Derivative of protein arginine methyltransferase inhibitor and application of derivative in medicine

Abstract

The invention relates to a crystal form of a compound (S)-1-((2 ', 6-bis (difluoromethyl)-[2, 4'-bipyridyl]-5-yl) oxy)-2, 4-dimethyl pent-4-ene-2-amine as shown in a formula (I) and a salt thereof, a preparation method of the crystal form, and application of the crystal form in a pharmaceutical composition and medicine of the compound (S)-1-((2 ', 6-bis (difluoromethyl)-[2, 4'-bipyridyl]-5-yl) oxy)-2, 4-dimethyl pent-4-ene-2-amine and the salt thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a crystal form of a compound and a salt thereof, a preparation method and application thereof, and in particular to a protein arginine methyltransferase inhibitor compound and a crystal form of a salt thereof, a preparation method thereof and application thereof in preparing drugs for treating AAK1-mediated related diseases, and belongs to the field of pharmaceutical chemistry. Background Art

[0002] Connexin-associated kinase 1 (AAK1) is a member of the Ark1 / Prk1 family of serine / threonine kinases. AAK1 mRNA exists in two spliced ​​forms, referred to as the short form and the long form. The long form is predominant and is highly expressed in the brain and heart. AAK1 is enriched in synaptosomal preparations and colocalizes with endocytic structures in cultured cells. AAK1 regulates endocytosis of clathrin-coated cells, an important process in synaptic vesicle recycling and receptor-mediated endocytosis. AAK1 binds to the AP2 complex, a heterotetramer that connects receptor cargo to the clathrin coating. Binding of clathrin to AAK1 stimulates AAK1 kinase activity. AAK1 phosphorylates the mu-2 subunit of AP-2, which promotes binding of mu-2 to the tyrosine-containing sorting motif on the cargo receptor. Mu2 phosphorylation is not essential for receptor uptake, but phosphorylation increases the efficiency of internalization.

[0003] AAK1 has been identified as an inhibitor of neuregulin-1 / ErbB4 signaling in PC12 cells. Loss of AAK1 expression via RNA interference-mediated gene silencing or treatment with the kinase inhibitor K252a (which inhibits AAK1 kinase activity) leads to enhanced neuregulin-1-induced neurite outgrowth. These treatments lead to increased ErbB4 expression and increased accumulation of ErbB4 in or near the plasma membrane. NRG1 and ErbB4 are putative schizophrenia susceptibility genes. SNPs in the two genes are associated with a variety of schizophrenia endophenotypes. Neuregulin 1 and ErbB4KO mouse models have shown morphological changes and behavioral phenotypes associated with schizophrenia. In addition, single nucleotide polymorphisms in the introns of the AAK1 gene are associated with the age of onset of Parkinson's disease. These results suggest that inhibition of AAK1 activity may be useful in treating schizophrenia, cognitive deficits in schizophrenia, Parkinson's disease, neuropathic pain, bipolar disorder, and Alzheimer's disease. Administration of therapeutically effective doses is problematic when used as a therapeutic agent in humans and may result in toxic side effects or ineffectiveness of treatment. Therefore, it is important to select a crystalline or salt form that is stable, reproducible, and has physicochemical properties that are favorable for its use as a therapeutic agent.

[0004] WO2023284838A1 discloses an AAK1 inhibitor and its use, which involves a compound of the following formula (I):

[0005]

[0006] When used as a therapeutic agent in humans, administration of therapeutically effective doses is problematic and can result in toxic side effects or therapeutic ineffectiveness. Therefore, it is important to select a crystalline form that is stable, reproducible, and has physicochemical properties that are favorable for its use as a therapeutic agent. Summary of the invention

[0007] The present invention provides several crystal forms of a compound represented by formula (I) and its salt.

[0008]

[0009] The present invention provides a crystalline form 1 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 4.96°±0.2°, 11.54°±0.2°, 17.41°±0.2°, 19.81°±0.2°, and 26.27°±0.2°;

[0010] In some embodiments, the crystalline form 1 of the compound represented by the aforementioned formula (I), using Cu-Kα radiation, has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions: 4.64°±0.2°, 4.96°±0.2°, 11.54°±0.2°, 17.23°±0.2°, 17.41°±0.2°, 19.81°±0.2°, 21.74°±0.2°, 26.27°±0.2°;

[0011] In some embodiments, the crystalline form 1 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.64°±0.2°, 4.96°±0.2°, 9.91°±0.2°, 11.54°±0.2°, 17.23°±0.2°, 17.41°±0.2°, 18.77°±0.2°, 19.81°±0.2°, 21.74°±0.2°, 25.09°±0.2°, 26.27°±0.2°, 28.57°±0.2°;

[0012] In some embodiments, the crystalline form 1 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 1 As shown;

[0013] In some embodiments, the thermogravimetric analysis curve, differential scanning calorimetry analysis curve and isothermal adsorption curve of the crystalline form 1 of the compound represented by the aforementioned formula (I) are substantially as follows: Figure 2 , Figure 3 , Figure 4 shown.

[0014] The present invention provides a crystalline form 2 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 4.62°±0.2°, 12.12°±0.2°, 17.25°±0.2°, 21.06°±0.2°, and 25.33°±0.2°;

[0015] In some embodiments, the crystalline form 2 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.62°±0.2°, 4.94°±0.2°, 12.12°±0.2°, 17.25°±0.2°, 20.28°±0.2°, 21.06°±0.2°, 21.25°±0.2°, 25.33°±0.2°;

[0016] In some embodiments, the crystalline form 2 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.62°±0.2°, 4.94°±0.2°, 11.10°±0.2°, 12.12°±0.2°, 13.77°±0.2°, 17.25°±0.2°, 18.36°±0.2°, 20.28°±0.2°, 21.06°±0.2°, 21.25°±0.2°, 24.32°±0.2°, 25.33°±0.2°;

[0017] In some embodiments, the crystal form 2 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 5 As shown;

[0018] In some embodiments, the thermogravimetric analysis curve and differential scanning calorimetry analysis curve of the crystalline form 2 of the compound represented by the aforementioned formula (I) are substantially as follows: Figure 6 , Figure 7 shown.

[0019] The present invention provides a crystalline form 3 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 4.65°±0.2°, 4.98°±0.2°, 11.69°±0.2°, 17.18°±0.2°, and 20.80°±0.2°;

[0020] In some embodiments, the crystalline form 3 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.65°±0.2°, 4.98°±0.2°, 11.69°±0.2°, 17.18°±0.2°, 18.93°±0.2°, 20.80°±0.2°, 26.55°±0.2°, 27.87°±0.2°;

[0021] In some embodiments, the crystalline form 3 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.65°±0.2°, 4.98°±0.2°, 11.69°±0.2°, 17.18°±0.2°, 18.50°±0.2°, 18.68°±0.2°, 18.93°±0.2°, 20.80°±0.2°, 23.45°±0.2°, 26.13°±0.2°, 26.55°±0.2°, 26.76°±0.2°, 27.87°±0.2°;

[0022] In some embodiments, the crystalline form 3 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 8 As shown;

[0023] In some embodiments, the thermogravimetric analysis curve, differential scanning calorimetry analysis curve and isothermal adsorption curve of the crystalline form 3 of the compound represented by the aforementioned formula (I) are substantially as follows: Fig. 9 , Fig.10 , Fig.11 shown.

[0024] The present invention provides a citrate salt crystal form 1 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 7.78°±0.2°, 8.94°±0.2°, 9.80°±0.2°, 17.96°±0.2°, and 21.84°±0.2°;

[0025] In some embodiments, the citrate salt form 1 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 5.94°±0.2°, 7.78°±0.2°, 8.94°±0.2°, 9.80°±0.2°, 16.07°±0.2°, 17.96°±0.2°, 19.60°±0.2°, 21.84°±0.2°;

[0026] In some embodiments, the citrate salt form 1 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 5.94°±0.2°, 7.78°±0.2°, 8.94°±0.2°, 9.80°±0.2°, 14.73°±0.2°, 16.07°±0.2°, 17.96°±0.2°, 19.47°±0.2°, 19.60°±0.2°, 19.73°±0.2°, 20.28°±0.2°, 21.84°±0.2°, 24.78°±0.2°;

[0027] In some embodiments, the citrate salt form 1 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.12 shown.

[0028] The present invention provides a citrate salt form 2 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 8.66°±0.2°, 10.76°±0.2°, 15.56°±0.2°, 16.84°±0.2°, and 24.37°±0.2°;

[0029] In some embodiments, the citrate salt form 2 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 8.66°±0.2°, 10.76°±0.2°, 15.14°±0.2°, 15.56°±0.2°, 16.84°±0.2°, 21.59°±0.2°, 22.29°±0.2°, 24.37°±0.2°;

[0030] In some embodiments, the citrate salt form 2 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 8.66°±0.2°, 10.76°±0.2°, 15.14°±0.2°, 15.56°±0.2°, 16.84°±0.2°, 17.32°±0.2°, 18. 74°±0.2°, 21.11°±0.2°, 21.59°±0.2°, 22.29°±0.2°, 22.87°±0.2°, 23.08°±0.2°, 24.37°±0.2°, 25.11°±0.2°, 25.99°±0.2°, 26.21°±0.2°, 27.45°±0.2°, 30.53°±0.2°;

[0031] In some embodiments, the citrate salt form 2 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.13 As shown;

[0032] In some embodiments, the thermogravimetric analysis curve, differential scanning calorimetry analysis curve and isothermal adsorption curve of the citrate salt form 2 of the compound represented by the aforementioned formula (I) are substantially as follows: Fig.14 , Fig.15 , Fig.16 shown.

[0033] The present invention provides a phosphate crystal form 1 of a compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 6.13°±0.2°, 7.52°±0.2°, 18.64°±0.2°, 24.59°±0.2°, and 25.45°±0.2°;

[0034] In some embodiments, the phosphate crystal form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 6.13°±0.2°, 7.52°±0.2°, 16.62°±0.2°, 18.64°±0.2°, 19.56°±0.2°, 24.59°±0.2°, 24.97°±0.2°, 25.45°±0.2°;

[0035] In some embodiments, the phosphate crystal form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 6.13°±0.2°, 7.52°±0.2°, 11.21°±0.2°, 15.03°±0.2°, 16.39°±0.2°, 16.62°±0.2°, 17.4 1°±0.2°, 18.64°±0.2°, 19.56°±0.2°, 19.79°±0.2°, 21.40°±0.2°, 21.56°±0.2°, 22.48°±0.2°, 23.16°±0.2°, 24.59°±0.2°, 24.97°±0.2°, 25.45°±0.2°, 27.07°±0.2°;

[0036] In some embodiments, the phosphate crystal form 1 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.17 shown.

[0037] The present invention provides a phosphate crystal form 2 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 3.90°±0.2°, 5.49°±0.2°, 12.60°±0.2°, 12.93°±0.2°, and 22.23°±0.2°;

[0038] In some embodiments, the phosphate crystal form 2 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 3.90°±0.2°, 5.49°±0.2°, 6.01°±0.2°, 12.60°±0.2°, 12.93°±0.2°, 16.05°±0.2°, 17.38°±0.2°, 22.23°±0.2°;

[0039] In some embodiments, the phosphate crystal form 2 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 3.90°±0.2°, 5.49°±0.2°, 6.01°±0.2°, 12.60°±0.2°, 12.93°±0.2°, 15.82°±0.2°, 16.05°±0.2°, 17.38°±0.2°, 18.00°±0.2°, 18.55°±0.2°, 19.81°±0.2°, 22.23°±0.2°;

[0040] In some embodiments, the phosphate crystal form 2 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.18 shown.

[0041] The present invention provides a phosphate crystal form 3 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 5.52°±0.2°, 6.02°±0.2°, 16.25°±0.2°, 17.12°±0.2°, and 17.45°±0.2°;

[0042] In some embodiments, the phosphate crystal form 3 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 5.52°±0.2°, 6.02°±0.2°, 10.58°±0.2°, 14.26°±0.2°, 16.25°±0.2°, 17.12°±0.2°, 17.45°±0.2°, 19.63°±0.2°;

[0043] In some embodiments, the phosphate crystal form 3 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 4.60°±0.2°, 5.52°±0.2°, 6.02°±0.2°, 9.16°±0.2°, 10.58°±0.2°, 10.96°±0.2°, 13.73°±0.2°, 14.26 °±0.2°, 15.22°±0.2°, 16.25°±0.2°, 17.12°±0.2°, 17.45°±0.2°, 19.63°±0.2°, 19.81°±0.2°, 21.15°±0.2°, 21.44°±0.2°, 22.02°±0.2°, 22.45°±0.2°, 23.81°±0.2°, 24.09°±0.2°;

[0044] In some embodiments, the phosphate crystal form 3 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.19 As shown;

[0045] In some embodiments, the phosphate crystal form 3 of the compound represented by the aforementioned formula (I) has a thermogravimetric analysis curve and a differential scanning calorimetry analysis curve substantially as follows: Fig. 20 , Fig.21 shown.

[0046] The present invention provides a sulfate crystal form 1 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 4.56°±0.2°, 6.37°±0.2°, 6.77°±0.2°, 25.60°±0.2°, and 26.00°±0.2°;

[0047] In some embodiments, the sulfate crystalline form 1 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.56°±0.2°, 6.37°±0.2°, 6.77°±0.2°, 9.04°±0.2°, 11.18°±0.2°, 17.04°±0.2°, 25.60°±0.2°, 26.00°±0.2°;

[0048] In some embodiments, the sulfate crystalline form 1 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.56°±0.2°, 6.37°±0.2°, 6.77°±0.2°, 7.21°±0.2°, 7.82°±0.2°, 9.04°±0.2°, 10.94°±0.2°, 11.18°±0.2°, 17.04°±0.2°, 18.07°±0.2°, 19.16°±0.2°, 20.32°±0.2°, 21.36°±0.2°, 25.60°±0.2°, 26.00°±0.2°, 28.04°±0.2°;

[0049] In some embodiments, the sulfate salt form 1 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig. 22 As shown;

[0050] In some embodiments, the thermogravimetric analysis curve, differential scanning calorimetry analysis curve and isothermal adsorption curve of the sulfate salt form 1 of the compound represented by the aforementioned formula (I) are substantially as follows: Fig.23 , Fig.24 , Fig.25 shown.

[0051] The present invention provides L-tartrate salt form 1 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 3.81°±0.2°, 6.33°±0.2°, 7.17°±0.2°, 20.47°±0.2°, 25.50°±0.2°;

[0052] In some embodiments, the L-tartrate salt form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 3.81°±0.2°, 6.33°±0.2°, 7.17°±0.2°, 13.43°±0.2°, 19.09°±0.2°, 19.25°±0.2°, 20.47°±0.2°, 25.50°±0.2°;

[0053] In some embodiments, the L-tartrate salt form 1 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 3.81°±0.2°, 6.33°±0.2°, 7.17°±0.2°, 12.65°±0.2°, 13.03°±0.2°, 13.43°±0.2°, 14.20°±0.2°, 15.23°±0.2°, 19.09°±0.2°, 19.25°±0.2°, 19.67°±0.2°, 20.47°±0.2°, 21.60°±0.2°, 25.50°±0.2°;

[0054] In some embodiments, the L-tartrate salt form 1 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.26 shown.

[0055] The present invention provides L-tartrate salt form 2 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.26°±0.2°, 6.39°±0.2°, 20.45°±0.2°, 21.14°±0.2°, and 25.56°±0.2°;

[0056] In some embodiments, the L-tartrate salt form 2 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.26°±0.2°, 6.39°±0.2°, 16.92°±0.2°, 19.42°±0.2°, 20.05°±0.2°, 20.45°±0.2°, 21.14°±0.2°, 25.56°±0.2°;

[0057] In some embodiments, the L-tartrate salt form 2 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.26°±0.2°, 6.07°±0.2°, 6.39°±0.2°, 9.13°±0.2°, 12.70°±0.2°, 15.24°±0.2°, 16.92°±0.2°, 19.42°±0.2°, 20.05°±0.2°, 20.45°±0.2°, 21.14°±0.2°, 25.56°±0.2°;

[0058] In some embodiments, the L-tartrate salt form 2 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig. 27 shown.

[0059] The present invention provides L-tartrate salt form 3 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.51°±0.2°, 10.35°±0.2°, 15.92°±0.2°, 18.15°±0.2°, 19.52°±0.2°;

[0060] In some embodiments, the L-tartrate salt form 3 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.51°±0.2°, 10.35°±0.2°, 15.92°±0.2°, 18.15°±0.2°, 19.52°±0.2°, 20.42°±0.2°, 23.86°±0.2°, 25.01°±0.2°;

[0061] In some embodiments, the L-tartrate salt form 3 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.51°±0.2°, 6.37°±0.2°, 8.96°±0.2°, 10.35°±0.2°, 15.92°±0.2°, 16.53°±0.2°, 17.88°±0.2°, 18.15°±0.2°, 19.52°±0.2°, 20.42°±0.2°, 20.68°±0.2°, 21.79°±0.2°, 23.86°±0.2°, 25.01°±0.2°, 25.80°±0.2°, 28.66°±0.2°;

[0062] In some embodiments, the L-tartrate salt form 3 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.28 As shown;

[0063] In some embodiments, the L-tartrate salt form 3 of the compound represented by the aforementioned formula (I) has a thermogravimetric analysis curve, a differential scanning calorimetry analysis curve and an isothermal adsorption curve substantially as follows: Fig.29 , Fig.30 , Fig.31 shown.

[0064] The present invention provides L-tartrate salt form 4 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.47°±0.2°, 10.05°±0.2°, 18.04°±0.2°, 18.97°±0.2°, and 19.35°±0.2°;

[0065] In some embodiments, the L-tartrate salt form 4 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.47°±0.2°, 10.05°±0.2°, 15.63°±0.2°, 18.04°±0.2°, 18.97°±0.2°, 19.35°±0.2°, 20.04°±0.2°, 20.47°±0.2°;

[0066] In some embodiments, the L-tartrate salt form 4 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.47°±0.2°, 6.22°±0.2°, 8.89°±0.2°, 10.05°±0.2°, 14.13°±0.2°, 15.63°±0.2°, 15.86°±0.2°, 18.04°±0.2°, 18.97°±0.2°, 19.35°±0.2°, 20.04°±0.2°, 20.47°±0.2°, 21.75°±0.2°, 23.77°±0.2°, 24.99°±0.2°;

[0067] In some embodiments, the L-tartrate salt form 4 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.32 As shown;

[0068] The present invention provides L-tartrate salt form 5 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.14°±0.2°, 5.80°±0.2°, 11.67°±0.2°, 16.79°±0.2°, 20.26°±0.2°, 23.64°±0.2°, 24.76°±0.2°;

[0069] In some embodiments, the L-tartrate salt form 5 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.33 As shown;

[0070] In some embodiments, the L-tartrate salt form 5 of the compound represented by the aforementioned formula (I) has a thermogravimetric analysis curve, a differential scanning calorimetry analysis curve and an isothermal adsorption curve substantially as follows: Fig.34 , Fig.35 , Fig.36 shown.

[0071] The present invention provides a fumarate salt form 1 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 8.98°±0.2°, 9.80°±0.2°, 14.85°±0.2°, 19.45°±0.2°, and 21.54°±0.2°;

[0072] In some embodiments, the fumarate salt form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 8.98°±0.2°, 9.80°±0.2°, 14.85°±0.2°, 19.45°±0.2°, 21.54°±0.2°, 24.46°±0.2°, 25.46°±0.2°, 27.14°±0.2°;

[0073] In some embodiments, the fumarate salt form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 7.02°±0.2°, 8.98°±0.2°, 9.80°±0.2°, 14.05°±0.2°, 14.85°±0.2°, 15.88°±0.2°, 18.0 0°±0.2°, 18.53°±0.2°, 18.74°±0.2°, 19.45°±0.2°, 20.34°±0.2°, 20.70°±0.2°, 21.54°±0.2°, 24.46°±0.2°, 25.46°±0.2°, 26.68°±0.2°, 27.14°±0.2°, 29.56°±0.2°;

[0074] In some embodiments, the fumarate salt form 1 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.37 As shown;

[0075] The present invention provides a fumarate crystalline form 2 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 11.08°±0.2°, 11.27°±0.2°, 20.91°±0.2°, 22.95°±0.2°, and 26.97°±0.2°;

[0076] In some embodiments, the fumarate salt form 2 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 9.44°±0.2°, 11.08°±0.2°, 11.27°±0.2°, 15.62°±0.2°, 20.91°±0.2°, 22.95°±0.2°, 25.10°±0.2°, 26.97°±0.2°;

[0077] In some embodiments, the fumarate salt form 2 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 9.44°±0.2°, 11.08°±0.2°, 11.27°±0.2°, 11.58°±0.2°, 15.62°±0.2°, 17.12°±0.2°, 17.96°±0.2°, 18. 91°±0.2°, 19.90°±0.2°, 20.91°±0.2°, 22.22°±0.2°, 22.61°±0.2°, 22.95°±0.2°, 23.22°±0.2°, 23.64°±0.2°, 24.02°±0.2°, 24.55°±0.2°, 25.10°±0.2°, 26.51°±0.2°, 26.97°±0.2°;

[0078] In some embodiments, the fumarate salt form 2 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.38 As shown;

[0079] In some embodiments, the thermogravimetric analysis curve, differential scanning calorimetry analysis curve and isothermal adsorption curve of the fumarate salt form 2 of the compound represented by the aforementioned formula (I) are substantially as follows: Fig.39 , Fig.40 , Fig.41 shown.

[0080] The present invention provides a hydrochloride salt crystalline form 1a of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 8.00°±0.2°, 11.46°±0.2°, 13.63°±0.2°, 24.00°±0.2°, and 26.09°±0.2°;

[0081] In some embodiments, the hydrochloride salt form 1a of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 8.00°±0.2°, 11.46°±0.2°, 13.63°±0.2°, 14.28°±0.2°, 15.96°±0.2°, 22.97°±0.2°, 24.00°±0.2°, 26.09°±0.2°;

[0082] In some embodiments, the hydrochloride crystalline form 1a of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation in its X-ray powder diffraction pattern: 8.00°±0.2°, 11.46°±0.2°, 13.63°±0.2°, 14.28°±0.2°, 15.96°±0.2°, 16.15°±0. 2°, 16.76°±0.2°, 19.18°±0.2°, 20.05°±0.2°, 20.46°±0.2°, 22.63°±0.2°, 22.97°±0.2°, 24.00°±0.2°, 25.90°±0.2°, 26.09°±0.2°, 26.69°±0.2°, 33.66°±0.2°;

[0083] In some embodiments, the hydrochloride crystalline form 1a of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.42 As shown;

[0084] The present invention provides a hydrochloride salt form 1b of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 8.06°±0.2°, 13.55°±0.2°, 16.13°±0.2°, 24.26°±0.2°, 26.25°±0.2°;

[0085] In some embodiments, the hydrochloride salt form 1b of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 8.06°±0.2°, 11.38°±0.2°, 13.55°±0.2°, 16.13°±0.2°, 20.03°±0.2°, 22.85°±0.2°, 24.26°±0.2°, 26.25°±0.2°;

[0086] In some embodiments, the hydrochloride salt form 1b of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation in its X-ray powder diffraction pattern: 8.06°±0.2°, 11.38°±0.2°, 13.55°±0.2°, 14.32°±0.2°, 15.90°±0.2°, 16.13°±0. 2°, 16.95°±0.2°, 17.80°±0.2°, 19.21°±0.2°, 20.03°±0.2°, 20.34°±0.2°, 22.85°±0.2°, 24.26°±0.2°, 25.81°±0.2°, 26.25°±0.2°, 26.76°±0.2°, 32.53°±0.2°;

[0087] In some embodiments, the hydrochloride salt form 1b of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.43 As shown;

[0088] In some embodiments, the hydrochloride crystal form 1b of the compound represented by the aforementioned formula (I) has a thermogravimetric analysis curve, a differential scanning calorimetry analysis curve and an isothermal adsorption curve substantially as follows: Fig.44 , Fig.45 , Fig.46 shown.

[0089] The present invention provides a hydrochloride salt form 1c of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 8.01°±0.2°, 13.55°±0.2°, 20.39°±0.2°, 24.07°±0.2°, 25.96°±0.2°;

[0090] In some embodiments, the hydrochloride salt form 1c of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 8.01°±0.2°, 11.72°±0.2°, 13.55°±0.2°, 16.01°±0.2°, 20.39°±0.2°, 24.07°±0.2°, 25.96°±0.2°, 26.51°±0.2°;

[0091] In some embodiments, the hydrochloride salt form 1c of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 8.01°±0.2°, 11.52°±0.2°, 11.72°±0.2°, 13.55°±0.2°, 14.49°±0.2°, 16.1°±0.2°, 18.1 9°±0.2°, 19.04°±0.2°, 20.11°±0.2°, 20.39°±0.2°, 23.12°±0.2°, 24.07°±0.2°, 25.04°±0.2°, 25.96°±0.2°, 26.26°±0.2°, 26.51°±0.2°, 27.52°±0.2°, 28.36°±0.2°;

[0092] In some embodiments, the hydrochloride salt form 1c of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.47 As shown;

[0093] In some embodiments, the hydrochloride crystal form 1c of the compound represented by the aforementioned formula (I) has a thermogravimetric analysis curve, a differential scanning calorimetry analysis curve and an isothermal adsorption curve substantially as follows: Fig.48 , Fig.49 , Fig.50 shown.

[0094] The present invention provides a maleate salt crystalline form 1 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 13.10°±0.2°, 18.38°±0.2°, 19.65°±0.2°, 23.63°±0.2°, and 25.12°±0.2°;

[0095] In some embodiments, the maleate salt form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 11.33°±0.2°, 13.10°±0.2°, 18.38°±0.2°, 19.65°±0.2°, 21.60°±0.2°, 22.38°±0.2°, 23.63°±0.2°, 25.12°±0.2°;

[0096] In some embodiments, the maleate salt form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 4.68°±0.2°, 11.33°±0.2°, 12.22°±0.2°, 13.10°±0.2°, 16.03°±0.2°, 16.51°±0.2°, 17.31°±0.2°, 17.90°±0. 2°, 18.38°±0.2°, 19.65°±0.2°, 21.08°±0.2°, 21.60°±0.2°, 22.38°±0.2°, 23.63°±0.2°, 25.12°±0.2°, 26.25°±0.2°, 27.61°±0.2°, 27.92°±0.2°, 28.68°±0.2°, 29.06°±0.2°, 30.13°±0.2°;

[0097] In some embodiments, the maleate salt form 1 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.51 As shown;

[0098] In some embodiments, the maleate salt crystalline form 1 of the compound represented by the aforementioned formula (I) has a thermogravimetric analysis curve, a differential scanning calorimetry analysis curve and an isothermal adsorption curve substantially as follows: Fig.52 , Fig.53 , Fig.54 shown.

[0099] The present invention provides a hydrobromide salt crystalline form 1 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 7.86°±0.2°, 18.78°±0.2°, 20.32°±0.2°, 23.64°±0.2°, and 25.56°±0.2°;

[0100] In some embodiments, the hydrobromide salt form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 6.85°±0.2°, 7.86°±0.2°, 18.78°±0.2°, 19.87°±0.2°, 20.32°±0.2°, 22.97°±0.2°, 23.64°±0.2°, 25.56°±0.2°;

[0101] In some embodiments, the hydrobromide salt form 1 of the compound represented by the aforementioned formula (I) has a characteristic diffraction peak at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 6.85°±0.2°, 7.86°±0.2°, 11.44°±0.2°, 14.35°±0.2°, 14.97°±0.2°, 15.71°±0.2°, 18.78°±0.2°, 19.87°±0.2°, 20.32°±0.2°, 22.97°±0.2°, 23.31°±0.2°, 23.64°±0.2°, 25.56°±0.2°, 25.85°±0.2°, 26.19°±0.2°, 32.99°±0.2°;

[0102] In some embodiments, the hydrobromide salt form 1 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.55 shown.

[0103] The present invention provides a hydrobromide salt crystalline form 2 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 7.91°±0.2°, 20.01°±0.2°, 22.56°±0.2°, 23.88°±0.2°, and 25.75°±0.2°;

[0104] In some embodiments, the hydrobromide salt form 2 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 6.73°±0.2°, 7.91°±0.2°, 18.83°±0.2°, 20.01°±0.2°, 22.56°±0.2°, 23.88°±0.2°, 25.75°±0.2°, 26.09°±0.2°;

[0105] In some embodiments, the hydrobromide salt form 2 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 6.73°±0.2°, 7.91°±0.2°, 11.23°±0.2°, 14.18°±0.2°, 15.86°±0.2°, 18.83°±0.2 °, 20.01°±0.2°, 21.52°±0.2°, 22.56°±0.2°, 22.95°±0.2°, 23.12°±0.2°, 23.41°±0.2°, 23.88°±0.2°, 25.75°±0.2°, 26.09°±0.2°, 27.62°±0.2°, 32.00°±0.2°;

[0106] In some embodiments, the hydrobromide salt form 2 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.56 As shown;

[0107] In some embodiments, the hydrobromide salt form 2 of the compound represented by the aforementioned formula (I) has a thermogravimetric analysis curve, a differential scanning calorimetry analysis curve and an isothermal adsorption curve substantially as follows: Fig.57 , Fig.58 , Fig.59 shown.

[0108] The present invention provides a mesylate salt form 1 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 10.28°±0.2°, 16.63°±0.2°, 19.29°±0.2°, 22.51°±0.2°, and 24.49°±0.2°;

[0109] In some embodiments, the mesylate salt form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 10.28°±0.2°, 16.63°±0.2°, 17.77°±0.2°, 19.29°±0.2°, 19.46°±0.2°, 22.51°±0.2°, 24.49°±0.2°, 28.23°±0.2°;

[0110] In some embodiments, the mesylate salt form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation in its X-ray powder diffraction pattern: 5.64°±0.2°, 10.28°±0.2°, 11.25°±0.2°, 16.63°±0.2°, 17.77°±0.2°, 19.29°±0. 2°, 19.46°±0.2°, 21.04°±0.2°, 22.51°±0.2°, 22.80°±0.2°, 24.49°±0.2°, 24.77°±0.2°, 26.23°±0.2°, 27.83°±0.2°, 28.23°±0.2°, 29.65°±0.2°, 31.12°±0.2°;

[0111] In some embodiments, the mesylate salt form 1 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.60 As shown;

[0112] In some embodiments, the thermogravimetric analysis curve, differential scanning calorimetry analysis curve and isothermal adsorption curve of the mesylate salt form 1 of the compound represented by the aforementioned formula (I) are substantially as follows: Fig.61 , Fig.62 , Fig.63 shown.

[0113] The present invention provides a benzoate salt form 1 of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ positions in an X-ray powder diffraction pattern using Cu-Kα radiation: 9.34°±0.2°, 9.76°±0.2°, 18.54°±0.2°, 23.35°±0.2°, and 24.85°±0.2°;

[0114] In some embodiments, the benzoate salt form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 9.34°±0.2°, 9.76°±0.2°, 11.70°±0.2°, 18.54°±0.2°, 22.48°±0.2°, 23.35°±0.2°, 24.85°±0.2°, 27.17°±0.2°;

[0115] In some embodiments, the benzoate salt form 1 of the compound represented by the aforementioned formula (I) has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 9.34°±0.2°, 9.76°±0.2°, 11.70°±0.2°, 13.58°±0.2°, 15.58°±0.2°, 16.36°±0.2 °, 17.52°±0.2°, 18.54°±0.2°, 19.15°±0.2°, 20.32°±0.2°, 22.48°±0.2°, 23.35°±0.2°, 24.51°±0.2°, 24.85°±0.2°, 25.83°±0.2°, 27.17°±0.2°, 27.88°±0.2°;

[0116] In some embodiments, the benzoate salt form 1 of the compound represented by the aforementioned formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Fig.64 As shown;

[0117] In some embodiments, the benzoate salt form 1 of the compound represented by the aforementioned formula (I) has a thermogravimetric analysis curve, a differential scanning calorimetry analysis curve and an isothermal adsorption curve substantially as follows: Fig.65 , Fig.67 shown.

[0118] The invention relates to a method for preparing a crystalline form of a compound represented by formula (I), wherein the method comprises: a method for preparing a compound represented by formula (I); in some embodiments, the solvent used is selected from one or more of C1-6 halogenated alkane solvents, C2-6 ester solvents, C2-6 ether solvents, C1-6 alcohol solvents or water; in some embodiments, the solvent used is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, propanol, ether, tetrahydrofuran and water.

[0119] In one aspect, the present invention further provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of a salt form of the compound represented by the aforementioned formula (I) and a pharmaceutically acceptable carrier or excipient.

[0120] The present invention also relates to the use of the compound described in any of the technical solutions described above, its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable crystal forms or salt forms, or compositions in the preparation of drugs for treating AAK1-mediated diseases; the AAK1-mediated diseases are neuropathic pain, such as diabetic neuropathy and postherpetic pain.

[0121] The present invention also provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a crystalline form of a compound of formula (I) or a salt thereof as described in any one of the aforementioned technical solutions, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount being preferably 1-1500 mg; the disease being preferably neuropathic pain; the disease being more preferably diabetic neuropathy or postherpetic pain.

[0122] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a crystalline form of the compound of formula (I) or a salt thereof or a pharmaceutical composition thereof. In some embodiments, the mammal in the present invention includes a human.

[0123] "Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition being treated to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0124] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable crystal form or salt form and a carrier and / or excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification"). In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg 1500 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, pharmaceutically acceptable crystal form or salt form thereof.

[0125] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable crystal form or salt form, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg; the disease is preferably neuropathic pain; and the disease is more preferably diabetic neuropathy or postherpetic pain.

[0126] A method for treating a disease in a mammal, the method comprising administering a pharmaceutical compound of the present invention, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable crystal form or salt form, and a pharmaceutically acceptable carrier and / or excipient to a subject at a daily dose of 1-1500 mg / day, the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day In some embodiments, the daily dose includes but is not limited to 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day.

[0127] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, wherein the kit comprises a crystalline form of a compound of formula (I) or a salt thereof of the present invention, and the amount of the crystalline form of the compound of formula (I) or a salt thereof of the present invention is the same as that in the above-mentioned pharmaceutical composition.

[0128] The amount of the crystalline form of the compound of the formula (I) according to the invention or its salt is in each case calculated as the free base.

[0129] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0130] In another aspect, the present invention also provides a crystalline form of the aforementioned compound of formula (I) or its salt or the aforementioned pharmaceutical composition for use in the preparation of neuropathic pain; the diseases described are more preferably diabetic neuropathy and postherpetic pain.

[0131] It can be understood that the expressions such as “preferably, ..., its X-ray powder diffraction pattern further has a characteristic diffraction peak at the following 2θ position” or “more preferably, ..., its X-ray powder diffraction pattern further has a characteristic diffraction peak at the following 2θ position” described in the present invention mean that on the basis of having a characteristic diffraction peak at the aforementioned 2θ position, there is further a characteristic diffraction peak at the “following 2θ position”.

[0132] The X-ray powder diffraction or DSC graph, TGA graph disclosed in the present invention and those substantially the same also belong to the scope of the present invention.

[0133] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0134] As used herein, "the crystal of the present invention", "the crystalline form of the present invention", "the polymorph of the present invention" and the like may be used interchangeably.

[0135] The "room temperature" mentioned in the present invention generally refers to 4-30°C, preferably refers to 20±5°C.

[0136] The crystalline structure of the present invention can be analyzed using various analytical techniques known to those of ordinary skill in the art, including but not limited to, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC) and / or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).

[0137] The "2θ or 2θ angle" mentioned in the present invention refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree. The error range of the 2θ can be ±0.3, ±0.2 or ±0.1.

[0138] It is understood that the numerical values ​​described and protected by the present invention are approximate values. The variation in the numerical values ​​may be due to the calibration of the equipment, equipment error, purity of the crystal, crystal size, sample size and other factors.

[0139] It is to be understood that the crystal forms of the present invention are not limited to characteristic spectra that are completely identical to the characteristic spectra described in the accompanying drawings disclosed in the present invention, such as XRD, DSC, TGA, and any crystal forms having characteristic spectra that are substantially the same or essentially the same as those described in the accompanying drawings fall within the scope of the present invention.

[0140] It is understood that the melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, and the peak position is relatively insensitive to experimental details, as is well known in the field of differential scanning calorimetry (DSC). Therefore, in some embodiments, the crystalline compound of the present invention is characterized by a DSC pattern with a characteristic peak position, having substantially the same properties as the DSC pattern provided in the accompanying drawings of the present invention, with an error tolerance of ± 3 ° C.

[0141] The crystal form disclosed in the present invention can be prepared by the following common methods for preparing crystal forms:

[0142] 1. The volatilization experiment is to evaporate the clear solution of the sample at different temperatures until the solvent is dry.

[0143] 2. The slurry experiment is to stir the supersaturated solution of the sample (with insoluble solids) at a certain temperature in different solvent systems.

[0144] 3. The anti-solvent test is to dissolve the sample in a good solvent, add an anti-solvent, stir the precipitated solid for a short time and then filter it immediately.

[0145] 4. The cooling crystallization experiment is to dissolve a certain amount of sample into the corresponding solvent at high temperature, and then stir and crystallize directly at room temperature or low temperature.

[0146] 5. The polymer template experiment is to add different types of polymer materials to the sample clear solution and leave it open at room temperature to evaporate until the solvent is dry.

[0147] 6. The thermal method experiment is to treat the sample under certain thermal method crystallization conditions and cool it to room temperature.

[0148] 7. The water vapor diffusion experiment is to place the sample in a certain humidity environment at room temperature. BRIEF DESCRIPTION OF THE DRAWINGS

[0149] Figure 1 The X-ray powder diffraction pattern of the crystalline form 1 of the compound of formula (I).

[0150] Figure 2 This is the thermogravimetric analysis spectrum of Form 1 of the compound of formula (I).

[0151] Figure 3 The differential scanning calorimetry analysis curve of the crystalline form 1 of the compound of formula (I) is shown in FIG.

[0152] Figure 4 It is the isothermal adsorption curve of the crystalline form 1 of the compound of formula (I).

[0153] Figure 5 The X-ray powder diffraction pattern of Form 2 of the compound of formula (I) is shown in FIG.

[0154] Figure 6 This is the thermogravimetric analysis spectrum of Form 2 of the compound of formula (I).

[0155] Figure 7 The differential scanning calorimetry analysis curve of the crystalline form 2 of the compound of formula (I) is shown in FIG.

[0156] Figure 8 The X-ray powder diffraction pattern of the crystalline form 3 of the compound of formula (I).

[0157] Fig. 9 This is the thermogravimetric analysis spectrum of Form 3 of the compound of formula (I).

[0158] Fig.10 The differential scanning calorimetry analysis curve of the crystalline form 3 of the compound of formula (I) is shown in FIG.

[0159] Fig.11 It is the isothermal adsorption curve of the crystalline form 3 of the compound of formula (I).

[0160] Fig.12 The X-ray powder diffraction pattern of the citrate salt form 1 of the compound of formula (I).

[0161] Fig.13 The X-ray powder diffraction pattern of the citrate crystalline form 2 of the compound of formula (I).

[0162] Fig.14 This is the thermogravimetric analysis spectrum of the citrate salt form 2 of the compound of formula (I).

[0163] Fig.15 The differential scanning calorimetry analysis curve of the citrate salt form 2 of the compound of formula (I) is shown in FIG.

[0164] Fig.16 The isothermal adsorption curve of the citrate crystal form 2 of the compound of formula (I).

[0165] Fig.17 The X-ray powder diffraction pattern of the phosphate crystal form 1 of the compound of formula (I).

[0166] Fig.18 The X-ray powder diffraction pattern of the phosphate crystal form 2 of the compound of formula (I).

[0167] Fig.19 The X-ray powder diffraction pattern of the phosphate crystal form 3 of the compound of formula (I).

[0168] Fig. 20 The thermogravimetric analysis spectrum of the phosphate crystal form 3 of the compound of formula (I).

[0169] Fig.21 The differential scanning calorimetry analysis curve of the phosphate crystal form 3 of the compound of formula (I) is shown in FIG.

[0170] Fig. 22 The X-ray powder diffraction pattern of the sulfate crystal form 1 of the compound of formula (I).

[0171] Fig.23 This is the thermogravimetric analysis spectrum of the sulfate crystal form 1 of the compound of formula (I).

[0172] Fig.24 The differential scanning calorimetry analysis curve of the sulfate salt form 1 of the compound of formula (I) is shown in FIG.

[0173] Fig.25 It is the isothermal adsorption curve of the sulfate crystal form 1 of the compound of formula (I).

[0174] Fig.26 The X-ray powder diffraction pattern of the tartaric acid form 1 of the compound of formula (I).

[0175] Fig. 27 The X-ray powder diffraction pattern of the tartaric acid form 2 of the compound of formula (I).

[0176] Fig.28 The X-ray powder diffraction pattern of the tartaric acid form 3 of the compound of formula (I).

[0177] Fig.29 This is the thermogravimetric analysis spectrum of the tartaric acid form 3 of the compound of formula (I).

[0178] Fig.30 The differential scanning calorimetry analysis curve of the tartaric acid crystal form 3 of the compound of formula (I) is shown in FIG.

[0179] Fig.31 The isothermal adsorption curve of the tartaric acid form 3 of the compound of formula (I).

[0180] Fig.32 The X-ray powder diffraction pattern of the tartaric acid form 4 of the compound of formula (I).

[0181] Fig.33 The X-ray powder diffraction pattern of the tartaric acid form 5 of the compound of formula (I).

[0182] Fig.34 The thermogravimetric analysis spectrum of the tartaric acid form 5 of the compound of formula (I).

[0183] Fig.35 The differential scanning calorimetry analysis curve of the tartaric acid crystal form 5 of the compound of formula (I) is shown in FIG.

[0184] Fig.36 The isothermal adsorption curve of the tartaric acid crystal form 5 of the compound of formula (I).

[0185] Fig.37 The X-ray powder diffraction pattern of the fumaric acid crystal form 1 of the compound of formula (I).

[0186] Fig.38 The X-ray powder diffraction pattern of the fumaric acid crystal form 2 of the compound of formula (I).

[0187] Fig.39 The thermogravimetric analysis spectrum of the fumaric acid crystal form 2 of the compound of formula (I).

[0188] Fig.40 The differential scanning calorimetry analysis curve of the fumaric acid crystal form 2 of the compound of formula (I) is shown in FIG.

[0189] Fig.41 It is the isothermal adsorption curve of fumaric acid crystal form 2 of the compound of formula (I).

[0190] Fig.42 The X-ray powder diffraction pattern of the hydrochloride crystal form 1a of the compound of formula (I).

[0191] Fig.43 The X-ray powder diffraction pattern of the hydrochloride crystal form 1b of the compound of formula (I).

[0192] Fig.44 This is the thermogravimetric analysis spectrum of the hydrochloride crystal form 1b of the compound of formula (I).

[0193] Fig.45 The differential scanning calorimetry analysis curve of the hydrochloride crystal form 1b of the compound of formula (I) is shown in FIG.

[0194] Fig.46 The isothermal adsorption curve of the hydrochloride crystal form 1b of the compound of formula (I).

[0195] Fig.47 The X-ray powder diffraction pattern of the hydrochloride crystal form 1c of the compound of formula (I).

[0196] Fig.48 This is the thermogravimetric analysis spectrum of the hydrochloride crystal form 1c of the compound of formula (I).

[0197] Fig.49 The differential scanning calorimetry analysis curve of the hydrochloride crystal form 1c of the compound of formula (I) is shown in FIG.

[0198] Fig.50 It is the isothermal adsorption curve of the hydrochloride crystal form 1c of the compound of formula (I).

[0199] Fig.51 The X-ray powder diffraction pattern of maleic acid form 1 of the compound of formula (I) is shown.

[0200] Fig.52This is the thermogravimetric analysis spectrum of maleic acid form 1 of the compound of formula (I).

[0201] Fig.53 The differential scanning calorimetry analysis curve of the maleic acid crystal form 1 of the compound of formula (I) is shown in FIG.

[0202] Fig.54 The isothermal adsorption curve of maleic acid form 1 of the compound of formula (I).

[0203] Fig.55 The X-ray powder diffraction pattern of the hydrobromide salt form 1 of the compound of formula (I).

[0204] Fig.56 The X-ray powder diffraction pattern of the hydrobromide salt form 2 of the compound of formula (I).

[0205] Fig.57 The thermogravimetric analysis spectrum of the hydrobromide salt form 2 of the compound of formula (I).

[0206] Fig.58 The differential scanning calorimetry analysis curve of the hydrobromide salt form 2 of the compound of formula (I) is shown in FIG.

[0207] Fig.59 The isothermal adsorption curve of the hydrobromide salt form 2 of the compound of formula (I).

[0208] Fig.60 The X-ray powder diffraction pattern of the mesylate salt form 1 of the compound of formula (I).

[0209] Fig.61 The thermogravimetric analysis spectrum of the mesylate salt form 1 of the compound of formula (I).

[0210] Fig.62 The differential scanning calorimetry analysis curve of the mesylate salt form 1 of the compound of formula (I) is shown in FIG.

[0211] Fig.63 The isothermal adsorption curve of the mesylate salt form 1 of the compound of formula (I).

[0212] Fig.64 The X-ray powder diffraction pattern of the benzoate salt form 1 of the compound of formula (I).

[0213] Fig.65 This is the thermogravimetric analysis spectrum of the benzoate salt form 1 of the compound of formula (I).

[0214] Fig.66 The differential scanning calorimetry analysis curve of the benzoate salt form 1 of the compound of formula (I) is shown in FIG.

[0215] Fig.67It is the isothermal adsorption curve of the benzoate salt form 1 of the compound of formula (I). DETAILED DESCRIPTION

[0216] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were measured in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Ascend 500 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0217] HPLC determination was performed using a 126 Infinity II high pressure liquid chromatograph (Waters Symmetry C18 3.5 μm (250*4.6 mm).

[0218] XRD was analyzed using an X-ray powder diffractometer, Bruker D8Advance Diffractometer. The 2θ scanning angle was from 3-40°2θ / 3-30°, and the scanning step was 0.02°. When testing the sample, the tube voltage and current were 40 kV and 40 mA, respectively, and the sample pan was a zero background sample pan.

[0219] TGA test conditions: The model of the thermogravimetric analyzer is TA Instruments Q500TGA. 1-10 mg of sample is placed in a balanced sample pan and automatically weighed in the TGA heating furnace. The sample is heated to the final temperature at a rate of 10°C / min, and the nitrogen purge rate at the sample is 40 mL / min.

[0220] DSC test conditions: The model of differential scanning calorimeter is TA Instruments Q200DSC. 0.5mg-5mg sample is accurately weighed and placed in a standard pan or a perforated aluminum crucible sample pan, and heated to the final temperature at a rate of 10℃ / min, and the nitrogen purge rate in the furnace is 50mL / min.

[0221] The known starting materials of the present invention can be synthesized by using or according to methods known in the art.

[0222] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0223] Unless otherwise specified in the examples, the room temperature is 20°C to 30°C.

[0224] The implementation process of the present invention and the beneficial effects produced are described in detail below through specific embodiments, which is intended to help readers better understand the essence and characteristics of the present invention, and is not intended to limit the scope of implementation of the present invention.

[0225] Example 1: Preparation of Formula (I)

[0226] The compound of formula (I) was prepared according to the method described in WO2023284838A1.

[0227] Example 2: Preparation of Form 1 of the Compound of Formula (I)

[0228] Take about 200 μl of the sample, add 1.4 mL of DMSO to dissolve, and obtain solution 1; add water dropwise to solution 1, and precipitate immediately; continue stirring overnight until the sample solidifies to obtain a suspension; centrifuge the suspension, and place the solid at 40° C. and vacuum dry overnight to obtain a solid, i.e., crystal form 1 of the compound of formula (I).

[0229] 1 H NMR(400MHz,DMSO)δ8.81(s,1H),8.41(s,1H),8.35(s,1H),8.24(s,1H),7.82(s,1H),7.42(s,1H),7.29(s,1H),7.20(s,1H),7.15(s,1 H),7.06(s,1H),6.93(s,1H),4.87(s,1H),4.72(s,1H),3.90(s,2H),3.35(s,2H),2.23(s,1H),1.80(s,3H),1.71(s,1H),1.14(s,1H).

[0230] Example 3: Preparation of Form 2 of the Compound of Formula (I)

[0231] About 200 g of Form 1 was taken, 1.4 mL of trifluoroethanol was added to dissolve it, and it was evaporated at room temperature to obtain a solid, i.e. Form 2 of the compound of formula (I).

[0232] Example 4: Preparation of Form 3 of the Compound of Formula (I)

[0233] About 150 mg of Form 1 was taken and placed in an open container at 40°C / 75% RH for 4 days to obtain Form 3 of the compound of formula (I).

[0234] Example 5: Preparation of Citrate Form 1 of the Compound of Formula (I)

[0235] About 50 mg of free crystalline form 1 was added to 0.5 mL of isopropanol to obtain solution 1; about 28 mg of citric acid was dissolved in 0.1 mL of isopropanol to obtain solution 2; solution 2 was added dropwise to solution 1, and it precipitated immediately, and became oil after stirring, and the sample was solidified by stirring overnight to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain the citrate crystalline form 1 of the compound of formula (I).

[0236] Example 6: Preparation of Citrate Form 2 of the Compound of Formula (I)

[0237] About 200 mg of free crystalline form 1 was added to 1 mL of isopropanol to obtain solution 1; about 110 mg of citric acid was dissolved in 0.6 mL of isopropanol to obtain solution 2; solution 2 was added dropwise to solution 1, and it precipitated immediately, and became oil after stirring. The sample was solidified by stirring for 2 days to obtain a suspension; the suspension was centrifuged, and the solid was dried at 40° C. overnight to obtain a citrate crystalline form 2 of the compound of formula (I).

[0238] 1 H NMR (400MHz, DMSO) δ7.93 (t, J = 6.6 Hz, 1H), 2.58 (dd, J = 14.1, 5.0 Hz, 3H), 2.50 (s, 1H).

[0239] Example 7: Preparation of Phosphate Form 1 of the Compound of Formula (I)

[0240] About 50 mg of free crystalline form 1 was added with 0.5 mL of ethyl acetate to obtain solution 1; about 17 mg of phosphoric acid was dissolved in 0.1 mL of methanol to obtain solution 2; solution 2 was added dropwise to solution 1 to obtain solution 3; solution 3 was stirred overnight without precipitation, and 3 mL of n-heptane was added to precipitate to obtain a suspension; the suspension was stirred for 4 hours, centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain the phosphate crystalline form 1 of the compound of formula (I).

[0241] Example 8: Preparation of Phosphate Form 2 of the Compound of Formula (I)

[0242] About 50 mg of free crystalline form 1 was added to 0.5 mL of dichloromethane to obtain solution 1; about 17 mg of phosphoric acid was dissolved in 0.1 mL of dichloromethane to obtain solution 2; solution 2 was added dropwise to solution 1 to precipitate oil, and the mixture was stirred overnight to solidify to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40° C. and dried in vacuum overnight to obtain phosphate crystalline form 2 of the compound of formula (I).

[0243] Example 9: Preparation of Phosphate Form 3 of the Compound of Formula (I)

[0244] About 200 mg of free form 1 was added with 1 mL of dichloromethane to obtain solution 1; about 70 mg of phosphoric acid was dissolved in 0.1 mL of methanol to obtain solution 2; solution 2 was added dropwise to solution 1 to obtain solution 3; solution 3 was stirred overnight to precipitate a small amount, and 2 mL of isopropyl ether was added and stirred for 1 hour to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40° C. and dried in vacuum overnight to obtain the phosphate form 3 of the compound of formula (I).

[0245] Example 10: Preparation of Sulfate Crystalline Form 1 of the Compound of Formula (I)

[0246] About 200 mg of free form 1 was dissolved in 1 mL of acetonitrile to obtain solution 1; about 56 mg of sulfuric acid was dissolved in 0.1 mL of acetonitrile to obtain solution 2; solution 2 was added dropwise to solution 1 to obtain solution 3; solution 3 was stirred for 0.5 hour to precipitate to obtain a suspension; the suspension was stirred for 2 days, centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain sulfate form 1 of the compound of formula (I).

[0247] Example 11: Preparation of L-tartrate salt form 1 of the compound of formula (I)

[0248] About 50 mg of free crystalline form 1 was added to 0.5 mL of ethanol to obtain solution 1; about 22 mg of L-tartaric acid was dissolved in 0.1 mL of ethanol to obtain solution 2; solution 2 was added dropwise to solution 1, and precipitation occurred immediately to obtain a suspension; the suspension was stirred overnight, centrifuged, and the solid was dried under vacuum at 40° C. overnight to obtain L-tartrate crystalline form 1 of the compound of formula (I).

[0249] Example 12: Preparation of L-tartrate salt form 2 of the compound of formula (I)

[0250] About 50 mg of free form 1 was added to 0.5 mL of acetone to obtain solution 1; about 22 mg of L-tartaric acid was dissolved in 0.1 mL of acetone and 0.1 mL of ethanol to obtain solution 2; solution 2 was added dropwise to solution 1, and precipitation occurred immediately to obtain a suspension; the suspension was stirred overnight, centrifuged, and the solid was placed at 40° C. and dried overnight in vacuum to obtain L-tartrate salt form 2 of the compound of formula (I).

[0251] Example 13: Preparation of L-tartrate salt form 3 of the compound of formula (I)

[0252] About 200 mg of free form 1 was added to 1 mL of tetrahydrofuran to dissolve and obtain solution 1; about 86 mg of L-tartaric acid was dissolved in 0.1 mL of methanol and 0.2 mL of tetrahydrofuran to obtain solution 2; solution 2 was added dropwise to solution 1 to obtain solution 3; solution 3 was stirred for 0.5 hour to precipitate and obtain a suspension; the suspension was stirred for 2 days, centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain L-tartrate salt form 3 of the compound of formula (I).

[0253] 1 H NMR (400MHz, DMSO) δ7.90 (dd, J=8.9, 3.5Hz, 1H), 4.16 (s, 2H).

[0254] Example 14: Preparation of L-tartrate salt form 4 of the compound of formula (I)

[0255] About 50 mg of free crystalline form 1 was added to 0.5 mL of tetrahydrofuran to dissolve and obtain solution 1; about 22 mg of L-tartaric acid was dissolved in 0.1 mL of tetrahydrofuran and 0.1 mL of methanol to obtain solution 2; solution 2 was added dropwise to solution 1, and precipitation occurred immediately to obtain a suspension; the suspension was stirred overnight, centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain L-tartrate crystalline form 4 of the compound of formula (I).

[0256] Example 15: Preparation of L-tartrate salt form 5 of the compound of formula (I)

[0257] About 200 mg of free form 1 was added to 1 mL of ethanol to obtain solution 1; about 86 mg of L-tartaric acid was dissolved in 0.4 mL of ethanol to obtain solution 2; solution 2 was added dropwise to solution 1 to obtain solution 3; solution 3 was stirred for 2 days to precipitate, and stirred overnight to obtain a gel suspension; the gel suspension was centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain L-tartrate salt form 5 of the compound of formula (I).

[0258] 1 H NMR (400MHz, DMSO) δ7.90 (t, J = 6.5Hz, 1H), 4.27–4.09 (m, 2H).

[0259] Example 16: Preparation of Fumarate Form 1 of the Compound of Formula (I)

[0260] About 50 mg of free form 1 was added with 0.5 mL of ethanol to obtain solution 1; about 17 mg of fumaric acid was dissolved in 0.3 mL of ethanol to obtain solution 2; solution 2 was added dropwise to solution 1 to obtain solution 3; solution 3 was stirred overnight without precipitation, and 3 mL of n-heptane was added to precipitate to obtain a suspension; the suspension was stirred for 4 h, centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain the fumarate salt form 1 of the compound of formula (I).

[0261] Example 17: Preparation of Fumarate Form 2 of the Compound of Formula (I)

[0262] About 200 mg of free form 1 was added to 1 mL of ethanol to obtain solution 1; about 67 mg of fumaric acid was dissolved in 1.2 mL of ethanol to obtain solution 2; solution 2 was added dropwise to solution 1 to obtain solution 3; solution 3 was stirred for 2 days to precipitate to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain a fumarate salt form 2 of the compound of formula (I).

[0263] 1 H NMR (400MHz, DMSO) δ7.87 (t, J = 6.4 Hz, 1H), 6.51 (d, J = 2.6 Hz, 2H).

[0264] Example 18: Preparation of Hydrochloride Form 1a of the Compound of Formula (I)

[0265] About 50 mg of free form 1 was added to 0.5 mL of ethanol to obtain solution 1; about 12 μL of concentrated hydrochloric acid was dissolved in 0.1 mL of ethanol to obtain solution 2; solution 2 was added dropwise to solution 1, and precipitation occurred immediately to obtain a suspension; the suspension was stirred overnight, centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain hydrochloride form 1a of the compound of formula (I).

[0266] Example 19: Preparation of Hydrochloride Form 1b of the Compound of Formula (I)

[0267] About 200 mg of free crystalline form 1 was added to 1 mL of ethyl acetate to obtain solution 1; about 48 μL of concentrated hydrochloric acid was dissolved in 0.1 mL of methanol to obtain solution 2; solution 2 was added dropwise to solution 1, and precipitation occurred immediately to obtain a suspension; the suspension was stirred for 2 days, centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain hydrochloride crystalline form 1b of the compound of formula (I).

[0268] Example 20: Preparation of Hydrochloride Form 1c of the Compound of Formula (I)

[0269] About 200 mg of free form 1 was added to 1 mL of ethanol to obtain solution 1; about 48 μL of concentrated hydrochloric acid was dissolved in 0.1 mL of ethanol to obtain solution 2; solution 2 was added dropwise to solution 1, and precipitation occurred immediately to obtain a suspension; the suspension was stirred for 2 days and centrifuged, and the solid was placed at 40°C and vacuum dried overnight to obtain hydrochloride form 1c of the compound of formula (I).

[0270] Example 21: Preparation of maleate salt form 1 of the compound of formula (I)

[0271] About 200 mg of free form 1 was added to 1 mL of isopropanol to obtain solution 1; about 67 mg of maleic acid was dissolved in 0.2 mL of isopropanol to obtain solution 2; solution 2 was added dropwise to solution 1, precipitated for 10 minutes, and stirred overnight to obtain a suspension; the suspension was stirred for 2 days and centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain maleate form 1 of the compound of formula (I).

[0272] 1 H NMR (400MHz, DMSO) δ7.93 (dd, J=9.0, 3.7Hz, 1H), 6.05 (d, J=2.7Hz, 2H).

[0273] Example 22: Preparation of Hydrobromide Form 1 of the Compound of Formula (I)

[0274] About 50 mg of free form 1 was added to 0.5 mL of ethanol to obtain solution 1; about 29 mg of hydrobromic acid was dissolved in 0.1 mL of ethanol to obtain solution 2; solution 2 was added dropwise to solution 1, and precipitation occurred immediately to obtain a suspension; the suspension was stirred overnight, centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain hydrobromide salt form 1 of the compound of formula (I).

[0275] Example 23: Preparation of Hydrobromide Form 2 of the Compound of Formula (I)

[0276] About 200 mg of free form 1 was added to 1 mL of acetonitrile to obtain solution 1; about 116 mg of hydrobromic acid was dissolved in 0.1 mL of acetonitrile to obtain solution 2; solution 2 was added dropwise to solution 1, and precipitation occurred immediately to obtain a suspension; the suspension was stirred for 2 days, centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain hydrobromide salt form 2 of the compound of formula (I).

[0277] Example 24: Preparation of Methanesulfonate Form 1 of the Compound of Formula (I)

[0278] About 200 mg of free form 1 was added to 1 mL of ethanol to obtain solution 1; about 55 mg of methanesulfonic acid was dissolved in 0.1 mL of ethanol to obtain solution 2; solution 2 was added dropwise to solution 1 to obtain solution 3; solution 3 was stirred for 2 days to precipitate to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40° C. and vacuum dried overnight to obtain the mesylate form 1 of the compound of formula (I).

[0279] 1 H NMR (400MHz, DMSO) δ7.92 (d, J = 8.9Hz, 1H), 2.35 (s, 3H).

[0280] Example 25: Preparation of Benzoate Crystal Form 1 of the Compound of Formula (I)

[0281] About 200 mg of free form 1 was added to 1 mL of ethyl acetate to obtain solution 1; about 70 mg of benzoic acid was dissolved in 0.1 mL of methanol to obtain solution 2; solution 2 was added dropwise to solution 1 to obtain solution 3; solution 3 was stirred overnight to precipitate a suspension; the suspension was centrifuged, and the solid was placed at 40° C. and dried overnight in vacuum to obtain benzoate form 1 of the compound of formula (I).

[0282] 1 H NMR (400MHz, DMSO) δ8.24 (t, J=4.7Hz, 1H), 7.95 (dd, J=7.6, 3.4Hz, 2H), 7.58 (s, 1H), 7.50–

[0283] 7.42(m,2H).

[0284] Test Case

[0285] 1. Crystal form test example

[0286] Table 1. Instrument information and detection method parameters

[0287]

[0288]

[0289]

[0290]

[0291]

[0292] 2. Specific peak characterization results of XRD test of each crystal form obtained in the above examples

[0293] X-ray powder diffraction pattern (XRD) of Form 1 of Compound I Figure 1 The specific peak values ​​are shown in Table 2.

[0294] Table 2

[0295]

[0296]

[0297] X-ray powder diffraction pattern (XRD) of Form 2 of Compound I Figure 5 The specific peak values ​​are shown in Table 3.

[0298] Table 3

[0299]

[0300]

[0301] X-ray powder diffraction pattern (XRD) of Form 3 of Compound I Figure 8 The specific peak values ​​are shown in Table 4.

[0302] Table 4

[0303]

[0304] X-ray powder diffraction pattern (XRD) of citrate salt form 1 of compound I Fig.12 The specific peak values ​​are shown in Table 5.

[0305] Table 5

[0306]

[0307]

[0308] X-ray powder diffraction pattern (XRD) of citrate salt form 2 of compound I Fig.13 The specific peak values ​​are shown in Table 6.

[0309] Table 6

[0310]

[0311] X-ray powder diffraction pattern (XRD) of phosphate form 1 of compound I Fig.17 The specific peak values ​​are shown in Table 7.

[0312] Table 7

[0313]

[0314] X-ray powder diffraction pattern (XRD) of phosphate form 2 of compound I Fig.18 The specific peak values ​​are shown in Table 8.

[0315] Table 8

[0316]

[0317]

[0318] X-ray powder diffraction pattern (XRD) of phosphate form 3 of compound I Fig.19 The specific peak values ​​are shown in Table 9.

[0319] Table 9

[0320]

[0321]

[0322] X-ray powder diffraction pattern (XRD) of sulfate salt form 1 of compound I Fig. 22 The specific peak values ​​are shown in Table 10.

[0323] Table 10

[0324]

[0325] X-ray powder diffraction pattern (XRD) of L-tartrate salt form 1 of compound I Fig.26 The specific peak values ​​are shown in Table 11.

[0326] Table 11

[0327]

[0328] X-ray powder diffraction pattern (XRD) of L-tartrate salt form 2 of compound I Fig. 27 The specific peak values ​​are shown in Table 12.

[0329] Table 12

[0330]

[0331] X-ray powder diffraction pattern (XRD) of L-tartrate salt form 3 of compound I Fig.28 The specific peak values ​​are shown in Table 13.

[0332] Table 13

[0333]

[0334]

[0335] X-ray powder diffraction pattern (XRD) of L-tartrate salt form 4 of compound I Fig.32 The specific peak values ​​are shown in Table 14.

[0336] Table 14

[0337]

[0338] X-ray powder diffraction pattern (XRD) of L-tartrate salt form 5 of compound I Fig.33 The specific peak values ​​are shown in Table 15.

[0339] Table 15

[0340]

[0341] X-ray powder diffraction pattern (XRD) of fumarate salt form 1 of compound I Fig.37 The specific peak values ​​are shown in Table 16.

[0342] Table 16

[0343]

[0344]

[0345] X-ray powder diffraction pattern (XRD) of fumarate salt form 2 of compound I Fig.38 The specific peak values ​​are shown in Table 17.

[0346] Table 17

[0347]

[0348]

[0349] X-ray powder diffraction pattern (XRD) of the hydrochloride salt form 1a of compound I Fig.42 The specific peak values ​​are shown in Table 18.

[0350] Table 18

[0351]

[0352] X-ray powder diffraction pattern (XRD) of the hydrochloride salt form 1b of compound I Fig.43 The specific peak values ​​are shown in Table 19.

[0353] Table 19

[0354]

[0355] X-ray powder diffraction pattern (XRD) of the hydrochloride salt form 1c of compound I Fig.47 The specific peak values ​​are shown in Table 20.

[0356] Table 20

[0357]

[0358]

[0359] X-ray powder diffraction pattern (XRD) of maleate salt form 1 of compound I Fig.51 The specific peak values ​​are shown in Table 21.

[0360] Table 21

[0361]

[0362]

[0363] X-ray powder diffraction pattern (XRD) of the hydrobromide salt form 1 of compound I Fig.55 The specific peak values ​​are shown in Table 22.

[0364] Table 22

[0365]

[0366] X-ray powder diffraction pattern (XRD) of the hydrobromide salt form 2 of compound I Fig.56 The specific peak values ​​are shown in Table 23.

[0367] Table 23

[0368]

[0369] X-ray powder diffraction pattern (XRD) of mesylate salt form 1 of compound I Fig.60 The specific peak values ​​are shown in Table 24.

[0370] Table 24

[0371]

[0372]

[0373] X-ray powder diffraction pattern (XRD) of benzoate salt form 1 of compound I Fig.64 The specific peak values ​​are shown in Table 25.

[0374] Table 25

[0375]

[0376]

[0377] 3. DSC (Differential Scanning Calorimetry) Test Results of Each Crystalline Form Prepared in the Above Examples

[0378] Figure 3 The differential scanning calorimetry analysis curve of the crystalline form 1 of the compound of formula (I) is shown in FIG. 1 , wherein the differential scanning calorimetry analysis curve (DSC) shows an endothermic peak, which are T 开始 =75.11℃、T 峰 =76.44℃, △H=60.67J / g.

[0379] Figure 7 The differential scanning calorimetry analysis curve of the crystalline form 2 of the compound of formula (I) is shown in FIG. 1 , wherein the differential scanning calorimetry analysis curve (DSC) shows an endothermic peak, which are T 开始 =49.48℃、T 峰 =51.68℃, △H=55.29J / g.

[0380] Fig.10 The differential scanning calorimetry analysis curve of the crystalline form 3 of the compound of formula (I) is shown in FIG. 1 , wherein the differential scanning calorimetry analysis curve (DSC) shows an endothermic peak, which are T 开始 =58.42℃、T 峰 =60.43℃, △H=191.0J / g.

[0381] Fig.15 The differential scanning calorimetry analysis curve of the citrate salt form 2 of the compound of formula (I) is shown in FIG. The differential scanning calorimetry analysis curve (DSC) shows two endothermic peaks, namely, T 开始 =79.82℃、T 峰=98.10℃, △H=20.67J / g, T 开始 =130.80℃、T 峰 =138.03℃, △H=55.67J / g.

[0382] Fig.21 The differential scanning calorimetry analysis curve of the phosphate crystal form 3 of the compound of formula (I) is shown in FIG. The differential scanning calorimetry analysis curve (DSC) shows three endothermic peaks, namely, T 开始 =75.89℃、T 峰 =87.75℃, △H=69.06J / g, T 开始 =121.55℃、T 峰 =129.15℃、△H=6.872J / g,T 开始 =139.57℃、T 峰 =143.23℃, △H=10.70J / g.

[0383] Fig.24 The differential scanning calorimetry analysis curve of the sulfate salt form 1 of the compound of formula (I) is shown in FIG. The differential scanning calorimetry analysis curve (DSC) shows two endothermic peaks, namely, T 开始 =31.74℃、T 峰 =53.19℃、△H=18.88J / g,T 开始 =109.49℃、T 峰 =123.69℃, △H=79.55J / g.

[0384] Fig.30 The differential scanning calorimetry analysis curve of the tartaric acid crystal form 3 of the compound of formula (I) is shown in FIG. The differential scanning calorimetry analysis curve (DSC) shows four endothermic peaks, namely, T 开始 =52.77℃、T 峰 =84.43℃, △H=17.24J / g, T 开始 =122.82℃、T 峰 =130.77℃, △H=10.52J / g, T 开始 =150.20℃、T 峰 =160.12℃, △H=3.087J / g, T 开始 =179.24℃、T 峰 =183.19℃, △H=60.54J / g.

[0385] Fig.35 The differential scanning calorimetry analysis curve of the tartaric acid crystal form 5 of the compound of formula (I) is shown in FIG. The differential scanning calorimetry analysis curve (DSC) shows four endothermic peaks, namely, T 开始 =33.83℃、T峰 =56.05℃, △H=15.35J / g, T 开始 =107.21℃、T 峰 =131.64℃, △H=7.879J / g, T 开始 =148.76℃、T 峰 =158.58℃, △H=40.21J / g, T 开始 =176.28℃、T 峰 =178.75℃, △H=26.74J / g.

[0386] Fig.40 The differential scanning calorimetry analysis curve of the fumaric acid crystal form 2 of the compound of formula (I) is shown in FIG. 1 , wherein the differential scanning calorimetry analysis curve (DSC) shows an endothermic peak, which are T 开始 =172.96℃、T 峰 =174.83℃, △H=108.8J / g.

[0387] Fig.45 The differential scanning calorimetry analysis curve of the hydrochloride crystal form 1b of the compound of formula (I) is shown in FIG. The differential scanning calorimetry analysis curve (DSC) shows two endothermic peaks, namely, T 开始 =207.21℃、T 峰 =207.57℃, △H=60.27J / g, T 开始 =228.22℃、T 峰 =231.63℃, △H=52.88J / g.

[0388] Fig.49 The differential scanning calorimetry analysis curve of the hydrochloride crystal form 1c of the compound of formula (I) is shown in FIG. The differential scanning calorimetry analysis curve (DSC) shows two endothermic peaks, namely, T 开始 =92.50℃、T 峰 =140.67℃, △H=23.68J / g, T 开始 =223.34℃、T 峰 =229.44℃, △H=142.0J / g.

[0389] Fig.53 The differential scanning calorimetry analysis curve of the maleic acid crystal form 1 of the compound of formula (I) is shown in FIG. 1 , wherein the differential scanning calorimetry analysis curve (DSC) shows an endothermic peak, which are T 开始 =164.26℃、T 峰 =169.49℃, △H=79.02J / g.

[0390] Fig.58The differential scanning calorimetry analysis curve of the hydrobromide salt form 2 of the compound of formula (I) is shown in FIG. The differential scanning calorimetry analysis curve (DSC) shows four endothermic peaks, namely, T 开始 =33.63℃、T 峰 =47.20℃, △H=1.890J / g, T 开始 =115.99℃、T 峰 =133.53℃, △H=1.949J / g, T 开始 =141.10℃、T 峰 =161.72℃, △H=25.18J / g, T 开始 =141.84℃、T 峰 =183.78℃, △H=21.96J / g.

[0391] Fig.62 The differential scanning calorimetry analysis curve of the mesylate salt form 1 of the compound of formula (I) is shown in FIG. 1 , wherein the differential scanning calorimetry analysis curve (DSC) shows an endothermic peak, which are T 开始 =164.87℃、T 峰 =168.30℃, △H=84.51J / g.

[0392] Fig.66 The differential scanning calorimetry analysis curve of the benzoate salt form 1 of the compound of formula (I) is shown in FIG. 1 , wherein the differential scanning calorimetry analysis curve (DSC) shows an endothermic peak, which are T 开始 =137.72℃、T 峰 =139.08℃, △H=122.0J / g.

[0393] 4. TGA (thermogravimetric analysis) test results of each crystal form obtained in the above examples

[0394] Figure 2 The thermogravimetric analysis spectrum of the crystalline form 1 of the compound of formula (I) is shown in FIG. 1 , wherein the thermogravimetric analysis curve (TGA) thereof shows a weight loss of 0.8304% before 150° C.

[0395] Figure 6 The thermogravimetric analysis spectrum of the crystalline form 2 of the compound of formula (I) is shown in FIG. 1 , wherein the thermogravimetric analysis curve (TGA) thereof shows a 10.11% weight loss before 100° C.

[0396] Fig. 9 The thermogravimetric analysis spectrum of Form 3 of the compound of formula (I) is shown in FIG. 1 , wherein the thermogravimetric analysis curve (TGA) shows a 2.127% weight loss before 150° C. Fig.14 The thermogravimetric analysis spectrum of the citrate crystal form 2 of the compound of formula (I) is shown in the thermogravimetric analysis curve (TGA) thereof, which shows a 2.089% weight loss before 140°C.

[0397] Fig. 20 The thermogravimetric analysis spectrum of the phosphate crystal form 3 of the compound of formula (I) is shown in the thermogravimetric analysis curve (TGA) thereof, which shows a weight loss of 8.906% before 110°C.

[0398] Fig.23 The thermogravimetric analysis spectrum of the sulfate crystal form 1 of the compound of formula (I) is shown in the thermogravimetric analysis curve (TGA) thereof, which shows a weight loss of 1.326% before 50°C and a weight loss of 1.740% at 50-120°C.

[0399] Fig.29 The thermogravimetric analysis spectrum of the tartaric acid crystal form 3 of the compound of formula (I) is shown in the thermogravimetric analysis curve (TGA) thereof, which shows a 2.429% weight loss before 140°C.

[0400] Fig.34 The thermogravimetric analysis spectrum of the tartaric acid crystal form 5 of the compound of formula (I) is shown in FIG. 1 , wherein the thermogravimetric analysis curve (TGA) shows a 4.948% weight loss before 150° C.

[0401] Fig.39 The thermogravimetric analysis spectrum of the fumaric acid crystal form 2 of the compound of formula (I) is shown in the thermogravimetric analysis curve (TGA) thereof, which shows a weight loss of 0.2694% before 140°C.

[0402] Fig.40 The thermogravimetric analysis spectrum of the hydrochloride crystal form 1b of the compound of formula (I) is shown in the thermogravimetric analysis curve (TGA) thereof, which shows a 6.522% weight loss before 170°C.

[0403] Fig.48 The thermogravimetric analysis spectrum of the hydrochloride crystal form 1c of the compound of formula (I) is shown in the thermogravimetric analysis curve (TGA) thereof, which shows a 3.990% weight loss before 120°C.

[0404] Fig.52 The thermogravimetric analysis spectrum of maleic acid crystal form 1 of the compound of formula (I) is shown in the thermogravimetric analysis curve (TGA) thereof, which shows a weight loss of 0.9616% before 140°C.

[0405] Fig.57 The thermogravimetric analysis spectrum of the hydrobromide salt form 2 of the compound of formula (I) is shown in the thermogravimetric analysis curve (TGA) thereof, which shows a weight loss of 3.803% before 150°C.

[0406] Fig.61 The thermogravimetric analysis spectrum of the mesylate salt form 1 of the compound of formula (I) is shown in the thermogravimetric analysis curve (TGA) thereof, which shows a weight loss of 0.1946% before 150°C.

[0407] Fig.65The thermogravimetric analysis spectrum of the benzoate salt form 1 of the compound of formula (I) is shown in the thermogravimetric analysis curve (TGA) thereof, which shows a weight loss of 0.2706% before 100°C.

[0408] 5. Test results of isothermal adsorption curves of each crystal form obtained in the above examples

[0409] Figure 4 The isothermal adsorption curve of the crystalline form 1 of the compound of formula (I) shows that there is 0.1540% hygroscopicity in the range of 0-80% RH.

[0410] Fig.11 The isotherm adsorption curve of the crystalline form 3 of the compound of formula (I) shows that the isotherm adsorption curve (DVS) shows that there is 1.640% moisture absorption in the 0-60% RH range and 1.342% moisture absorption in the 60-80% RH range.

[0411] Fig.16 The isothermal adsorption curve of the citrate crystal form 2 of the compound of formula (I) shows that the isothermal adsorption curve (DVS) shows that there is 0.3756% moisture absorption in the 0-50% RH range and 0.5948% moisture absorption in the 50-80% RH range.

[0412] Fig.25 The isotherm adsorption curve of the sulfate crystal form 1 of the compound of formula (I) shows that the isotherm adsorption curve (DVS) shows that there is 5.603% moisture absorption in the 0-80% RH range.

[0413] Fig.31 The isotherm adsorption curve of the tartaric acid crystal form 3 of the compound of formula (I) is shown in FIG. 1 . The isotherm adsorption curve (DVS) shows that there is 1.518% moisture absorption in the 0-80% RH range.

[0414] Fig.36 The isotherm adsorption curve of the tartaric acid crystal form 5 of the compound of formula (I) is shown in FIG. 1 . The isotherm adsorption curve (DVS) shows that there is 2.843% moisture absorption in the 0-80% RH range.

[0415] Fig.41 The isotherm adsorption curve of the fumaric acid crystal form 2 of the compound of formula (I) is shown in FIG. 1 . The isotherm adsorption curve (DVS) shows that there is 0.075% moisture absorption in the RH range of 0-80%.

[0416] Fig.46 The isothermal adsorption curve of the hydrochloride crystal form 1b of the compound of formula (I) shows that there is 0.1707% moisture absorption in the 0-80% RH range.

[0417] Fig.50The isotherm adsorption curve of the hydrochloride crystal form 1c of the compound of formula (I) shows that there is 0.9832% moisture absorption in the 0-80% RH range.

[0418] Fig.54 The isothermal adsorption curve of maleic acid form 1 of the compound of formula (I) shows that the isothermal adsorption curve (DVS) shows that there is 0.7699% moisture absorption in the 0-80% RH range.

[0419] Fig.59 The isotherm adsorption curve of the hydrobromide salt form 2 of the compound of formula (I) is shown in FIG. 1 . The isotherm adsorption curve (DVS) shows that there is 1.334% moisture absorption in the 0-80% RH range.

[0420] Fig.63 : isothermal adsorption curve of mesylate crystal form 1 of the compound of formula (I). Its isothermal adsorption curve (DVS) shows that there is 7.440% moisture absorption in the range of 0-80% RH.

[0421] Fig.67 The isotherm adsorption curve of the benzoate salt form 1 of the compound of formula (I) is shown in FIG. 1 . The isotherm adsorption curve (DVS) shows that there is 0.05975% moisture absorption in the 0-80% RH range.

[0422] 6. Stability study

[0423] Solution stability

[0424] Table 26. Salt solution stability test

[0425]

[0426] Solid stability

[0427] Table 27. Salt type solid state stability test table

[0428]

[0429] Table 28. Fumarate Form 2 Solid State Stability Study Experimental Results

[0430]

[0431] Table 29. Solid-state stability study results of maleate crystal form 1

[0432]

[0433] Conclusion: Fumarate Form 2 and maleate Form 1 have good solid-state stability under the above conditions.

Claims

1. A crystalline form of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, 2. The crystal form according to claim 1, which is the crystal form 1 of the compound represented by formula (I), using Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.96°±0.2°, 11.54°±0.2°, 17.41°±0.2°, 19.81°±0.2°, and 26.27°±0.2°.

3. The crystal form according to claim 2, wherein the X-ray powder diffraction pattern of the crystal form 1 has characteristic diffraction peaks at the following 2θ positions: 4.64°±0.2°, 4.96°±0.2°, 11.54°±0.2°, 17.23°±0.2°, 17.41°±0.2°, 19.81°±0.2°, 21.74°±0.2°, and 26.27°±0.2°.

4. The crystal form according to claim 3, wherein the X-ray powder diffraction pattern of the crystal form 1 is substantially as shown in FIG1 .

5. The crystalline form according to claim 1, which is crystalline form 2 of the compound represented by formula (I), using Cu-Kα radiation, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.62°±0.2°, 12.12°±0.2°, 17.25°±0.2°, 21.06°±0.2°, 25.33°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 4.62°±0.2°, 4.94°±0.2°, 12.12°±0.2°, 17.25°±0.2°, 20.28°±0.2°, 21.06°±0.2°, 21.25°±0.2°, 25.33°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in FIG5; Or it is form 3 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.65°±0.2°, 4.98°±0.2°, 11.69°±0.2°, 17.18°±0.2°, 20.80°±0.2°; or it has characteristic diffraction peaks at the following 2θ positions: 4.65°±0.2°, 4.98°±0.2°, 11.69°±0.2°, 17.18°±0.2°, 18.93°±0.2°, 20.80°±0.2°, 26.55°±0.2°, 27.87°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 8.

6. The crystalline form according to claim 1, which is a crystalline form of a pharmaceutically acceptable salt of the compound represented by formula (I), wherein the pharmaceutically acceptable salt is selected from citrate, L-tartrate, methanesulfonate, benzoate, succinate, maleate, fumarate, naphthalene disulfonate, p-toluenesulfonate, benzenesulfonate, oxalate, gentisate, hydrochloride, sulfate, hydrobromide, and phosphate.

7. The crystal form according to claim 6, which is a citrate crystal form 1 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.78°±0.2°, 8.94°±0.2°, 9.80°±0.2°, 17.96°±0.2°, 21.84°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 5.94°±0.2°, 7.78°±0.2°, 8.94°±0.2°, 9.80°±0.2°, 16.07°±0.2°, 17.96°±0.2°, 19.60°±0.2°, 21.84°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 12; Or it is the citrate salt form 2 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.66°±0.2°, 10.76°±0.2°, 15.56°±0.2°, 16.84°±0.2°, 24.37°±0.2°; or it has characteristic diffraction peaks at the following 2θ positions: 8.66°±0.2°, 10.76°±0.2°, 15.14°±0.2°, 15.56°±0.2°, 16.84°±0.2°, 21.59°±0.2°, 22.29°±0.2°, 24.37°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 13.

8. The crystal form according to claim 6, which is a phosphate crystal form 1 of the compound represented by formula (I), using Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions (2θ±0.2°): 6.13°±0.2°, 7.52°±0.2°, 18.64°±0.2°, 24.59°±0.2°, 25.45°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 6.13°±0.2°, 7.52°±0.2°, 16.62°±0.2°, 18.64°±0.2°, 19.56°±0.2°, 24.59°±0.2°, 24.97°±0.2°, 25.45°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 17; Or it is the phosphate crystal form 2 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions (2θ±0.2°): 3.90°±0.2°, 5.49°±0.2°, 12.60°±0.2°, 12.93°±0.2°, 22.23°±0.2°; or it has characteristic diffraction peaks at the following 2θ positions: 3.90°±0.2°, 5.49°±0.2°, 6.01°±0.2°, 12.60°±0.2°, 12.93°±0.2°, 16.05°±0.2°, 17.38°±0.2°, 22.23°±0.2°; or its X-ray powder diffraction spectrum is substantially as shown in Figure 18; Or it is the phosphate crystal form 3 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.52°±0.2°, 6.02°±0.2°, 16.25°±0.2°, 17.12°±0.2°, 17.45°±0.2°; or it has characteristic diffraction peaks at the following 2θ positions: 5.52°±0.2°, 6.02°±0.2°, 10.58°±0.2°, 14.26°±0.2°, 16.25°±0.2°, 17.12°±0.2°, 17.45°±0.2°, 19.63°±0.2°; or the X-ray powder diffraction pattern is substantially as shown in Figure 19.

9. The crystal form according to claim 6, which is the sulfate crystal form 1 of the compound represented by formula (I), using Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions (2θ±0.2°): 4.56°±0.2°, 6.37°±0.2°, 6.77°±0.2°, 25.60°±0.2°, 26.00°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 4.56°±0.2°, 6.37°±0.2°, 6.77°±0.2°, 9.04°±0.2°, 11.18°±0.2°, 17.04°±0.2°, 25.60°±0.2°, 26.00°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 22.

10. The crystalline form according to claim 6, which is L-tartrate crystalline form 1 of the compound represented by formula (I), using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.81°±0.2°, 6.33°±0.2°, 7.17°±0.2°, 20.47°±0.2°, 25.50°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 3.81°±0.2°, 6.33°±0.2°, 7.17°±0.2°, 13.43°±0.2°, 19.09°±0.2°, 19.25°±0.2°, 20.47°±0.2°, 25.50°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 26; Or it is L-tartrate salt form 2 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 4.26°±0.2°, 6.39°±0.2°, 20.45°±0.2°, 21.14°±0.2°, 25.56°±0.2°; or it has characteristic diffraction peaks at the following 2θ positions: 4.26°±0.2°, 6.39°±0.2°, 16.92°±0.2°, 19.42°±0.2°, 20.05°±0.2°, 20.45°±0.2°, 21.14°±0.2°, 25.56°±0.2°; or its X-ray powder diffraction spectrum is substantially as shown in Figure 27; Or it is L-tartrate salt form 3 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions (2θ±0.2°): 4.51°±0.2°, 10.35°±0.2°, 15.92°±0.2°, 18.15°±0.2°, 19.52°±0.2°; or it has characteristic diffraction peaks at the following 2θ positions: 4.51°±0.2°, 10.35°±0.2°, 15.92°±0.2°, 18.15°±0.2°, 19.52°±0.2°, 20.42°±0.2°, 23.86°±0.2°, 25.01°±0.2°; or its X-ray powder diffraction spectrum is substantially as shown in Figure 28; Or it is L-tartrate salt form 4 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.47°±0.2°, 10.05°±0.2°, 18.04°±0.2°, 18.97°±0.2°, 19.35°±0.2°; or it has characteristic diffraction peaks at the following 2θ positions: 4.47°±0.2°, 10.05°±0.2°, 15.63°±0.2°, 18.04°±0.2°, 18.97°±0.2°, 19.35°±0.2°, 20.04°±0.2°, 20.47°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 32; Or it is L-tartrate salt form 5 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.14°±0.2°, 5.80°±0.2°, 11.67°±0.2°, 16.79°±0.2°, 20.26°±0.2°, 23.64°±0.2°, 24.76°±0.2°; or its X-ray powder diffraction pattern is basically as shown in Figure 33.

11. The crystalline form according to claim 6, which is a fumarate crystalline form 1 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.98°±0.2°, 9.80°±0.2°, 14.85°±0.2°, 19.45°±0.2°, 21.54°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 8.98°±0.2°, 9.80°±0.2°, 14.85°±0.2°, 19.45°±0.2°, 21.54°±0.2°, 24.46°±0.2°, 25.46°±0.2°, 27.14°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 37.

12. The crystal form according to claim 6, which is a fumarate crystal form 2 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 11.08°±0.2°, 11.27°±0.2°, 20.91°±0.2°, 22.95°±0.2°, and 26.97°±0.2°.

13. The crystal form according to claim 12, wherein the X-ray powder diffraction pattern of the fumarate salt crystal form 2 has characteristic diffraction peaks at the following 2θ positions (2θ±0.2°): 9.44°±0.2°, 11.08°±0.2°, 11.27°±0.2°, 15.62°±0.2°, 20.91°±0.2°, 22.95°±0.2°, 25.10°±0.2°, and 26.97°±0.2°.

14. The crystal form according to claim 13, wherein the X-ray powder diffraction pattern of the fumarate crystal form 2 is substantially as shown in Figure 38.

15. The crystal form according to claim 6, which is the hydrochloride crystal form 1a of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.00°±0.2°, 11.46°±0.2°, 13.63°±0.2°, 24.00°±0.2°, and 26.09°±0.2°.

16. The crystal form according to claim 15, wherein the X-ray powder diffraction pattern of the hydrochloride crystal form 1a has characteristic diffraction peaks at the following 2θ positions: 8.00°±0.2°, 11.46°±0.2°, 13.63°±0.2°, 14.28°±0.2°, 15.96°±0.2°, 22.97°±0.2°, 24.00°±0.2°, and 26.09°±0.2°.

17. The crystal form according to claim 16, wherein the X-ray powder diffraction pattern of the hydrochloride crystal form 1a is substantially as shown in Figure 42.

18. The crystal form according to claim 6, which is the hydrochloride crystal form 1b of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.06°±0.2°, 13.55°±0.2°, 16.13°±0.2°, 24.26°±0.2°, 26.25°±0.2°.

19. The crystal form according to claim 18, wherein the X-ray powder diffraction pattern of the hydrochloride crystal form 1b has characteristic diffraction peaks at the following 2θ positions (2θ±0.2°): 8.06°±0.2°, 11.38°±0.2°, 13.55°±0.2°, 16.13°±0.2°, 20.03°±0.2°, 22.85°±0.2°, 24.26°±0.2°, and 26.25°±0.2°.

20. The crystal form according to claim 19, wherein the X-ray powder diffraction pattern of the hydrochloride crystal form 1b is substantially as shown in FIG.

43.

21. The crystal form according to claim 6, which is a hydrochloride crystal form 1c of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.01°±0.2°, 13.55°±0.2°, 20.39°±0.2°, 24.07°±0.2°, and 25.96°±0.2°.

22. The crystal form according to claim 21, wherein the X-ray powder diffraction pattern of the hydrochloride crystal form 1c has characteristic diffraction peaks at the following 2θ positions: 8.01°±0.2°, 11.72°±0.2°, 13.55°±0.2°, 16.01°±0.2°, 20.39°±0.2°, 24.07°±0.2°, 25.96°±0.2°, and 26.51°±0.2°.

23. The crystal form according to claim 22, wherein the X-ray powder diffraction pattern of the hydrochloride crystal form 1c is substantially as shown in Figure 47.

24. The crystalline form according to claim 6, which is a maleate crystalline form 1 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 13.10°±0.2°, 18.38°±0.2°, 19.65°±0.2°, 23.63°±0.2°, and 25.12°±0.2°.

25. The crystalline form according to claim 24, wherein the X-ray powder diffraction pattern of the maleate salt crystalline form 1 has characteristic diffraction peaks at the following 2θ positions: 11.33°±0.2°, 13.10°±0.2°, 18.38°±0.2°, 19.65°±0.2°, 21.60°±0.2°, 22.38°±0.2°, 23.63°±0.2°, and 25.12°±0.2°.

26. The crystalline form according to claim 25, wherein the X-ray powder diffraction pattern of the maleate salt crystalline form 1 is substantially as shown in Figure 51.

27. The crystalline form according to claim 6, which is a hydrobromide crystalline form 1 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.86°±0.2°, 18.78°±0.2°, 20.32°±0.2°, 23.64°±0.2°, 25.56°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 6.85°±0.2°, 7.86°±0.2°, 18.78°±0.2°, 19.87°±0.2°, 20.32°±0.2°, 22.97°±0.2°, 23.64°±0.2°, 25.56°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 55; Or it is the hydrobromide salt form 2 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.91°±0.2°, 20.01°±0.2°, 22.56°±0.2°, 23.88°±0.2°, 25.75°±0.2°; or it has characteristic diffraction peaks at the following 2θ positions: 6.73°±0.2°, 7.91°±0.2°, 18.83°±0.2°, 20.01°±0.2°, 22.56°±0.2°, 23.88°±0.2°, 25.75°±0.2°, 26.09°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 56.

28. The crystalline form according to claim 6, which is a mesylate crystalline form 1 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 10.28°±0.2°, 16.63°±0.2°, 19.29°±0.2°, 22.51°±0.2°, 24.49°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 10.28°±0.2°, 16.63°±0.2°, 17.77°±0.2°, 19.29°±0.2°, 19.46°±0.2°, 22.51°±0.2°, 24.49°±0.2°, 28.23°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 60.

29. The crystal form according to claim 6, which is a benzoate crystal form 1 of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.34°±0.2°, 9.76°±0.2°, 18.54°±0.2°, 23.35°±0.2°, 24.85°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 9.34°±0.2°, 9.76°±0.2°, 11.70°±0.2°, 18.54°±0.2°, 22.48°±0.2°, 23.35°±0.2°, 24.85°±0.2°, 27.17°±0.2°; or its X-ray powder diffraction pattern is substantially as shown in Figure 64.

30. A method for preparing a crystalline form of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising: The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is subjected to slurry crystallization, volatile crystallization, antisolvent crystallization, cooling crystallization, water vapor stress crystallization or diffusion crystallization, 31. The preparation method according to claim 30, wherein: The solvent used for the crystallization is selected from one or more of C1-6 halogenated alkane solvents, C2-6 ester solvents, C2-6 ether solvents, C1-6 alcohol solvents or water.

32. The preparation method according to claim 31, wherein The solvent used for the crystallization is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, propanol, ether, tetrahydrofuran or water.

33. A method for preparing a pharmaceutically acceptable salt of a compound represented by formula (I), comprising the steps of forming a salt with the compound represented by formula (I) and an acid, 34. A pharmaceutical composition comprising the crystal form according to any one of claims 1 to 29, and a medically acceptable carrier.

35. A unit dose pharmaceutical composition or pharmaceutical preparation comprising 1-1500 mg of the crystalline form according to any one of claims 1-29 and a pharmaceutically acceptable excipient.

36. Use of the crystalline form according to any one of claims 1 to 29 or the pharmaceutical composition or pharmaceutical preparation according to claim 34 or 35 in AAK1-mediated diseases, wherein the disease is preferably neuropathic pain.

37. The use according to claim 36, wherein the neuropathic pain is diabetic neuropathy or postherpetic pain.

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