was initiated by adding 30. mu.L of the working solution to each well of a deep-well plate, and then 15. mu.L of a preheated 6mM NADPH solution, and incubated at 37 ℃. At 0, 5, 15, 30, 45 minutes of incubation, the reaction was stopped by adding 135 μ L of acetonitrile to the corresponding wells. After terminating the reaction with acetonitrile at the last 45 minute time point, the deep well plate was vortexed for 10 minutes (600rpm/min) and then centrifuged for 15 minutes. Centrifuging, taking the supernatant, adding purified water at a ratio of 1:1, performing LC-MS/MS detection to obtain the peak area of the compound at each time point and the peak area of an internal standard, comparing the peak area ratios of the compound at 5, 15, 30 and 45 minutes with the peak area ratio at 0 minute, calculating the residual percentage of the compound at each time point, and calculating T by using Excel_1/2。

TABLE 16-2 human liver microsome stability test results

The compound of formula (I) shows more excellent hepatic metabolic stability, slower metabolism in human body and higher exposure compared with the control compound, and the compound of formula (I) shows stable T of liver microsome_1/2Is superior to the contrast compound, even can reach more than 2 times of the contrast compound, which can reduce the clinical administration dosage and the administration frequency, reduce the toxic and side effect of the clinical administration and improve the clinical compliance.

Test example 3: inhibition effect of full-automatic electrophysiological patch clamp QPatch detection compound on hERG

The inhibition of hERG by compounds was examined using a fully automated electrophysiological patch clamp QPatch. The cells used in this experiment were transfected with hERG cDNA and stably expressed hERG channelsThe CHO cell line (supplied by Sophion Bioscience, Denmark) having a cell passage number of P24. The cells were cultured in a medium containing the following components (all from Invitrogen): ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100. mu.g/ml hygromycin B, 100. mu.g/ml Geneticin. CHO hERG cells were grown in a petri dish containing the above culture medium and containing 5% CO at 37 deg.C₂The incubator of (2) for cultivation.

Preparation of extracellular fluid (2mM CaCl)₂、1mM MgCl₂4mM KCl, 145mM NaCl, 10mM Glucose, 10mM HEPES, pH about 7.4, osmotic pressure about 305mOsm) and intracellular fluid (5.374mM CaCl₂、1.75mM MgCl₂120mM KCl, 10mM HEPES, 5mM EGTA, 4mM Na-ATP, pH about 7.25, osmolality about 295 mOsm).

Test compounds were prepared as 10mM stock solutions in DMSO solvent and compounds were diluted to 3, 1, 0.3, 0.1mM using DMSO and then to 30, 10, 3, 1, 0.3 and 0.1 μ M using extracellular fluid, with the exception of the 30 μ M compound DMSO at 0.3% final concentration, the compound solutions at other concentrations had DMSO at 0.1% final concentration.

After the CHO hERG cells were digested and resuspended, they were added to a fully automated QPatch system (Sophion, Denmark) and tested according to the following pre-established protocol.

After the initial membrane rupture whole cell configuration was achieved, whole cell current was recorded at room temperature (about 25 ℃), cells were recorded for at least 120 seconds to stabilize, and stable cells were selected for testing. Throughout the experiment, the cells were clamped at a voltage of-80 mV, depolarized to +20mV to activate the hERG potassium channel, and clamped to-50 mV after 2.5 seconds to eliminate inactivation and generate an outward tail current. The tail current peak value is used as a value for the magnitude of the hERG current. The voltage pattern described above was applied to cells every 15 seconds for electrophysiological experiments. Add external solution containing 0.1% dimethyl sulfoxide (solvent) to the cells, establish baseline, and allow the current to stabilize for 3 minutes. The cells were kept in the test environment after the compound solution was added until the effect of the compound reached steady state or 4 minutes limit. In the test experiments of different concentration gradients of the compound, the compound is added to the clamped cells from low to high concentration. After completion of the compound test, the cells were washed with external liquid until the current returned to a steady state.

The experimental data were analyzed by Qpatch analysis software supplied by Sophion, Excel, Graphpad Prism, and the like.

Results of inhibition of hERG by the Compounds of tables 16-3

Compound (I)	hERG IC₅₀(μM)	hERG IC₅₀/ATX IC₅₀
			Control Compounds	6.69	6.69/2.60＝2.6
A compound of formula (I)	9.48	9.48/1.59＝6.0

The compounds of formula (I) of the invention exhibit weaker hERG inhibitory activity compared to control compounds, and the IC of the compounds for the inhibition of ATX enzyme activity₅₀The inhibition of hERG by the compound of formula (I) shows a better safety window, and has obvious cardiac safety advantage.

Test example 4: thermodynamic solubility test

Phosphate Buffer (PBS) solution (pH7.4), FeSSIF solution (containing 10mM of sodium taurocholate, 2mM of lecithin, 81.65mM of sodium hydroxide, 125.5mM of sodium chloride, 0.8mM of sodium oleate, 5mM of glycerol monooleate, 55.02mM of maleic acid) at pH5.8, FaSSGF solution (1L of solution containing 80. mu.M of sodium taurocholate, 20. mu.M of lecithin, 0.1g of pepsin, 34.2mM of sodium chloride) at pH1.6 were prepared.

The compound was weighed out accurately, added with the prepared phosphate buffer solution of pH7.4, FeSSIF solution of pH5.8 and FaSSGF solution of pH1.6 to prepare a solution of 4mg/mL, shaken at 1000rpm for 1 hour and then incubated overnight at room temperature. The incubated solution was centrifuged at 12000rpm for 10 minutes to remove undissolved particles and the supernatant was transferred to a fresh centrifuge tube. And (3) after the supernatant is diluted properly, adding acetonitrile solution containing an internal standard, and quantifying by adopting a standard curve prepared by the same matrix.

TABLE 16-4 thermodynamic solubility test results

The experimental results show that the solubility of the control compound is poor, and the gastrointestinal absorption is expected to be poor, so that the control compound is not beneficial to being developed into oral medicines. Compared with a control compound, the thermodynamic solubility of the compound shown in the formula (I) in simulated gastric juice, simulated intestinal juice and neutral conditions is obviously improved, so that the absorption degree of the compound in intestinal tracts of a human body is expected to be greatly improved, the exposure amount of oral administration is higher, the clinical administration dosage can be reduced, and the clinical compliance is improved.

Test example 5: pharmacokinetic testing

In vivo pharmacokinetic experiments in rats, male SD rats 6 were used, 180-240g, fasted overnight. 3 rats were orally administered with 10mg/kg by gavage, and blood was collected before and 15, 30 minutes and 1,2, 4, 8, 24 hours after administration. Another 3 rats were administered 1mg/kg by intravenous injection and blood was collected before administration and at 5, 15, 30 minutes and 1,2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4 ℃ and plasma was collected and stored at-20 ℃. And (3) adding 3-5 times of acetonitrile solution containing an internal standard into the plasma at each time point, mixing, carrying out vortex mixing for 1 minute, centrifuging at 4 ℃ for 10 minutes at 13000 rpm, taking supernatant, adding 3 times of water, mixing, and taking a proper amount of mixed solution to carry out LC-MS/MS analysis. The major pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.

In vivo pharmacokinetic experiments in mice, 18 male ICR mice, 20-25g, were fasted overnight. Taking 9 mice, orally taking the mice for intragastric administration at a dose of 10mg/kg, and taking blood of 3 mice at each blood-taking time point, wherein the total number of 9 mice is alternately taken; another 9 mice were administered 1mg/kg by intravenous injection, and 3 mice were collected at each blood collection time point, and a total of 9 mice were collected alternately. The rest of the procedure was the same as the rat pharmacokinetic experiment.

TABLE 16-5 results of in vivo pharmacokinetic experiments in mice

TABLE 16-6 results of in vivo pharmacokinetic experiments in rats

The experimental results show that the compounds of formula (I) according to the invention exhibit superior pharmacokinetic properties compared to the control compounds. In particular, the compound of formula (I) of the present invention has a lower Clearance (CL) in rats, about 1/6 for the control compound, indicating that the compound of formula (I) is more stable in vivo and that it is orally administered C_maxAnd AUC_0-t6.1-fold and 4.2-fold of the control compound, respectively.

Test example 6: inhibition assay of ATX enzymatic Activity in human plasma

Whole blood from healthy volunteers was collected, anticoagulated with heparin, tubes were centrifuged at 3000rpm for 10 minutes, and plasma was collected and stored at-80 ℃ for future use.

The compounds were serially diluted with DMSO as required for the conventional concentration, then 3 μ L was added to a 96-well plate, 147 μ L each of PBS was added to a well containing 3 μ L of the compound, mixed well, and 50 μ L was taken out therefrom and added to a new 96-well plate. Human plasma was thawed by rapid shaking in a 37 ℃ water bath using a freezer at-80 ℃ and 50. mu.L of human plasma was added to a 96-well plate containing 50. mu.L of the diluted compound (final system was 1% DMSO). The group containing no compound was set as the positive group. Shaking and mixing the 96-well plate, and incubating for 3 hours at 37 ℃; a blank was also set and plasma stored at-80 ℃ for the blank to measure baseline endogenous LPA concentrations.

After the incubation is finished, the blank group is unfrozen on ice and transferred to an incubation plate, excess acetonitrile containing an internal standard LPA17:0 is added into the incubation plate to precipitate plasma protein, after vortex centrifugation, supernatant is diluted, and peak areas of LPA18:2 and an internal standard LPA17:0 are detected by LC-MSMS mass spectrometry.

The peak area ratio of LPA18:2 to internal standard LPA17:0 was calculated, and the inhibition of LPA18:2 formation was calculated according to the following formula:

inhibition (%) of 100- (different concentrations of compound group-blank)/(positive group-blank) 100%

Calculating the inhibition IC of ATX enzymatic activity of the compound in human plasma according to the inhibition rate of the compound at different concentrations₅₀The value is obtained.

TABLE 16-7 results of ATX enzyme Activity inhibitory Activity of test Compounds in human plasma

Test compounds	IC₅₀(nM)
		Control Compounds	13.0
A compound of formula (I)	4.7

Experimental results show that the compound of the formula (I) has good inhibitory activity on ATX enzyme in human blood plasma, can effectively inhibit the activity of the ATX enzyme, and is obviously superior to a control compound.

Test example 7: rat bleomycin induced IPF model

The bleomycin-induced IPF model (idiopathic pulmonary fibrosis model) was performed at a dose of 5U/kg using male BN rats, 180-240 g. Animals after molding are randomly grouped, a solvent control group, a GLPG-1690 group (a clinical III-phase compound of Galapagos company), a control compound group and a compound of a formula (I) are orally administrated with gastric lavage twice a day on the second day after molding, the administration group is administrated with 30mg/kg once, the solvent control group is administrated with a blank solvent, and the administration is carried out for 21 days continuously.

During dosing, body weights were weighed every three days. Alveolar lavage was performed 2h after the first dose on day 21 of dosing, inflammatory cells in lavage were counted, and relevant biomarkers in lavage supernatant were detected; after irrigation, the left lung of the rat is fixed, Masson trichrome staining is adopted, fibrosis pathology scoring is carried out, and the other lung lobes are frozen and stored. The supernatant of alveolar lavage fluid from the group of Compound 3 and freshly cryopreserved lung tissue were taken and assayed for TGF- β 1 protein content and total protein amount by ELISA and the amount of TGF- β 1 per mg of total protein was calculated.

The results of the experiment show that the animal body weight loss of the compound of the formula (I) is obviously less than that of the control compound group, and the compound of the formula (1) has better safety (the results are shown in figure 36); the content of TGF-beta 1 in alveolar lavage fluid supernatant and freshly frozen lung tissue of the compound of the formula (I) is obviously lower than that in a vehicle control group, and the compound of the formula (I) has obvious anti-fibrosis effect (the result is shown in figure 37).

The above description is directed to exemplary embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A solid form of a compound of formula (I) or a solvate thereof:

wherein the solid form comprises a crystalline and/or amorphous form; the solvent in the solvate may be selected from aqueous and/or non-aqueous solvents; the non-aqueous solvent includes, but is not limited to, one or more of ethanol, acetonitrile, toluene, chloroform, dichloromethane, isopropanol, propylene glycol, isobutanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl-t-butyl ether, and methyl-isobutyl ketone.

2. The solid form of claim 1, the crystalline form is form a having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-ka radiation: 8.05 plus or minus 0.20 degree, 8.30 plus or minus 0.20 degree, 14.11 plus or minus 0.20 degree, 16.18 plus or minus 0.20 degree, 22.73 plus or minus 0.20 degree and 25.16 plus or minus 0.20 degree;

preferably, the form a has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 8.05 plus or minus 0.20 degree, 8.30 plus or minus 0.20 degree, 14.11 plus or minus 0.20 degree, 16.18 plus or minus 0.20 degree, 16.65 plus or minus 0.20 degree, 21.85 plus or minus 0.20 degree, 22.73 plus or minus 0.20 degree, 25.16 plus or minus 0.20 degree and 26.23 plus or minus 0.20 degree;

more preferably, the form a has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 8.05 +/-0.20 degrees, 8.30 +/-0.20 degrees, 14.11 +/-0.20 degrees, 16.18 +/-0.20 degrees, 16.65 +/-0.20 degrees, 19.19 +/-0.20 degrees, 21.85 +/-0.20 degrees, 22.73 +/-0.20 degrees, 25.16 +/-0.20 degrees, 26.23 +/-0.20 degrees and 29.91 +/-0.20 degrees;

still more preferably, the form a has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 8.05 plus or minus 0.20 degree, 8.30 plus or minus 0.20 degree, 14.11 plus or minus 0.20 degree, 16.18 plus or minus 0.20 degree, 16.65 plus or minus 0.20 degree, 18.19 plus or minus 0.20 degree, 18.91 plus or minus 0.20 degree, 19.19 plus or minus 0.20 degree, 21.85 plus or minus 0.20 degree, 22.73 plus or minus 0.20 degree, 25.16 plus or minus 0.20 degree, 26.23 plus or minus 0.20 degree and 29.91 plus or minus 0.20 degree;

still more preferably, the form a has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 8.05 plus or minus 0.20 degree, 8.30 plus or minus 0.20 degree, 10.77 plus or minus 0.20 degree, 12.95 plus or minus 0.20 degree, 14.11 plus or minus 0.20 degree, 16.18 plus or minus 0.20 degree, 16.65 plus or minus 0.20 degree, 17.35 plus or minus 0.20 degree, 18.19 plus or minus 0.20 degree, 18.91 plus or minus 0.20 degree, 19.19 plus or minus 0.20 degree, 20.93 plus or minus 0.20 degree, 21.53 plus or minus 0.20 degree, 21.85 plus or minus 0.20 degree, 22.31 plus or minus 0.20 degree, 22.73 plus or minus 0.20 degree, 24.38 plus or minus 0.20 degree, 25.16 plus or minus 0.20 degree, 26.23 plus or minus 0.20 degree, 27.39 plus or minus 0.20 degree, 28.44 plus or minus 0.20 degree, 28.99 plus or minus 0.20 degree, 29.20 plus or minus 0.20 degree, 29.91 plus or minus 0.20 degree, 32.77 plus or minus 0.20 degree, 36.68 plus or minus 0.20 degree;

the form a has one, two, three, or four of the following characteristics:

(1) the TGA curve for form a lost about 2.59% weight at 150.0 ± 3 ℃;

3. The solid form of claim 1, the crystalline form is form B having an X-ray powder diffraction pattern obtained with Cu-ka radiation with characteristic peaks at the following 2 Θ angles: 4.93 plus or minus 0.2 degree, 5.30 plus or minus 0.2 degree, 7.37 plus or minus 0.2 degree, 7.93 plus or minus 0.2 degree and 15.95 plus or minus 0.2 degree;

preferably, the X-ray powder diffraction pattern of form B has characteristic peaks at the following 2 Θ angles: 4.93 plus or minus 0.2 degree, 5.30 plus or minus 0.2 degree, 7.37 plus or minus 0.2 degree, 7.93 plus or minus 0.2 degree, 8.59 plus or minus 0.2 degree, 14.04 plus or minus 0.2 degree, 15.95 plus or minus 0.2 degree and 24.15 plus or minus 0.2 degree;

more preferably, the form B has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 4.93 plus or minus 0.2 degree, 5.30 plus or minus 0.2 degree, 7.37 plus or minus 0.2 degree, 7.93 plus or minus 0.2 degree, 8.59 plus or minus 0.2 degree, 14.04 plus or minus 0.2 degree, 15.95 plus or minus 0.2 degree, 17.24 plus or minus 0.2 degree, 23.33 plus or minus 0.2 degree and 24.15 plus or minus 0.2 degree;

the form B has one, two, or three of the following characteristics:

(1) the TGA curve of form B lost about 9.72% weight at 150.0 ± 3 ℃;

4. The solid form of claim 1, wherein the crystalline form is form C having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-ka radiation: 6.80 +/-0.2 degrees, 13.65 +/-0.2 degrees, 16.27 +/-0.2 degrees, 24.69 +/-0.2 degrees and 25.65 +/-0.2 degrees;

preferably, the form C has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 6.80 +/-0.2 degrees, 13.65 +/-0.2 degrees, 16.27 +/-0.2 degrees, 18.92 +/-0.2 degrees, 19.32 +/-0.2 degrees, 21.49 +/-0.2 degrees, 24.69 +/-0.2 degrees and 25.65 +/-0.2 degrees;

more preferably, the form C has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 6.80 +/-0.2 degrees, 7.58 +/-0.2 degrees, 12.55 +/-0.2 degrees, 13.65 +/-0.2 degrees, 16.27 +/-0.2 degrees, 18.92 +/-0.2 degrees, 19.32 +/-0.2 degrees, 20.39 +/-0.2 degrees, 21.49 +/-0.2 degrees, 24.69 +/-0.2 degrees and 25.65 +/-0.2 degrees;

still more preferably, the form C has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 6.80 +/-0.2 degrees, 7.58 +/-0.2 degrees, 8.32 +/-0.2 degrees, 12.55 +/-0.2 degrees, 13.65 +/-0.2 degrees, 16.27 +/-0.2 degrees, 17.73 +/-0.2 degrees, 18.92 +/-0.2 degrees, 19.32 +/-0.2 degrees, 20.39 +/-0.2 degrees, 21.49 +/-0.2 degrees, 23.44 +/-0.2 degrees, 24.69 +/-0.2 degrees, 25.65 +/-0.2 degrees, 28.27 +/-0.2 degrees and 30.25 +/-0.2 degrees;

the form C has one, two, or three of the following characteristics:

(1) the TGA curve for form C lost about 12.89% weight at 150.0 ± 3 ℃;

5. The solid form of claim 1, wherein the crystalline form is form D having an X-ray powder diffraction pattern obtained with Cu-ka radiation having characteristic peaks at the following 2 Θ angles: 7.57 +/-0.2 degrees and 14.31 +/-0.2 degrees;

the form D has one or both of the following characteristics:

(1) the TGA curve of form D lost about 12.93% weight at 150.0 ± 3 ℃;

6. The solid form of claim 1, wherein the crystalline form is form E having an X-ray powder diffraction pattern obtained with Cu-ka radiation having characteristic peaks at the following 2 Θ angles: 7.32 +/-0.2 degrees, 19.44 +/-0.2 degrees, 22.06 +/-0.2 degrees, 25.25 +/-0.2 degrees and 29.54 +/-0.2 degrees;

preferably, the form E has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 7.32 +/-0.2 degrees, 11.72 +/-0.2 degrees, 14.66 +/-0.2 degrees, 16.53 +/-0.2 degrees, 19.44 +/-0.2 degrees, 20.54 +/-0.2 degrees, 22.06 +/-0.2 degrees, 25.25 +/-0.2 degrees and 29.54 +/-0.2 degrees;

more preferably, the form E has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 7.32 +/-0.2 degrees, 11.72 +/-0.2 degrees, 14.66 +/-0.2 degrees, 16.09 +/-0.2 degrees, 16.53 +/-0.2 degrees, 19.44 +/-0.2 degrees, 20.54 +/-0.2 degrees, 20.81 +/-0.2 degrees, 22.06 +/-0.2 degrees, 25.25 +/-0.2 degrees and 29.54 +/-0.2 degrees;

still more preferably, the form E has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 7.32 +/-0.2 °, 10.25 +/-0.2 °, 11.72 +/-0.2 °, 14.33 +/-0.2 °, 14.66 +/-0.2 °, 16.09 +/-0.2 °, 16.53 +/-0.2 °, 17.57 +/-0.2 °, 18.14 +/-0.2 °, 18.77 +/-0.2 °, 19.44 +/-0.2 °, 19.75 +/-0.2 °, 20.54 +/-0.2 °, 20.81 +/-0.2 °, 22.06 +/-0.2 °, 22.77 +/-0.2 °, 23.19 +/-0.2 °, 25.25 +/-0.2 °, 26.04 +/-0.2 °, 27.06 +/-0.2 °, 27.35 +/-0.2 °, 29.54 +/-0.2 °, 30.41 +/-0.2 ° and 32.99 +/-0.2 °;

the form E has one, two, or three of the following characteristics:

7. The solid form of claim 1, the crystalline form is form G having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-ka radiation: 7.08 +/-0.2 degrees, 7.54 +/-0.2 degrees, 14.15 +/-0.2 degrees, 15.10 +/-0.2 degrees, 18.85 +/-0.2 degrees, 25.49 +/-0.2 degrees and 26.06 +/-0.2 degrees;

preferably, the form G has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 7.08 +/-0.2 degrees, 7.54 +/-0.2 degrees, 13.54 +/-0.2 degrees, 14.15 +/-0.2 degrees, 15.10 +/-0.2 degrees, 18.85 +/-0.2 degrees, 21.34 +/-0.2 degrees, 22.12 +/-0.2 degrees, 25.49 +/-0.2 degrees and 26.06 +/-0.2 degrees;

more preferably, the form G has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 7.08 +/-0.2 °, 7.54 +/-0.2 °, 8.62 +/-0.2 °, 11.82 +/-0.2 °, 13.54 +/-0.2 °, 14.15 +/-0.2 °, 15.10 +/-0.2 °, 16.36 +/-0.2 °, 18.05 +/-0.2 °, 18.85 +/-0.2 °, 19.49 +/-0.2 °, 20.32 +/-0.2 °, 21.34 +/-0.2 °, 22.12 +/-0.2 °, 22.74 +/-0.2 °, 25.49 +/-0.2 °, 26.06 +/-0.2 °, 26.93 +/-0.2 °, 28.57 +/-0.2 ° and 31.82 +/-0.2 °;

form G has one, two, or three of the following characteristics:

(1) the TGA curve for form G lost about 15.06% weight at 150.0 ± 3 ℃;

8. The solid form of claim 1, being form H having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-ka radiation: 5.76 plus or minus 0.2 degree, 6.81 plus or minus 0.2 degree, 11.54 plus or minus 0.2 degree and 18.68 plus or minus 0.2 degree;

more preferably, the form H has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 5.76 +/-0.2 degrees, 6.81 +/-0.2 degrees, 7.95 +/-0.2 degrees, 8.74 +/-0.2 degrees, 11.54 +/-0.2 degrees, 13.86 +/-0.2 degrees, 18.68 +/-0.2 degrees and 19.90 +/-0.2 degrees;

the form H has one or both of the following characteristics:

(1) the TGA curve of form H lost about 3.62% weight at 150.0 ± 3 ℃;

9. The solid form of claim 1, being crystalline form J-1 of a hemi-2-methyltetrahydrofuran compound or crystalline form J-2 of a monomethyl isobutyl ketone compound,

the crystal form J-1 of the semi-2-methyltetrahydrofuran compound has characteristic peaks at the following 2 theta angles by adopting an X-ray powder diffraction pattern obtained by Cu-Kalpha rays: 4.43 plus or minus 0.2 degree, 8.73 plus or minus 0.2 degree, 11.53 plus or minus 0.2 degree and 15.72 plus or minus 0.2 degree;

preferably, the X-ray powder diffraction pattern of form J-1 has characteristic peaks at the following 2 Θ angles: 4.43 plus or minus 0.2 degree, 8.73 plus or minus 0.2 degree, 11.53 plus or minus 0.2 degree, 15.72 plus or minus 0.2 degree, 20.13 plus or minus 0.2 degree, 21.93 plus or minus 0.2 degree and 23.99 plus or minus 0.2 degree;

the crystalline form J-1 has one or both of the following characteristics:

(1) the TGA curve for form J-1 loses about 7.91% weight at 150.0 + -3 ℃;

(2) the DSC curve of the crystal form J-1 has two endothermic peaks at 96.6 +/-3 ℃ and 157.6 +/-3 ℃;

the X-ray powder diffraction pattern of the crystal form J-2 of the monomethyl isobutyl ketone compound obtained by Cu-Kalpha ray has characteristic peaks at the following 2 theta angles: 4.31 +/-0.2 degrees, 8.56 +/-0.2 degrees, 11.32 +/-0.2 degrees, 15.44 +/-0.2 degrees and 19.64 +/-0.2 degrees;

preferably, the X-ray powder diffraction pattern of form J-2 has characteristic peaks at the following 2 Θ angles: 4.31 +/-0.2 degrees, 8.56 +/-0.2 degrees, 11.32 +/-0.2 degrees, 15.44 +/-0.2 degrees, 19.64 +/-0.2 degrees, 21.80 +/-0.2 degrees and 23.90 +/-0.2 degrees;

more preferably, the crystalline form J-2 has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 4.31 +/-0.2 °, 8.56 +/-0.2 °, 11.32 +/-0.2 °, 14.84 +/-0.2 °, 15.44 +/-0.2 °, 16.46 +/-0.2 °, 17.15 +/-0.2 °, 19.64 +/-0.2 °, 21.80 +/-0.2, 23.42 +/-0.2 °, 23.90 +/-0.2 ° and 24.24 +/-0.2 °;

the crystalline form J-2 has one or both of the following characteristics:

(1) the TGA curve for form J-2 loses about 19.07% weight at 150.0 ± 3 ℃;

10. The solid form of claim 1, the crystalline form is form K having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-ka radiation: 6.93 plus or minus 0.2 degree, 13.89 plus or minus 0.2 degree, 14.81 plus or minus 0.2 degree, 20.91 plus or minus 0.2 degree, 25.00 plus or minus 0.2 degree and 25.72 plus or minus 0.2 degree;

preferably, the form K has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles: 6.93 plus or minus 0.2 degree, 13.89 plus or minus 0.2 degree, 14.81 plus or minus 0.2 degree, 18.77 plus or minus 0.2 degree, 20.91 plus or minus 0.2 degree, 25.00 plus or minus 0.2 degree, 25.72 plus or minus 0.2 degree and 28.04 plus or minus 0.2 degree;

more preferably, the form K has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 6.93 plus or minus 0.2 degree, 11.49 plus or minus 0.2 degree, 13.89 plus or minus 0.2 degree, 14.81 plus or minus 0.2 degree, 18.77 plus or minus 0.2 degree, 20.05 plus or minus 0.2 degree, 20.91 plus or minus 0.2 degree, 21.87 plus or minus 0.2 degree, 25.00 plus or minus 0.2 degree, 25.72 plus or minus 0.2 degree and 28.04 plus or minus 0.2 degree;

the form K has one, two, or three of the following characteristics:

(1) the TGA curve of form K loses about 10.13% weight at 150.0 + -3 ℃;

11. The solid form of claim 1, the crystalline form is form L having an X-ray powder diffraction pattern obtained with Cu-ka radiation having characteristic peaks at the following 2 Θ angles: 6.07 +/-0.2 degrees, 7.01 +/-0.2 degrees, 7.48 +/-0.2 degrees, 14.05 +/-0.2 degrees, 19.44 +/-0.2 degrees and 21.73 +/-0.2 degrees;

preferably, the X-ray powder diffraction pattern of said crystalline form L has characteristic peaks at the following 2 Θ angles: 6.07 +/-0.2 degrees, 7.01 +/-0.2 degrees, 7.48 +/-0.2 degrees, 9.16 +/-0.2 degrees, 12.13 +/-0.2 degrees, 14.05 +/-0.2 degrees, 14.44 +/-0.2 degrees, 16.49 +/-0.2 degrees, 19.44 +/-0.2 degrees and 21.73 +/-0.2 degrees;

more preferably, the crystalline form L has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 6.07 +/-0.2 degrees, 7.01 +/-0.2 degrees, 7.48 +/-0.2 degrees, 9.16 +/-0.2 degrees, 10.22 +/-0.2 degrees, 11.41 +/-0.2 degrees, 12.13 +/-0.2 degrees, 14.05 +/-0.2 degrees, 14.44 +/-0.2 degrees, 16.49 +/-0.2 degrees, 18.32 +/-0.2 degrees, 19.44 +/-0.2 degrees and 21.73 +/-0.2 degrees;

still more preferably, the crystalline form L has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 6.07 +/-0.2 degrees, 7.01 +/-0.2 degrees, 7.48 +/-0.2 degrees, 8.19 +/-0.2 degrees, 9.16 +/-0.2 degrees, 10.22 +/-0.2 degrees, 11.41 +/-0.2 degrees, 12.13 +/-0.2 degrees, 14.05 +/-0.2 degrees, 14.44 +/-0.2 degrees, 16.49 +/-0.2 degrees, 18.32 +/-0.2 degrees, 19.44 +/-0.2 degrees, 20.55 +/-0.2 degrees, 21.73 +/-0.2 degrees, 24.21 +/-0.2 degrees and 25.54 +/-0.2 degrees;

the crystalline form L has one, two or three of the following characteristics:

(1) the TGA curve of form L lost about 3.00% weight at 150.0 ± 3 ℃;

12. The solid form of claim 1, being form M-1 of a monohydrate or form M-2 of an acetonitrile compound,

the X-ray powder diffraction pattern of the crystal form M-1 of the monohydrate, which is obtained by adopting Cu-Kalpha rays, has characteristic peaks at the following 2 theta angles: 5.02 +/-0.2 degrees, 7.45 +/-0.2 degrees, 7.96 +/-0.2 degrees, 8.63 +/-0.2 degrees, 10.05 +/-0.2 degrees and 15.97 +/-0.2 degrees;

preferably, the X-ray powder diffraction pattern of said crystalline form M-1 has characteristic peaks at the following 2 Θ angles: 5.02 +/-0.2 degrees, 7.45 +/-0.2 degrees, 7.96 +/-0.2 degrees, 8.63 +/-0.2 degrees, 9.42 +/-0.2 degrees, 10.05 +/-0.2 degrees, 12.25 +/-0.2 degrees, 15.97 +/-0.2 degrees and 21.60 +/-0.2 degrees;

preferably, the X-ray powder diffraction pattern of said crystalline form M-1 has characteristic peaks at the following 2 Θ angles: 5.02 +/-0.2 °, 7.45 +/-0.2 °, 7.96 +/-0.2 °, 8.63 +/-0.2 °, 9.42 +/-0.2 °, 10.05 +/-0.2 °, 12.25 +/-0.2 °, 13.31 +/-0.2 °, 14.16 +/-0.2 °, 15.97 +/-0.2 °, 18.96 +/-0.2 °, 20.02 +/-0.2 ° and 21.60 +/-0.2 °;

the crystalline form M-1 has one or both of the following characteristics:

(1) the TGA curve for form M-1 loses about 4.31% weight at 150.0 + -3 deg.C;

(2) the DSC curve of the crystal form M-1 has two endothermic peaks at 77.7 +/-3 ℃ and 96.5 +/-3 ℃;

the crystal form M-2 of the acetonitrile compound has characteristic peaks at the following 2 theta angles by adopting an X-ray powder diffraction pattern obtained by Cu-Kalpha rays: 5.01 +/-0.2 degrees, 7.10 +/-0.2 degrees, 7.45 +/-0.2 degrees, 7.96 +/-0.2 degrees, 8.63 +/-0.2 degrees, 9.41 +/-0.2 degrees, 15.94 +/-0.2 degrees, 21.57 +/-0.2 degrees and 23.51 +/-0.2 degrees;

preferably, the X-ray powder diffraction pattern of said crystalline form M-2 has characteristic peaks at the following 2 Θ angles: 5.01 +/-0.2 °, 7.10 +/-0.2 °, 7.45 +/-0.2 °, 7.96 +/-0.2 °, 8.63 +/-0.2 °, 9.41 +/-0.2 °, 15.94 +/-0.2 °, 19.66 +/-0.2 °, 21.57 +/-0.2 °, 23.51 +/-0.2 °, 24.30 +/-0.2 ° and 25.22 +/-0.2 °;

preferably, the X-ray powder diffraction pattern of said crystalline form M-2 has characteristic peaks at the following 2 Θ angles: 5.01 +/-0.2 °, 7.10 +/-0.2 °, 7.45 +/-0.2 °, 7.96 +/-0.2 °, 8.63 +/-0.2 °, 9.41 +/-0.2 °, 9.99 +/-0.2 °, 15.94 +/-0.2 °, 17.29 +/-0.2 °, 19.66 +/-0.2 °, 21.57 +/-0.2 °, 22.48 +/-0.2 °, 23.51 +/-0.2 °, 24.30 +/-0.2 °, 25.22 +/-0.2 ° and 27.14 +/-0.2 °;

the crystalline form M-2 has one or both of the following characteristics:

(1) the TGA curve for form M-2 loses about 8.36% weight at 150.0 + -3 deg.C; and

13. The solid form of claim 1, the crystalline form is form N having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-ka radiation: 7.07 +/-0.2 degrees, 7.21 +/-0.2 degrees, 14.41 +/-0.2 degrees, 19.46 +/-0.2 degrees, 21.30 +/-0.2 degrees, 21.93 +/-0.2 degrees and 25.37 +/-0.2 degrees;

preferably, the X-ray powder diffraction pattern of form N has characteristic peaks at the following 2 Θ angles: 7.07 +/-0.2 degrees, 7.21 +/-0.2 degrees, 14.41 +/-0.2 degrees, 19.46 +/-0.2 degrees, 20.28 +/-0.2 degrees, 21.30 +/-0.2 degrees, 21.93 +/-0.2 degrees, 25.37 +/-0.2 degrees and 26.04 +/-0.2 degrees;

more preferably, the X-ray powder diffraction pattern of form N has characteristic peaks at the following 2 Θ angles: 7.07 +/-0.2 degrees, 7.21 +/-0.2 degrees, 14.41 +/-0.2 degrees, 16.33 +/-0.2 degrees, 19.46 +/-0.2 degrees, 19.73 +/-0.2 degrees, 20.28 +/-0.2 degrees, 20.82 +/-0.2 degrees, 21.30 +/-0.2 degrees, 21.93 +/-0.2 degrees, 25.37 +/-0.2 degrees and 26.04 +/-0.2 degrees;

still more preferably, the crystalline form N has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles: 7.07 +/-0.2 degrees, 7.21 +/-0.2 degrees, 10.08 +/-0.2 degrees, 13.75 +/-0.2 degrees, 14.41 +/-0.2 degrees, 15.06 +/-0.2 degrees, 16.33 +/-0.2 degrees, 19.46 +/-0.2 degrees, 19.73 +/-0.2 degrees, 20.28 +/-0.2 degrees, 20.82 +/-0.2 degrees, 21.30 +/-0.2 degrees, 21.93 +/-0.2 degrees, 25.37 +/-0.2 degrees, 26.04 +/-0.2 degrees, 27.33 +/-0.2 degrees, 28.53 +/-0.2 degrees and 29.39 +/-0.2 degrees.

The form N has one, two, three, or four of the following characteristics:

(3) a DSC curve of the crystal form N has an endothermic peak at 118.9 +/-10 ℃; in particular, the DSC curve of the crystal form N has an endothermic peak at 118.9 +/-5 ℃;

(4) of crystal form N¹H NMR spectrum having the specificity of methylene chlorideAnd (4) characterizing a hydrogen signal.

14. The solid form of claim 1, the crystalline form is form P having characteristic peaks at the following 2 Θ angles in an X-ray powder diffraction pattern obtained with Cu-ka radiation: 7.13 +/-0.2 degrees, 9.63 +/-0.2 degrees, 14.43 +/-0.2 degrees, 19.12 +/-0.2 degrees, 21.03 +/-0.2 degrees, 21.53 +/-0.2 degrees, 25.46 +/-0.2 degrees and 25.91 +/-0.2 degrees;

preferably, the X-ray powder diffraction pattern of form P has characteristic peaks at the following 2 Θ angles: 7.13 +/-0.2 °, 9.63 +/-0.2 °, 11.69 +/-0.2 °, 13.59 +/-0.2 °, 14.43 +/-0.2 °, 19.12 +/-0.2 °, 20.55 +/-0.2 °, 21.03 +/-0.2 °, 21.53 +/-0.2 °, 25.46 +/-0.2 °, 25.91 +/-0.2 ° and 27.03 +/-0.2 °;

more preferably, the X-ray powder diffraction pattern of form P has characteristic peaks at the following 2 Θ angles: 7.13 +/-0.2 °, 9.63 +/-0.2 °, 11.69 +/-0.2 °, 13.59 +/-0.2 °, 14.43 +/-0.2 °, 15.18 +/-0.2 °, 16.35 +/-0.2 °, 17.75 +/-0.2 °, 19.12 +/-0.2 °, 20.55 +/-0.2 °, 21.03 +/-0.2 °, 21.53 +/-0.2 °, 23.46 +/-0.2 °, 25.46 +/-0.2 °, 25.91 +/-0.2 °, 27.03 +/-0.2 ° and 28.89 +/-0.2 °;

the crystalline form P has one, two or three of the following characteristics:

(1) the TGA curve of form P lost about 10.85% weight at 150.0 ± 3 ℃;

15. The solid form of claim 1, which is an amorphous having an X-ray powder diffraction pattern substantially as shown in figure 14.

16. A pharmaceutical composition comprising a solid form of a compound of formula (I), or a solvate thereof, as claimed in any one of claims 1 to 15, or a mixture of any two or more thereof.

17. Use of the solid form of any one of claims 1-15 or a mixture of any two or more thereof, or the pharmaceutical composition of claim 16 for the preparation of a medicament for the treatment and/or prevention of an autotaxin ATX-related disease;

for example, the ATX-related disease comprises at least one selected from the group consisting of: cancer, metabolic disease, kidney disease, liver disease, fibrotic disease, interstitial lung disease, proliferative disease, inflammatory disease, pain, autoimmune disease, respiratory disease, cardiovascular disease, neurodegenerative disease, dermatological disorder, and/or abnormal angiogenesis-related disease;

for example, the ATX-related disease comprises at least one selected from the group consisting of: interstitial lung disease, pulmonary fibrosis, liver fibrosis, kidney fibrosis; for example, the ATX-related diseases include idiopathic pulmonary fibrosis, type II diabetes, nonalcoholic steatohepatitis, neuropathic pain, inflammatory pain; for example, the ATX-related disorder includes osteoarthritis-related pain.