Salt form and crystal form of PARG inhibitor and composition thereof, preparation method therefor and use thereof

Abstract

The present invention relates to a salt form and crystal form of a compound as represented by formula (I) and a composition thereof, a preparation method therefor and the use thereof. The salt form and crystal form of the compound as represented by formula (I) of the present invention can effectively inhibit PARG-mediated diseases, such as cancers.

Description

Salt forms, crystal forms and compositions of PARG inhibitors, preparation methods and applications Technical Field

[0001] This invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to the salt forms, crystal forms, and compositions thereof of PARG inhibitors, their preparation methods, and their applications. Background Technology

[0002] DNA damage repair (DDR) is a series of processes by which cells recognize and correct damage to DNA molecules that encode their genome. However, once cancer develops, DNA repair pathways become a double-edged sword, as they can promote the repair of DNA damage caused by chemotherapy and radiation therapy and cell survival in cancer cells. On the other hand, cancers with impaired DNA repair are highly susceptible to DNA damage and rely on other complementary repair pathways, which can serve as strategies for treating cancer.

[0003] Abnormal DNA repair defects (DDRs) often suscept cancer cells to specific types of DNA damage, thus defective DDRs can be developed into targeted cancer therapies. Targeting DNA repair defects has become a proven and effective strategy in cancer treatment. For example, poly(ADP-ribose) polymerase (PARP) has been successful in treating BRCA-deficient breast, ovarian, prostate, and pancreatic cancers (Audeh MW et al., 2010).

[0004] PARP (ADP-ribosylation) is a unique post-translational modification that maintains genome stability through various molecular pathways, particularly DNA repair (Kraus WL et al., 2015). The binding of PARP to broken DNA and the rapid synthesis of PARP's own poly-ADP-ribose (PAR) are among the earliest events in single-strand and DNA repair processes. Currently, PARP inhibitors primarily inhibit PARP1 and PARP2 enzyme activity, thereby suppressing PARP1 / 2-dependent DNA repair. Recently, clinical resistance to PARP inhibitors has been reported (Drost and Jonkers, 2014) (Barber LJ et al., 2013) (Tobalina L et al., 2021), thus necessitating alternative inhibitors for DNA damage repair mechanisms.

[0005] ADP-ribosylation is a transient post-translational modification that can be rapidly degraded by PAR glycohydrolase (PARG) (Barkauskaite E et al., 2015). When PARP binds to PAR, its catalytic activity decreases; therefore, PARG activity helps restore PARP to its catalytically active form (Curtin and Szabo, 2013). Similar to PARP, PARG also promotes the repair of DNA double-strand breaks (DSBs) and single-strand breaks (SSBs) (Mortusewicz O et al., 2011). In addition to its major role in DNA repair, PARG also influences PAR signaling in RNA splicing, transcription, and epigenetic regulation (Ji and Tulin 2009) (Le May N et al., 2012) (Dahl M et al., 2014) (Guastafierro T et al., 2013) (Caiafa P et al., 2009). Some evidence suggests that PARG deficiency inhibits SSB repair and reduces the survival rate of BRCA2-deficient cells (Fathers C et al., 2012). However, other tumor mutations may lead to defects in DSB repair mechanisms (so-called "BRCA ness"), or may make tumor cells sensitive to PARG inhibition.

[0006] However, not all drugs (e.g., gemcitabine, camptothecin) are sensitive to PARG deletion, suggesting that PARG function is specific to certain pathways of DDR, chemotherapy, and radiotherapy (Fujihara H et al., 2009) (Shirai H et al., 2013) (Zhou Y et al., 2011). In humans, PARG knockout or deletion can sensitize lung cancer, cervical cancer, and pancreatic cancer cells to radiation or experimental DNA-damaging agents (e.g., hydrogen peroxide, methyl methanesulfonate) (Ame JC et al., 2009) (Nakadate Y et al., 2013) (Shirai H et al., 2013).

[0007] Some studies have shown that PARG inhibition may provide a therapeutic advantage for PARP-resistant cells (Fisher AE et al., 2007). Furthermore, it has been reported that the gene expression patterns induced by PARG deficiency in breast cancer cells are significantly different from those induced by PARP deficiency (Frizzell KM et al., 2009). Ovarian cancer cells respond differently to PARP inhibitors and PARG inhibitors, with a greater sensitivity to the latter, due to persistent replication fork arrest and replication catastrophe (Pillay N et al., 2019) (Coulson-Gilmer C et al., 2021).

[0008] Recent studies have also shown that there are mechanistic differences between inhibiting PARG and inhibiting PARP. Compared with PARP deficiency, PARG gene deletion toxicity leads to decreased NAD levels and causes lung cancer cell death, possibly due to energy depletion (Erdelyi K et al., 2009). Inhibition of PARG can also deplete NAD+, thereby enhancing the metabolic lethality of alkylation chemotherapy in IDH-mutant tumor cells (Nagashima H et al., 2020).

[0009] Currently known PARG inhibitors with cell permeability are very limited, such as tannic acid, gallotannin, or PDD00017273, which have low specificity for PARG and limited bioavailability (Sun Y et al., 2012) (Fathers C et al., 2012) (Blenn C et al., 2011) (James DI et al., 2016).

[0010] International publication number WO2023208092 and PCT international application number PCT / CN2024 / 089971 describe a novel PARG inhibitor that can effectively inhibit PARG. Therefore, this invention provides a salt form and a crystal form of a PARG inhibitor to improve its drug-likeness, aiming to meet unmet clinical needs. Summary of the Invention

[0011] This invention provides a crystal form of the compound shown in formula (I):

[0012] In some embodiments, the crystal form of the compound represented by formula (I) is selected from one or more of crystal form A and crystal form B.

[0013] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form A shown in formula (I) has characteristic peaks containing at least three or more (e.g., three, four, five, or six) diffraction angles 2θ as follows: 5.8±0.2°, 6.9±0.2°, 9.6±0.2°, 12.5±0.2°, 15.6±0.2°, and 19.5±0.2°; furthermore, the compound crystal form A shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG1.

[0014] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (I) has characteristic peaks containing at least three or more (e.g., three, four, five, or six) diffraction angles 2θ as follows: 5.8±0.2°, 7.5±0.2°, 9.7±0.2°, 12.1±0.2°, 13.1±0.2°, and 15.0±0.2°; furthermore, the compound crystal form A shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG2.

[0015] On the other hand, the present invention also provides pharmaceutically acceptable salts of the compounds represented by formula (I) or their hydrates or solvates.

[0016] In some embodiments, the compound represented by formula (I) forms a corresponding salt or a hydrate or solvate thereof with an acid. The salt can exist in various physical forms, for example, as a solution, suspension, or solid. In some embodiments, the salt is in solid form; further, the salt can be an amorphous substance, a crystalline substance, or a mixture thereof.

[0017] For example, a pharmaceutically acceptable salt of the compound represented by formula (I) or its hydrate or solvation is a p-toluenesulfonate, fumarate, tartrate, hydrochloride, sulfate, phosphate, maleate, mucilage, citrate, malate, hippurate, lactate, succinate, adipate, methanesulfonate, oxalate, or hydrobromide of the compound represented by formula (I) or its hydrate or solvation.

[0018] The present invention also provides a pharmaceutically acceptable salt or hydrate or solvation of the compound represented by formula (I) in solid form.

[0019] In some embodiments, the solid form is amorphous or crystalline.

[0020] The following are exemplary examples of p-toluenesulfonates or hydrates or solvates of compounds represented by formula (I).

[0021] In some embodiments, the p-toluenesulfonate salt of the compound shown in formula (I) has the structure of the compound shown in formula (II):

[0022] The present invention provides the solid form of the compound represented by formula (II).

[0023] In some embodiments, the solid form is amorphous or crystalline.

[0024] In some embodiments, the crystal form of the compound represented by formula (II) is selected from one or more of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J, and crystal form K.

[0025] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form A shown in formula (II) has characteristic peaks containing at least three or more (e.g., three, four, five, or six) diffraction angles 2θ as follows: 6.3±0.2°, 7.6±0.2°, 9.4±0.2°, 12.8±0.2°, 14.6±0.2°, and 16.4±0.2°.

[0026] In some embodiments, the compound crystal form A shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in FIG3.

[0027] In some embodiments, the crystal form A of the compound represented by formula (II) is substantially pure, having a crystal form purity ≥ 85%; further, the crystal form purity ≥ 90%; further, the crystal form purity ≥ 95%; further, the crystal form purity ≥ 99%; further, the crystal form purity ≥ 99.5%.

[0028] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more (e.g., two or three) diffraction angles 2θ as follows: 5.8±0.2°, 9.5±0.2°, 14.1±0.2°.

[0029] Furthermore, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more (e.g., two, three, four, or five) diffraction angles 2θ as follows: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, and 14.1±0.2°.

[0030] Furthermore, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more (e.g., two, three, four, five, six, seven, eight) diffraction angles 2θ as follows: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, 12.4±0.2°, 13.1±0.2°, 14.1±0.2°, 16.2±0.2°.

[0031] Furthermore, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more (e.g., two, three, four, five, six, or seven) diffraction angles 2θ as follows: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, 14.1±0.2°, 20.3±0.2°, and 20.5±0.2°.

[0032] Furthermore, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11) with the following diffraction angles 2θ: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, 12.4±0.2°, 13.1±0.2°, 14.1±0.2°, 16.2±0.2°, 17.8±0.2°, 18.5±0.2°, 23.7±0.2°.

[0033] Furthermore, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) with the following diffraction angles 2θ: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, 12.4±0.2°, 13.1±0.2°, 14.1±0.2°, 16.2±0.2°, 17.3±0.2°, 17.8±0.2°, 18.5±0.2°, 20.3±0.2°, 20.5±0.2°, 22.0±0.2°, 23.7±0.2°.

[0034] Furthermore, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) with the following diffraction angles 2θ: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, 12.4±0.2°, 13.1±0.2°, 14.1±0.2°, 15.4±0.2°, 17.8±0.2°, 18.5±0.2°, 20.3±0.2°, 20.5±0.2°, 22.0±0.2°, 25.0±0.2°, 26.3±0.2°.

[0035] Furthermore, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18) with the following diffraction angles 2θ: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10. 1±0.2°, 12.4±0.2°, 13.1±0.2°, 14.1±0.2°, 15.4±0.2°, 16.2±0.2°, 17.3±0.2°, 17.8±0.2°, 18.5±0.2°, 20.3±0.2°, 20.5±0.2°, 22.0±0.2°, 23.7±0.2°, 25.0±0.2°, 26.3±0.2°.

[0036] In some embodiments, the compound crystal form B represented by formula (II) has an X-ray powder diffraction pattern substantially as shown in FIG4.

[0037] In some embodiments, the compound B represented by formula (II) has a thermogravimetric analysis (TGA) spectrum substantially as shown in Figure 5.

[0038] In some embodiments, the compound crystal form B represented by formula (II) has a DSC spectrum including an onset temperature of approximately 229.07 ± 10 °C (e.g., 229.07 ± 9 °C, 229.07 ± 8 °C, 229.07 ± 7 °C, 229.07 ± 6 °C, 229.07 ± 5 °C, 229.07 ± 4 °C, 229.07 ± 3 °C, 229.07 ± 2 °C, 229.07 ± 1 °C, 229.07 °C). Further, the compound crystal form B represented by formula (II) has a DSC spectrum including an onset temperature of approximately 229.07 °C.

[0039] In some embodiments, the compound of formula (II) in crystal form B has a DSC spectrum containing an endothermic peak that has a maximum value at approximately 231.77 ± 10 °C (e.g., 231.77 ± 9 °C, 231.77 ± 8 °C, 231.77 ± 7 °C, 231.77 ± 6 °C, 231.77 ± 5 °C, 231.77 ± 4 °C, 231.77 ± 3 °C, 231.77 ± 2 °C, 231.77 ± 1 °C, 231.77 °C). Further, the compound of formula (II) in crystal form B has a DSC spectrum containing an endothermic peak that has a maximum value at approximately 231.77 °C.

[0040] In some embodiments, the compound of formula (II) in crystal form B has a DSC spectrum containing an endothermic peak with an onset temperature of about 229.07 ± 10 °C and a maximum value at 231.77 ± 10 °C. Further, the compound of formula (II) in crystal form B has a DSC spectrum containing an endothermic peak with an onset temperature of about 229.07 °C and a maximum value at 231.77 °C.

[0041] In some embodiments, the compound crystal form B represented by formula (II) has a differential scanning calorimetry (DSC) curve that is substantially as shown in FIG6.

[0042] In some embodiments, the crystal form B of the compound represented by formula (II) is substantially pure, having a crystal form purity ≥ 85%; further, the crystal form purity ≥ 90%; further, the crystal form purity ≥ 95%; further, the crystal form purity ≥ 99%; further, the crystal form purity ≥ 99.5%.

[0043] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form C shown in formula (II) has characteristic peaks containing at least two or more (e.g., two, three, four, five, or six) diffraction angles 2θ as follows: 4.9±0.2°, 9.6±0.2°, 10.4±0.2°, 11.3±0.2°, 13.3±0.2°, and 15.5±0.2°.

[0044] In some embodiments, the compound crystal form C represented by formula (II) has an X-ray powder diffraction pattern substantially as shown in FIG8.

[0045] In some embodiments, the crystal form C of the compound represented by formula (II) is substantially pure, with a crystal form purity ≥ 85%; further, the crystal form purity ≥ 90%; further, the crystal form purity ≥ 95%; further, the crystal form purity ≥ 99%; further, the crystal form purity ≥ 99.5%.

[0046] In some embodiments, the compound crystal form D shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in FIG9.

[0047] In some embodiments, the crystal form D of the compound represented by formula (II) is substantially pure, with a crystal form purity ≥ 85%; further, the crystal form purity ≥ 90%; further, the crystal form purity ≥ 95%; further, the crystal form purity ≥ 99%; further, the crystal form purity ≥ 99.5%.

[0048] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form E shown in formula (II) has characteristic peaks containing at least one or more (e.g., 1, 2, 3) diffraction angles 2θ as follows: 4.8±0.2°, 5.9±0.2°, 21.7±0.2°.

[0049] In some embodiments, the crystal form E of the compound represented by formula (II) has an X-ray powder diffraction pattern substantially as shown in FIG10.

[0050] In some embodiments, the crystal form E of the compound represented by formula (II) is substantially pure, with a crystal form purity ≥ 85%; further, the crystal form purity ≥ 90%; further, the crystal form purity ≥ 95%; further, the crystal form purity ≥ 99%; further, the crystal form purity ≥ 99.5%.

[0051] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form F shown in formula (II) has characteristic peaks containing at least one or more (e.g., 1, 2, 3) diffraction angles 2θ as follows: 6.6±0.2°, 13.2±0.2°, 15.0±0.2°.

[0052] In some embodiments, the compound crystal form F represented by formula (II) has an X-ray powder diffraction pattern substantially as shown in FIG11.

[0053] In some embodiments, the crystal form F of the compound represented by formula (II) is substantially pure, with a crystal form purity ≥ 85%; further, the crystal form purity ≥ 90%; further, the crystal form purity ≥ 95%; further, the crystal form purity ≥ 99%; further, the crystal form purity ≥ 99.5%.

[0054] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form G shown in formula (II) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4) diffraction angles 2θ as follows: 5.9±0.2°, 11.8±0.2°, 13.8±0.2°, 15.3±0.2°.

[0055] In some embodiments, the compound crystal form G shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in FIG12.

[0056] In some embodiments, the crystal form G of the compound represented by formula (II) is substantially pure, with a crystal form purity ≥ 85%; further, the crystal form purity ≥ 90%; further, the crystal form purity ≥ 95%; further, the crystal form purity ≥ 99%; further, the crystal form purity ≥ 99.5%.

[0057] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form H shown in formula (II) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 6.7±0.2°, 13.6±0.2°, 14.7±0.2°, 15.5±0.2°, 17.9±0.2°, 26.2±0.2°.

[0058] In some embodiments, the compound crystal form H represented by formula (II) has an X-ray powder diffraction pattern substantially as shown in FIG13.

[0059] In some embodiments, the crystal form H of the compound represented by formula (II) is substantially pure, with a crystal form purity ≥ 85%; further, the crystal form purity ≥ 90%; further, the crystal form purity ≥ 95%; further, the crystal form purity ≥ 99%; further, the crystal form purity ≥ 99.5%.

[0060] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form I shown in formula (II) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 4.9±0.2°, 6.4±0.2°, 9.6±0.2°, 18.1±0.2°, 24.4±0.2°, 25.2±0.2°.

[0061] In some embodiments, the compound crystal form I represented by formula (II) has an X-ray powder diffraction pattern substantially as shown in FIG14.

[0062] In some embodiments, the compound I represented by formula (II) is substantially pure, with a crystal form purity ≥ 85%; further, the crystal form purity ≥ 90%; further, the crystal form purity ≥ 95%; further, the crystal form purity ≥ 99%; further, the crystal form purity ≥ 99.5%.

[0063] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form J shown in formula (II) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 5.4±0.2°, 5.8±0.2°, 10.0±0.2°, 14.4±0.2°, 16.2±0.2°, 23.1±0.2°.

[0064] In some embodiments, the crystal form J of the compound represented by formula (II) has an X-ray powder diffraction pattern substantially as shown in FIG15.

[0065] In some embodiments, the crystal form J of the compound represented by formula (II) is substantially pure, with a crystal form purity ≥ 85%; further, the crystal form purity ≥ 90%; further, the crystal form purity ≥ 95%; further, the crystal form purity ≥ 99%; further, the crystal form purity ≥ 99.5%.

[0066] In some embodiments, the X-ray powder diffraction pattern of the compound crystal form K shown in formula (II) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 5.7±0.2°, 6.5±0.2°, 8.1±0.2°, 12.9±0.2°, 13.5±0.2°, 17.5±0.2°.

[0067] In some embodiments, the crystal form K of the compound represented by formula (II) has an X-ray powder diffraction pattern substantially as shown in FIG16.

[0068] In some embodiments, the crystal form K of the compound represented by formula (II) is substantially pure, with a crystal form purity ≥ 85%; further, the crystal form purity ≥ 90%; further, the crystal form purity ≥ 95%; further, the crystal form purity ≥ 99%; further, the crystal form purity ≥ 99.5%.

[0069] The following are exemplary examples of fumarates or hydrates or solvates of compounds represented by formula (I).

[0070] The present invention provides a solid form of the fumarate of the compound shown in formula (I).

[0071] In some embodiments, the solid form is amorphous or crystalline.

[0072] In some embodiments, the fumarate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A and crystal form B.

[0073] In some embodiments, the X-ray powder diffraction pattern of the fumarate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least two or more (e.g., two, three, four, five) diffraction angles 2θ as follows: 7.5±0.2°, 13.9±0.2°, 15.0±0.2°, 17.5±0.2°, 22.0±0.2°.

[0074] In some embodiments, the compound fumarate crystal form A shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG17a.

[0075] In some embodiments, the compound fumarate crystal form A of formula (I) has a thermogravimetric analysis (TGA) spectrum substantially as shown in Figure 17b.

[0076] In some embodiments, the fumarate crystal form A of the compound shown in formula (I) has a DSC spectrum including an onset temperature of about 260.1 ± 10 °C (e.g., 260.1 ± 9 °C, 260.1 ± 8 °C, 260.1 ± 7 °C, 260.1 ± 6 °C, 260.1 ± 5 °C, 260.1 ± 4 °C, 260.1 ± 3 °C, 260.1 ± 2 °C, 260.1 ± 1 °C, 260.1 °C). Further, the fumarate crystal form A of the compound shown in formula (I) has a DSC spectrum including an onset temperature of about 260.1 °C.

[0077] In some embodiments, the fumarate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 262.5 ± 10 °C (e.g., 262.5 ± 9 °C, 262.5 ± 8 °C, 262.5 ± 7 °C, 262.5 ± 6 °C, 262.5 ± 5 °C, 262.5 ± 4 °C, 262.5 ± 3 °C, 262.5 ± 2 °C, 262.5 ± 1 °C, 262.5 °C). Further, the fumarate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 262.5 °C.

[0078] In some embodiments, the fumarate crystal form A of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 260.1 ± 10 °C and a maximum value at about 262.5 ± 10 °C. Further, the fumarate crystal form A of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 260.1 °C and a maximum value at about 262.5 °C.

[0079] In some embodiments, the compound fumarate crystal form A shown in formula (I) has a differential scanning calorimetry (DSC) curve that is substantially as shown in Figure 17c.

[0080] In some embodiments, the X-ray powder diffraction pattern of the fumarate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least two or more (e.g., two, three, four, five, six, seven, eight) diffraction angles 2θ as follows: 6.4±0.2°, 8.4±0.2°, 12.8±0.2°, 13.2±0.2°, 15.3±0.2°, 16.7±0.2°, 21.0±0.2°, 25.7±0.2°.

[0081] In some embodiments, the compound fumarate crystal form B of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG18a.

[0082] In some embodiments, the compound fumarate crystal form B of formula (I) has a thermogravimetric analysis (TGA) spectrum substantially as shown in Figure 18b.

[0083] In some embodiments, the fumarate crystal form B of the compound shown in formula (I) has a DSC spectrum including an onset temperature of approximately 262.8 ± 10 °C (e.g., 262.8 ± 9 °C, 262.8 ± 8 °C, 262.8 ± 7 °C, 262.8 ± 6 °C, 262.8 ± 5 °C, 262.8 ± 4 °C, 262.8 ± 3 °C, 262.8 ± 2 °C, 262.8 ± 1 °C, 262.8 °C). Further, the fumarate crystal form B of the compound shown in formula (I) has a DSC spectrum including an onset temperature of approximately 262.8 °C.

[0084] In some embodiments, the fumarate crystal form B of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 263.7 ± 10 °C (e.g., 263.7 ± 9 °C, 263.7 ± 8 °C, 263.7 ± 7 °C, 263.7 ± 6 °C, 263.7 ± 5 °C, 263.7 ± 4 °C, 263.7 ± 3 °C, 263.7 ± 2 °C, 263.7 ± 1 °C, 263.7 °C). Further, the fumarate crystal form B of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 263.7 °C.

[0085] In some embodiments, the fumarate crystal form B of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 262.8 ± 10 °C and a maximum value of about 263.7 ± 10 °C. Further, the fumarate crystal form B of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 262.8 °C and a maximum value of about 263.7 °C.

[0086] In some embodiments, the compound fumarate crystal form B of formula (I) has a differential scanning calorimetry (DSC) curve that is substantially as shown in Figure 17c.

[0087] The following are exemplary examples of tartrate salts or hydrates or solvates of compounds represented by formula (I).

[0088] The present invention provides the solid form of the tartrate salt of the compound shown in formula (I).

[0089] In some embodiments, the solid form is amorphous or crystalline.

[0090] In some embodiments, the tartrate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A and crystal form B.

[0091] In some embodiments, the X-ray powder diffraction pattern of the tartrate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5) diffraction angles 2θ as follows: 7.2±0.2°, 13.3±0.2°, 14.4±0.2°, 18.0±0.2°, 21.6±0.2°.

[0092] In some embodiments, the tartrate crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG19a.

[0093] In some embodiments, the tartrate crystal form A of the compound represented by formula (I) has a thermogravimetric analysis (TGA) spectrum substantially as shown in Figure 19b.

[0094] In some embodiments, the tartrate crystal form A of the compound shown in formula (I) has a DSC spectrum including an onset temperature of approximately 267.3 ± 10 °C (e.g., 267.3 ± 9 °C, 267.3 ± 8 °C, 267.3 ± 7 °C, 267.3 ± 6 °C, 267.3 ± 5 °C, 267.3 ± 4 °C, 267.3 ± 3 °C, 267.3 ± 2 °C, 267.3 ± 1 °C, 267.3 °C). Further, the tartrate crystal form A of the compound shown in formula (I) has a DSC spectrum including an onset temperature of approximately 267.3 °C.

[0095] In some embodiments, the tartrate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 270.4 ± 10 °C (e.g., 270.4 ± 9 °C, 270.4 ± 8 °C, 270.4 ± 7 °C, 270.4 ± 6 °C, 270.4 ± 5 ​​°C, 270.4 ± 4 °C, 270.4 ± 3 °C, 270.4 ± 2 °C, 270.4 ± 1 °C, 270.4 °C). Further, the tartrate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 270.4 °C.

[0096] In some embodiments, the tartrate crystal form A of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 267.3 ± 10 °C and a maximum value of about 270.4 ± 10 °C. Further, the tartrate crystal form A of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 267.3 °C and a maximum value of about 270.4 °C.

[0097] In some embodiments, the tartrate crystal form A of the compound represented by formula (I) has a differential scanning calorimetry (DSC) curve that is substantially as shown in Figure 19c.

[0098] In some embodiments, the X-ray powder diffraction pattern of the tartrate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 7.8±0.2°, 11.9±0.2°, 14.8±0.2°, 18.8±0.2°, 20.7±0.2°, 25.9±0.2°.

[0099] In some embodiments, the tartrate crystal form B of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG20a.

[0100] In some embodiments, the tartrate crystal form B of the compound represented by formula (I) has a thermogravimetric analysis (TGA) spectrum substantially as shown in Figure 20b.

[0101] In some embodiments, the tartrate crystal form B of the compound shown in formula (I) has a DSC spectrum including an onset temperature of approximately 267.8 ± 10 °C (e.g., 267.8 ± 9 °C, 267.8 ± 8 °C, 267.8 ± 7 °C, 267.8 ± 6 °C, 267.8 ± 5 °C, 267.8 ± 4 °C, 267.8 ± 3 °C, 267.8 ± 2 °C, 267.8 ± 1 °C, 267.8 °C). Further, the tartrate crystal form B of the compound shown in formula (I) has a DSC spectrum including an onset temperature of approximately 267.8 °C.

[0102] In some embodiments, the tartrate crystal form B of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 270.0 ± 10 °C (e.g., 270.0 ± 9 °C, 270.0 ± 8 °C, 270.0 ± 7 °C, 270.0 ± 6 °C, 270.0 ± 5 °C, 270.0 ± 4 °C, 270.0 ± 3 °C, 270.0 ± 2 °C, 270.0 ± 1 °C, 270.0 °C). Further, the tartrate crystal form B of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 270.0 °C.

[0103] In some embodiments, the tartrate crystal form B of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 267.8 ± 10 °C and a maximum value of about 270.0 ± 10 °C. Further, the tartrate crystal form B of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 267.8 °C and a maximum value of about 270.0 °C.

[0104] In some embodiments, the tartrate crystal form B of the compound represented by formula (I) has a differential scanning calorimetry (DSC) curve that is substantially as shown in Figure 20c.

[0105] The following are exemplary examples of hydrochloride salts or hydrates or solvates of compounds represented by formula (I).

[0106] The present invention provides a solid form of the hydrochloride salt of the compound shown in formula (I).

[0107] In some embodiments, the solid form is amorphous or crystalline.

[0108] In some embodiments, the hydrochloride crystal form of the compound represented by formula (I) is selected from crystal form A.

[0109] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 7.2±0.2°, 7.9±0.2°, 10.8±0.2°, 15.0±0.2°, 17.1±0.2°, 20.3±0.2°.

[0110] In some embodiments, the hydrochloride crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG21.

[0111] The following are exemplary examples of sulfates or hydrates or solvates of compounds represented by formula (I).

[0112] The present invention provides a solid form of the sulfate of the compound shown in formula (I).

[0113] In some embodiments, the solid form is amorphous or crystalline.

[0114] In some embodiments, the sulfate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A and crystal form B.

[0115] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 6.0±0.2°, 6.8±0.2°, 14.4±0.2°, 15.4±0.2°, 16.7±0.2°, 19.7±0.2°.

[0116] In some embodiments, the sulfate crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG22.

[0117] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least three or more (e.g., three, four, five, or six) diffraction angles 2θ as follows: 7.1±0.2°, 8.9±0.2°, 12.5±0.2°, 14.5±0.2°, 16.1±0.2°, and 19.8±0.2°.

[0118] In some embodiments, the sulfate crystal form B of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG23.

[0119] The following are exemplary examples of phosphates or hydrates or solvates of compounds represented by formula (I).

[0120] The present invention provides a solid form of the phosphate of the compound shown in formula (I).

[0121] In some embodiments, the solid form is amorphous or crystalline.

[0122] In some embodiments, the phosphate crystal form of the compound represented by formula (I) is selected from crystal form A.

[0123] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 10.2±0.2°, 11.1±0.2°, 12.0±0.2°, 14.3±0.2°, 15.0±0.2°, 25.5±0.2°.

[0124] In some embodiments, the phosphate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG24.

[0125] The following are exemplary examples of maleate salts or hydrates or solvates of compounds represented by formula (I).

[0126] The present invention provides the solid form of the maleate salt of the compound shown in formula (I).

[0127] In some embodiments, the solid form is amorphous or crystalline.

[0128] In some embodiments, the maleate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A, crystal form B and crystal form C.

[0129] In some embodiments, the X-ray powder diffraction pattern of maleate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least three or more (e.g., three, four, five, or six) diffraction angles 2θ as follows: 5.9±0.2°, 7.3±0.2°, 13.6±0.2°, 14.5±0.2°, 21.2±0.2°, and 27.0±0.2°.

[0130] In some embodiments, the maleate crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 25.

[0131] In some embodiments, the X-ray powder diffraction pattern of maleate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least two or more (e.g., two, three, four, five) diffraction angles 2θ as follows: 5.5±0.2°, 7.2±0.2°, 16.1±0.2°, 16.6±0.2°, 17.3±0.2°, 24.6±0.2°.

[0132] In some embodiments, the maleate crystal form B of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG26.

[0133] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form C of the compound shown in formula (I) has characteristic peaks containing at least three or more (e.g., three, four, five, or six) diffraction angles 2θ as follows: 5.9±0.2°, 7.6±0.2°, 9.9±0.2°, 12.7±0.2°, 19.3±0.2°, and 22.3±0.2°.

[0134] In some embodiments, the maleate crystal form C of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 27.

[0135] The following are exemplary examples of mucilage salts or hydrates or solvates of compounds represented by formula (I).

[0136] The present invention provides a solid form of the mucilage salt of the compound shown in formula (I).

[0137] In some embodiments, the solid form is amorphous or crystalline.

[0138] In some embodiments, the mucilage crystal form of the compound represented by formula (I) is selected from crystal form A.

[0139] In some embodiments, the X-ray powder diffraction pattern of the mucilage crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6, 7) diffraction angles 2θ as follows: 5.6±0.2°, 5.9±0.2°, 6.3±0.2°, 10.5±0.2°, 12.1±0.2°, 15.7±0.2°, 19.7±0.2°.

[0140] In some embodiments, the compound of formula (I) in mucilage form A has an X-ray powder diffraction pattern substantially as shown in FIG28.

[0141] The following are exemplary examples of citrate salts or hydrates or solvates of compounds represented by formula (I).

[0142] The present invention provides the solid form of the citrate of the compound shown in formula (I).

[0143] In some embodiments, the solid form is amorphous or crystalline.

[0144] In some embodiments, the citrate crystal form of the compound represented by formula (I) is selected from crystal form A.

[0145] In some embodiments, the X-ray powder diffraction pattern of the citrate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 4.8±0.2°, 6.6±0.2°, 16.2±0.2°, 17.4±0.2°, 19.1±0.2°, 22.5±0.2°.

[0146] In some embodiments, the citrate crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 29.

[0147] The following are exemplary examples of malates or hydrates or solvates of compounds represented by formula (I).

[0148] The present invention provides a solid form of the malate of the compound shown in formula (I).

[0149] In some embodiments, the solid form is amorphous or crystalline.

[0150] In some embodiments, the malate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A and crystal form B.

[0151] In some embodiments, the X-ray powder diffraction pattern of the malate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least two or more (e.g., two, three, four, five, or six) diffraction angles 2θ as follows: 7.7±0.2°, 11.9±0.2°, 14.7±0.2°, 15.3±0.2°, 20.8±0.2°, and 26.0±0.2°.

[0152] In some embodiments, the compound malate crystal form A shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG30.

[0153] In some embodiments, the X-ray powder diffraction pattern of the compound malate crystal form B shown in formula (I) has characteristic peaks containing at least two or more (e.g., two, three, four, five, or six) diffraction angles 2θ as follows: 6.2±0.2°, 8.5±0.2°, 11.3±0.2°, 14.5±0.2°, 17.0±0.2°, and 25.6±0.2°.

[0154] In some embodiments, the compound malate crystal form B shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG31.

[0155] The following are exemplary examples of hippurates or their hydrates or solvates of compounds represented by formula (I).

[0156] The present invention provides a solid form of the hippurate of the compound shown in formula (I).

[0157] In some embodiments, the solid form is amorphous or crystalline.

[0158] In some embodiments, the hippurate crystal form of the compound represented by formula (I) is selected from crystal form A.

[0159] In some embodiments, the X-ray powder diffraction pattern of the hippurate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) the following diffraction angles 2θ: 5.7±0.2°, 7.0±0.2°, 11.3±0.2°, 16.0±0.2°, 19.2±0.2°, 27.0±0.2°.

[0160] In some embodiments, the compound (I) represented by hippurate crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG32a.

[0161] In some embodiments, the compound hippurate crystal form A of formula (I) has a thermogravimetric analysis (TGA) spectrum substantially as shown in Figure 32b.

[0162] In some embodiments, the hippurate crystal form A of the compound shown in formula (I) has a DSC spectrum including an onset temperature of approximately 216.7 ± 10 °C (e.g., 216.7 ± 9 °C, 216.7 ± 8 °C, 216.7 ± 7 °C, 216.7 ± 6 °C, 216.7 ± 5 °C, 216.7 ± 4 °C, 216.7 ± 3 °C, 216.7 ± 2 °C, 216.7 ± 1 °C, 216.7 °C). Further, the hippurate crystal form A of the compound shown in formula (I) has a DSC spectrum including an onset temperature of approximately 216.7 °C.

[0163] In some embodiments, the hippurate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 218.6 ± 10 °C (e.g., 218.6 ± 9 °C, 218.6 ± 8 °C, 218.6 ± 7 °C, 218.6 ± 6 °C, 218.6 ± 5 °C, 218.6 ± 4 °C, 218.6 ± 3 °C, 218.6 ± 2 °C, 218.6 ± 1 °C, 218.6 °C). Further, the hippurate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 218.6 °C.

[0164] In some embodiments, the hippurate crystal form A of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 216.7 ± 10 °C and a maximum value of about 218.6 ± 10 °C. Further, the hippurate crystal form A of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 216.7 °C and a maximum value of about 218.6 °C.

[0165] In some embodiments, the hippurate crystal form A of the compound represented by formula (I) has a differential scanning calorimetry (DSC) curve that is substantially as shown in Figure 32c.

[0166] The following are exemplary examples of lactates or hydrates or solvates of compounds represented by formula (I).

[0167] The present invention provides the solid form of the lactate of the compound shown in formula (I).

[0168] In some embodiments, the solid form is amorphous or crystalline.

[0169] In some embodiments, the lactate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A and crystal form B.

[0170] In some embodiments, the X-ray powder diffraction pattern of the lactate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 6.7±0.2°, 9.7±0.2°, 13.0±0.2°, 16.6±0.2°, 24.2±0.2°, 26.4±0.2°.

[0171] In some embodiments, the compound of formula (I) in lactate form A has an X-ray powder diffraction pattern substantially as shown in FIG33.

[0172] In some embodiments, the X-ray powder diffraction pattern of the lactate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 7.6±0.2°, 10.5±0.2°, 13.8±0.2°, 15.4±0.2°, 21.7±0.2°, 27.5±0.2°.

[0173] In some embodiments, the compound of formula (I) in lactate form B has an X-ray powder diffraction pattern substantially as shown in FIG34.

[0174] The following are exemplary examples of succinates or hydrates or solvates of compounds represented by formula (I).

[0175] The present invention provides a solid form of the succinate of the compound shown in formula (I).

[0176] In some embodiments, the solid form is amorphous or crystalline.

[0177] In some embodiments, the succinate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A and crystal form B.

[0178] In some embodiments, the X-ray powder diffraction pattern of the succinate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least four or more (e.g., four, five, or six) diffraction angles 2θ as follows: 7.1±0.2°, 13.4±0.2°, 14.1±0.2°, 15.9±0.2°, 21.1±0.2°, and 25.9±0.2°.

[0179] In some embodiments, the succinate crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 35.

[0180] In some embodiments, the X-ray powder diffraction pattern of the succinate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least two or more (e.g., two, three, four, five, or six) diffraction angles 2θ as follows: 6.3±0.2°, 7.2±0.2°, 13.2±0.2°, 14.4±0.2°, 16.1±0.2°, and 21.6±0.2°.

[0181] In some embodiments, the succinate crystal form B of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 36.

[0182] The following are exemplary examples of adipates or hydrates or solvates of compounds represented by formula (I).

[0183] The present invention provides a solid form of the adipate of the compound shown in formula (I).

[0184] In some embodiments, the solid form is amorphous or crystalline.

[0185] In some embodiments, the adipate crystal form of the compound represented by formula (I) is selected from crystal form A.

[0186] In some embodiments, the X-ray powder diffraction pattern of adipate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 6.7±0.2°, 11.6±0.2°, 16.5±0.2°, 17.5±0.2°, 18.5±0.2°, 21.1±0.2°.

[0187] In some embodiments, the adipate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 37.

[0188] The following are exemplary examples of methanesulfonates or hydrates or solvates of compounds represented by formula (I).

[0189] The present invention provides a solid form of the methanesulfonate salt of the compound shown in formula (I).

[0190] In some embodiments, the solid form is amorphous or crystalline.

[0191] In some embodiments, the methanesulfonate crystal form of the compound represented by formula (I) is selected from crystal form A.

[0192] In some embodiments, the X-ray powder diffraction pattern of the methanesulfonate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 6.6±0.2°, 10.3±0.2°, 15.0±0.2°, 20.0±0.2°, 21.7±0.2°, 24.2±0.2°.

[0193] In some embodiments, the methanesulfonate crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG38a.

[0194] In some embodiments, the methanesulfonate crystal form A of the compound represented by formula (I) has a thermogravimetric analysis (TGA) spectrum substantially as shown in Figure 38b.

[0195] In some embodiments, the methanesulfonate crystal form A of the compound shown in formula (I) has a DSC spectrum including an onset temperature of approximately 283.7 ± 10 °C (e.g., 283.7 ± 9 °C, 283.7 ± 8 °C, 283.7 ± 7 °C, 283.7 ± 6 °C, 283.7 ± 5 °C, 283.7 ± 4 °C, 283.7 ± 3 °C, 283.7 ± 2 °C, 283.7 ± 1 °C, 283.7 °C). Further, the methanesulfonate crystal form A of the compound shown in formula (I) has a DSC spectrum including an onset temperature of approximately 283.7 °C.

[0196] In some embodiments, the methanesulfonate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 289.8 ± 10 °C (e.g., 289.8 ± 9 °C, 289.8 ± 8 °C, 289.8 ± 7 °C, 289.8 ± 6 °C, 289.8 ± 5 °C, 289.8 ± 4 °C, 289.8 ± 3 °C, 289.8 ± 2 °C, 289.8 ± 1 °C, 289.8 °C). Further, the methanesulfonate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 289.8 °C.

[0197] In some embodiments, the methanesulfonate crystal form A of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 283.7 ± 10 °C and a maximum value of about 289.8 ± 10 °C. Further, the methanesulfonate crystal form A of the compound represented by formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature of about 283.7 °C and a maximum value of about 289.8 °C.

[0198] In some embodiments, the methanesulfonate crystal form A of the compound represented by formula (I) has a differential scanning calorimetry (DSC) curve that is substantially as shown in Figure 38c.

[0199] The following are exemplary examples of oxalates or hydrates or solvates of compounds represented by formula (I).

[0200] The present invention provides the solid form of the oxalate of the compound shown in formula (I).

[0201] In some embodiments, the solid form is amorphous or crystalline.

[0202] In some embodiments, the oxalate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A, crystal form B, and crystal form C.

[0203] In some embodiments, the X-ray powder diffraction pattern of the oxalate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 7.5±0.2°, 9.6±0.2°, 16.0±0.2°, 19.2±0.2°, 24.1±0.2°, 26.2±0.2°.

[0204] In some embodiments, the oxalate crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG39.

[0205] In some embodiments, the X-ray powder diffraction pattern of the oxalate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least two or more (e.g., two, three, four, or five) diffraction angles 2θ as follows: 6.0±0.2°, 6.8±0.2°, 15.4±0.2°, 23.1±0.2°, and 26.2±0.2°.

[0206] In some embodiments, the oxalate crystal form B of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG40.

[0207] In some embodiments, the X-ray powder diffraction pattern of the oxalate crystal form C of the compound shown in formula (I) has characteristic peaks containing at least two or more (e.g., two, three, four, five, or six) diffraction angles 2θ as follows: 6.8±0.2°, 7.7±0.2°, 13.7±0.2°, 16.5±0.2°, 17.3±0.2°, and 22.2±0.2°.

[0208] In some embodiments, the oxalate crystal form C of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG41.

[0209] The following are exemplary examples of hydrobromide salts or hydrates or solvates of compounds represented by formula (I).

[0210] The present invention provides a solid form of the hydrobromide of the compound shown in formula (I).

[0211] In some embodiments, the solid form is amorphous or crystalline.

[0212] In some embodiments, the hydrobromide crystal form of the compound represented by formula (I) is selected from crystal form A.

[0213] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more (e.g., 1, 2, 3, 4, 5, 6) diffraction angles 2θ as follows: 7.2±0.2°, 10.7±0.2°, 14.9±0.2°, 17.1±0.2°, 25.5±0.2°, 26.2±0.2°.

[0214] In some embodiments, the hydrobromide crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG42.

[0215] The present invention also provides a pharmaceutical composition comprising a crystal form of a compound of formula (I), a pharmaceutically acceptable salt of a compound of formula (I) or a hydrate or solvate thereof, or a crystal form of a pharmaceutically acceptable salt of a compound of formula (I), and a pharmaceutically acceptable excipient.

[0216] The present invention further provides the use of the crystal form of the compound shown in formula (I), a pharmaceutically acceptable salt of the compound shown in formula (I), a crystal form of a pharmaceutically acceptable salt of the compound shown in formula (I), a pharmaceutical composition of the crystal form of the compound shown in formula (I), a pharmaceutical composition of a pharmaceutically acceptable salt of the compound shown in formula (I), and a pharmaceutical composition of the crystal form of a pharmaceutically acceptable salt of the compound shown in formula (I) in the preparation of a cancer treatment drug.

[0217] In some embodiments, the cancers include, but are not limited to, breast cancer, ovarian cancer, stomach cancer, prostate cancer, pancreatic cancer, uterine cancer, cervical cancer, endometrial cancer, lung cancer, brain cancer, bile duct cancer, and blood cancers.

[0218] In some embodiments, the route of administration of the drug includes, but is not limited to, oral, injection, topical, and inhalation.

[0219] In some implementations, the drug may be used alone or in combination with other treatment methods.

[0220] This invention provides intermediates or salts thereof as shown below:

[0221] A method for preparing a compound of formula (I) or a salt thereof, the method comprising:

[0222] Method 1: React the compound shown in formula (1-1) or its salt with the compound shown in formula (2) in the presence of a base:

[0223] Where X is a halogen (such as F, Cl, Br or I);

[0224] The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, DIPEA, etc.

[0225] Method 2: React the compound or its salt shown in formula (1-3) with the compound or its salt shown in formula (3) in the presence of a base:

[0226] The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, DIPEA, etc.

[0227] Method 3: React the compound or its salt shown in formula (1-6) with the compound or its salt shown in formula (3) in the presence of a base:

[0228] The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, DIPEA, etc.

[0229] A method for preparing a compound of formula (1-1) or a salt thereof, the method comprising:

[0230] The compound shown in formula (1) or its salt is reacted with the compound shown in formula (3) or its salt in the presence of a base:

[0231] The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, DIPEA, etc.

[0232] A method for preparing a compound of formula (1-3) or a salt thereof, the method comprising:

[0233] Method 1: React the compound shown in formula (1-2) or its salt with the compound shown in formula (2) in the presence of a base:

[0234] The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, DIPEA, etc.

[0235] Method 2: React the compound shown in formula (1-5) or its salt with an oxidizing agent:

[0236] The oxidant is 3-chloroperoxybenzoic acid, etc.

[0237] A method for preparing a compound of formula (1-6) or a salt thereof, the method comprising:

[0238] Method 1: React the compound shown in formula (1-5) or its salt with a chlorinating agent:

[0239] The chlorinating agent is sulfonyl chloride, etc.;

[0240] Method 2: React the compound shown in formula (1) or its salt with the compound shown in formula (2) in the presence of a base:

[0241] The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, DIPEA, etc.

[0242] A method for preparing a compound of formula (1-5) or a salt thereof, the method comprising:

[0243] React the compounds shown in formulas (1-4) or their salts with the compound shown in formula (2) in the presence of a base:

[0244] The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, DIPEA, etc.

[0245] A method for preparing a compound of formula (1-4) or a salt thereof, the method comprising:

[0246] The compound shown in formula (1) is reacted with NaSCH3:

[0247] A method for preparing the compound shown in formula (2), the method comprising:

[0248] The compound shown in formula (2-2) or its salt is reacted with a halogenating agent in the presence of tert-butyl nitrite:

[0249] The halogenating agent is a ketone(II) halide (such as ketone(II) bromide, ketone(II) chloride, etc.).

[0250] A method for preparing a compound of formula (2-2) or a salt thereof, the method comprising:

[0251] The compound shown in formula (2-1) or its salt is reacted with difluoroacetic acid in the presence of POCl3:

[0252] A method for preparing a compound of formula (3) or a salt thereof, the method comprising:

[0253] React the compound shown in formula (3-5) or its salt under acidic conditions:

[0254] PG 1 For -Boc, etc.;

[0255] The acidic conditions include TFA, hydrochloric acid, dioxane hydrochloride solution, tetrahydrofuran hydrochloride solution, etc.

[0256] A method for preparing a compound of formula (3-5) or a salt thereof, the method comprising:

[0257] The compound shown in formula (3-4) was reacted with acetaldehyde in the presence of a reducing agent:

[0258] The reducing agent is sodium borohydride, sodium cyanoborohydride, sodium borohydride acetate, etc.

[0259] A method for preparing a compound of formula (3-4) or a salt thereof, the method comprising:

[0260] Method 1: The compound shown in formula (3-3) or its salt is reacted with an amine or its salt in the presence of an enzyme to carry out an asymmetric chiral synthesis reaction:

[0261] The amine is isopropylamine, a salt of isopropylamine (such as isopropylamine hydrochloride), etc.

[0262] The enzyme is ATA-303;

[0263] Method 2: Chiral separation is achieved by reacting the compound shown in formula (3-7) or its salt with a chiral reagent.

[0264] The chiral reagent is (S)-(+)-O-acetyl-L-mandelic acid.

[0265] A method for preparing a compound of formula (3-3) or a salt thereof, the method comprising:

[0266] The compound shown in formula (3-2) or its salt is reacted with a selective fluorinating agent:

[0267] The selective fluorinating agent is Selectfluor (Select-F, 1-chloromethyl-4-fluoro-1,4-diazobicyclo2,2,2-octanebis(tetrafluoroborate) salt);

[0268] The PG 2 For protection groups, such as -TMS, -TBDMS, -Ac, etc.;

[0269] A method for preparing a compound of formula (3-2) or a salt thereof, the method comprising:

[0270] The compound shown in formula (3-1) is combined with PG 2 -X or PG 2 -O-PG 2 The reaction will proceed as follows:

[0271] X is a halogen (such as F, Cl, Br, or I);

[0272] The PG 2 For protection groups, such as -TMS, -TBDMS, -Ac, etc.

[0273] A method for preparing a compound of formula (3-7) or a salt thereof, the method comprising:

[0274] The compound shown in formula (3-6) or its salt is reacted under acidic conditions:

[0275] The acidic conditions include TFA, hydrochloric acid, dioxane hydrochloride solution, tetrahydrofuran hydrochloride solution, etc.

[0276] A method for preparing a compound of formula (3-6) or a salt thereof, the method comprising:

[0277] The compound shown in formula (3-3) or its salt is subjected to a reductive amination reaction with an amine source:

[0278] The amine source is (R)-2-methylpropane-2-sulfinamide or its salt. Attached Figure Description

[0279] Figure 1 shows the XRPD pattern of crystal form A of the compound represented by formula (I);

[0280] Figure 2 shows the XRPD pattern of crystal form B of the compound shown in formula (I);

[0281] Figure 3 shows the XRPD pattern of crystal form A of the compound shown in formula (II);

[0282] Figure 3a shows the crystal form A of the compound represented by formula (II). 1 HNMR spectrum;

[0283] Figure 4 shows the XRPD pattern of crystal form B of the compound represented by formula (II);

[0284] Figure 4a shows the crystal form B of the compound represented by formula (II). 1 HNMR spectrum;

[0285] Figure 5 shows the TGA spectrum of crystal form B of the compound represented by formula (II);

[0286] Figure 6 shows the DSC spectrum of crystal form B of the compound represented by formula (II);

[0287] Figure 7a is a schematic diagram of the asymmetric unit of the single crystal structure model of compound B shown in formula (II);

[0288] Figure 7b shows the atomic thermal vibration ellipsoid of one of the cations in the asymmetric structural unit of the single crystal structure model of compound B shown in formula (II) (the atomic thermal vibration ellipsoid in the figure is drawn at a 50% probability level).

[0289] Figure 7c shows the atomic thermal vibration ellipsoid of another cation in the asymmetric structural unit of the single crystal structure model of compound B shown in formula (II) (the atomic thermal vibration ellipsoid in the figure is drawn at a 50% probability level).

[0290] Figure 8 shows the XRPD pattern of crystal form C of the compound shown in formula (II);

[0291] Figure 9 shows the XRPD pattern of crystal form D of the compound shown in formula (II);

[0292] Figure 10 shows the XRPD pattern of crystal form E of the compound shown in formula (II);

[0293] Figure 11 shows the XRPD pattern of crystal form F of the compound represented by formula (II);

[0294] Figure 12 shows the XRPD pattern of the crystal form G of the compound shown in formula (II);

[0295] Figure 13 shows the XRPD pattern of crystal form H of the compound represented by formula (II);

[0296] Figure 14 shows the XRPD pattern of crystal form I of the compound shown in formula (II);

[0297] Figure 15 shows the XRPD pattern of crystal form J of compound (II);

[0298] Figure 16 shows the XRPD pattern of crystal form K of the compound shown in formula (II);

[0299] Figure 17a shows the XRPD pattern of the fumarate crystal form A of the compound shown in formula (I);

[0300] Figure 17b shows the TGA spectrum of fumarate crystal form A of the compound shown in formula (I);

[0301] Figure 17c shows the DSC spectrum of fumarate crystal form A of the compound shown in formula (I);

[0302] Figure 18a shows the XRPD pattern of the fumarate crystal form B of the compound shown in formula (I);

[0303] Figure 18b shows the TGA spectrum of the fumarate crystal form B of the compound shown in formula (I).

[0304] Figure 18c shows the DSC spectrum of the fumarate crystal form B of the compound shown in formula (I);

[0305] Figure 18d shows the crystal form B of the fumarate of compound (I). 1 HNMR spectrum;

[0306] Figure 19a shows the XRPD pattern of tartrate crystal form A of the compound shown in formula (I);

[0307] Figure 19b shows the TGA spectrum of tartrate crystal form A of the compound shown in formula (I);

[0308] Figure 19c shows the DSC spectrum of tartrate crystal form A of the compound shown in formula (I);

[0309] Figure 19d shows the crystal form A of the tartrate salt of compound (I). 1 HNMR spectrum;

[0310] Figure 20a shows the XRPD pattern of tartrate crystal form B of compound (I);

[0311] Figure 20b shows the TGA spectrum of tartrate crystal form B of compound (I);

[0312] Figure 20c shows the DSC spectrum of tartrate crystal form B of compound (I);

[0313] Figure 21 shows the XRPD pattern of the hydrochloride crystal form A of the compound shown in formula (I);

[0314] Figure 22 shows the XRPD pattern of sulfate crystal form A of the compound shown in formula (I);

[0315] Figure 23 shows the XRPD pattern of the sulfate crystal form B of the compound shown in formula (I);

[0316] Figure 24 shows the XRPD pattern of phosphate crystal form A of the compound shown in formula (I);

[0317] Figure 25 shows the XRPD pattern of maleate crystal form A of the compound shown in formula (I);

[0318] Figure 26 shows the XRPD pattern of maleate crystal form B of compound (I);

[0319] Figure 27 shows the XRPD pattern of maleate crystal form C of the compound shown in formula (I);

[0320] Figure 28 shows the XRPD pattern of the mucilage crystal form A of the compound shown in formula (I);

[0321] Figure 29 shows the XRPD pattern of citrate crystal form A of the compound shown in formula (I);

[0322] Figure 30 shows the XRPD pattern of the malate crystal form A of the compound shown in formula (I);

[0323] Figure 31 shows the XRPD pattern of the malate crystal form B of the compound shown in formula (I);

[0324] Figure 32a shows the XRPD pattern of the hippurate crystal form A of the compound shown in formula (I);

[0325] Figure 32b shows the TGA spectrum of the hippurate crystal form A of the compound shown in formula (I);

[0326] Figure 32c shows the DSC spectrum of hippurate crystal form A of compound (I);

[0327] Figure 33 shows the XRPD pattern of the lactate crystal form A of the compound shown in formula (I);

[0328] Figure 34 shows the XRPD pattern of the lactate crystal form B of the compound shown in formula (I);

[0329] Figure 35 shows the XRPD pattern of succinate crystal form A of the compound shown in formula (I);

[0330] Figure 36 shows the XRPD pattern of succinate crystal form B of the compound shown in formula (I);

[0331] Figure 37 shows the XRPD pattern of adipate crystal form A of compound (I);

[0332] Figure 38a shows the XRPD pattern of the methanesulfonate crystal form A of the compound shown in formula (I);

[0333] Figure 38b shows the TGA spectrum of the methanesulfonate crystal form A of the compound shown in formula (I);

[0334] Figure 38c shows the DSC spectrum of the methanesulfonate crystal form A of the compound shown in formula (I);

[0335] Figure 39 shows the XRPD pattern of oxalate crystal form A of the compound shown in formula (I);

[0336] Figure 40 shows the XRPD pattern of oxalate crystal form B of compound (I);

[0337] Figure 41 shows the XRPD pattern of oxalate crystal form C of the compound shown in formula (I);

[0338] Figure 42 shows the XRPD pattern of the hydrobromide crystal form A of the compound shown in formula (I);

[0339] Figure 43 is a flow chart of the reaction of intermediate 2;

[0340] In the XRPD figures above, the horizontal axis (X-axis) represents the diffraction angle 2θ, in "°"; the vertical axis (Y-axis) represents the diffraction intensity, in "counts".

[0341] Definitions and Explanations

[0342] Unless otherwise stated, the following terms and phrases used in this invention are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear in this invention, they are intended to refer to the corresponding product or its active ingredient.

[0343] As described in this invention, new crystal forms can be identified using X-ray powder diffraction (XRPD). However, those skilled in the art know that the peak intensity and / or peak characteristics of XRPD can vary depending on experimental conditions, such as different diffraction test conditions and / or orientation preference. Furthermore, due to differences in the accuracy of different instruments, the measured diffraction angle 2θ may have an error of approximately ±0.2°. However, it is known that the relative intensity of a peak depends more on certain properties of the sample being measured than on its position, such as the size of the crystals in the sample, the orientation effect of crystallization, and the purity of the material being analyzed; therefore, peak intensity deviations of approximately ±20% or greater are possible. Nevertheless, despite experimental errors, instrumental errors, and orientation preference, those skilled in the art can obtain sufficient information for identifying crystal forms from the XRPD data provided in this patent.

[0344] In this invention, "having an X-ray powder diffraction pattern substantially as shown in FIG1" or "having an X-ray powder diffraction pattern substantially as shown in FIG2" means that the main peaks shown in the X-ray powder diffraction pattern are those peaks whose relative intensity values ​​exceed 10%, preferably exceed 30%, compared with the highest peak in FIG1 or FIG2 (whose relative intensity is specified as 100%).

[0345] The "crystal form" described in this invention can exist in a sample at a concentration of 0.0001% to 100%. Therefore, any sample containing even trace amounts of the "crystal form" described in this invention, such as greater than 0.0001%, 0.001%, 0.001%, or 0.01%, should be understood as falling within the scope of protection of this invention. To describe the various parameters of the "crystal form" described in this invention more clearly, this invention characterizes and identifies the crystal form by testing various parameters on samples containing a substantially pure "crystal form." The term "substantially pure" means that the sample is substantially composed of one main crystal form and substantially does not contain another one or more other crystal forms or amorphous forms, with a main crystal form purity of at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%.

[0346] Unless otherwise specified, the terms "crystal form," "crystalline form," "form," and related terms used in this invention are used interchangeably and refer to a crystalline solid form. Crystalline forms include single-component crystalline forms and multi-component crystalline forms, including but not limited to solvent-free forms (e.g., amorphous forms), solvates, hydrates, eutectics, and other molecular complexes and their polymorphs, as well as salts, salt solvates, salt hydrates, salt eutectics, other molecular complexes of salts, and their polymorphs. In some embodiments, the crystalline form of a substance may be substantially free of amorphous and / or other crystalline forms. In some embodiments, the crystalline form of a substance may contain less than about 50% by weight of one or more amorphous and / or other crystalline forms. In some embodiments, the crystalline form of a substance may be physically and / or chemically pure.

[0347] Unless otherwise specified, the term "solvent" as used in this invention refers to a molecular complex comprising a pharmaceutical ingredient and stoichiometric or non-stoichiometric amounts of solvent molecules, wherein the pharmaceutical ingredient may be a free base, or a pharmaceutically acceptable salt, eutectic, salt eutectic, or other molecular complex thereof. When the solvent is water, the solvate is referred to as a "hydrate".

[0348] Hydrates can be stoichiometric hydrates, where water exists in a defined molar equivalent in the crystal lattice, independent of humidity, such as hemihydrates, monohydrates, dihydrates, etc. Hydrates can also be non-stoichiometric hydrates, also known as variable hydrates, where the water content is variable and depends on external conditions such as humidity, temperature, and drying conditions. Therefore, other hydrate forms, such as channel hydrates, are also included in the meaning of this term.

[0349] Unless otherwise specified, the compounds of this invention may also exist in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Pharmaceutically acceptable acidic / anionic salts are typically in the form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, dihydroxynaphthyl acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfonic acid, salicylic acid, saccharin, or trifluoroacetic acid, etc. Pharmaceutically acceptable basic / cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc.

[0350] Unless otherwise stated, the term "aqueous type" as used in this invention refers to an anhydrous and solvent-free crystalline form.

[0351] Unless otherwise stated, the term "amorphous" as used in this invention refers to a disordered solid form of molecules and / or ions that is not crystalline. Amorphous forms do not exhibit definite X-ray diffraction patterns with sharp, defined peaks. Unless otherwise stated, the compounds are intended to cover any single solid form of free base, or mixtures of multiple solid forms.

[0352] Polymorphs of compounds can be obtained by many methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation.

[0353] In this invention, the term "therapeutic effective amount" refers to the amount of a compound / crystalline form applied to a therapeutic subject that is sufficient to affect the treatment of a disease, condition, or symptom, or at least one clinical symptom of a disease or symptom. The "therapeutic effective amount" can vary with the compound, the disease, condition, and / or the symptoms of the disease or condition, the severity of the disease, condition, and / or the symptoms of the disease or condition, the age of the patient being treated, and / or the weight of the patient being treated. In any given case, a suitable amount may be obvious to those skilled in the art or may be determined by conventional experiments. In the case of combination therapy, the "therapeutic effective amount" refers to the total amount of the combined treatments that are effective in treating the disease, condition, or symptom.

[0354] All dosage forms of the pharmaceutical compositions of the present invention can be prepared using conventional methods in the pharmaceutical field. For example, the active ingredient is mixed with one or more excipients and then formulated into the desired dosage form.

[0355] "Pharmaceuticalally acceptable excipients" refer to conventional pharmaceutical excipients suitable for the desired drug formulation, such as: diluents and excipients such as water and various organic solvents; fillers such as starch and sucrose; binders such as cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP); humectants such as glycerin; disintegrants such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as hexadecyl alcohol; absorption carriers such as kaolin and bentonite; and lubricants such as talc, calcium stearate, magnesium stearate, and polyethylene glycol. Other pharmaceutically acceptable excipients may also be added to the drug composition, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, flavorings, sweeteners, and dyes. Excipients suitable for the desired dosage form and route of administration are preferred.

[0356] The terms “disease,” “symptom,” or “condition” refer to any disease, discomfort, illness, symptom, or indication.

[0357] The term "multiple" means two or more. For example, "multiple kinds" means "two or more kinds, such as 3, 4, 5, 6, 7, 8, 9, 10, etc." and "more than" means "two or more, such as 3, 4, 5, 6, 7, 8, 9, 10, etc."

[0358] Unless otherwise specified, the compounds of this invention include various types such as free bases, salts, crystal forms, and solvates. The solvates refer to compounds in which solvent molecules participate in the crystal lattice formation of the compound molecules, such as hydrates, tetrahydrofuran solvates, methanol solvates, and ethanol solvates.

[0359] It should be noted that for the same crystal form, the position of the endothermic peak in DSC may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, the position of the endothermic peak may have an error, which can be ±10℃ (e.g., errors can be ±9℃, ±8℃, ±6℃, ±5℃, ±4℃, ±3℃, ±2℃, ±1℃, ±0.5℃). Therefore, this error should be taken into account when determining each crystal form, and anything within this error range is still within the scope of this invention.

[0360] It should be noted that, for the same crystal form, the location of the weight loss temperature in TGA may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, the location of the weight loss temperature may have an error, which can be ±10℃ (e.g., errors could be ±9℃, ±8℃, ±6℃, ±5℃, ±4℃, ±3℃, ±2℃, ±1℃, ±0.5℃, etc.). Therefore, this error should be taken into account when determining each crystal form, and anything within this error range is still within the scope of this invention. Detailed Implementation

[0361] The present invention will be further illustrated by specific embodiments below, but these are not intended to limit the scope of protection of the present invention. Those skilled in the art can make improvements to the preparation method and the instruments used within the scope of the claims, and these improvements should also be considered within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

[0362] Those skilled in the art will understand that XRPD, TGA, DSC, 1 In the acquisition of X-ray NMR spectra, etc., relevant data can be subjected to appropriate scientific processing, such as baseline correction, to reduce errors. Those skilled in the art will also understand that XRPD, TGA, DSC, and other data obtained under different laboratory conditions will vary. 1 Slight differences may exist in the 1H NMR spectra or separation. It should be understood that the XRPD, TGA, DSC, and other spectra of the crystal form provided by this invention may vary. 1 The H NMR spectrum is not limited to the spectrum shown in the attached figure. Crystals with essentially the same spectrum as those shown in the attached figure of this invention fall within the scope of this invention.

[0363] In specific embodiments of the present invention, unless otherwise specified, the techniques or methods described are conventional techniques or methods in the art. The solvents used in the present invention are commercially available, and the raw materials used are not specifically stated to be commercially available products or prepared by conventional techniques or methods.

[0364] Unless otherwise specified, "room temperature" in this invention usually refers to 22°C to 28°C.

[0365] The abbreviations used in this invention are explained as follows:

[0366] XRPD: X-ray powder diffraction

[0367] DSC: Differential Scanning Calorimetry

[0368] TGA: Thermogravimetric Analysis

[0369] 1 H NMR: Liquid proton NMR

[0370] EtOAc: Ethyl acetate

[0371] MTBE: Methyl tert-butyl ether

[0372] ACN: Acetonitrile

[0373] Instruments and methods used for data collection:

[0374] The X-ray powder diffraction patterns described in this invention were acquired using a PANalytical Empyrean X-ray powder diffractometer and a PANalytical X'Pert3 X-ray powder diffractometer.

[0375] The method parameters for PANalytical X'Pert3 and Empyrean X-ray powder diffraction are as follows:

[0376] X-ray type: Cu, Kα

[0377] Kα1 1.540598; Kα2 1.544426

[0378] Kα2 / Kα1 intensity ratio: 0.50

[0379] Voltage: 45 kV

[0380] Current: 40 milliamperes (mA)

[0381] Diverging slit: 1 / 8 degree

[0382] Scanning mode: Continuous

[0383] Scan range: from 3.0 to 40.0 degrees

[0384] Scanning time per step: 46.7 seconds

[0385] Step size: 0.0263 degrees

[0386] The differential scanning calorimetry (DSC) data described in this invention were acquired using a TA Instruments Discovery DSC 2500 / DSC 250 differential scanning calorimeter. The instrument control software was TRIOS, and the analysis software was Universal Analysis. Typically, 1–5 mg of sample was placed in a covered (unless otherwise specified) aluminum crucible. The sample was heated from room temperature to the desired temperature at a rate of 10 °C / min under a 50 mL / min dry N2 atmosphere. Simultaneously, the TA software recorded the heat change of the sample during the heating process.

[0387] The thermogravimetric analysis (TGA) data described in this invention were acquired using a Discovery TGA5500 / TGA 550 thermogravimetric analyzer. The instrument control software was TRIOS, and the analysis software was Universal Analysis. Typically, 1–5 mg of sample was placed in a platinum crucible. Using a segmented high-resolution detection method, the sample was heated from room temperature to 350°C at a heating rate of 10°C / min under the protection of dry N2 at a rate of 50 mL / min. Simultaneously, the TA software recorded the weight change of the sample during the heating process.

[0388] The liquid hydrogen NMR spectrum of this invention 1 H NMR was acquired on a Bruker 400M NMR spectrometer, with DMSO-d6 as the solvent.

[0389] Intermediate 1: 5-(difluoromethyl)-1,3,4-thiadiazole-2-amine

[0390] At 20–25°C, 1,4-dioxane (31.0 kg), aminothiourea (5.0 kg, 54.87 mol), and 2,2-difluoroacetic acid (5.27 kg, 54.87 mol) were added to a 50 L reactor. Then, phosphorus oxychloride (8.41 kg, 54.87 mol) was added through a feeding funnel, with the temperature controlled to not exceed 75°C. A noticeable reaction was observed during the addition of the first half of the phosphorus oxychloride, followed by a slight temperature rise during the addition of the second half. The mixture was stirred at 78–82°C for 7–8 hours. The reaction was monitored by HPLC until complete. The reaction mixture was cooled to 20–30°C, and then water (10.0 kg) was added at 20–30°C, exhibiting a significant exothermic reaction. The resulting clear solution was stirred for 30–40 minutes and then concentrated under reduced pressure at 40–45°C. The residue was washed with water (20.0 kg), and the pH was adjusted to 6-7 with 40% NaOH aq., while maintaining the temperature below 30°C. The resulting slurry was stirred for 0.5-1 h, then filtered. The filter cake was washed with water (2.0 kg) and dried in a forced-air dryer at 45-50°C for 12 h to obtain the target product (7.53 kg, purity 98.9%, yield 90.8%), which was a light yellow solid. 1 H NMR (600MHz, DMSO-d6) δ7.78 (s, 2H), 7.25 (t, J=53.4Hz, J=53.4Hz, 1H).

[0391] Intermediate 2: 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole

[0392] A solution of 5-(difluoromethyl)-1,3,4-thiadiazole-2-amine (13.2 kg, 87.34 mol) in acetonitrile (41.5 kg) and acetic acid (55.4 kg) was prepared and labeled as Solution I.

[0393] Prepare an acetonitrile (30.3 kg) solution of tert-butyl nitrite (13.51 kg, 131.0 mol) and label it as Solution II.

[0394] Solutions I and II were simultaneously pumped into a continuous flow reactor (solution I, flow rate: 176.0 mL / min; solution II, flow rate: 84.0 mL / min; temperature: -20 to -10 °C). The solutions passing through the continuous flow reactor were collected and added to an acetonitrile (31.1 kg) solution of ketone (II) bromide (23.41 kg, 104.81 mol) at 10–20 °C. The mixture was stirred at 20–30 °C for 2–4 h. The reaction was monitored by HPLC until completion. Ammonium hydroxide (22–25%, 48.0 kg) was added to the above reaction mixture at 10–30 °C, resulting in a significant exothermic reaction. The mixture was then stirred for another 2 h. The organic phase was separated, collected, and concentrated under reduced pressure. The residue was diluted with methyl tert-butyl ether (48.8 kg), then washed with ammonium hydroxide (5%, 39.6 kg x 3) and NaCl aq. (20%, 41.2 kg), followed by the addition of activated carbon (2.64 kg) and anhydrous magnesium sulfate (1.32 kg). The resulting mixture was stirred at 20–30 °C for 12 h, filtered, and the filter cake was washed with methyl tert-butyl ether (9.8 kg). The filtrate was collected, concentrated under reduced pressure, and the residue was dried to obtain the target product (13.21 kg, purity 99.6%, yield 70.3%), a light yellow liquid. The reaction flow chart is shown in Figure 43. 1 H NMR (600MHz, DMSO-d6) δ7.58 (t, J=52.8Hz, J=53.4Hz, 1H).

[0395] Intermediate 3: 4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0396] At 15–25°C, tert-butyl 4-oxopiperidinium-1-carboxylate (6.00 kg, 30.1 mol), DMF (15.0 L), triethylamine (7.62 kg, 75.3 mol), and TMSCl (3.93 kg, 36.2 mol) were added to a 100 L reactor. The mixture was heated to 90–95°C and stirred for 12 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to 15–25°C, and then n-butane (12.0 L) was added. The reaction was quenched at 5–15°C by adding a mixture of 8% NaHCO3 aqueous solution (48.0 L) and n-hexane (24.0 L). The aqueous phase was separated, and the organic phase was collected and washed with H2O (30 L x 2) and 10% NaCl (30 L) respectively. The organic phase was concentrated at 40°C under reduced pressure, and the resulting residue (7.35 kg, purity 95.70%, yield 89.9%) was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ4.76(s,1H),3.85-3.84(m,2H),3.51-3.48(m,2H),2.43-2.39(m,2H),1.44(s,9H),0.17(s,9H).

[0397] Intermediate 4: tert-butyl 3-fluoro-4-oxopiperidin-1-carboxylate

[0398] To a 200 L reactor, tert-butyl 4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (6.50 kg, 23.9 mol) and acetonitrile (97.5 L) were added. The mixture was cooled to 0–5 °C, and then 1-chloromethyl-4-fluoro-1,4-diazobicyclo2,2,2-octanebis(tetrafluoroborate) salt (8.48 kg, 23.9 mol) was added in portions at 0–5 °C. After the addition was complete, the mixture was stirred at 0–5 °C for 2 h. The reaction was monitored by TLC until the reaction was complete. The reaction mixture was concentrated under reduced pressure at 35 °C. It was extracted with EtOAc (26.0 L) and 8% sodium bicarbonate aqueous solution (19.5 L). After separating the aqueous phase, NaCl was added until saturation, and then extracted again with EtOAc (19.5 L x 2). The organic phases were combined and concentrated under reduced pressure. The residue was cooled to room temperature, and then n-hexane (58.5 L) was slowly added. The mixture was stirred at room temperature for about 12 h. The mixture was filtered, the solid was collected, washed with n-hexane (6.5 L), and dried in a vacuum drying oven at 20–30 °C for 15 h to obtain the target product (4.7 kg, purity 97.70%, yield 90.4%). 1HNMR (400MHz, CDCl3) δ4.93-4.77(m,1H),4.48(s,1H),4.22-4.17(m,1H),3.31-3.24(m,2H),2.65-2.50(m,2H),1.52(s,9H).

[0399] Intermediate 5: (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester

[0400] Sodium tetraborate decahydrate (3.04 kg, 7.97 mol), isopropylamine (1.47 kg, 24.87 mol), and H₂O (40.00 kg) were added to a 100 L reactor. The pH was adjusted to 10.5 with concentrated hydrochloric acid, and then pyridoxal phosphate (50.0 g, 1.0% wt) and aminotransferase 303 (ATA-303) (100.0 g, 2.0% wt) were added at 20–25 °C. A DMSO solution of tert-butyl 3-fluoro-4-oxopiperidin-1-carboxylate (5.00 kg, 23.02 mol) in 10.0 L was added dropwise at 15–25 °C. After the addition was complete, the mixture was heated to 40–45 °C and stirred for 12 h. The reaction was monitored by HPLC until completion. The reaction mixture was concentrated under reduced pressure, and then 30.0 L of 2-MeTHF, 4.0 kg of sodium chloride aqueous solution (0.8% wt), and 7.5 L of methanol were added. The mixture was cooled to 10–20 °C and stirred for 30 min. The mixture was filtered, and the filter cake was washed with 2-MeTHF (5.0 L x 2). The filtrate was separated, the organic phase was collected, and the aqueous phase was extracted with 2-MeTHF (20.0 L x 2). The organic phases were combined and concentrated under reduced pressure.

[0401] The residue was diluted with DCM (50.0 L) and then cooled to 5–15 °C. At 5–15 °C, a solution of (S)-(+)-O-acetyl-L-mandelic acid (3.13 kg, 16.11 mol) in DCM (25.0 L) was added dropwise and stirred for 2.5 h. The solid was filtered, collected, washed with DCM (10.0 L), and dried in a vacuum drying oven at 20–30 °C for 12 h to obtain crude salt (5.10 kg).

[0402] The crude salt (4.12 kg) was dissolved in 2-MeTHF (33.0 L) and cooled to 10–20 °C. At 10–20 °C, 12.4 L of 20% NaOH solution was added to the mixture, and the mixture was stirred to obtain a clear solution. The organic phase was separated, and the aqueous phase was extracted with 12.4 L of 2-MeTHF. The combined organic phases were washed with 12.4 L of 25% NaCl aqueous solution and concentrated under reduced pressure. The residue (2.12 kg, purity 97.57%, yield 42.2%) was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ4.58-4.46(m,1H),4.09-3.86(m,2H),3.25-2.55(m,3H),1.55-1.51(m,2H),1.44(s,9H).

[0403] Method 2:

[0404] To a 2000 mL round-bottom flask, add 44.0 g (0.20 mol) of tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate and 880.0 mL of EtOH. Heat the reaction mixture to reflux, add (S)-(+)-O-acetyl-L-mandelic acid (23.8 g, 0.12 mol), and stir for at least 2 h. Slowly cool the reaction mixture to 20–25 °C and stir for at least 5 h. Filter, collect the solid, and wash with 88.0 mL of EtOH. Heat the filter cake with the EtOH mixture to reflux and stir for 2 h. Slowly cool the mixture to 20–25 °C and stir for 5 h. Filter, collect the solid, and wash with 88.0 mL of EtOH. Collect the solid and dry it in a vacuum drying oven at 40–50 °C for 15 h to give the target product (16.2 g, yield 19.3%).

[0405] Intermediate 6: (3S,4R)-4-(diethylamino)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester

[0406] At 25–30°C, dichloromethane (6.3 kg) and sodium borohydride acetate (3.2 kg, 15.2 mol) were added to a 50 L reactor. The mixture was cooled to 0–5°C. Then, at 0–5°C, a solution of acetic acid (78.4 g, 1.3 mol) in dichloromethane (2.5 kg) and a solution of (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (950.0 g, 4.35 mol) in dichloromethane (3.8 kg) were added sequentially through a feeding funnel. The mixture was stirred at 0–5°C for 10 min. Then, a solution of acetaldehyde in tetrahydrofuran (5 M, 3.5 L, 17.4 mol) was added at 0–5°C. The mixture was stirred at 0–5°C for 2 h. The reaction was monitored by HPLC until completion. The reaction mixture was quenched with water (4.7 kg) at 0–5 °C, and the pH was adjusted to 9–10 with a 4 M sodium hydroxide aqueous solution. The resulting mixture was stirred at 20–25 °C for 20–30 min. The mixture was separated, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (13.3 kg). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (13.3 kg), filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the target product (1.2 kg, purity 99.3%, yield 100%), a pale yellow liquid. LCMS (ESI) calculated value C 14 H 28 FN2O2[M+H] + m / z = 275.2; Measured value: 275.3.

[0407] Intermediate 7: (3S,4R)-N,N-diethyl-3-fluoropiperidine-4-amine dihydrochloride

[0408] At room temperature, a 1,4-dioxane solution (4M, 5.8L) of HCl was added to a 30L reactor. The solution was heated to 45–50°C, and then a solution of (3S,4R)-4-(diethylamino)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (1.1kg, 4.0mol) in methyl tert-butyl ether (2.1kg) was added through a feeding funnel, while maintaining the temperature below 50°C. The reaction mixture was stirred at 45–50°C for 1 h. The reaction was monitored until complete. The reaction mixture was concentrated to approximately 3.5L under reduced pressure, and then methyl tert-butyl ether (6.0kg) was added. The resulting slurry was stirred at 20–30°C for 1 h, filtered, and the solid was collected, washed with methyl tert-butyl ether (1.7kg), and dried in a vacuum drying oven at 45–50°C for 15 h to obtain the target product (1.0kg, yield 99.1%), which was an off-white solid. 1¹H NMR (400MHz, DMSO-d⁶) δ 5.63 (d, J = 1.6Hz, 1H), 3.91–3.76 (m, 2H), 3.65–3.14 (m, 7H), 2.43–2.39 (m, 1H), 2.26–2.20 (m, 1H), 1.27 (t, J = 7.2Hz, 1H). Calculated LCMS (ESI) m / z values ​​C9H 20 FN2[M+H] + m / z = 175.2; Detected value: 175.2.

[0409] Intermediate 8: 4-(((R)-tert-butylsulfinyl)amino)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester

[0410] To a 2000 mL round-bottom flask, add tert-butyl 3-fluoro-4-oxopiperidin-1-carboxylate (87.9 g, 0.40 mol), THF (790.0 mL), (R)-2-methylpropane-2-sulfinamide (145.4 g, 1.20 mol), and tetraethyl titanate (365.0 g, 1.60 mol). Heat the mixture to reflux and stir for 2 h. Monitor the reaction by HPLC until complete. Cool the reaction mixture to 0–5 °C, then add LiBH4 (9.6 g, 0.44 mol) in portions. After the addition is complete, heat the reaction mixture to room temperature and stir for 2 h. Monitor the reaction by HPLC until complete. Cool the reaction mixture to 0–5 °C, then quench with H2O (439.5 mL) at 0–10 °C, then add EtOAc (879.0 mL) and stir at room temperature for 30–40 min until the solid completely precipitates. The mixture was filtered, and the filtrate was collected. The filter cake was washed with EtOAc (879.0 mL). The organic phases were combined and concentrated under reduced pressure. The residue was dissolved in EtOAc (2.64 L), and the solution was washed accordingly with water (879.0 mL x 3) and saturated NaCl aq. (879.0 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / DCM (20%) to give the target product (75.5 g, yield 57.9%).

[0411] Intermediate 9: tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate

[0412] To a 2000 mL round-bottom flask, add 75.0 g (0.23 mol) of 4-(((R)-tert-butylsulfinyl)amino)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester and i-PrOAc (675.0 mL). Stir the mixture until clear and cool to 0–5 °C. Then, add 100.5 mL (4 M) of HCl / dioxane solution dropwise at 0–5 °C and stir for 4 h at 0–5 °C. Monitor the reaction by HPLC until complete. Filter, collect the solid, and wash with i-PrOAc (150.0 mL). Transfer the filter cake to a 2000 mL round-bottom flask, add 600.0 mL of MTBE, and cool to 0–5 °C. Add 27.9 g of NaOH aqueous solution (172.5 mL of water) dropwise at 0–5 °C. After the addition is complete, heat the mixture to 1 °C and stir for another 1 h. The aqueous phase was separated and extracted with MTBE (600.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (44.8 g, yield 88.3%).

[0413] Intermediate 10: 4-chloro-N-(1-cyanocyclopropyl)-3-nitrobenzenesulfonamide

[0414] Acetonitrile (75.4 kg), 4-chloro-3-nitrobenzenesulfonyl chloride (47.6 kg, 185.9 mol), 1-aminocyclopropyl-1-carboxynitrile hydrochloride (22.1 kg, 185.9 mol), and N,N-dimethylpyridine-4-amine (2.4 kg, 18.5 mol) were added to a 1000 L reactor at room temperature, yielding a dark brown suspension. The mixture was cooled to 0–10 °C, and then pyridine (44.4 kg, 557.7 mol) was added via a peristaltic pump at 0–10 °C over approximately 1.5 h. The reaction mixture was stirred at 10–20 °C for 1 h. The reaction was monitored by HPLC until complete. At 0–15 °C, the reaction mixture was added to water (286.7 kg), and then stirred for 6–8 h. The mixture was filtered, the solid was collected, and washed with water. The filter cake was dried in a vacuum drying oven for 12-20 hours to obtain the target product (43.7 kg, purity 98.7%, yield 78.0%), which was a light yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.58 (s, 1H), 8.51 (d, J = 1.6Hz, 1H), 8.14–8.10 (m, 2H), 1.50–1.48 (m, 2H), 1.34–1.32 (m, 2H). LCMS (ESI) calculated C 10 H7ClN3O4S[MH] - m / z = 300.0; Measured value: 300.0.

[0415] Intermediate 11: 2-Cyano-2-(4-(N-(1-cyanocyclopropyl)aminosulfonyl)-2-nitrophenyl)acetamide

[0416] At room temperature, 82.5 kg of N,N-dimethylformamide and 32.4 kg (579.2 mol) of potassium hydroxide were added to a 1000 L reactor. The reactor was then cooled to -10 to 0 °C. A solution of 2-cyanoacetamide (24.7 kg, 289.6 mol) in N,N-dimethylformamide (62.1 kg) was added via a peristaltic pump, maintaining the temperature between -10 and 0 °C. The mixture was stirred at -10 to 0 °C for 1 h. Then, a solution of 4-chloro-N-(1-cyanocyclopropyl)-3-nitrobenzenesulfonamide (43.7 kg, 144.8 mol) in N,N-dimethylformamide (62.1 kg) was added via a peristaltic pump, maintaining the temperature between -10 and 0 °C. The reaction mixture was stirred at -10 to 0 °C for 12 h. The reaction was monitored by HPLC until completion. The reaction was quenched by slowly adding water (86.8 kg) to the reaction mixture at -10 to 5 °C, and the pH was adjusted to 2 to 3 with 4N HCl aq. The resulting mixture was heated to 10 to 20 °C, and water (437.0 kg) was slowly added. The resulting mixture was stirred at 10 to 20 °C for 12 to 14 h. The filter cake was washed with water (65.2 kg), the solid was collected, and dried in a vacuum drying oven at 45 to 55 °C for 12 to 20 h to obtain the target product (38.6 kg, purity 99.0%, yield 76.3%), which was a brown solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.58 (s, 1H), 8.77 (s, 1H), 8.51 (s, 1H), 8.31 (d, 1H, J = 4.8Hz), 8.04 (t, J = 2.8Hz, 2H), 7.82 (d, J = 6.4Hz, 2H), 7.62 (d, J = 5.6Hz, 1H), 7.41 (d, J = 5.6Hz, 1H), 1.50 (t, J = 1.6Hz, 2H), 1.40 (d, J = 1.2Hz, 2H), 1.30 (d, J = 3.2Hz, 2H), 1.22 (s, 2H). LCMS (ESI) calculated C 13 H 10 N5O5S[MH] - m / z = 348.0; Measured value: 348.8.

[0417] Intermediate 12: 2-amino-6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1H-indole-3-carboxamide

[0418] Method 1: At 0°C, NaH (39.8 g, 994 mmol, 60% suspended in mineral oil) was added to a DMF (750 mL) solution of 41.8 g (497 mmol) of 2-cyanoacetamide. The mixture was stirred at 0°C for 30 min, and then 75.0 g (249 mmol) of 4-chloro-N-(1-cyanocyclopropyl)-3-nitrobenzenesulfonamide was added at 0°C. The mixture was stirred at 20°C for 1 h. The reaction solution was poured into ice water (500 mL) in portions, and the pH was adjusted to approximately 3 with concentrated HCl solution (12N) at 0–5°C. DMF (750 mL) was added to the above solution, and then FeCl3 (120 g, 744 mmol) was added at 20°C. The mixture was heated to 60°C, and then Zn (162 g, 2.48 mol) was added in portions. The mixture was heated to 100°C and stirred for 2 h. The reaction was monitored by LCMS to ensure completion. After cooling, the reaction mixture was filtered through diatomaceous earth. The filtrate was extracted with DCM (500 mL x 6). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EtOAc / PE (0-100%), to give the target product (30.0 g, 18.9% yield) as a yellow frothy substance. LCMS calculated value C 13 H 12 N5O3S[MH] - m / z = 318.1; measured value: 318.0.

[0419] Method 2:

[0420] At room temperature, water (186.1 kg), concentrated HCl (5.6 kg, 106.6 mol), and ammonium chloride (28.6 kg, 533.2 mol) were added to a 1000 L reactor to obtain a clear solution. Then, ethanol (146.9 kg) and 2-cyano-2-(4-(N-(1-cyanocyclopropyl)aminosulfonyl)-2-nitrophenyl)acetamide (37.3 kg, 106.6 mol) were added. The mixture was heated to 70–80 °C to obtain a clear brown solution. Iron powder (29.8 kg, 533.2 mol) was added in batches, controlling the temperature between 65 and 80 °C. The mixture was stirred at 70–80 °C for 2 h. The reaction was monitored by HPLC until complete. The reaction mixture was cooled to 35–45 °C, diatomaceous earth (37.2 kg) was added, and the mixture was filtered. Water was slowly added to the filtrate, causing a solid to precipitate. The solid was filtered, washed with water (30.0 kg), and dried to obtain the target product (22.4 kg, purity 85.1%, yield 65.9%), which was a brown solid. 1¹H NMR (400MHz, DMSO-d⁶) δ 10.96 (s, ¹H), 8.72 (s, ¹H), 7.71 (s, ¹H), 7.59 (s, ¹H), 7.381 (s, ¹H), 7.20 (s, 2H), 6.69 (s, 2H), 1.34 (s, 2H), 1.18 (s, 2H). LCMS (ESI) calculated C 13 H 10 N5O5S[M+H] + m / z = 320.1; measured value: 320.4.

[0421] Intermediate 13: N-(1-cyanocyclopropyl)-4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indole-7-sulfonamide

[0422] Method 1:

[0423] At 20 °C, a concentrated HCl solution (12N, 161 mL) was added to a mixture of 2-amino-6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1H-indole-3-carboxamide (28.0 g, 87.7 mmol) and trimethyl orthoformate (560 mL). The mixture was stirred at 60 °C for 1 h. The consumption of the starting material was monitored by LCMS. The reaction mixture was filtered. The filter cake was dried under vacuum to give the target product (20.0 g, 69.3% yield) as a yellow solid. 1 HNMR: (400MHz, DMSO-d6) δ 12.7 (s, 1H), 12.5 (s, 1H), 9.07 (s, 1H), 8.24 (s, 1H), 8.17 (d, J = 8.0Hz, 1H), 7.96 (s, 1H), 7.71 (d, J = 10.0Hz, 1H), 1.37–1.42 (m, 2H), 1.22–1.27 (m, 2H). LCMS calculated C 14 H 10 N5O3S[MH] - m / z = 328.1; Measured value: 328.1.

[0424] Method 2:

[0425] N-methylpyrrolidone (85.2 kg), 2-amino-6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1H-indole-3-carboxamide (22.4 kg, 70.1 mol), p-toluenesulfonic acid (1.4 kg, 7.0 mol), and trimethyl orthoformate (14.8 kg, 139.5 mol) were added to a 1000 L reactor to obtain a dark brown suspension. The mixture was stirred at 70–80 °C for 1–2 h. The reaction was monitored by HPLC until complete. The reaction mixture was cooled to 30–40 °C, and then acetonitrile (66.2 kg) was added. The mixture was further cooled to 5–15 °C and stirred at 5–15 °C for 1–2 h. The solid was filtered, collected, and then slurried in acetonitrile (99.8 kg) at 30–40 °C for 1–2 h, and then cooled to 5–25 °C. The solid was filtered, collected, washed with acetonitrile (30.0 kg), and dried in a vacuum drying oven at 45–55 °C for 12–20 h to obtain the target product (13.8 kg, purity 99.0%, yield 59.7%), which was a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.68 (s, ¹H), 12.44 (s, ¹H), 9.06 (s, ¹H), 8.25 (s, ¹H), 8.17 (d, J = 3.6Hz, ¹H), 7.96 (s, ¹H), 7.72 (s, ¹H), 1.40 (s, 2H), 1.25 (s, 2H). LCMS (ESI) calculated C 14 H 12 N5O3S[M+H] + m / z = 330.1; Measured value: 330.4.

[0426] Intermediate 14: 4-chloro-N-(1-cyanocyclopropyl)-9H-pyrimido[4,5-b]indole-7-sulfonamide

[0427] Method 1:

[0428] A mixture of N-(1-cyanocyclopropyl)-4-oxo-4,9-dihydro-3H-pyrimidino[4,5-b]indole-7-sulfonamide (18.0 g, 54.7 mmol) and POCl3 (720 mL) was stirred at 100 °C for 16 h. The starting material was monitored by LCMS until consumed. The mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography, eluting with EtOAc / PE (0-100%), to give the target product (10 g, 47.3% yield) as a pale yellow solid. LCMS calculated C 14 H9ClN5O2S[MH] - m / z = 346.0; measured value: 345.9.

[0429] Method 2:

[0430] At room temperature, sulfolane (23.4 kg), N-(1-cyanocyclopropyl)-4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indole-7-sulfonamide (6.2 kg, 18.8 mol), and N,N-dimethylpyridin-4-amine (0.23 kg, 1.88 mol) were added to a 50 L reactor, followed by phosphorus oxychloride (7.22 kg, 47.09 mol). The mixture was heated to 97–103 °C and stirred for 8 h. The reaction was monitored by HPLC until complete. The reaction mixture was cooled to 40–50 °C and concentrated under reduced pressure. The residue was further cooled to 15–25 °C, and then acetonitrile (43.86 kg) was added to obtain a clear, dark brown solution. Water (6.2 kg) was then added at 20–30 °C. The resulting mixture was stirred for 1–2 h, centrifuged, and washed with acetonitrile (4.87 kg). The crude product was slurried with water (31.0 kg) and acetonitrile (24.5 kg), filtered, and a solid was obtained. The filter cake was dried in a forced-air dryer at 45–55 °C for 12–20 h to obtain the target compound (5.37 kg, purity 98.4%, yield 82.0%), which was a light yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 13.23 (s, 1H), 9.29 (s, 1H), 8.89 (s, 1H), 8.51 (d, J = 8.36Hz, 1H), 8.10 (d, J = 0.92Hz, 1H), 7.89 (dd, J = 8.38, 1.44Hz, 1H), 1.44 (d, J = 2.96Hz, 2H), 1.29 (d, J = 2.92Hz, 2H). LCMS (ESI) calculated C 14 H9ClN5O2S[MH] - m / z = 346.0; Measured value: 345.9.

[0431] Intermediate 15: N-(1-cyanocyclopropyl)-4-(methylthio)-9H-pyrimido[4,5-b]indole-7-sulfonamide

[0432] Method 1:

[0433] To a DMF (2 mL) solution of 4-chloro-N-(1-cyanocyclopropyl)-9H-pyrimido[4,5-b]indole-7-sulfonamide (100 mg, 0.3 mmol), NaSMe (35 mg, 0.5 mmol) was added. The reaction mixture was stirred at 100 °C for 2 h. It was then cooled to rt, diluted with water (4 mL), and filtered. The filter cake was dried under reduced pressure to give the target compound (90 mg) as a yellow solid. LCMS calculated Cp 15 H14 N5O2S2[M+H] + m / z = 360.1; measured value: 360.0.

[0434] Method 2:

[0435] At room temperature, N-methylpyrrolidone (10.3 kg) and 4-chloro-N-(1-cyanocyclopropyl)-9H-pyrimido[4,5-b]indole-7-sulfonamide (2.0 kg, 5.75 mol.) were added to a 50 L reactor. The mixture was heated to 95–105 °C to obtain a clear brown solution. The mixture was stirred at 95–105 °C for 2 h, and sodium methanethiol (806.0 g, 11.50 mol.) was added. The reaction was monitored by HPLC until completion. The reaction mixture was cooled to 0–10 °C and then quenched with water (40.0 kg). The pH was adjusted to 6–7 by adding 2N HCl aq. The mixture was filtered, the solid was collected, washed with water (10.0 kg), and dried in a vacuum drying oven at 40–50 °C for 12–20 h to obtain the target product (2.0 kg, purity 98.3%, yield 96.8%), a light yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.87 (s, 1H), 9.22 (s, 1H), 8.88 (s, 1H), 8.29 (d, J = 5.2Hz, 1H), 8.06 (d, J = 0.80Hz, 1H), 7.87 (dd, J = 5.2, 1.2Hz, 1H), 2.81 (s, 3H), 1.43 (t, J = 3.6Hz, 2H), 1.29–1.26 (m, 2H). LCMS (ESI) calculated C 15 H 12 N5O2S2[MH] - m / z = 358.0; Measured value: 358.1.

[0436] Intermediate 16: N-(1-cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(methylthio)-9H-pyrimido[4,5-b]indole-7-sulfonamide

[0437] At room temperature, N,N-dimethylformamide (8.9 kg), acetonitrile (3.7 kg), and N-(1-cyanocyclopropyl)-4-(methylthio)-9H-pyrimido[4,5-b]indole-7-sulfonamide (1.9 kg) were added to a 50 L reactor. The mixture was heated to 50–55 °C, and then cesium carbonate (4.3 kg) was added. At 55–60 °C, 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (1.37 kg) was added, and the reaction mixture was stirred at 62–68 °C for 5 h. The reaction was monitored by HPLC until complete. The reaction mixture was cooled to 0–5 °C. At 0–10 °C, the mixture was quenched with an aqueous citric acid solution (2.0 kg citric acid / 14.3 kg water), and then water (23.8 kg) was added. The mixture was stirred at 0–10 °C for 30–40 min until the precipitate was completely formed. Filter, collect the precipitate, and then further slurry the precipitate in water (9.5 kg). Filter, and further purify the filter cake by slurrying with acetonitrile (5.9 kg) at room temperature. Filter, collect the solid, wash with acetonitrile (1.5 kg), and dry in a vacuum drying oven at 45–50 °C for at least 15 h to obtain the target product (2.2 kg, purity 91.10%, yield 84.3%), as a pale yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.46 (t, J = 6.4Hz, 2H), 9.12 (s, 1H), 8.38 (d, J = 5.6Hz, 1H), 8.14 (dd, J = 5.6, 1.2Hz, 1H), 7.70 (t, J = 35.6Hz, 1H), 1.46–1.45 (m, 2H), 1.30–1.27 (m, 2H), 1.11 (s, 3H). LCMS (ESI) calculated C 18 H 12 F2N7O2S3[MH] - m / z = 492.0; Measured value: 492.0.

[0438] Intermediate 17: 4-chloro-N-(1-cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9H-pyrimido[4,5-b]indole-7-sulfonamide

[0439] Method 1:

[0440] At 0–5 °C, sulfonyl chloride (10.7 g, 101 mmol) was added to a MeCN (100 mL) solution of N-(1-cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(methylthio)-9H-pyrimido[4,5-b]indole-7-sulfonamide (10.0 g, 20.3 mmol, Example 25). The resulting mixture was stirred at rt for 5 h. The precipitate was filtered, collected, washed with MeCN (10 mL x 3), and then dried under reduced pressure to give the target compound (8.2 g) as a yellow solid. LCMS calculated value C 17 H 11 ClF2N7O2S2[M+H] + m / z = 482.0. Measured value: 482.1.

[0441] Method 2:

[0442] At room temperature, N-(1-cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(methylthio)-9H-pyrimido[4,5-b]indole-7-sulfonamide (1.0 kg) and sulfolane (6.3 kg) were added to a 50 L reactor. The mixture was stirred at room temperature for 10–15 min, and then acetonitrile (15.7 kg) was added. After stirring for 10–15 min, sulfonyl chloride (2.2 kg) was added via a peristaltic pump at 30–35 °C over approximately 20 min. The reaction mixture was stirred at 30–35 °C for 30 min until it became a clear solution. The reaction was monitored by HPLC until the reaction was complete. The reaction mixture was cooled to 0–10 °C, and then 20.0 kg was slowly added while maintaining the temperature below 10 °C. The resulting slurry was stirred at 0–10 °C for 30–40 min. The solid was filtered and collected, then further stirred in water (15.0 kg). The solid was filtered again and collected, then slurried in water (15.0 kg) until the pH of the solid was between 5 and 7. The resulting solid was further slurried in acetonitrile (3.9 kg), filtered, and washed with acetonitrile (1.6 kg). The filter cake was collected and dried in a vacuum drying oven at 40–45 °C for 15 h to obtain the target product (786 g, purity 96.24%, yield 80.4%), which was an off-white solid. 1¹H NMR (400MHz, DMSO-d⁶) δ 9.56(s, 1H), 9.51(s, 1H), 9.24(s, 1H), 8.71(d, J = 5.6Hz, 1H), 8.17(dd, J = 5.6, 0.8Hz, 1H), 7.72(t, J = 35.6Hz, 1H), 1.48–1.46(m, 2H), 1.30–1.28(m, 2H). LCMS (ESI) calculated C 17 H9ClF2N7O2S2[MH] - m / z = 480.0; Measured value: 480.0.

[0443] Intermediate 18: N-(1-cyanocyclopropyl)-4-((3S,4R)-4-(diethylamino)-3-fluoropiperidin-1-yl)-9H-pyrimido[4,5-b]indole-7-sulfonamide

[0444] Acetonitrile (240 mL), (3S,4R)-N,N-diethyl-3-fluoropiperidin-4-amine dihydrochloride (10.2 g, 41.3 mmol), and 4-chloro-N-(1-cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9H-pyrimido[4,5-b]indole-7-sulfonamide (12.0 g, 34.5 mmol) were added to a 500 mL round-bottom three-necked flask at 20–30 °C. Then, N,N-diisopropylethylamine (15.6 g, 120.8 mmol) was added through a feeding funnel at 20–30 °C. The mixture was stirred at 75–80 °C for 3 h. The reaction was monitored by HPLC until complete. The reaction mixture was concentrated under reduced pressure, and then water (180 mL) was added at 20–30 °C. The resulting slurry was adjusted to pH 8-9 with a saturated sodium carbonate aqueous solution. The slurry was stirred at 0-10℃ for 30-40 min. After filtration, the solid was collected and washed with water (60 mL). The solid was then re-slurried with water (120 mL). After filtration, the filter cake was dried in a vacuum drying oven at 40-45℃ for 15 h to obtain the target product (15.1 g, purity 95.13%, yield 90.1%), a light yellow solid. LCMS (ESI) calculated value C. 23 H 27 FN7O2S[MH] - m / z = 484.2; Measured value: 484.2.

[0445] Intermediate 19: N-(1-cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(methylsulfonyl)-9H-pyrimido[4,5-b]indole-7-sulfonamide

[0446] Method 1:

[0447] To a 50 mL round-bottom flask, add N-methylpyrrolidone (1 mL) and N-(1-cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(methylthio)-9H-pyrimido[4,5-b]indole-7-sulfonamide (100 mg, 0.20 mmol). Cool the mixture to 0–5 °C, then add 3-chloroperoxybenzoic acid (105 mg, 0.61 mmol). Stir the mixture at rt for 1 h, then quench with an aqueous sodium carbonate solution (2 mL). Extract the resulting mixture with dichloromethane (5 mL x 2). Combine the organic phases, wash with water (2 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is further purified by Prep-HPLC on a C18 column, eluting with acetonitrile / water (50–74%) to obtain the target product (63 mg). LCMS (ESI) calculated value C 18 H 12 F2N7O4S3[MH] - m / z = 524.0; measured value: 524.1.

[0448] Method 2:

[0449] At room temperature, N,N-dimethylformamide (2.5 mL), acetonitrile (1.25 mL), cesium carbonate (1.04 g, 3.20 mmol), and N-(1-cyanocyclopropyl)-4-(methanesulfonyl)-9H-pyrimido[4,5-b]indole-7-sulfonamide (500 mg, 1.28 mmol) were added to a 25 mL round-bottom three-necked flask, followed by the addition of 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (330 mg, 1.53 mmol). The mixture was stirred at 60–70 °C for 5 h. The reaction was monitored by HPLC until complete. The reaction mixture was filtered through diatomaceous earth, and the filtrate was directly purified by Prep-HPLC on a C18 column, eluting with acetonitrile / water (20–50%) to give the target product (130 mg, purity 98.12%, yield 19.4%) as a white solid. LCMS (ESI) calculated value C 18 H 12 F2N7O4S3[MH] - m / z = 524.0; measured value: 524.1.

[0450] Intermediate 20: N-(1-cyanocyclopropyl)-4-(methanesulfonyl)-9H-pyrimido[4,5-b]indole-7-sulfonamide

[0451] At room temperature, dimethyl sulfoxide (1 mL), 4-chloro-N-(1-cyanocyclopropyl)-9H-pyrimido[4,5-b]indole-7-sulfonamide (100 mg, 0.29 mmol), potassium phosphate (91 mg, 0.43 mmol), cuprous iodide (5.7 mg, 0.029 mmol), L-proline (3.5 mg, 0.03 mmol), and sodium methyl sulfinate (67.9 mg, 0.58 mmol) were added to a 50 mL round-bottom flask. The mixture was degassed and purged with nitrogen three times. The mixture was stirred at 60 °C for 1 h. The reaction mixture was filtered through diatomaceous earth and washed with dimethyl sulfoxide (2 mL). The filtrate was collected and directly purified by Prep-HPLC on a C18 column, eluting with acetonitrile / water (40–47%) to give the target product (50 mg, 99% purity, 44.4% yield). LCMS (ESI) calculated value C 15 H 12 N5O4S2[MH] - m / z = 390.0; measured value: 390.1.

[0452] Example I: N-(1-cyanocyclopropyl)-4-((3S,4R)-4-(diethylamino)-3-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9H-pyrimidino[4,5-b]indole-7-sulfonamide

[0453] Method 1:

[0454] At room temperature, N,N-dimethylformamide (35 mL), acetonitrile (17.5 mL), cesium carbonate (14.1 g, 43.2 mmol), and N-(1-cyanocyclopropyl)-4-((3S,4R)-4-(diethylamino)-3-fluoropiperidin-1-yl)-9H-pyrimido[4,5-b]indole-7-sulfonamide (7.0 g, 14.4 mmol) were added to a 100 mL round-bottom three-necked flask, followed by 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (9.30 g, 43.3 mmol). The reaction mixture was stirred at 20–30 °C for 16 h. The reaction was monitored by HPLC until complete. The reaction mixture was cooled to 0–5 °C, quenched with an aqueous citric acid solution (5.5 g citric acid, 310 mL water), and then water (70 mL) was added. The mixture was stirred until the solid precipitated completely. The solid was filtered, collected, and recrystallized in N,N-dimethylformamide / water (17.5 mL / 17.5 mL). The recrystallized solid was further slurried with ethyl acetate (21 mL) at 70–80 °C for 1 h, followed by dropwise addition of methyl tert-butyl ether (21 mL). The solid was filtered, collected, washed with methyl tert-butyl ether (14 mL), and dried in a vacuum drying oven at 45–50 °C for 15 h to obtain the target product (4.5 g, purity 98.12%, yield 50.6%), as an off-white solid. LCMS (ESI) calculated value C 26 H 27 F3N9O2S2[MH] - m / z = 618.2; measured value: 618.1.

[0455] Method 2:

[0456] At 20–30 °C, acetonitrile (1 mL), (3S,4R)-N,N-diethyl-3-fluoropiperidin-4-amine dihydrochloride (50 mg, 0.2 mmol), and N-(1-cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(methanesulfonyl)-9H-pyrimidino[4,5-b]indole-7-sulfonamide (100 mg, 0.19 mmol) were added to a 50 mL round-bottom flask. Then, N,N-diisopropylethylamine (86 mg, 0.67 mmol) was added. The mixture was stirred at 20–30 °C for 3 h. The reaction was monitored by HPLC until complete. The reaction mixture was purified directly on a C18 column by Prep-HPLC, eluting with acetonitrile / water (40–60%) to give the target product (30 mg, purity 98.89%, yield 25.4%) as a white solid. LCMS (ESI) calculated value C 26 H 27 F3N9O2S2[MH] -m / z = 618.2; measured value: 618.1.

[0457] Example 1: Preparation of the compound (N-(1-cyanocyclopropyl)-4-((3S,4R)-4-(diethylamino)-3-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9H-pyrimidino[4,5-b]indole-7-sulfonamide) crystal form A of formula (I)

[0458] At 20–30°C, acetonitrile (10.5 kg), (3S,4R)-N,N-diethyl-3-fluoropiperidin-4-amine dihydrochloride (484.8 g), N,N-diisopropylethylamine (844.8 g), and 4-chloro-N-(1-cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9H-pyrimido[4,5-b]indole-7-sulfonamide (900.1 g) were added to a 50 L reactor. The reaction mixture was stirred at 20–30°C for 4 h. The reaction was monitored by HPLC until complete. The reaction mixture was concentrated to 4–5 volumes under reduced pressure at 40–45°C, and then water (13.5 kg) was added at 20–30°C. The resulting slurry was adjusted to pH 8–9 with saturated sodium carbonate solution at 20–30°C. The obtained slurry was cooled to 0–10°C and stirred at 0–10°C for 30–40 min. The mixture was filtered, and the solid was collected. It was then washed with water (4.5 kg) at 20–30°C for 30–40 min. The filter cake was dissolved in THF (4.0 kg) at 50–60°C until a clear solution was obtained. Ethanol (7.1 kg) was then added through a funnel at 50–60°C. The resulting slurry was gradually cooled to 20–25°C and stirred for another 30–40 min. The mixture was filtered, and the solid was collected. The obtained solid was dried in a vacuum drying oven at 40–45°C for 15 h to obtain the target product (888 g, purity 98.43%, yield 76.7%), which was an off-white solid. 1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),9.49(s,1H),8.78(s,1H),8.15(d,J=5.6Hz,1H) ,8.05(dd,J=5.6Hz,J=1.2Hz,1H,),7.68(t,J=35.6Hz,1H),5.08(d,1H),4.57-4.48(m ,2H), 3.73-3.64(m,1H), 3.30-3.28(m,1H), 3.03-2.95(m,1H), 2.69-2.60(m,4H), 2.21-2.15(m,1H), 1.85-1.82(m,1H), 1.45-1.43(m,2H), 1.30-1.27(m,2H), 0.99(m,6H). LCMS(ESI) calculated value C 26 H 27 F3N9O2S2[MH] - m / z = 618.2; measured value: 618.1.

[0459] X-ray powder diffraction was performed using Cu-Kα radiation, which showed that the compound of formula (I) prepared in this example was in crystalline form, denoted as crystal form A, and had an XRPD pattern that was essentially as shown in Figure 1. The representative characteristic diffraction angle 2θ and relative intensity are shown in Table 1.

[0460] Table 1

[0461] Example 2: Preparation of crystal form B of the compound shown in formula (I) (stirring method)

[0462] Weigh 25.4 mg of the compound (I) crystal form A and place it in an HPLC glass bottle. Add 0.5 mL of ACN (acetonitrile). Stir at room temperature for 4 days (speed: 1000 rpm). Separate the solid and dry it under vacuum at room temperature for 5 hours to obtain the solid of the compound (I).

[0463] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the solid compound of formula (I) prepared in this example was in crystalline form, denoted as crystal form B, and had the XRPD spectrum shown in Figure 2. The representative characteristic diffraction peaks and relative intensities are shown in Table 2.

[0464] Table 2

[0465] Example 3: Preparation of crystal form A of the compound shown in formula (II) (stirring method)

[0466] Weigh 7.7 mg of p-toluenesulfonic acid and 25.0 mg of the compound of formula (I) crystal form A, place them in an HPLC glass bottle, add 0.5 mL of EtOAc, stir at room temperature for 4 days (1000 rpm), separate the solid, and dry under vacuum at room temperature for 5 hours to obtain the target solid. 1 The H NMR results (as shown in Figure 3a) indicate that the molar ratio of p-toluenesulfonic acid to free base in the target solid is 1:1.

[0467] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the solid compound (II) prepared in this example was in crystalline form, denoted as crystal form A, and had the XRPD spectrum shown in Figure 3. The representative characteristic diffraction peaks and relative intensities are shown in Table 3.

[0468] Table 3

[0469] Example 4: Preparation of p-toluenesulfonate crystal form B (stirring method)

[0470] Method 1: Weigh 7.7 mg of p-toluenesulfonic acid and 24.8 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of ACN to the HPLC vial. Stir at room temperature for 4 days (1000 rpm), then separate the solid and dry it under vacuum at room temperature for 5 hours to obtain the target solid.

[0471] Method 2: At 20–30°C, add acetone (5.5 kg), 2-butanone (5.6 kg), and N-(1-cyanocyclopropyl)-4-((3S,4R)-4-(diethylamino)-3-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9H-pyrimido[4,5-b]indole-7-sulfonamide (700.0 g) to a 50 L reactor. At 48–53°C, add p-toluenesulfonic acid monohydrate (214.8 g). Stir the reaction mixture at 48–53°C for 10–15 min, and slowly cool the resulting slurry to 20–30°C. Stir the mixture at 20–30°C for 15–16 h. Filter, collect the solid, and wash with acetone (1.1 kg). The filter cake was dried in a vacuum drying oven at 70–75 °C for 15–16 h to obtain the target product (800.1 g, 98.97% purity, 89.5% yield), which was an off-white solid. 1 The 1H NMR results (as shown in Figure 4a) indicate that the molar ratio of p-toluenesulfonic acid to free base in the solid is 1:1.

[0472] X-ray powder diffraction was performed using Cu-Kα radiation to determine that the compound p-toluenesulfonate of formula (I) is in crystalline form, represented by crystal form B, and has the XRPD spectrum shown in Figure 4, the TGA spectrum shown in Figure 5, and the DSC spectrum shown in Figure 6. Its representative characteristic diffraction peaks and relative intensities are shown in Table 4.

[0473] Table 4

[0474] Example 5: Preparation of p-toluenesulfonate crystal form C (suspension stirring method)

[0475] Weigh 21.5 mg of the compound (II) crystal form B at room temperature and place it in an HPLC glass bottle. Add 0.5 mL of CHCl3 and suspend and stir at 50 °C for 3 days (1000 rpm). Then centrifuge at room temperature (10000 rpm, 2 min) to remove the supernatant and air dry at room temperature for about 4 days to obtain the target solid.

[0476] X-ray powder diffraction was performed using Cu-Kα radiation, which showed that the compound of formula (II) prepared in this example is a new crystal form, represented by crystal form C, and has the XRPD spectrum shown in Figure 8. Its representative characteristic diffraction peaks and relative intensities are shown in Table 5.

[0477] Table 5

[0478] Example 6: Preparation of p-toluenesulfonate crystal form D (slow cooling method)

[0479] 22.5 mg of compound B (formula II) was weighed at room temperature and placed in a 3 mL glass bottle. 1.0 mL of MeOH was added to obtain a suspension. The suspension was stirred at 50 °C (1000 rpm) for about 2 hours to obtain a clear solution. The solution was filtered through a 0.45 μm PTFE membrane, and the filtrate was collected. The resulting clear solution was cooled from 50 °C to 5 °C (0.1 °C / min) and then maintained at 5 °C. After 2 days at 5 °C, the solution became clear. After 1 day at -20 °C, a solid precipitated. A wet sample (without removing the supernatant) was taken at room temperature for XRPD testing.

[0480] X-ray powder diffraction was performed using Cu-Kα radiation, which showed that the compound of formula (II) prepared in this example was a new crystal form, represented by crystal form D, and had the XRPD spectrum shown in Figure 9. Its representative characteristic diffraction peaks and relative intensities are shown in Table 6.

[0481] Table 6

[0482] Example 7: Preparation of p-toluenesulfonate crystal form E (slow cooling and volatilization method)

[0483] 20.2 mg of compound B (formula II) was weighed at room temperature and placed in a 3 mL glass bottle. 2.0 mL of THF / H₂O (2:1, v / v) was added to obtain a suspension. The suspension was stirred at 50 °C (1000 rpm) for approximately 2 hours to obtain a clear solution, which was then filtered through a 0.45 μm PTFE membrane. The resulting clear solution was cooled from 50 °C to 5 °C (0.1 °C / min) and maintained at 5 °C. The sample became clear after 2 days at 5 °C, and was then allowed to slowly evaporate at room temperature for 1 day to obtain a solid. A wet sample (without removing the supernatant) was taken at room temperature for XRPD testing.

[0484] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the compound of formula (II) prepared in this example is a new crystal form, represented by crystal form E, and has the XRPD spectrum shown in Figure 10. Its representative characteristic diffraction peaks and relative intensities are shown in Table 7.

[0485] Table 7

[0486] Example 8: Preparation of p-toluenesulfonate crystal form F (antisolvent addition method)

[0487] Weigh 19.8 mg of compound B (formula II) at room temperature into a 20 mL glass bottle, add 0.7 mL of DMSO, dissolve the solid completely, and filter through a 0.45 μm PTFE membrane. While stirring (1000 rpm), add 10.0 mL of the antisolvent IPAc (isopropyl acetate). The sample becomes clear at room temperature. After stirring at 5 °C for 1 day, a solid precipitates. Transfer the sample to a 4 mL centrifuge tube, centrifuge (10000 rpm, 2 min), discard the supernatant, and take a wet sample at room temperature for XRPD testing.

[0488] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the compound of formula (II) prepared in this example is a new crystal form, represented by crystal form F, and has the XRPD spectrum shown in Figure 11. Its representative characteristic diffraction peaks and relative intensities are shown in Table 8.

[0489] Table 8

[0490] Example 9: Preparation of p-toluenesulfonate crystal form G (antisolvent addition method)

[0491] Weigh 20.7 mg of compound B (formula II) at room temperature into a 20 mL glass bottle, add 0.7 mL of NMP (N-methylpyrrolidone), dissolve the solid completely, and filter through a 0.45 μm PTFE membrane. While stirring (1000 rpm), add 8.0 mL of the antisolvent MTBE (methyl tert-butyl ether). The sample gels at room temperature. After stirring for 1 day under cyclic heating and cooling conditions (50℃~5℃, 0.1℃ / min), a solid precipitates. Transfer the sample to a 4 mL centrifuge tube, centrifuge (10000 rpm, 2 min), discard the supernatant, and take a wet sample at room temperature for XRPD testing.

[0492] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the compound p-toluenesulfonate of formula (II) prepared in this embodiment is in crystalline form, denoted as crystal form G, and has the XRPD spectrum shown in Figure 12. Its representative characteristic diffraction peaks and relative intensities are shown in Table 9.

[0493] Table 9

[0494] Example 10: Preparation of p-toluenesulfonate crystal form H (nitrogen purging method)

[0495] At room temperature, a suitable amount of the compound crystal form A shown in formula (II) was placed on a silicon wafer and purged for 20 minutes under the protection of dry N2. XRPD was then tested in situ.

[0496] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the compound of formula (II) prepared in this example is a new crystal form, represented by crystal form H, and has the XRPD spectrum shown in Figure 13. Its representative characteristic diffraction peaks and relative intensities are shown in Table 10.

[0497] Table 10

[0498] Example 11: Preparation of p-Toluenesulfonate crystal form I (antisolvent addition method)

[0499] Weigh 20.4 mg of compound B (formula II) at room temperature into a 20 mL glass bottle, add 2.0 mL of MeOH, dissolve the solid completely, and filter through a 0.45 μm PTFE membrane. While stirring (1000 rpm), add 10.0 mL of the antisolvent ACN dropwise to the clear solution. The sample becomes clear at room temperature, then clears again after stirring at 5°C for 1 day, then clears again after stirring at -20°C for 1 day, and finally precipitates as a solid after slow evaporation at room temperature for 4 days. A wet sample (without removing the supernatant) is taken at room temperature for XRPD testing.

[0500] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the compound of formula (II) prepared in this example is in crystalline form, denoted as crystal form I, and has the XRPD spectrum shown in Figure 14. Its representative characteristic diffraction peaks and relative intensities are shown in Table 11.

[0501] Table 11

[0502] Example 12: Preparation of p-toluenesulfonate crystal form J (heating method)

[0503] Weigh an appropriate amount of the compound in crystal form C of formula (II) at room temperature and place it in a covered aluminum crucible. Raise the sample from room temperature to 200°C at a heating rate of 10°C / min under the protection of dry N2 at 50 mL / min, maintain for 3 minutes, and then lower the sample from 200°C to room temperature at a cooling rate of 30°C / min under the protection of dry N2 at 50 mL / min. Collect the solid at room temperature.

[0504] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the compound of formula (II) prepared in this embodiment is in crystalline form, denoted as crystal form J, and has the XRPD spectrum shown in Figure 15. The representative characteristic diffraction peaks and relative intensities are shown in Table 12.

[0505] Table 12

[0506] Example 13: Preparation of p-toluenesulfonate crystal form K (reactive crystallization method)

[0507] Weigh 50.0 mg of compound A (formula I) at room temperature and dissolve it in 1.0 mL of acetone. Add 40 μL of EtOH and stir at room temperature for 10 min (1000 rpm) to form a solution. Separately weigh 7.8 mg of p-toluenesulfonic acid and dissolve it in 0.1 mL of acetone. Add the acetone solution of p-toluenesulfonic acid dropwise to the acetone / ethanol solution of compound A (formula I) at room temperature. Stir at room temperature for about 10 min to precipitate a solid. Centrifuge at room temperature (10000 rpm, 2 min) and take the wet sample (without removing the supernatant) to coat the solid for XRPD testing.

[0508] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the compound of formula (II) prepared in this example is a new crystal form, represented by crystal form K, and has the XRPD spectrum shown in Figure 16. Its representative characteristic diffraction peaks and relative intensities are shown in Table 13.

[0509] Table 134

[0510] Example 14: Preparation of fumarate crystal form A (stirring method)

[0511] Weigh 2.4 mg of fumaric acid and 24.9 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of LEtOAc to the HPLC vial. Stir at room temperature for 1 day (1000 rpm), centrifuge (10000 rpm, 2 min) to remove the supernatant, and vacuum dry the solid at room temperature for 15 hours to obtain the target solid.

[0512] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the fumarate compound (I) prepared in this embodiment is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 17a. Representative characteristic diffraction peaks and relative intensities are shown in Table 14. Its TGA is shown in the attached figure. Its DSC is shown in Appendix 17c.

[0513] Table 14

[0514] Example 15: Preparation of fumarate crystal form B (stirring method)

[0515] Weigh 4.7 mg of fumaric acid and 25.0 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of ACN to the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0516] X-ray powder diffraction (XRD) using Cu-Kα radiation revealed that the compound (I) prepared in this embodiment, representing fumarate, is a novel crystalline form, denoted as crystal form B, and exhibits the XRPD spectrum shown in Figure 18a. Representative characteristic diffraction peaks and relative intensities are shown in Table 15. Its TGA is shown in the attached figure. Its DSC is shown in Figure 18c. 1 The H NMR results (as shown in Figure 18d) indicate that the molar ratio of fumaric acid to the compound shown in formula (I) in the crystal form of this example is 1:1.

[0517] Table 15

[0518] Example 16: Preparation of tartrate crystal form A (stirring method)

[0519] Weigh 3.1 mg of tartaric acid and 24.8 mg of the compound of formula (I) crystal form A (acid / base 0.5:1) at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of EtOAc to the HPLC vial. Stir at room temperature for 1 day (1000 rpm), then centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 15 hours to obtain the target solid.

[0520] X-ray powder diffraction (XRD) using Cu-Kα radiation revealed that the tartrate salt of formula (I) prepared in this example is in crystalline form, denoted as crystal form A, and exhibits the XRPD spectrum shown in Figure 19a. Representative characteristic diffraction peaks and relative intensities are shown in Table 16. Its TGA is shown in Figure 19b. Its DSC is shown in Figure 19c. ¹H NMR results (Figure 19d) indicate that the molar ratio of tartaric acid to the compound of formula (I) in this example crystal form is 0.5:1.

[0521] Table 16

[0522] Example 17: Preparation of tartrate crystal form B (stirring method)

[0523] Weigh 3.1 mg of tartaric acid and 24.8 mg of the compound of formula (I) crystal form A (acid / base 0.5:1) at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of MTBE to the HPLC vial and stir at room temperature for 1 day (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 15 hours to obtain the target solid.

[0524] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the tartrate compound (I) prepared in this embodiment is in crystalline form, denoted as crystal form B, and has the XRPD spectrum shown in Figure 20a. Representative characteristic diffraction peaks and relative intensities are shown in Table 17. Its TGA is shown in the attached figure. Its DSC is shown in Figure 20c.

[0525] Table 5

[0526] Example 18: Preparation of hydrochloride crystal form A (stirring method)

[0527] Weigh 24.9 mg of the compound (I) crystal form A at room temperature and place it in an HPLC glass bottle. Add 0.5 mL of ACN and 3.4 μL of 12 M HCl solution to the HPLC glass bottle. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0528] X-ray powder diffraction was performed using Cu-Kα radiation to determine that the compound hydrochloride shown in formula (I) is in crystalline form, represented by crystal form A, and has the XRPD spectrum shown in Figure 21. Its representative characteristic diffraction peaks and relative intensities are shown in Table 18.

[0529] Table 6

[0530] Example 19: Preparation of sulfate crystal form A (stirring method)

[0531] Weigh 25.1 mg of the compound (I) crystal form A as shown in formula (I) into an HPLC glass bottle at room temperature, add 0.5 mL of MTBE, add 10.1 μL of 4 M H2SO4 solution into the HPLC vial, stir at room temperature for 4 days (1000 rpm), centrifuge (10000 rpm, 2 min) to remove the supernatant, and vacuum dry the solid at room temperature for 5 hours to obtain the target solid.

[0532] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the sulfate compound (I) prepared in this embodiment is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 22. The representative characteristic diffraction peaks and relative intensities are shown in Table 19.

[0533] Table 7

[0534] Example 20: Preparation of sulfate crystal form B (stirring method)

[0535] Weigh 25.1 mg of the compound (I) crystal form A at room temperature and place it in an HPLC glass bottle. Add 0.5 mL of ACN and 10.1 μL of 4 M H2SO4 solution to the HPLC vial. Stir at room temperature for 4 days (1000 rpm), centrifuge (10000 rpm, 2 min) to remove the supernatant, and dry the solid under vacuum at room temperature for 5 hours.

[0536] X-ray powder diffraction was performed using Cu-Kα radiation, which showed that the sulfate compound shown in formula (I) was a new crystal form, represented by crystal form B, and had the XRPD spectrum shown in Figure 23. Its representative characteristic diffraction peaks and relative intensities are shown in Table 20.

[0537] Table 20

[0538] Example 21: Preparation of phosphate crystal form A (stirring method)

[0539] Weigh 24.9 mg of the compound (I) crystal form A as shown in formula (I) into an HPLC glass bottle at room temperature, add 0.5 mL of ACN, add 2.7 μL of 15 M H3PO4 solution into the HPLC vial, stir at room temperature for 4 days (1000 rpm), centrifuge (10000 rpm, 2 min) to remove the supernatant, and vacuum dry the solid at room temperature for 5 hours to obtain the target solid.

[0540] X-ray powder diffraction (XRD) was performed using Cu-Kα radiation to determine that the phosphate compound (I) prepared in this embodiment is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 24. Its representative characteristic diffraction peaks and relative intensities are shown in Table 21.

[0541] Table 21

[0542] Example 22: Preparation of maleate crystal form A (stirring method)

[0543] Weigh 4.7 mg of maleic acid and 25.1 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of EtOAc to the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0544] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the maleate of formula (I) prepared in this embodiment is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 25. The representative characteristic diffraction peaks and relative intensities are shown in Table 22.

[0545] Table 22

[0546] Example 23: Preparation of maleate crystal form B (stirring method)

[0547] Weigh 4.7 mg of maleic acid and 25.1 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of MTBE to the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0548] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the maleate of formula (I) prepared in this example is a new crystal form, denoted as crystal form B, and has the XRPD spectrum shown in Figure 26. Its representative characteristic diffraction peaks and relative intensities are shown in Table 23.

[0549] Table 23

[0550] Example 24: Preparation of maleate crystal form C (stirring method)

[0551] Weigh 4.7 mg of maleic acid and 25.0 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of ACN to the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0552] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the maleate of formula (I) prepared in this example is a new crystal form, represented by crystal form C, and has the XRPD spectrum shown in Figure 27. Its representative characteristic diffraction peaks and relative intensities are shown in Table 24.

[0553] Table 24

[0554] Example 25: Preparation of mucilage crystal form A (stirring method)

[0555] Weigh 8.5 mg of viscous acid and 24.9 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of ACN to the HPLC vial. Stir at room temperature for 4 days (1000 rpm), centrifuge (10000 rpm, 2 min) to remove the supernatant, and dry the solid under vacuum for 5 hours to obtain the target solid.

[0556] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the viscous acid salt of formula (I) prepared in this embodiment is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 28. The representative characteristic diffraction peaks and relative intensities are shown in Table 25.

[0557] Table 25

[0558] Example 26: Preparation of citrate crystal form A (stirring method)

[0559] Weigh 8.6 mg of citric acid and 25.0 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of ACN to the HPLC vial. Stir at room temperature for 4 days (1000 rpm), centrifuge (10000 rpm, 2 min) to remove the supernatant, and dry the solid under vacuum for 5 hours to obtain the target solid.

[0560] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the citrate compound (I) prepared in this example is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 29. Its representative characteristic diffraction peaks and relative intensities are shown in Table 26.

[0561] Table 26

[0562] Example 27: Preparation of malate crystal form A (stirring method)

[0563] Weigh 5.6 mg of malic acid and 25.0 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of MTBE to the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum for 5 hours to obtain the target solid.

[0564] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the malate compound (I) prepared in this embodiment is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 30. The representative characteristic diffraction peaks and relative intensities are shown in Table 27.

[0565] Table 27

[0566] Example 28: Preparation of malate crystal form B (stirring method)

[0567] Weigh 5.5 mg of malic acid and 25.1 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of ACN to the HPLC vial. Stir at room temperature for 4 days (1000 rpm), centrifuge (10000 rpm, 2 min) to remove the supernatant, and dry the solid under vacuum for 5 hours to obtain the target solid.

[0568] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the compound malate prepared in this example (I) is a new crystalline form, denoted as crystal form B, and has the XRPD spectrum shown in Figure 31. Its representative characteristic diffraction peaks and relative intensities are shown in Table 28.

[0569] Table 28

[0570] Example 29: Preparation of hippurate crystal form A (stirring method)

[0571] Weigh 7.3 mg hippuric acid and 25.1 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of ACN to the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0572] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the hippurate compound (I) prepared in this embodiment is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 32a. Representative characteristic diffraction peaks and relative intensities are shown in Table 29. Its TGA is shown in Figure 32b, and its DSC is shown in Figure 32c.

[0573] Table 29

[0574] Example 30: Preparation of lactate crystal form A (stirring method)

[0575] Weigh 3.7 mg of L-lactic acid at room temperature and place it in an HPLC glass bottle. Add 0.5 mL of EtOAc. Weigh 25.1 mg of the compound (I) crystal form A in the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0576] X-ray powder diffraction was performed using Cu-Kα radiation to determine that the compound lactate shown in formula (I) is in crystalline form, represented by crystal form A, and has the XRPD spectrum shown in Figure 33. Its representative characteristic diffraction peaks and relative intensities are shown in Table 30.

[0577] Table 30

[0578] Example 31: Preparation of lactate crystal form B (stirring method)

[0579] Weigh 3.7 mg of L-lactic acid at room temperature and place it in an HPLC glass bottle. Add 0.5 mL of MTBE. Weigh 25.1 mg of the compound (I) crystal form A in the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0580] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the lactate compound (I) prepared in this embodiment is in crystalline form, denoted as crystal form B, and has the XRPD spectrum shown in Figure 34. Its representative characteristic diffraction peaks and relative intensities are shown in Table 31.

[0581] Table 31

[0582] Example 32: Preparation of succinate crystal form A (stirring method)

[0583] Weigh 4.8 mg of succinic acid and 25.2 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of EtOAc to the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0584] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the succinate compound (I) prepared in this embodiment is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 35. Its representative characteristic diffraction peaks and relative intensities are shown in Table 32.

[0585] Table 32

[0586] Example 33: Preparation of succinate crystal form B (stirring method)

[0587] Weigh 4.8 mg of succinic acid and 25.2 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of ACN to the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0588] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the succinate compound (I) prepared in this embodiment is in crystalline form, denoted as crystal form B, and has the XRPD spectrum shown in Figure 36. Its representative characteristic diffraction peaks and relative intensities are shown in Table 33.

[0589] Table 33

[0590] Example 34: Preparation of adipate crystal form A (stirring method)

[0591] Weigh 5.9 mg of adipic acid and 24.8 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of EtOAc to the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0592] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the compound adipic acid salt prepared in this embodiment (I) is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 37. Its representative characteristic diffraction peaks and relative intensities are shown in Table 34.

[0593] Table 34

[0594] Example 35: Preparation of methanesulfonate crystal form A (stirring method)

[0595] Weigh 5.2 mg of methanesulfonic acid into an HPLC glass vial at room temperature, add 0.5 mL of EtOAc, weigh 25.1 mg of the compound (I) crystal form A into an HPLC vial, stir at room temperature for 4 days (1000 rpm), centrifuge (10000 rpm, 2 min) to remove the supernatant, and dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0596] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the methanesulfonate compound (I) prepared in this embodiment is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 38a. Representative characteristic diffraction peaks and relative intensities are shown in Table 35. Its TGA is shown in Figure 38b, and its DSC is shown in Figure 38c.

[0597] Table 35

[0598] Example 36: Preparation of oxalate crystal form A (stirring method)

[0599] Weigh 5.2 mg of oxalic acid and 25.1 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of EtOAc to the HPLC vial. Stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0600] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the oxalate compound (I) prepared in this example is in crystalline form, denoted as crystal form A, and has the XRPD spectrum shown in Figure 39. The representative characteristic diffraction peaks and relative intensities are shown in Table 36.

[0601] Table 36

[0602] Example 37: Preparation of Oxalate Crystal Form B (Stirring Method)

[0603] Weigh 5.1 mg of oxalic acid and 24.8 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of MTBE to the HPLC vial and stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0604] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the oxalate compound (I) prepared in this example is a new crystal form, denoted as crystal form B, and has the XRPD spectrum shown in Figure 40. Its representative characteristic diffraction peaks and relative intensities are shown in Table 37.

[0605] Table 37

[0606] Example 38: Preparation of Oxalate Crystal Form C (Stirring Method)

[0607] Weigh 5.1 mg of oxalic acid and 25.0 mg of the compound (I) crystal form A at room temperature and place them in an HPLC glass bottle. Add 0.5 mL of ACN to the HPLC vial and stir at room temperature for 4 days (1000 rpm). Centrifuge (10000 rpm, 2 min) to remove the supernatant. Dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0608] X-ray powder diffraction (XRD) using Cu-Kα radiation showed that the oxalate compound (I) prepared in this example is in crystalline form, represented by crystal form C, and has the XRPD spectrum shown in Figure 41. Its representative characteristic diffraction peaks and relative intensities are shown in Table 38.

[0609] Table 38

[0610] Example 39: Preparation of hydrobromide crystal form A (stirring method)

[0611] Weigh 25.0 mg of the compound (I) crystal form A as shown in formula (I) into an HPLC glass bottle at room temperature, add 0.5 mL of MTBE, add 4.7 μL of 4 M HBr solution into the HPLC vial, stir at room temperature for 4 days (1000 rpm), centrifuge (10000 rpm, 2 min) to remove the supernatant, and dry the solid under vacuum at room temperature for 5 hours to obtain the target solid.

[0612] X-ray powder diffraction was performed using Cu-Kα radiation to determine that the compound hydrobromide shown in formula (I) is in crystalline form, represented by crystal form A, and has the XRPD spectrum shown in Figure 42. Its representative characteristic diffraction peaks and relative intensities are shown in Table 39.

[0613] Table 39

[0614] Example 40: Single crystal culture of compound B as shown in formula (II)

[0615] Weigh 19.9 mg of the compound (II) in crystal form B, add 0.5 mL of a methanol / dichloromethane (1:1, v / v) mixture, and sonicate to dissolve. Filter. Transfer the filtrate to a single crystal growth flask, add a very small amount of the above-mentioned crystal particles of the starting sample in crystal form B as seed crystals to induce crystallization, and slowly evaporate for 6 days. Collect the single crystal sample and characterize it by XRPD to confirm that it is the compound (II) in crystal form B.

[0616] SCXRD characterization was performed on it. Single-crystal diffraction characterization results showed that the single crystal belongs to the triclinic crystal system, space group P1, and its unit cell parameters are: { α=82.8595(8)°, β=80.5467(10)°, γ=88.4335(9)°, }

[0617] Figure 7a shows a schematic diagram of the asymmetric unit of the single-crystal structure model of compound B shown in formula (II); Figure 7b shows the atomic thermal vibration ellipsoid of one of the cations in the asymmetric structural unit of the single-crystal structure model of compound B shown in formula (the atomic thermal vibration ellipsoid is drawn at a 50% probability level); Figure 7c shows the atomic thermal vibration ellipsoid of the other cation in the asymmetric structural unit of the single-crystal structure model of compound B shown in formula (the atomic thermal vibration ellipsoid is drawn at a 50% probability level).

[0618] Example A: Solubility

[0619] Evaluate the dynamic solubility of compound A (formula I), p-toluenesulfonate (formula I), fumarate (formula I), and tartrate (formula I) in FeSSGF biosolvent and water.

[0620] At a concentration of 5 or 10 mg / mL, the crystal form A of compound (I), the crystal form B of p-toluenesulfonate of compound (I), the crystal form B of fumarate of compound (I), and the crystal form A of tartrate of compound (I) were added to FeSSGF solvent and water, respectively. The mixture was stirred at 37°C for 1 hour (25 rpm). Approximately 0.8 mL of the mixture was taken, centrifuged, and filtered. The HPLC concentration of the liquid was tested, and the solubility test results are shown in Table 40.

[0621] Table 40

[0622] Test results show that in FeSSGF, the solubility of the salt form of the compound shown in formula (I) is higher than that of the free alkali crystal form A of the compound shown in formula (I); in H2O, the solubility of the salt form of the compound shown in formula (I) is also higher than that of the free alkali crystal form A.

[0623] Example B: Hygroscopicity

[0624] The hygroscopicity of compound A (formula I), compound B (formula I) toluenesulfonate, and compound B (formula I) fumarate was evaluated using a dynamic moisture adsorption (DVS) instrument.

[0625] The test measured the percentage change in sample mass under constant temperature of 25°C as humidity changed (60%RH-95%RH-0%RH-95%RH or 0%RH-95%RH-0%RH). The DVS evaluation results are shown in Table 41.

[0626] Table 41

[0627] The test results showed that the water adsorption at 25℃ / 80% RH for crystal form A of compound (I), crystal form B of p-toluenesulfonate of compound (I), crystal form B of fumarate of compound (I), and crystal form A of tartrate of compound (I) were 1.397%, 0.326%, and 0.5018%, respectively. This indicates that the hygroscopicity of crystal form B of p-toluenesulfonate of compound (I), crystal form B of fumarate of compound (I), and crystal form A of tartrate of compound (I) is less than that of crystal form A of compound (I). Furthermore, no crystal transformation occurred in any of the samples after DVS testing.

[0628] Example C: Pharmacokinetic Test

[0629] A pharmacokinetic (PK) study was conducted using male beagle dogs via oral administration. The test compounds (compound shown in Formula I (solvent: 5% TPGS (vitamin E polyethylene glycol succinate), 95% (20% SBE-β-CD (sulfobutyl-β-cyclodextrin) aqueous solution)), fumarate form B of Formula I (solvent: 10% Solutol aqueous solution), methanesulfonate form B of Formula I (solvent: 10% Solutol aqueous solution), and p-toluenesulfonate form B of Formula I (solvent: 10% Solutol, 10% PEG400, 80% water))) were prepared into dosing solutions. The oral administration was 5 mL / kg, at a dose of 400 mg / kg. Blood was collected from the canine forelimb vein. 0.8 mL of blood was collected at each time point (15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h) into EDTA-K2 anticoagulant tubes, properly mixed, and centrifuged on ice before centrifugation (4000 rpm, 4 °C for 5 min) to separate the plasma. The plasma was stored at -80 °C before analysis. The concentration of the test compounds in the plasma was determined by LC-MS / MS. The results are shown in Table 42.

[0630] Table 42

[0631] Test results show that the salts of the compounds shown in formula (I) of this invention all have excellent pharmacokinetic characteristics.

[0632] The foregoing description illustrates exemplary embodiments of the present invention. It should be understood that the scope of protection of the present invention includes, but is not limited to, the above exemplary embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A crystalline form of a compound of Formula (I) ###0001### characterized in that, The compound of formula (I) is selected from one or more of the following: Form A and Form B: Wherein, the X-ray powder diffraction pattern of the compound crystal form A shown in formula (I) has characteristic peaks containing at least three or more of the following diffraction angles 2θ: 5.8±0.2°, 6.9±0.2°, 9.6±0.2°, 12.5±0.2°, 15.6±0.2°, 19.5±0.2°; furthermore, the compound crystal form A shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 1; The X-ray powder diffraction pattern of the compound crystal form B shown in formula (I) has characteristic peaks containing at least three or more of the following diffraction angles 2θ: 5.8±0.2°, 7.5±0.2°, 9.7±0.2°, 12.1±0.2°, 13.1±0.2°, 15.0±0.2°; furthermore, the compound crystal form A shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 2.

2. A pharmaceutically acceptable salt of a compound of formula (I) or a hydrate or solvate thereof, characterized in that: ###0001### (I) Pharmaceutically acceptable salts of the compound represented by formula (I) are p-toluenesulfonate, fumarate, tartrate, hydrochloride, sulfate, phosphate, maleate, mucilage, citrate, malate, hippurate, lactate, succinate, adipate, methanesulfonate, oxalate, or hydrobromide. 3.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the p-toluenesulfonate salt of the compound represented by formula (I). 4.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 3, characterized in that, The p-toluenesulfonic acid salt of the compound of formula (I) has the structure of the compound of formula (II): 5.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 4, characterized in that, The solid form of the compound represented by formula (II) is either amorphous or crystalline. 6.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The crystal form of the compound represented by formula (II) is selected from one or more of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J, and crystal form K; The X-ray powder diffraction pattern of the compound crystal form A shown in formula (II) has at least three or more characteristic peaks with diffraction angles of 2θ as follows: 6.3±0.2°, 7.6±0.2°, 9.4±0.2°, 12.8±0.2°, 14.6±0.2°, 16.4±0.2°; furthermore, the compound crystal form A shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in Figure 3. The X-ray powder diffraction pattern of compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 5.8±0.2°, 9.5±0.2°, 14.1±0.2°; further, the X-ray powder diffraction pattern of compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, 14.1±0.2°; further, the X-ray powder diffraction pattern of compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, 14.1±0.2°. °, 9.5±0.2°, 10.1±0.2°, 12.4±0.2°, 13.1±0.2°, 14.1±0.2°, 16.2±0.2°; Further, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, 14.1±0.2°, 20.3±0.2°, 20.5±0.2°; Further, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 5.8±0.2°, 9.5±0.2°, 10.1±0.2°, 12.4±0.2°, 13.1±0.2°, 14.1±0.2°, 16.2±0.2°. ±0.2°, 9.5±0.2°, 10.1±0.2°, 12.4±0.2°, 13.1±0.2°, 14.1±0.2°, 16.2±0.2°, 17.8±0.2°, 18.5±0.2°, 23.7±0.2°; furthermore, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, 12.4±0.2°, 13.1±0.2°, 14.1±0.2°, 16.2±0.2°, 17.3±0.2°, 17.8±0.2°, 1 8.5±0.2°, 20.3±0.2°, 20.5±0.2°, 22.0±0.2°, 23.7±0.2°; Further, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, 12.4±0.2°, 13.1±0.2°, 14.1±0.2°, 15.4±0.2°, 17.8±0.2°, 18.5±0.2°, 20.3±0.2°, 20.5±0.2°, 22.0±0.2°, 25.0±0.2°, 26.3±0.2°.2°; Further, the X-ray powder diffraction pattern of the compound crystal form B shown in formula (II) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 5.8±0.2°, 8.4±0.2°, 9.5±0.2°, 10.1±0.2°, 12.4±0.2°, 13.1±0.2°, 14.1±0.2°, 15.4±0.2°, 16.2±0.2°, 17.3±0.2°, 17.8±0.2°, 18.5±0.2°, 20 0.3±0.2°, 20.5±0.2°, 22.0±0.2°, 23.7±0.2°, 25.0±0.2°, 26.3±0.2°; further, the compound crystal form B represented by formula (II) has an X-ray powder diffraction pattern substantially as shown in Figure 4; further, the compound crystal form B represented by formula (II) has a thermogravimetric analysis pattern (TGA pattern) substantially as shown in Figure 5; further, the compound crystal form B represented by formula (II) has a concentration of approximately 229.07±1 Further, the compound crystal form B shown in formula (II) has a DSC spectrum with an onset temperature of approximately 229.07°C; further, the compound crystal form B shown in formula (II) has a DSC spectrum with an endothermic peak having a maximum value of approximately 231.77 ± 10°C; further, the compound crystal form B shown in formula (II) has a DSC spectrum with an endothermic peak having a maximum value of approximately 231.77°C; further, the compound crystal form B shown in formula (I) has a DSC spectrum with an endothermic peak having a maximum value of approximately 231.77°C; further, the compound crystal form B shown in formula (II) has a DSC spectrum with an endothermic peak having a maximum value of approximately 231.77°C; further, the compound crystal form B shown in formula (II) has a DSC spectrum with an onset temperature of approximately 229.0 ... The compound of formula (I) in crystal form B has a DSC spectrum containing an endothermic peak with an onset temperature of approximately 229.07 ± 10 °C and a maximum value at 231.77 ± 10 °C; further, the compound of formula (II) in crystal form B has a DSC spectrum containing an endothermic peak with an onset temperature of approximately 229.07 °C and a maximum value at 231.77 °C; further, the compound of formula (II) in crystal form B has a differential scanning calorimetry (DSC) curve substantially as shown in Figure 6. The X-ray powder diffraction pattern of the compound crystal form C shown in formula (II) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 4.9±0.2°, 9.6±0.2°, 10.4±0.2°, 11.3±0.2°, 13.3±0.2°, 15.5±0.2°; furthermore, the compound crystal form C shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in Figure 8; The compound of formula (II) has crystal form D and has an X-ray powder diffraction pattern that is substantially as shown in Figure 9. The X-ray powder diffraction pattern of the compound crystal form E shown in formula (II) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 4.8±0.2°, 5.9±0.2°, 21.7±0.2°; furthermore, the compound crystal form E shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in Figure 10. The X-ray powder diffraction pattern of the compound crystal form F shown in formula (II) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 6.6±0.2°, 13.2±0.2°, 15.0±0.2°; furthermore, the compound crystal form F shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in Figure 11. The X-ray powder diffraction pattern of the compound crystal form G shown in formula (II) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 5.9±0.2°, 11.8±0.2°, 13.8±0.2°, 15.3±0.2°; furthermore, the compound crystal form G shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in Figure 12; The X-ray powder diffraction pattern of the compound of crystal form H shown in formula (II) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 6.7±0.2°, 13.6±0.2°, 14.7±0.2°, 15.5±0.2°, 17.9±0.2°, 26.2±0.2°; furthermore, the compound of crystal form H shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in Figure 13; The X-ray powder diffraction pattern of compound crystal form I shown in formula (II) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 4.9±0.2°, 6.4±0.2°, 9.6±0.2°, 18.1±0.2°, 24.4±0.2°, 25.2±0.2°; furthermore, the compound crystal form I shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in Figure 14; The X-ray powder diffraction pattern of the compound crystal form J shown in formula (II) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 5.4±0.2°, 5.8±0.2°, 10.0±0.2°, 14.4±0.2°, 16.2±0.2°, 23.1±0.2°; furthermore, the compound crystal form J shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in Figure 15; The X-ray powder diffraction pattern of the compound crystal form K shown in formula (II) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 5.7±0.2°, 6.5±0.2°, 8.1±0.2°, 12.9±0.2°, 13.5±0.2°, 17.5±0.2°; furthermore, the compound crystal form K shown in formula (II) has an X-ray powder diffraction pattern substantially as shown in Figure 16. 7.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is a fumarate; further, the fumarate of the compound represented by formula (I) is in amorphous or crystalline form in solid form. 8.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The fumarate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A and crystal form B; The X-ray powder diffraction pattern of fumarate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least two or more diffraction angles 2θ as follows: 7.5±0.2°, 13.9±0.2°, 15.0±0.2°, 17.5±0.2°, 22.0±0.2°; further, the fumarate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 17a; further, the fumarate crystal form A of the compound shown in formula (I) has a thermogravimetric analysis (TGA) pattern substantially as shown in Figure 17b; further, the fumarate crystal form A of the compound shown in formula (I) has a DSC pattern containing an onset temperature of approximately 260.1±10°C; further, the fumarate crystal form A of the compound shown in formula (I) has a DSC pattern containing an onset temperature of approximately 260.1°C; Step one, the fumarate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at about 262.5 ± 10 °C; further, the fumarate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at about 262.5 °C; further, the fumarate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature at about 260.1 ± 10 °C and a maximum value at about 262.5 ± 10 °C; further, the fumarate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature at about 260.1 °C and a maximum value at about 262.5 °C; further, the fumarate crystal form A of the compound shown in formula (I) has a differential scanning calorimetry (DSC) curve substantially as shown in Figure 17c. The X-ray powder diffraction pattern of the fumarate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 6.4±0.2°, 8.4±0.2°, 12.8±0.2°, 13.2±0.2°, 15.3±0.2°, 16.7±0.2°, 21.0±0.2°, 25.7±0.2°; furthermore, the fumarate crystal form B of the compound shown in formula (I) has a basic The X-ray powder diffraction pattern is shown in Figure 18a; further, the fumarate crystal form B of the compound represented by formula (I) has a thermogravimetric analysis (TGA) pattern substantially as shown in Figure 18b; further, the fumarate crystal form B of the compound represented by formula (I) has a DSC pattern showing an onset temperature of approximately 262.8 ± 10 °C; further, the fumarate crystal form B of the compound represented by formula (I) has a DSC pattern showing an onset temperature of approximately 262.8 °C. The compound (I) has a DSC spectrum with an onset temperature; further, the compound (I) fumarate crystal form B has a DSC spectrum containing an endothermic peak with a maximum value at approximately 263.7 ± 10 °C; further, the compound (I) fumarate crystal form B has a DSC spectrum containing an endothermic peak with a maximum value at approximately 263.7 °C; further, the compound (I) fumarate crystal form B has a DSC spectrum containing an endothermic peak with an onset temperature at approximately 262.8 ± 10 °C and a maximum value at approximately 263.7 ± 10 °C; further, the compound (I) fumarate crystal form B has a DSC spectrum containing an endothermic peak with an onset temperature at approximately 262.8 °C and a maximum value at approximately 263.7 °C; further, the compound (I) fumarate crystal form B has a differential scanning calorimetry (DSC) curve substantially as shown in Figure 17c. 9.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the tartrate salt of the compound represented by formula (I); further, the solid form of the tartrate salt of the compound represented by formula (I) is amorphous or crystalline.

10. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 9, characterized in that, The tartrate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A and crystal form B; The X-ray powder diffraction pattern of tartrate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 7.2±0.2°, 13.3±0.2°, 14.4±0.2°, 18.0±0.2°, 21.6±0.2°; further, the X-ray powder diffraction pattern of tartrate crystal form A of the compound shown in formula (I) is substantially as shown in Figure 19a; further, the thermogravimetric analysis (TGA) pattern of tartrate crystal form A of the compound shown in formula (I) is substantially as shown in Figure 19b; further, the DSC pattern of tartrate crystal form A of the compound shown in formula (I) has a starting temperature of approximately 267.3±10°C; further, the DSC pattern of tartrate crystal form A of the compound shown in formula (I) has a starting temperature of approximately 267.3°C; Step one, the tartrate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 270.4 ± 10 °C; further, the tartrate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 270.4 °C; further, the tartrate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature at approximately 267.3 ± 10 °C and a maximum value at approximately 270.4 ± 10 °C; further, the tartrate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature at approximately 267.3 °C and a maximum value at approximately 270.4 °C; further, the tartrate crystal form A of the compound shown in formula (I) has a differential scanning calorimetry (DSC) curve substantially as shown in Figure 19c. The X-ray powder diffraction pattern of tartrate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 7.8±0.2°, 11.9±0.2°, 14.8±0.2°, 18.8±0.2°, 20.7±0.2°, 25.9±0.2°; further, the tartrate crystal form B of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 20a; further, the tartrate crystal form B of the compound shown in formula (I) has a thermogravimetric analysis (TGA) pattern substantially as shown in Figure 20b; further, the tartrate crystal form B of the compound shown in formula (I) has a DSC pattern containing an onset temperature of approximately 267.8±10°C; further, the tartrate crystal form B of the compound shown in formula (I) has a DSC pattern containing an onset temperature of approximately 267.8°C. Figure; Further, the tartrate crystal form B of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 270.0 ± 10 °C; Further, the tartrate crystal form B of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 270.0 °C; Further, the tartrate crystal form B of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature at approximately 267.8 ± 10 °C and a maximum value at approximately 270.0 ± 10 °C; Further, the tartrate crystal form B of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature at approximately 267.8 °C and a maximum value at approximately 270.0 °C; Further, the tartrate crystal form B of the compound shown in formula (I) has a differential scanning calorimetry (DSC) curve substantially as shown in Figure 20c. 11.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the hydrochloride salt of the compound represented by formula (I); further, the solid form of the hydrochloride salt of the compound represented by formula (I) is amorphous or crystalline. 12.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 11, characterized in that, The hydrochloride crystal form of the compound shown in formula (I) is selected from crystal form A; The X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 7.2±0.2°, 7.9±0.2°, 10.8±0.2°, 15.0±0.2°, 17.1±0.2°, 20.3±0.2°; furthermore, the hydrochloride crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 21. 13.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the sulfate of the compound represented by formula (I); further, the solid form of the sulfate of the compound represented by formula (I) is amorphous or crystalline. 14.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 13, characterized in that, The sulfate crystal form of the compound shown in formula (I) is selected from one or more of crystal form A and crystal form B; The X-ray powder diffraction pattern of the sulfate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 6.0±0.2°, 6.8±0.2°, 14.4±0.2°, 15.4±0.2°, 16.7±0.2°, 19.7±0.2°; furthermore, the sulfate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 22; The X-ray powder diffraction pattern of the sulfate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least three or more of the following diffraction angles 2θ: 7.1±0.2°, 8.9±0.2°, 12.5±0.2°, 14.5±0.2°, 16.1±0.2°, 19.8±0.2°; furthermore, the sulfate crystal form B of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 23.

15. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the phosphate of the compound represented by formula (I); further, the solid form of the phosphate of the compound represented by formula (I) is amorphous or crystalline.

16. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 15, characterized in that, The phosphate crystal form of the compound shown in formula (I) is selected from crystal form A; The X-ray powder diffraction pattern of the phosphate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 10.2±0.2°, 11.1±0.2°, 12.0±0.2°, 14.3±0.2°, 15.0±0.2°, 25.5±0.2°; furthermore, the phosphate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 24. 17.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the maleate salt of the compound represented by formula (I); further, the maleate salt of the compound represented by formula (I) is in amorphous or crystalline form in solid form. 18.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 17, wherein The maleate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A, crystal form B and crystal form C; The X-ray powder diffraction pattern of maleate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least three or more of the following diffraction angles 2θ: 5.9±0.2°, 7.3±0.2°, 13.6±0.2°, 14.5±0.2°, 21.2±0.2°, 27.0±0.2°; furthermore, the maleate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 25. The X-ray powder diffraction pattern of maleate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 5.5±0.2°, 7.2±0.2°, 16.1±0.2°, 16.6±0.2°, 17.3±0.2°, 24.6±0.2°; furthermore, the maleate crystal form B of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 26; The X-ray powder diffraction pattern of the maleate crystal form C of the compound shown in formula (I) has characteristic peaks containing at least three or more of the following diffraction angles 2θ: 5.9±0.2°, 7.6±0.2°, 9.9±0.2°, 12.7±0.2°, 19.3±0.2°, 22.3±0.2°; furthermore, the maleate crystal form C of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 27. 19.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the mucilage salt of the compound represented by formula (I); further, the solid form of the mucilage salt of the compound represented by formula (I) is amorphous or crystalline.

20. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 19, characterized in that, The acetic acid salt crystal form of the compound shown in formula (I) is selected from crystal form A; The X-ray powder diffraction pattern of the compound mucilage crystal form A shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 5.6±0.2°, 5.9±0.2°, 6.3±0.2°, 10.5±0.2°, 12.1±0.2°, 15.7±0.2°, 19.7±0.2°; furthermore, the compound mucilage crystal form A shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 28.

21. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the citrate salt of the compound represented by formula (I); further, the solid form of the citrate salt of the compound represented by formula (I) is amorphous or crystalline.

22. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 21, characterized in that, The citrate crystal form of the compound represented by formula (I) is selected from crystal form A; The X-ray powder diffraction pattern of citrate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 4.8±0.2°, 6.6±0.2°, 16.2±0.2°, 17.4±0.2°, 19.1±0.2°, 22.5±0.2°; furthermore, the citrate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 29.

23. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the malate of the compound represented by formula (I); further, the malate of the compound represented by formula (I) is in solid form either amorphous or crystalline.

24. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 23, characterized in that, The compound represented by formula (I) has a malate crystal form selected from one or more of crystal form A and crystal form B; The X-ray powder diffraction pattern of the compound malate crystal form A shown in formula (I) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 7.7±0.2°, 11.9±0.2°, 14.7±0.2°, 15.3±0.2°, 20.8±0.2°, 26.0±0.2°; furthermore, the compound malate crystal form A shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 30. The X-ray powder diffraction pattern of the compound malate crystal form B shown in Formula (I) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 6.2±0.2°, 8.5±0.2°, 11.3±0.2°, 14.5±0.2°, 17.0±0.2°, 25.6±0.2°; furthermore, the compound malate crystal form B shown in Formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 31.

25. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the hippurate salt of the compound represented by formula (I); further, the hippurate salt of the compound represented by formula (I) is in amorphous or crystalline form in solid form. 26.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 25, wherein The compound hippurate shown in formula (I) has a crystal form selected from crystal form A; The X-ray powder diffraction pattern of hippurate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 5.7±0.2°, 7.0±0.2°, 11.3±0.2°, 16.0±0.2°, 19.2±0.2°, 27.0±0.2°; further, the X-ray powder diffraction pattern of hippurate crystal form A of the compound shown in formula (I) is substantially as shown in Figure 32a; further, the thermogravimetric analysis (TGA) pattern of hippurate crystal form A of the compound shown in formula (I) is substantially as shown in Figure 32b; further, the DSC pattern of hippurate crystal form A of the compound shown in formula (I) has a starting temperature of approximately 216.7±10°C; further, the DSC pattern of hippurate crystal form A of the compound shown in formula (I) has a starting temperature of approximately 216.7°C. The compound (I) hippurate crystal form A has a DSC spectrum containing an endothermic peak with a maximum value at approximately 218.6 ± 10 °C. Further, the compound (I) hippurate crystal form A has a DSC spectrum containing an endothermic peak with a maximum value at approximately 218.6 °C. Further, the compound (I) hippurate crystal form A has a DSC spectrum containing an endothermic peak with an onset temperature at approximately 216.7 ± 10 °C and a maximum value at approximately 218.6 ± 10 °C. Further, the compound (I) hippurate crystal form A has a DSC spectrum containing an endothermic peak with an onset temperature at approximately 216.7 °C and a maximum value at approximately 218.6 °C. Further, the compound (I) hippurate crystal form A has a differential scanning calorimetry (DSC) curve substantially as shown in Figure 32c. 27.The pharmaceutically acceptable salt of the compound of Formula (I) according to claim 2, wherein The pharmaceutically acceptable salt of the compound represented by formula (I) is the lactate salt of the compound represented by formula (I); further, the solid form of the lactate salt of the compound represented by formula (I) is amorphous or crystalline. 28.The pharmaceutically acceptable salt of the compound of formula (I) according to claim 27, wherein The lactate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A and crystal form B; The X-ray powder diffraction pattern of the lactate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 6.7±0.2°, 9.7±0.2°, 13.0±0.2°, 16.6±0.2°, 24.2±0.2°, 26.4±0.2°; furthermore, the lactate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 33; The X-ray powder diffraction pattern of the compound lactate crystal form B shown in Formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 7.6±0.2°, 10.5±0.2°, 13.8±0.2°, 15.4±0.2°, 21.7±0.2°, 27.5±0.2°; furthermore, the compound lactate crystal form B shown in Formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 34.

29. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the succinate of the compound represented by formula (I); further, the solid form of the succinate of the compound represented by formula (I) is amorphous or crystalline.

30. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 29, characterized in that, The succinate crystal form of the compound represented by formula (I) is selected from one or more of crystal form A and crystal form B; The X-ray powder diffraction pattern of succinate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least four or more diffraction angles 2θ as follows: 7.1±0.2°, 13.4±0.2°, 14.1±0.2°, 15.9±0.2°, 21.1±0.2°, 25.9±0.2°; furthermore, the succinate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 35. The X-ray powder diffraction pattern of succinate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 6.3±0.2°, 7.2±0.2°, 13.2±0.2°, 14.4±0.2°, 16.1±0.2°, 21.6±0.2°; furthermore, the succinate crystal form B of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 36.

31. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the adipate of the compound represented by formula (I); further, the adipate of the compound represented by formula (I) is in solid form either amorphous or crystalline.

32. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 31, characterized in that, The adipate crystal form of the compound shown in formula (I) is selected from crystal form A; The X-ray powder diffraction pattern of adipate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 6.7±0.2°, 11.6±0.2°, 16.5±0.2°, 17.5±0.2°, 18.5±0.2°, 21.1±0.2°; furthermore, the adipate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 37.

33. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the methanesulfonate salt of the compound represented by formula (I); further, the methanesulfonate salt of the compound represented by formula (I) is in solid form either amorphous or crystalline.

34. The pharmaceutically acceptable salt of the compound of Formula (I) according to claim 33, wherein The methanesulfonate crystal form of the compound shown in formula (I) is selected from crystal form A; The X-ray powder diffraction pattern of the methanesulfonate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 6.6±0.2°, 10.3±0.2°, 15.0±0.2°, 20.0±0.2°, 21.7±0.2°, 24.2±0.2°; further, the methanesulfonate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 38a; further, the methanesulfonate crystal form A of the compound shown in formula (I) has a thermogravimetric analysis (TGA) pattern substantially as shown in Figure 38b; further, the methanesulfonate crystal form A of the compound shown in formula (I) has a DSC pattern containing an onset temperature of approximately 283.7±10°C; further, the methanesulfonate crystal form A of the compound shown in formula (I) has a DSC pattern containing an onset temperature of approximately 283.7°C. C-spectrum; further, the methanesulfonate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 289.8 ± 10 °C; further, the methanesulfonate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with a maximum value at approximately 289.8 °C; further, the methanesulfonate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature at approximately 283.7 ± 10 °C and a maximum value at approximately 289.8 ± 10 °C; further, the methanesulfonate crystal form A of the compound shown in formula (I) has a DSC spectrum containing an endothermic peak with an onset temperature at approximately 283.7 °C and a maximum value at approximately 289.8 °C; further, the methanesulfonate crystal form A of the compound shown in formula (I) has a differential scanning calorimetry (DSC) curve substantially as shown in Figure 38c.

35. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the oxalate of the compound represented by formula (I); further, the solid form of the oxalate of the compound represented by formula (I) is amorphous or crystalline. 36.The pharmaceutically acceptable salt of the compound of Formula (I) according to claim 35, wherein The oxalate crystal form of the compound shown in formula (I) is selected from one or more of crystal form A, crystal form B and crystal form C; The X-ray powder diffraction pattern of oxalate crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 7.5±0.2°, 9.6±0.2°, 16.0±0.2°, 19.2±0.2°, 24.1±0.2°, 26.2±0.2°; furthermore, the oxalate crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 39. The X-ray powder diffraction pattern of oxalate crystal form B of the compound shown in formula (I) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 6.0±0.2°, 6.8±0.2°, 15.4±0.2°, 23.1±0.2°, 26.2±0.2°; furthermore, the oxalate crystal form B of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 40. The X-ray powder diffraction pattern of the oxalate crystal form C of the compound shown in formula (I) has characteristic peaks containing at least two or more of the following diffraction angles 2θ: 6.8±0.2°, 7.7±0.2°, 13.7±0.2°, 16.5±0.2°, 17.3±0.2°, 22.2±0.2°; furthermore, the oxalate crystal form C of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 41.

37. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, characterized in that, The pharmaceutically acceptable salt of the compound represented by formula (I) is the hydrobromide salt of the compound represented by formula (I); further, the hydrobromide salt of the compound represented by formula (I) is in solid form either amorphous or crystalline.

38. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 37, characterized in that, The hydrobromide crystal form of the compound shown in formula (I) is selected from crystal form A; The X-ray powder diffraction pattern of the hydrobromide crystal form A of the compound shown in formula (I) has characteristic peaks containing at least one or more of the following diffraction angles 2θ: 7.2±0.2°, 10.7±0.2°, 14.9±0.2°, 17.1±0.2°, 25.5±0.2°, 26.2±0.2°; furthermore, the hydrobromide crystal form A of the compound shown in formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 42.

39. A pharmaceutical composition comprising, It includes the crystal form of the compound of formula (I) according to any one of claims 1-39, a pharmaceutically acceptable salt of the compound of formula (I) or its hydrate or solvate, or the crystal form of a pharmaceutically acceptable salt of the compound of formula (I), and a pharmaceutically acceptable excipient.

40. The use of the crystal form of the compound of formula (I) according to any one of claims 1-39, a pharmaceutically acceptable salt of the compound of formula (I), a crystal form of a pharmaceutically acceptable salt of the compound of formula (I), a pharmaceutical composition of the crystal form of the compound of formula (I) according to claim 40, a pharmaceutical composition of a pharmaceutically acceptable salt of the compound of formula (I), and a pharmaceutical composition of the crystal form of a pharmaceutically acceptable salt of the compound of formula (I) in the preparation of a medicament for treating cancer.

41. The use of claim 40, wherein, The cancers mentioned include, but are not limited to, breast cancer, ovarian cancer, stomach cancer, prostate cancer, pancreatic cancer, uterine cancer, cervical cancer, endometrial cancer, lung cancer, brain cancer, bile duct cancer, and blood cancers.

42. An intermediate of the formula: ###0010### or a salt thereof, characterized by:

43. A method for preparing a compound of formula (I) or a salt thereof, characterized in that, The preparation method comprises: Method one: reacting a compound represented by formula (1-1) or a salt thereof with a compound represented by formula (2) in the presence of a base: Wherein, X is a halogen; further, X is F, Cl, Br or I; The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, or DIPEA; Method two: reacting a compound represented by formula (1-3) or a salt thereof with a compound represented by formula (3) or a salt thereof in the presence of a base: The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, or DIPEA; Method three: reacting a compound represented by formula (1-6) or a salt thereof with a compound represented by formula (3) or a salt thereof in the presence of a base: The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, or DIPEA.

44. A method for producing a compound represented by formula (1-1) or a salt thereof, characterized by comprising: Formula (1-1) The production method includes: reacting a compound represented by formula (1) or a salt thereof with a compound represented by formula (3) or a salt thereof in the presence of a base: ​ The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, or DIPEA.

45. A method for producing a compound represented by formula (1-3) or a salt thereof, characterized by comprising the step of, The preparation method includes: Method one: reacting a compound represented by formula (1-2) or a salt thereof with a compound represented by formula (2) in the presence of a base: The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, or DIPEA; Method two: reacting a compound represented by formula (1-5) or a salt thereof with an oxidizing agent: The oxidant is 3-chloroperoxybenzoic acid.

46. A method for producing a compound represented by formula (1-6) or a salt thereof, characterized by comprising the step of, The preparation method includes: Method one: reacting a compound represented by formula (1-5) or a salt thereof with a chlorinating reagent: The chlorinating agent is sulfonyl chloride; Method two: reacting a compound represented by formula (1) or a salt thereof with a compound represented by formula (2) in the presence of a base: The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, or DIPEA.

47. A method for producing a compound represented by formula (1-5) or a salt thereof, characterized by comprising the step of, The production method includes: reacting a compound represented by formula (1-4) or a salt thereof with a compound represented by formula (2) in the presence of a base: The alkali is potassium carbonate, sodium carbonate, cesium carbonate, TEA, or DIPEA.

48. A method for producing a compound represented by formula (1-4) or a salt thereof, characterized by comprising the step of, The preparation method includes: The compound represented by formula (1) or a salt thereof is reacted with NaSCH3:

49. A method for preparing a compound of formula (2), characterized in that, The preparation method comprises: The compound represented by formula (2-2) or a salt thereof is reacted with a halogenating reagent in the presence of tert-butyl nitrite: The halogenating agent is a ketone(II); further, the ketone(II) is a bromoketone(II) or a chlorinated ketone(II).

50. A method for preparing a compound of formula (2-2) or a salt thereof, characterized in that, The preparation method includes: The compound represented by formula (2-1) or a salt thereof is reacted with difluoroacetic acid in the presence of POCl3:

51. A method for preparing a compound of formula (3) or a salt thereof, characterized in that, The preparation method comprises: The compound represented by formula (3-5) or a salt thereof is reacted under acidic conditions: PG 1 is -Boc; The acidic conditions are TFA, hydrochloric acid, dioxane hydrochloride solution, and tetrahydrofuran hydrochloride solution.

52. A method for producing a compound represented by formula (3-5) or a salt thereof, characterized by comprising the step of, The preparation method comprises the following steps: reacting a compound shown in formula (3-4) with acetaldehyde in the presence of a reducing agent: The reducing agent is sodium borohydride, sodium cyanoborohydride, or sodium borohydride acetate.

53. A method for preparing a compound of formula (3-4) or a salt thereof, characterized in that, The preparation method comprises: Method one: the compound represented by formula (3-3) or a salt thereof is subjected to asymmetric hand synthesis reaction with amine or a salt thereof in the presence of an enzyme: The amine is isopropylamine or a salt of isopropylamine; further, the amine is isopropylamine or isopropylamine hydrochloride. The enzyme is ATA-303; Method two: the compound represented by formula (3-7) or salt thereof is reacted with a chiral reagent to perform chiral separation: The chiral reagent is (S)-(+)-O-acetyl-L-mandelic acid.

54. A method for producing a compound represented by formula (3-3) or a salt thereof, characterized by comprising the step of, The preparation method comprises: The compound represented by formula (3-2) or a salt thereof is reacted with a selective fluorinating reagent: The selective fluorinating agent is Selectfluor (Select-F, 1-chloromethyl-4-fluoro-1,4-diazobicyclo2,2,2-octanebis(tetrafluoroborate) salt); PG 2 protecting groups such as -TMS, -TBDMS, -Ac; 55. A method for preparing a compound of formula (3-2) or a salt thereof, characterized in that the preparation method comprises: The compound represented by formula (3-1) is reacted with PG 2 -X or PG 2 -O-PG 2 to give a compound represented by formula (3-2): X is a halogen; further, X is F, Cl, Br, or I; PG 2 protecting groups such as -TMS, -TBDMS, -Ac.

56. A method for preparing a compound of formula (3-7) or a salt thereof, characterized in that, The preparation method comprises: The compound represented by formula (3-6) or a salt thereof is reacted under acidic conditions: The acidic conditions are TFA, hydrochloric acid, dioxane hydrochloride solution, and tetrahydrofuran hydrochloride solution.

57. A method for preparing a compound of formula (3-6) or a salt thereof, characterized in that, The preparation method includes: The compound represented by formula (3-3) or a salt thereof is subjected to reductive amination with an amine source or a salt thereof: The amine source is (R)-2-methylpropane-2-sulfinamide or its salt.

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