Salt of pyrimidine fused ring compound, crystal form of salt, preparation method of salt and application of salt

Abstract

The invention provides a salt of a pyrimidine fused ring compound, and a crystal form, a preparation method and application thereof. The invention specifically provides D-tartrate, fumarate and a crystal form of a compound shown as a formula (I). The crystal form of the salt has good solubility and physical and chemical stability, can meet the medicinal requirements of production, transportation and storage, and has good patent medicine prospects. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a salt of a pyrimidine-fused ring compound, its crystal form, its preparation method and application. The present invention relates to a pharmaceutically acceptable salt of (3S,4S)-4-amino-8-{8-[(3-chloro-2-methylpyridin-4-yl)thio]imidazo[1,2-c]pyrimidin-5-yl}-3-methyl-2-oxa-8-azaspiro[4,5]decane. Background Art

[0002] SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene, which is involved in cell proliferation, differentiation and survival. It is an important signal regulatory molecule in the RAS / MAPK pathway in cells. Many oncogenic gene mutations rely on the activity of SHP2 to promote tumor growth. At the same time, SHP2 is also an important regulatory factor controlling cytokine production and immune cell responses. Therefore, targeted inhibition of SHP2 can achieve two goals at once, both slowing down cancer cell growth and regulating immune function to activate its anti-tumor effect. It is promising for treating cancer patients suffering from different types of tumors.

[0003] As a novel druggable target, SHP2 has attracted increasing attention. Regarding the development of SHP2 inhibitors, there are two major strategies: the development of inhibitors targeting the PTP catalytic region of SHP2 and the development of allosteric inhibitors targeting the non-catalytic region; due to the problems of poor selectivity and druggability of PTP catalytic region inhibitors, more current research tends to the development of allosteric inhibitors. It is particularly important to develop tyrosine phosphatase (SHP2) inhibitors and conduct drug research. Summary of the Invention

[0004] The present invention discloses a salt of a pyrimidine-fused ring compound, its crystal form, its preparation method and application. The crystal form of the salt of the present invention has good solubility and physical and chemical stability, and has good stability under high temperature, high humidity, grinding and pressure conditions, and has good prospects for drug development.

[0005] The present invention provides a D-tartrate salt of a compound represented by formula (I),

[0006]

[0007] The molar ratio of the compound represented by formula (I) to D-tartaric acid is 1:1.

[0008] The present invention provides polymorphic form I of the D-tartrate salt of a compound represented by formula (I), and its X-ray powder diffraction (XRPD) pattern expressed in 2θ angle using Cu-Kα radiation has diffraction peaks at 4.88 ± 0.20°, 10.24 ± 0.20°, 11.41 ± 0.20°, 14.74 ± 0.20°, 16.42 ± 0.20° and 20.56 ± 0.20°;

[0009]

[0010] The molar ratio of the compound represented by formula (I) to D-tartaric acid is 1:1.

[0011] In one embodiment, the X-ray powder diffraction (XRPD) pattern expressed in 2θ angle using Cu-Kα radiation of polymorphic form I of the D-tartrate salt of the compound represented by formula (I) further has diffraction peaks at one or more of 15.14 ± 0.20°, 22.08 ± 0.20°, 22.81 ± 0.20°, 26.86 ± 0.20°, 32.52 ± 0.20° and 39.29 ± 0.20°.

[0012] In one embodiment, the X-ray powder diffraction (XRPD) pattern expressed in 2θ angle using Cu-Kα radiation of polymorphic form I of the D-tartrate salt of the compound represented by formula (I) further has diffraction peaks at one or more of 15.38 ± 0.20°, 17.15 ± 0.20°, 18.94 ± 0.20°, 27.77 ± 0.20°, 34.85 ± 0.20° and 39.77 ± 0.20°.

[0013] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form I of the D-tartrate salt of the compound of formula (I) using Cu-Kα radiation and expressed in terms of 2θ angle has diffraction peaks at 4.88 ± 0.20°, 8.57 ± 0.20°, 10.24 ± 0.20°, 11.41 ± 0.20°, 13.66 ± 0.20°, 14.74 ± 0.20°, 15.14 ± 0.20°, 15.38 ± 0.20°, 16.11 ± 0.20°, 16.42 ± 0.20°, 17.15 ± 0.20°, 18.94 ± 0.20°, 19.56 ± 0.20°, 20.56 ± 0.20°, 21.55 ± 0.20°, 22.08 ± 0.20°, 22.81 ± 0.20°, 23.58 ± 0.20°, 24.06 ± 0.20°, 24.47 ± 0.20°, 26.86 ± 0.20°, 27.77 ± 0.20°, 29.28 ± 0.20°, 30.51 ± 0.20°, 32.52 ± 0.20°, 33.72 ± 0.20°, 34.85 ± 0.20°, 39.29 ± 0.20° and 39.77 ± 0.20°.

[0014] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form I of the D-tartrate salt of the compound of formula (I) using Cu-Kα radiation and expressed in terms of 2θ angle, the diffraction peak positions are shown in the following table:

[0015]

[0016]

[0017] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form I of the D-tartaric acid salt of the compound of formula (I) using Cu-Kα radiation and expressed in terms of 2θ angle, the diffraction peak positions and relative intensities are shown in the following table:

[0018]

[0019] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form I of the D-tartrate salt of the compound of formula (I) using Cu-Kα radiation and expressed in terms of 2θ angle is substantially as Figure 1 shown.

[0020] In one embodiment, the thermogravimetric analysis (TGA) curve of crystalline form I of the D-tartrate salt of the compound of formula (I) loses 0.3791% of its weight at 150 ± 3 °C (for example, in the range of 25 ± 3 °C to 150 ± 3 °C).

[0021] In one embodiment, the thermogravimetric analysis (TGA) curve of crystalline form I of the D-tartrate salt of the compound represented by formula (I) shows that it decomposes after 250 ± 3 °C.

[0022] In one embodiment, the thermogravimetric analysis (TGA) curve of crystalline form I of the D-tartrate salt of the compound represented by formula (I) is substantially as Figure 2 shown.

[0023] In one embodiment, the differential scanning calorimetry (DSC) curve of crystalline form I of the D-tartrate salt of the compound represented by formula (I) has an endothermic peak onset at 251.34 ± 3 °C, and / or the differential scanning calorimetry (DSC) curve of crystalline form I of the D-tartrate salt of the compound represented by formula (I) reaches a peak temperature at 254.51 ± 3 °C.

[0024] In one embodiment, the differential scanning calorimetry (DSC) curve of crystalline form I of the D-tartrate salt of the compound represented by formula (I) is substantially as Figure 3 shown.

[0025] The present invention provides a fumarate salt of a compound represented by formula (I),

[0026]

[0027] wherein the molar ratio of the compound represented by formula (I) to fumaric acid is 1:1.

[0028] The present invention provides a crystalline form I of a fumarate salt of a compound represented by formula (I), the X-ray powder diffraction (XRPD) pattern of which, using Cu-Kα radiation and expressed in 2θ angle, has diffraction peaks at 12.62 ± 0.20 °, 12.90 ± 0.20 °, 15.85 ± 0.20 °, 20.24 ± 0.20 °, 21.53 ± 0.20 °, and 25.00 ± 0.20 °;

[0029]

[0030] wherein the molar ratio of the compound represented by formula (I) to fumaric acid is 1:1.

[0031] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form I of the fumarate salt of the compound represented by formula (I), using Cu-Kα radiation and expressed in 2θ angle, further has diffraction peaks at one or more of 13.60 ± 0.20 °, 14.81 ± 0.20 °, 16.73 ± 0.20 °, 18.07 ± 0.20 °, 23.77 ± 0.20 °, and 25.90 ± 0.20 °.

[0032] In one embodiment, the X-ray powder diffraction (XRPD) pattern of Form I of the fumarate salt of the compound of formula (I), using Cu-Kα radiation and expressed in 2θ angle, further has diffraction peaks at one or more of 11.15±0.20°, 17.91±0.20°, 19.37±0.20°, 22.85±0.20°, 26.26±0.20° and 28.45±0.20°.

[0033] In one embodiment, the X-ray powder diffraction (XRPD) pattern of Form I of the fumarate salt of the compound of formula (I), using Cu-Kα radiation and expressed in 2θ angle, has diffraction peaks at 6.28±0.20°, 9.51±0.20°, 11.15±0.20°, 11.50±0.20°, 12.02±0.20°, 12.62±0.20°, 12.90±0.20°, 13.60±0.20°, 14.03±0.20°, 14.81±0.20°, 15.85±0.20°, 16.73±0.20°, 17.91±0.20°, 18.07±0.20°, 18.48±0.20°, 19.07±0.20°, 19.37±0.20°, 20.24±0.20°, 20.64±0.20°, 21.53±0.20°, 22.11±0.20°, 22.65±0.20°, 22.85±0.20°, 23.77±0.20°, 24.70±0.20°, 25.00±0.20°, 25.59±0.20°, 25.90±0.20°, 26.26±0.20°, 27.05±0.20°, 27.56±0.20°, 27.77±0.20°, 28.45±0.20° and 28.93±0.20°.

[0034] In one embodiment, the X-ray powder diffraction (XRPD) pattern of Form I of the fumarate salt of the compound of formula (I), using Cu-Kα radiation and expressed in 2θ angle, has diffraction peak positions as shown in the following table:

[0035]

[0036]

[0037] In one embodiment, the X-ray powder diffraction (XRPD) pattern of Form I of the fumarate salt of the compound of formula (I), using Cu-Kα radiation and expressed in 2θ angle, has diffraction peak positions and relative intensities as shown in the following table:

[0038]

[0039]

[0040] In one embodiment, the X-ray powder diffraction (XRPD) pattern of Form I of the fumarate of the compound represented by formula (I) using Cu-Kα radiation and expressed in 2θ angle is substantially as Figure 4 shown.

[0041] In one embodiment, the thermogravimetric analysis (TGA) curve of Form I of the fumarate of the compound represented by formula (I) shows a weight loss of 4.095% at 120 ± 3 °C (for example, in the range of 25 ± 3 °C to 120 ± 3 °C).

[0042] In one embodiment, the thermogravimetric analysis (TGA) curve of Form I of the fumarate of the compound represented by formula (I) is substantially as Figure 5 shown.

[0043] The present invention provides Form II of the fumarate of the compound represented by formula (I), the X-ray powder diffraction (XRPD) pattern of which using Cu-Kα radiation and expressed in 2θ angle has diffraction peaks at 10.94 ± 0.20 °, 13.33 ± 0.20 °, 17.35 ± 0.20 °, 17.59 ± 0.20 °, 20.38 ± 0.20 °, and 24.26 ± 0.20 °;

[0044]

[0045] The molar ratio of the compound represented by formula (I) to fumaric acid is 1:1.

[0046] In one embodiment, the X-ray powder diffraction (XRPD) pattern of Form II of the fumarate of the compound represented by formula (I) using Cu-Kα radiation and expressed in 2θ angle further has diffraction peaks at one or more of 11.63 ± 0.20 °, 15.67 ± 0.20 °, 20.83 ± 0.20 °, 23.37 ± 0.20 °, and 26.86 ± 0.20 °.

[0047] In one embodiment, the X-ray powder diffraction (XRPD) pattern of Form II of the fumarate of the compound represented by formula (I) using Cu-Kα radiation and expressed in 2θ angle further has diffraction peaks at one or more of 15.29 ± 0.20 °, 16.22 ± 0.20 °, 18.91 ± 0.20 °, 19.32 ± 0.20 °, 20.05 ± 0.20 °, 23.04 ± 0.20 °, and 25.35 ± 0.20 °.

[0048] In one embodiment, the polymorph II of the fumarate salt of the compound of formula (I) has X-ray powder diffraction (XRPD) peaks at 10.94±0.20°, 11.63±0.20°, 12.06±0.20°, 12.85±0.20°, 13.33±0.20°, 15.29±0.20°, 15.67±0.20°, 16.22±0.20°, 17.35±0.20°, 17.59±0.20°, 18.14±0.20°, 18.91±0.20°, 19.32±0.20°, 20.38±0.20°, 20.83±0.20°, 21.38±0.20°, 21.98±0.20°, 22.20±0.20°, 23.37±0.20°, 24.26±0.20°, 25.35±0.20°, 26.86±0.20° and 28.33±0.20° when using Cu-Kα radiation and expressed as 2θ angle in the X-ray powder diffraction (XRPD) pattern.

[0049] In one embodiment, the polymorph II of the fumarate salt of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed as 2θ angle, and the diffraction peak positions are shown in the following table:

[0050] Serial number 2θ (°) Serial number 2θ (°) 1 10.94 21 23.37 2 11.63 22 24.26 3 12.06 24 25.35 4 12.85 23 25.51 5 13.33 25 25.72 6 15.29 26 26.86 7 15.67 27 28.33 8 16.22 28 28.76 9 17.35 29 30.09 10 17.59 30 30.79 11 18.14 31 32.33 12 18.91 32 32.90 13 19.32 33 33.83 14 20.05 34 34.63 15 20.38 35 35.37 16 20.83 36 36.60 17 21.38 37 37.30 18 21.98 38 37.91 19 22.20 39 39.28 20 23.04 40 39.38 。

[0051] In one embodiment, the polymorph II of the fumarate salt of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed as 2θ angle, and the diffraction peak positions and relative intensities are shown in the following table:

[0052]

[0053] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the polymorph II of the fumarate salt of the compound of formula (I) using Cu-Kα radiation and expressed as 2θ angle is substantially as Figure 6 shown.

[0054] In one embodiment, the thermogravimetric analysis (TGA) curve of the polymorph II of the fumarate salt of the compound of formula (I) shows a weight loss of 0.990% at 50±3 °C (for example, in the range of 25±3 °C to 50±3 °C).

[0055] In one embodiment, the thermogravimetric analysis (TGA) curve of the polymorph II of the fumarate salt of the compound of formula (I) shows a weight loss of 1.224% at 150.55±3 °C (for example, in the range of 25±3 °C to 150.55±3 °C).

[0056] In one embodiment, the thermogravimetric analysis (TGA) curve of polymorph II of the fumarate salt of the compound represented by formula (I) is substantially as Figure 7 shown.

[0057] In one embodiment, the differential scanning calorimetry (DSC) curve of polymorph II of the fumarate salt of the compound represented by formula (I) has an endothermic peak onset at 216.00 ± 3 °C, and / or the differential scanning calorimetry (DSC) curve of polymorph II of the fumarate salt of the compound represented by formula (I) reaches a peak temperature at 219.55 ± 3 °C.

[0058] In one embodiment, the differential scanning calorimetry (DSC) curve of polymorph II of the fumarate salt of the compound represented by formula (I) is substantially as Figure 8 shown.

[0059] The present invention also provides a method for preparing polymorph I of the D-tartrate salt of the compound represented by formula (I), which comprises the following steps: crystallizing a mixture of D-tartaric acid, the compound represented by formula (I) and a solvent to obtain polymorph I of the D-tartrate salt of the compound represented by formula (I), wherein the solvent is an alcohol solvent or a mixed solvent of an alcohol solvent and water.

[0060] In one embodiment, the alcohol solvent is an alcohol solvent having 1 to 3 carbon atoms, such as methanol, ethanol, n-propanol or isopropanol, and more preferably ethanol.

[0061] In one embodiment, the mixed solvent of an alcohol solvent and water is a mixed solvent of ethanol and water with a volume ratio of 19:1.

[0062] In one embodiment, the crystallization is a conventional crystallization operation in the art, such as cooling crystallization.

[0063] In one embodiment, the preparation method further comprises filtration and drying.

[0064] In one embodiment, the drying is vacuum drying under reduced pressure at 40-60 °C.

[0065] The present invention also provides a method for preparing polymorph I of the fumarate salt of the compound represented by formula (I), which comprises the following steps: crystallizing a mixture of fumaric acid, the compound represented by formula (I) and a solvent to obtain polymorph I of the fumarate salt of the compound represented by formula (I); the solvent is an alcohol solvent.

[0066] In one embodiment, the alcohol solvent is an alcohol solvent having 1 to 3 carbon atoms, such as methanol, ethanol, n-propanol or isopropanol, and more preferably ethanol.

[0067] In one embodiment, the preparation method further comprises filtration and drying.

[0068] The present invention also provides a method for preparing polymorph II of the fumarate salt of a compound represented by formula (I), which comprises the following steps: crystallizing a mixture of fumaric acid, a compound represented by formula (I) and a solvent to obtain polymorph II of the fumarate salt of the compound represented by formula (I); the solvent is a ketone solvent.

[0069] In one embodiment, the ketone solvent is acetone.

[0070] In one embodiment, the preparation method further comprises filtration and drying.

[0071] The present invention also provides a pharmaceutical composition, which comprises substance Z and one or more pharmaceutically acceptable excipients, and the substance Z is polymorph I of the D-tartrate salt of the compound represented by formula (I) above, polymorph I of the fumarate salt of the compound represented by formula (I) above or polymorph II of the fumarate salt of the compound represented by formula (I) above. In the above pharmaceutical composition, one or more of polymorph I of the D-tartrate salt of the compound represented by formula (I) of the present invention, polymorph I of the fumarate salt of the compound represented by formula (I) and polymorph II of the fumarate salt of the compound represented by formula (I) are included as active ingredients.

[0072] The present invention also provides the use of substance Z or the above pharmaceutical composition in the preparation of a drug for treating and / or preventing a disease associated with abnormal SHP2 activity, and the substance Z is polymorph I of the D-tartrate salt of the compound represented by formula (I) above, polymorph I of the fumarate salt of the compound represented by formula (I) above or polymorph II of the fumarate salt of the compound represented by formula (I) above.

[0073] In one embodiment, the disease is (for example, malignant tumor) Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, acute myeloid leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, lung cancer, colon cancer, brain cancer, nasopharyngeal cancer, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma or glioblastoma.

[0074] Term explanation:

[0075] It should be noted that in the X-ray powder diffraction pattern, the position of the diffraction peak or the relative intensity of the diffraction peak may vary due to factors such as the measuring instrument, the measuring method / conditions, etc. For any specific crystal form, there may be an error in the position of the peak, and the measurement error of the 2θ value is, for example, ±0.2°. Therefore, when determining each crystal form, this error should be taken into account, and it is also within the scope of the present application within the error.

[0076] It should be noted that for the same crystal form, the occurrence positions of DSC thermal events (such as endothermic peaks, exothermic peaks, etc.) may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, there may be an error in the position of the endothermic peak, and the error can be ±5°C, can be ±3°C, or can be ±2°C. Therefore, when determining each crystal form, this error should be taken into account, and within the error range also belongs to the scope of this application.

[0077] It should be noted that for the same crystal form, the occurrence position 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, there may be an error in the position of the weight loss temperature, and the error can be ±5°C, can be ±3°C, or can be ±2°C. Therefore, when determining each crystal form, this error should be taken into account, and within the error range also belongs to the scope of this application.

[0078] In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium commonly accepted in the art for delivering a bioactive compound to a mammal (such as a human). This medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

[0079] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting with any component contained in the composition in an adverse manner. In this application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers that are permitted by the relevant government regulatory authorities for use in humans or livestock.

[0080] As used herein, the terms "preventive", "prevent" and "prevent" include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient.

[0081] As used herein, the terms "treat" and other similar synonyms include the following meanings: (i) preventing the occurrence of a disease or disorder in a mammal, especially when such a mammal is susceptible to the disease or disorder but has not been diagnosed as having the disease or disorder; (ii) inhibiting the disease or disorder, that is, curbing its development; (iii) alleviating the disease or disorder, that is, making the state of the disease or disorder subside; or (iv) relieving the symptoms caused by the disease or disorder.

[0082] As used herein and unless otherwise specified, the term "excipient" refers to those excipients widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to enable the active ingredient to dissolve at the desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredient after the subject receives the composition administration. Excipients can be inert fillers or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition.

[0083] As used herein, unless otherwise specified, the term "room temperature" generally refers to 10°C to 35°C, for example 25°C.

[0084] As used herein, the term "stirring" is completed by using conventional operating methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 revolutions per minute, wherein the magnetic stirring is 200 to 1500 revolutions per minute, preferably 300 to 1000 revolutions per minute, and the mechanical stirring is preferably 100 to 300 revolutions per minute.

[0085] Unless otherwise stated, the term "plural" as used herein refers to, for example, 2, 3, 4, 5 or 6.

[0086] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain the preferred examples of the present invention.

[0087] The reagents and raw materials used in the present invention are all commercially available.

[0088] The positive and progressive effects of the present invention are as follows: The crystal form of the salt of the present invention has good solubility and physicochemical stability, and has good stability under the conditions of high temperature, high humidity and high temperature and high humidity; and under the conditions of grinding, pressure and heat, the crystal form has good stability and can meet the pharmaceutical requirements for production, transportation and storage. BRIEF DESCRIPTION OF THE DRAWINGS

[0089] Figure 1 It is the XRPD pattern of crystal form I of the D-tartrate salt of the compound shown in formula (I).

[0090] Figure 2 It is the TGA pattern of crystal form I of the D-tartrate salt of the compound shown in formula (I).

[0091] Figure 3 It is the DSC pattern of crystal form I of the D-tartrate salt of the compound shown in formula (I).

[0092] Figure 4 It is the XRPD pattern of crystal form I of the fumarate salt of the compound shown in formula (I).

[0093] Figure 5TGA spectrum of Form I of the fumarate salt of the compound represented by formula (I).

[0094] Figure 6 XRPD spectrum of Form II of the fumarate salt of the compound represented by formula (I).

[0095] Figure 7 TGA spectrum of Form II of the fumarate salt of the compound represented by formula (I).

[0096] Figure 8 DSC spectrum of Form II of the fumarate salt of the compound represented by formula (I).

[0097] Figure 9 XRPD spectrum of the amorphous form of the compound represented by formula (I).

[0098] Figure 10 XRPD spectrum of Form A of the compound represented by formula (I). Detailed implementation manners

[0099] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0100] Testing instruments used in the experiments

[0101] 1. X-ray diffraction spectrum

[0102] Instrument model: Bruker D8 ADVANCE X-ray powder diffractometer

[0103] Ray: Monochromatic Cu-Kα ray (wavelength = 1.5418)

[0104] Scanning mode: θ / 2θ, scanning range: 3 - 40°

[0105] Voltage: 40 kV, current: 40 mA

[0106] 2. DSC spectrum

[0107] Instrument model: TA Discovery DSC 250

[0108] Purge gas: Nitrogen

[0109] Heating rate: 10 °C / min

[0110] Temperature range: 40 °C to 265 °C

[0111] 3. TGA spectrum

[0112] Instrument Model: TA Discovery TGA 550

[0113] Purge Gas: Nitrogen

[0114] Heating Rate: 10 °C / min

[0115] Temperature Range: Room Temperature to 300 °C

[0116] Example 1: Preparation of Crystal Form I of D-Tartrate Salt of Compound of Formula (I)

[0117] Take the compound shown in formula (I) (270 mg, 0.6 mmol) (the compound was prepared according to the method disclosed in Example 107 of WO2019158019). In a 25 mL single-necked flask, add 5 mL of 95% ethanol and (100 mg, 0.66 mmol) of D-tartaric acid. Heat to dissolve, cool to 20 °C and crystallize for 2 h. Filter, wash with 95% ethanol, and dry in vacuo at 50 °C to obtain 352 mg of solid, with a yield of 97.49%. The obtained solid was identified by XRPD, DSC, and TGA, and it was crystal form I of D-tartrate salt. The HPLC content test of D-tartaric acid (according to General Rule 0512 of Part IV of Chinese Pharmacopoeia 2020 Edition) results showed that the molar ratio of the compound shown in formula (I) to D-tartaric acid was 1:1.

[0118] Table 1 XRPD Peak List of Crystal Form I of D-Tartrate Salt of Compound of Formula (I)

[0119]

[0120]

[0121] The XRPD of crystal form I of D-tartrate salt of the compound shown in formula (I) is shown in Table 1. The XRPD pattern of this crystalline sample is shown in Figure 1 , in which there are characteristic absorption peaks at approximately 4.88, 8.57, 10.24, 11.41, 13.66, 14.74, 15.14, 15.38, 16.11, 16.42, 17.15, 18.94, 19.56, 20.56, 21.55, 22.08, 22.81, 23.58, 24.06, 24.47, 26.86, 27.77, 29.28, 30.51, 32.52, 33.72, 34.85, 39.29, and 39.77. The error range of the 2θ angle of each characteristic peak is ±0.2. The TGA pattern is shown in Figure 2 , with basically no weight loss before 100 °C, approximately 0.3791% weight loss at about 150 °C, and gradual melting and decomposition after 250 °C. The DSC pattern is shown in Figure 3, there is a starting point of the endothermic peak at 251.34 °C, with an enthalpy value of 212.1 J / g, and a sharp endothermic peak at 254.51 °C.

[0122] Example 2: Preparation of Crystal Form I of the Fumarate Salt of the Compound Shown by Formula (I)

[0123] Take (150 mg, 0.34 mmol) of the compound shown by formula (I), place it in a 25 mL single-neck flask, add 5 mL of ethanol and fumaric acid (43 mg, 0.37 mmol), heat to dissolve, cool to 20 °C and crystallize for 2 h, filter, wash with ethanol, and dry under vacuum at 50 °C to obtain 172 mg of solid, with a yield of 90.94%. The obtained solid was identified by XRPD and TGA, and it is Crystal Form I of the fumarate salt. The HPLC content test of fumaric acid (according to General Rule 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition) results show that the molar ratio of the compound shown by formula (I) to fumaric acid is 1:1.

[0124] Table 2 XRPD Peak List of Crystal Form I of the Fumarate Salt

[0125]

[0126]

[0127] The XRPD of Crystal Form I of the fumarate salt is shown in Table 2, and the XRPD pattern of this crystalline sample is shown in Figure 4 , where characteristic absorption peaks are present at approximately 6.28, 9.51, 11.15, 11.50, 12.02, 12.62, 12.90, 13.60, 14.03, 14.81, 15.85, 16.73, 17.91, 18.07, 18.48, 19.07, 19.37, 20.24, 20.64, 21.53, 22.11, 22.65, 22.85, 23.77, 24.70, 25.00, 25.59, 25.90, 26.26, 27.05, 27.56, 27.77, 28.45, and 28.93. The error range of the 2θ angle of each characteristic peak is ±0.2. The TGA pattern is shown in Figure 5 , with a weight loss of 4.095% at approximately 120 °C.

[0128] Example 3: Preparation of Crystal Form II of the Fumarate Salt of the Compound Shown by Formula (I)

[0129] Take (100 mg, 0.22 mmol) of the compound shown in formula (I). In a 25 mL single-necked flask, add 3 mL of acetone and fumaric acid (28.7 mg, 0.25 mmol). Heat and stir, then cool to room temperature and crystallize for 24 h. Filter, wash with acetone, and dry under vacuum at 50 °C to obtain 115 mg of a solid with a yield of 91.20%. The obtained solid was identified by XRPD, DSC, and TGA, and it was found to be polymorph II of the fumarate salt. The HPLC content test of fumaric acid (in accordance with General Rule 0512, Part IV of the Chinese Pharmacopoeia 2020 Edition) results showed that the molar ratio of the compound shown in formula (I) to fumaric acid was 1:1.

[0130] Table 3 XRPD peak list of polymorph II of the fumarate salt of the compound shown in formula (I)

[0131]

[0132]

[0133] The XRPD of polymorph II of the fumarate salt of the compound shown in formula (I) is shown in Table 3. The XRPD pattern of this crystalline sample is shown in Figure 6 , where characteristic absorption peaks are present at approximately 10.94, 11.63, 12.06, 12.85, 13.33, 15.29, 15.67, 16.22, 17.35, 17.59, 18.14, 18.91, 19.32, 20.38, 20.83, 21.38, 21.98, 22.20, 23.37, 24.26, 25.35, 26.86, and 28.33. The error range of the 2θ angle of each characteristic peak is ±0.2. The TGA pattern is shown in Figure 7 , with a weight loss of approximately 0.990% before approximately 50 °C, almost no weight loss before 100 °C, and a weight loss of approximately 1.224% (weight fraction 98.776%) before approximately 150 °C. The DSC pattern is shown in Figure 8 , with an endothermic peak starting point at 38.25 °C, an enthalpy value of 25.930 J / g, a sharp endothermic peak at 69.30 °C, an endothermic peak starting point at 216.00 °C, and an enthalpy value of 81.868 J / g, and a sharp endothermic peak at 219.55 °C.

[0134] Example 4: Preparation of polymorph A of the compound shown in formula (I)

[0135] The compound shown in formula (I) was prepared according to the method disclosed in Example 107 of WO2019158019. The obtained product after preparation was a freeze-dried amorphous solid, and the X-ray diffraction pattern is shown in Figure 9, an amorphous solid was added to an appropriate amount of ethyl acetate, acetone, or acetonitrile for recrystallization or slurry experiments. The same crystal form was found in all the obtained products through X-ray diffraction tests. Herein, the crystal form of the free base was defined as crystal form A of the compound shown in formula (I). The obtained solid was identified by XRPD, DSC, and TGA as crystal form A of the compound shown in formula (I).

[0136] Table 4 List of XRPD Peaks of Crystal Form A of the Compound Shown in Formula (I)

[0137]

[0138]

[0139] The XRPD of crystal form A of the compound shown in formula (I) is shown in Table 4, and the XRPD pattern is shown in Figure 10 , using Cu-Kα radiation, the diffraction 2θ angles have characteristic absorption peaks at 7.05, 9.39, 9.62, 10.58, 12.38, 13.14, 15.60, 15.81, 18.23, 18.88, 19.27, 19.58, 20.39, 20.82, 22.64, 23.57, 23.85, 24.27, 24.89, 25.81, 28.04, and 31.70. The error range of the 2θ angle of each characteristic peak is ±0.2. TGA shows a weight loss of about 0.67% before about 50°C, basically no weight loss before 100°C, another weight loss of about 1.036% before about 200°C, and gradual melting and decomposition after 165°C. DSC has an endothermic peak starting point at 21.18°C with an enthalpy value of 40.201 J / g, a sharp endothermic peak at 57.05°C, an endothermic peak starting point at 167.06°C with an enthalpy value of 76.482 J / g, and a sharp endothermic peak at 170.80°C.

[0140] Example 5

[0141] Samples of crystal form A of the compound shown in formula (I) (obtained in Example 4), crystal form I of D-tartrate (obtained in Example 1), crystal form I of fumarate (obtained in Example 2), and crystal form II of fumarate (obtained in Example 3) were respectively placed flat and open to the air, and were examined under light (5000 Lux ± 500 Lux), high temperature of 60°C, high humidity (25°C, RH 90% ± 5%), and high temperature and high humidity (40°C, relative humidity 75% ± 1%) for 10 days and 30 days to examine the stability of the crystal forms. The specific research data are shown in Table 5.

[0142] Table 5 Comparison of Crystal Form Stability Data after 30 Days under Different Conditions

[0143]

[0144]

[0145] The research data on crystal form stability showed that under stress conditions, for the free base under high temperature and high humidity conditions, a mixed crystal containing some amorphous solid appeared for crystal form A of the compound shown in formula (I); for fumarate crystal form I of the compound shown in formula (I), except being stable under light conditions, it was converted into fumarate crystal form II of the compound shown in formula (I) under the other conditions; for fumarate crystal form II of the compound shown in formula (I) and D-tartrate crystal form I of the compound shown in formula (I), their crystal form stabilities were good under various stress conditions.

[0146] Example 6

[0147] Samples of crystal form A of the compound shown in formula (I) (obtained in Example 4), D-tartrate crystal form I of the compound shown in formula (I) (obtained in Example 1), and fumarate crystal form II of the compound shown in formula (I) (obtained in Example 3) were respectively placed flat and open. Under the conditions of light (5000Lux ± 500Lux), high temperature of 60 °C, high humidity (25 °C, RH90% ± 5%), and high temperature and high humidity (40 °C, relative humidity 75% ± 1%), they were examined for 10 days and 30 days to investigate the stability of related substances. The specific research data are shown in Table 6.

[0148] Table 6. Comparison of related substance stability data under different conditions

[0149]

[0150] The results of the investigation on the stability of related substances showed that after salt formation, the chemical stability was improved to varying degrees. Under light conditions, all three samples degraded to varying degrees, indicating that the samples need to be stored away from light. The stability of related substances of fumarate crystal form II of the compound shown in formula (I) under high temperature conditions was not as good as that of D-tartrate crystal form I of the compound shown in formula (I), and D-tartrate crystal form I of the compound shown in formula (I) had the best chemical stability.

[0151] Example 7

[0152] The test results of the saturated solubility of samples of crystal form A of the compound shown in formula (I) (obtained in Example 4), D-tartrate crystal form I (obtained in Example 1), and fumarate crystal form II (obtained in Example 3) in water and at different pH values showed that after salt formation, the solubility of the free base in water and at different pH values increased significantly. Under the conditions of pH 4.5 and pH 6.8, the solubility increase of fumarate was the most obvious. The specific research data are shown in Table 7.

[0153] Table 7. Solubility data (mg / mL) under different conditions

[0154]

[0155] Example 8

[0156] The crystalline form I of the D-tartrate of the compound of formula (I) (obtained in Example 1) was ground, heated and tableted. The research results showed that the crystalline form was stable. For detailed experimental data, see Table 8 below.

[0157] Table 8. Study on the special stability of crystalline form I of the D-tartrate of the compound of formula (I)

[0158]

[0159] The results showed that crystalline form I of the D-tartrate had good stability under the conditions of grinding, heating and tabletting.

[0160] Example 9

[0161] Referring to the operation of Example 1 of this application, the compound of formula (I) was mixed with the acids and solvents shown in the following table, and the crystalline form of the salt could not be obtained.

[0162]

[0163] The results showed that the crystallinity of the hydrochloride and citrate was poor or average, the sulfate had strong hygroscopicity and was difficult to filter. For the salts formed with other different acids, there were more oily substances or amorphous solids, and the corresponding salts could not be obtained.

Claims

1. The D-tartrate or fumarate of a compound represented by formula (I), wherein the molar ratio of the compound represented by formula (I) to D-tartaric acid is 1:1; wherein the molar ratio of the compound represented by formula (I) to fumaric acid is 1:

1.

2. A crystalline form of a salt of a compound represented by formula (I), characterized in that, It is polymorph I of the D-tartrate of the compound represented by formula (I), polymorph I of the fumarate of the compound represented by formula (I), or polymorph II of the fumarate of the compound represented by formula (I); Among them, the structure of the compound shown in formula (I) is as follows: In polymorph I of the D-tartrate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to D-tartaric acid is 1:1; In polymorph I of the fumarate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to fumaric acid is 1:1; In polymorph II of the fumarate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to fumaric acid is 1:1; Polymorph I of the D-tartrate of the compound represented by formula (I) has diffraction peaks at 4.88 ± 0.20°, 10.24 ± 0.20°, 11.41 ± 0.20°, 14.74 ± 0.20°, 16.42 ± 0.20°, and 20.56 ± 0.20° in an X-ray powder diffraction pattern represented by 2θ angle using Cu-Kα radiation; Polymorph I of the fumarate of the compound represented by formula (I) has diffraction peaks at 12.62 ± 0.20°, 12.90 ± 0.20°, 15.85 ± 0.20°, 20.24 ± 0.20°, 21.53 ± 0.20°, and 25.00 ± 0.20° in an X-ray powder diffraction pattern represented by 2θ angle using Cu-Kα radiation; Polymorph II of the fumarate of the compound represented by formula (I) has diffraction peaks at 10.94 ± 0.20°, 13.33 ± 0.20°, 17.35 ± 0.20°, 17.59 ± 0.20°, 20.38 ± 0.20°, and 24.26 ± 0.20° in an X-ray powder diffraction pattern represented by 2θ angle using Cu-Kα radiation.

3. The crystal form of the salt of the compound represented by formula (I) as described in claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern represented by 2θ angle using Cu-Kα radiation of polymorph I of the D-tartrate of the compound represented by formula (I) further has diffraction peaks at one or more of 15.14 ± 0.20°, 22.08 ± 0.20°, 22.81 ± 0.20°, 26.86 ± 0.20°, 32.52 ± 0.20°, and 39.29 ± 0.20°; (2) The X-ray powder diffraction pattern represented by 2θ angle using Cu-Kα radiation of polymorph I of the fumarate of the compound represented by formula (I) further has diffraction peaks at one or more of 13.60 ± 0.20°, 14.81 ± 0.20°, 16.73 ± 0.20°, 18.07 ± 0.20°, 23.77 ± 0.20°, and 25.90 ± 0.20°; (3) The X-ray powder diffraction pattern of polymorph II of the fumarate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, also has diffraction peaks at one or more of 11.63±0.20°, 15.67±0.20°, 20.83±0.20°, 23.37±0.20° and 26.86±0.20°; Preferably, the polymorph of the salt of the compound represented by formula (I) satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of polymorph I of the D-tartrate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, also has diffraction peaks at one or more of 15.38±0.20°, 17.15±0.20°, 18.94±0.20°, 27.77±0.20°, 34.85±0.20° and 39.77±0.20°; (2) The X-ray powder diffraction pattern of polymorph I of the fumarate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, also has diffraction peaks at one or more of 11.15±0.20°, 17.91±0.20°, 19.37±0.20°, 22.85±0.20°, 26.26±0.20° and 28.45±0.20°; (3) The X-ray powder diffraction pattern of polymorph II of the fumarate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, also has diffraction peaks at one or more of 15.29±0.20°, 16.22±0.20°, 18.91±0.20°, 19.32±0.20°, 20.05±0.20°, 23.04±0.20° and 25.35±0.20°.

4. The crystal form of the salt of the compound represented by formula (I) as described in claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of Form I of the D-tartrate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 4.88 ± 0.20°, 8.57 ± 0.20°, 10.24 ± 0.20°, 11.41 ± 0.20°, 13.66 ± 0.20°, 14.74 ± 0.20°, 15.14 ± 0.20°, 15.38 ± 0.20°, 16.11 ± 0.20°, 16.42 ± 0.20°, 17.15 ± 0.20°, 18.94 ± 0.20°, 19.56 ± 0.20°, 20.56 ± 0.20°, 21.55 ± 0.20°, 22.08 ± 0.20°, 22.81 ± 0.20°, 23.58 ± 0.20°, 24.06 ± 0.20°, 24.47 ± 0.20°, 26.86 ± 0.20°, 27.77 ± 0.20°, 29.28 ± 0.20°, 30.51 ± 0.20°, 32.52 ± 0.20°, 33.72 ± 0.20°, 34.85 ± 0.20°, 39.29 ± 0.20° and 39.77 ± 0.20°; (2) The X-ray powder diffraction pattern of Form I of the fumarate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 6.28 ± 0.20°, 9.51 ± 0.20°, 11.15 ± 0.20°, 11.50 ± 0.20°, 12.02 ± 0.20°, 12.62 ± 0.20°, 12.90 ± 0.20°, 13.60 ± 0.20°, 14.03 ± 0.20°, 14.81 ± 0.20°, 15.85 ± 0.20°, 16.73 ± 0.20°, 17.91 ± 0.20°, 18.07 ± 0.20°, 18.48 ± 0.20°, 19.07 ± 0.20°, 19.37 ± 0.20°, 20.24 ± 0.20°, 20.64 ± 0.20°, 21.53 ± 0.20°, 22.11 ± 0.20°, 22.65 ± 0.20°, 22.85 ± 0.20°, 23.77 ± 0.20°, 24.70 ± 0.20°, 25.00 ± 0.20°, 25.59 ± 0.20°, 25.90 ± 0.20°, 26.26 ± 0.20°, 27.05 ± 0.20°, 27.56 ± 0.20°, 27.77 ± 0.20°, 28.45 ± 0.20° and 28.93 ± 0.20°; (3) The X-ray powder diffraction pattern of polymorph II of the fumarate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 10.94 ± 0.20°, 11.63 ± 0.20°, 12.06 ± 0.20°, 12.85 ± 0.20°, 13.33 ± 0.20°, 15.29 ± 0.20°, 15.67 ± 0.20°, 16.22 ± 0.20°, 17.35 ± 0.20°, 17.59 ± 0.20°, 18.14 ± 0.20°, 18.91 ± 0.20°, 19.32 ± 0.20°, 20.38 ± 0.20°, 20.83 ± 0.20°, 21.38 ± 0.20°, 21.98 ± 0.20°, 22.20 ± 0.20°, 23.37 ± 0.20°, 24.26 ± 0.20°, 25.35 ± 0.20°, 26.86 ± 0.20° and 28.33 ± 0.20°.

5. The crystalline form of the salt of the compound represented by formula (I) as described in claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of polymorph I of the D-tartrate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions as shown in the following table: ； (2) The X-ray powder diffraction pattern of polymorph I of the fumarate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions as shown in the following table: ； (3) The X-ray powder diffraction pattern of polymorph II of the fumarate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions as shown in the following table: ； Preferably, the crystal form of the salt of the compound represented by formula (I) satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of polymorph I of D-tartaric acid of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions and relative intensities as shown in the following table: (2) The X-ray powder diffraction pattern of polymorph I of the fumarate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions and relative intensities as shown in the following table: (3) The X-ray powder diffraction pattern of polymorph II of the fumarate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions and relative intensities as shown in the following table: More preferably, the crystal form of the salt of the compound represented by formula (I) satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of polymorph I of the D-tartrate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, is substantially as shown in Figure 1; (2) The X-ray powder diffraction pattern of polymorph I of the fumarate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, is substantially as shown in Figure 4; (3) The X-ray powder diffraction pattern of the polymorphic form II of the fumarate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, is substantially as shown in Figure 6.

6. The crystal form of the salt of the compound represented by formula (I) as described in claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The thermogravimetric analysis curve of the polymorphic form I of the D-tartrate salt of the compound represented by formula (I) shows a weight loss of 0.3791% at 150 ± 3 °C, for example, a weight loss of 0.3791% in the range of 25 ± 3 °C to 150 ± 3 °C; (2) The thermogravimetric analysis curve of the polymorphic form I of the D-tartrate salt of the compound represented by formula (I) shows its decomposition after 250 ± 3 °C; (3) The differential scanning calorimetry curve of the polymorphic form I of the D-tartrate salt of the compound represented by formula (I) has an endothermic peak onset at 251.34 ± 3 °C, and / or the differential scanning calorimetry curve of the polymorphic form I of the D-tartrate salt of the compound represented by formula (I) reaches a peak temperature at 254.51 ± 3 °C; (4) The thermogravimetric analysis curve of the polymorphic form I of the fumarate salt of the compound represented by formula (I) shows a weight loss of 4.095% at 120 ± 3 °C, for example, a weight loss of 4.095% in the range of 25 ± 3 °C to 120 ± 3 °C; (5) The thermogravimetric analysis curve of the polymorphic form II of the fumarate salt of the compound represented by formula (I) shows a weight loss of 0.990% at 50 ± 3 °C, for example, a weight loss of 0.990% in the range of 25 ± 3 °C to 50 ± 3 °C; (6) The thermogravimetric analysis curve of the polymorphic form II of the fumarate salt of the compound represented by formula (I) shows a weight loss of 1.224% at 150.55 ± 3 °C, for example, a weight loss of 1.224% in the range of 25 ± 3 °C to 150.55 ± 3 °C; (7) The differential scanning calorimetry curve of the polymorphic form II of the fumarate salt of the compound represented by formula (I) has an endothermic peak onset at 216.00 ± 3 °C, and / or the differential scanning calorimetry curve of the polymorphic form II of the fumarate salt of the compound represented by formula (I) reaches a peak temperature at 219.55 ± 3 °C; Preferably, the polymorphic form of the salt of the compound represented by formula (I) satisfies one or more of the following conditions: (1) The thermogravimetric analysis curve of the polymorphic form I of the D-tartrate salt of the compound represented by formula (I) is substantially as shown in Figure 2; (2) The differential scanning calorimetry curve of the polymorphic form I of the D-tartrate salt of the compound represented by formula (I) is substantially as shown in Figure 3; (3) The thermogravimetric analysis curve of the polymorphic form I of the fumarate salt of the compound represented by formula (I) is substantially as shown in Figure 5; (4) The thermogravimetric analysis curve of the polymorphic form II of the fumarate salt of the compound represented by formula (I) is substantially as shown in Figure 7; (5) The differential scanning calorimetry curve of the polymorphic form II of the fumarate salt of the compound represented by formula (I) is substantially as shown in Figure 8.

7. A method for preparing Form I of the D-tartrate salt of the compound represented by formula (I) according to any one of claims 2-6, Form I of the fumarate salt of the compound represented by formula (I) according to any one of claims 2-6, or Form II of the fumarate salt of the compound represented by formula (I) according to any one of claims 2-6, characterized in that The method for preparing Form I of the D-tartrate salt of the compound represented by formula (I) comprises the following steps: Crystallizing a mixture of D-tartaric acid, the compound represented by formula (I), and a solvent to obtain Form I of the D-tartrate salt of the compound represented by formula (I), and the solvent is an alcohol solvent or a mixed solvent of an alcohol solvent and water; The method for preparing Form I of the fumarate salt of the compound represented by formula (I) comprises the following steps: Crystallizing a mixture of fumaric acid, the compound represented by formula (I), and a solvent to obtain Form I of the fumarate salt of the compound represented by formula (I); the solvent is an alcohol solvent; The method for preparing Form II of the fumarate salt of the compound represented by formula (I) comprises the following steps: Crystallizing a mixture of fumaric acid, the compound represented by formula (I), and a solvent to obtain Form II of the fumarate salt of the compound represented by formula (I); the solvent is a ketone solvent.

8. The preparation method of crystalline form I of D-tartrate of the compound represented by formula (I), crystalline form I of fumarate of the compound represented by formula (I), or crystalline form II of fumarate of the compound represented by formula (I) as claimed in claim 7, characterized in that, It satisfies one or more of the following conditions: (1) In the method for preparing Form I of the D-tartrate salt of the compound represented by formula (I), the alcohol solvent is an alcohol solvent having 1-3 carbon atoms, such as methanol, ethanol, n-propanol or isopropanol, and for example ethanol; Preferably, the mixed solvent of the alcohol solvent and water is a mixed solvent of ethanol and water with a volume ratio of 19:1; (2) In the method for preparing Form I of the D-tartrate salt of the compound represented by formula (I), the crystallization is cooling crystallization; (3) The method for preparing Form I of the D-tartrate salt of the compound represented by formula (I) further comprises filtration and drying; the drying is preferably vacuum drying under reduced pressure at 40-60 °C; (4) In the method for preparing Form I of the fumarate salt of the compound represented by formula (I), the alcohol solvent is an alcohol solvent having 1-3 carbon atoms, such as methanol, ethanol, n-propanol or isopropanol, and for example ethanol; (5) The method for preparing Form I of the fumarate salt of the compound represented by formula (I) further comprises filtration and drying; (6) In the method for preparing Form II of the fumarate salt of the compound represented by formula (I), the ketone solvent is acetone; (7) The method for preparing Form II of the fumarate salt of the compound represented by formula (I) further comprises filtration and drying.

9. A pharmaceutical composition comprising substance Z and one or more pharmaceutically acceptable excipients, wherein substance Z is the D-tartrate salt of the compound of formula (I) as claimed in claim 1, the fumarate salt of the compound of formula (I) as claimed in claim 1, the polymorphic form I of the D-tartrate salt of the compound of formula (I) as claimed in any one of claims 2 - 6, the polymorphic form I of the fumarate salt of the compound of formula (I) as claimed in any one of claims 2 - 6, or the polymorphic form II of the fumarate salt of the compound of formula (I) as claimed in any one of claims 2 - 6.

10. Use of substance Z or the pharmaceutical composition as claimed in claim 9 in the preparation of a medicament for treating and / or preventing diseases associated with abnormal SHP2 activity, wherein substance Z is the D-tartrate salt of the compound of formula (I) as claimed in claim 1, the fumarate salt of the compound of formula (I) as claimed in claim 1, the polymorphic form I of the D-tartrate salt of the compound of formula (I) as claimed in any one of claims 2 - 6, the polymorphic form I of the fumarate salt of the compound of formula (I) as claimed in any one of claims 2 - 6, or the polymorphic form II of the fumarate salt of the compound of formula (I) as claimed in any one of claims 2 - 6; Preferably, the disease is a malignant tumor, preferably Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, acute myeloid leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, lung cancer, colon cancer, brain cancer, nasopharyngeal cancer, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, or glioblastoma.

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