Pharmaceutically acceptable salts of heterocyclic compounds, crystal forms thereof, methods of preparation and uses

Abstract

The application belongs to the technical field of medicine crystal form, and particularly relates to a kind of pharmaceutical salt of heterocyclic compound as shown in formula III and its crystal form, preparation method and purposes.The application provides the trihydrochloride of the above-mentioned heterocyclic compound and the sulfate with salt-forming ratio of 1:1.5, which has strong crystallinity, and under certain conditions, crystallization can obtain crystal with specific crystal form, wherein the XRPD pattern of the trihydrochloride of the above-mentioned heterocyclic compound with crystal form A has characteristic peaks at 2theta values of 6.5±0.2°, 24.2±0.2° and 27.6±0.2°.The solubility of the pharmaceutical salt of the heterocyclic compound or its crystal is good, the stability is high, the preparation is convenient, and the applicability as medicine is high.The preparation process of the pharmaceutical salt or its crystal is simple, the cost is low, the yield is high, and it is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical crystal form technology, specifically relating to a pharmaceutically acceptable salt of a heterocyclic compound that serves as an SHP2 inhibitor, its crystal form, preparation method, and pharmaceutical uses. Background Technology

[0002] Tyrosine phosphatase SHP2 consists of two N-terminal Src homology 2 domains (N-SH2 and C-SH2) and a protein tyrosine phosphatase catalytic domain (PTP). In the basal state, N-SH2 binds to PTP to form a ring structure, thereby hindering PTP binding to the substrate and inhibiting enzyme catalytic activity. When the tyrosine residue of the upstream receptor protein is phosphorylated, N-SH2 binds to it, releasing the PTP catalytic domain and thus exerting phosphatase activity.

[0003] At the cellular level, SHP2 participates in multiple tumor cell signaling pathways, such as RTK / Ras / MAPK, JAK / STAT, and PB3K / Akt, through its downstream cytoplasmic function with numerous receptor tyrosine kinases. Through its regulatory role in these kinases and signaling pathways, SHP2 is closely related to many important cellular life activities, such as cell proliferation, migration, differentiation, death, cytokine regulation, and tumorigenesis.

[0004] Simultaneously, SHP2 is also involved in programmed death receptor 1 (PD1)-mediated immunosuppression. After PD-1 binds to PD-L1 on T cells, it can recruit large amounts of SHP2 within the cell. SHP2 can dephosphorylate antigen receptor pathway proteins within T cells, thereby inhibiting T cell activation. Therefore, inhibiting SHP2 activity can reverse immunosuppression in the tumor microenvironment.

[0005] As an important cellular signaling cytokine, SHP2 mutations are closely associated with a variety of diseases. Studies have found SHP2 mutations in neuroblastoma, AML (4%), breast cancer, NSCLC (10%), lung adenocarcinoma (30%), esophageal cancer, head and neck tumors, melanoma, and gastric cancer.

[0006] Several allosteric inhibitors of SHP2 have entered clinical trials, such as TNO-155 developed by Novartis, RMC-4630 developed by Revolution Medicine, and JAB-3068 developed by Beijing Jiakosi. However, no SHP2 inhibitor has yet been developed and marketed for the treatment of Noonan syndrome, panther skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, lung cancer, or colon cancer.

[0007] The applicant filed a Chinese patent application with the application number of 202011196830.8 and the invention name of "Heterocyclic compound, preparation method, pharmaceutical composition and application thereof" on October 30, 2020, which describes a class of SHP2 inhibitor drugs with good drug properties, especially the compounds represented by the following formula III.

[0008]

[0009] However, the free base compound has the problems of poor solubility and stability, and the water solubility and lipid solubility are not good, and it only has certain solubility in alcohol; the salt type and crystal form of the free base can solve the above-mentioned solubility and stability problems to a certain extent. Therefore, it is urgent to develop a salt type and crystal form with good solubility, strong stability and high applicability as a medicine. SUMMARY

[0010] The problem the invention aims to solve

[0011] The purpose of the present application is to provide a pharmaceutically acceptable salt of a heterocyclic compound with good solubility, strong stability and high applicability as a medicine, and its crystal form, as well as its preparation method and medical use.

[0012] Solution for solving the problem

[0013] In a first aspect, the present application provides a pharmaceutically acceptable salt of the compound represented by formula III, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable inorganic salt.

[0014]

[0015] Preferably, the pharmaceutically acceptable inorganic salt is a hydrochloride or a sulfate.

[0016] In a second aspect, the present application provides a compound represented by formula 1 or a compound represented by formula 2.

[0017]

[0018] In a third aspect, the present application provides a compound represented by formula 1 with a crystal form A, a crystal form B or a crystal form C.

[0019] The compound represented by formula 1 with the crystal form A has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 2θ values of 6.5±0.2°, 24.2±0.2° and 27.6±0.2°.

[0020] Preferably, the XRPD pattern also has characteristic peaks at at least one of 2θ values of 7.3±0.2°, 13.5±0.2°, 16.9±0.2°, 26.9±0.2° and 27.9±0.2°.

[0021] More preferably, the XRPD pattern further has characteristic peaks at at least one of 2-theta values 12.9±0.2°, 15.1±0.2°, 18.0±0.2°, 19.6±0.2°, 20.6±0.2°, 22.8±0.2°, 23.4±0.2° and 25.2±0.2°.

[0022] Further preferably, the XRPD pattern is substantially as shown in Figure 1 .

[0023] Further, the differential scanning calorimetry (DSC) pattern of the compound of Formula 1 having the crystalline Form A has endothermic peaks at 192.5±5°C and 226.1±5°C, and an exothermic peak at 207.0±5°C.

[0024] Preferably, the DSC pattern is substantially as shown in Figure 2 .

[0025] Further, the thermogravimetric analysis (TGA) pattern of the compound of Formula 1 having the crystalline Form A has a weight loss of 16.1%±2% at 265±5°C.

[0026] Preferably, the TGA pattern is substantially as shown in Figure 3 .

[0027] The compound of Formula 1 having the crystalline Form B has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 2-theta values 6.5±0.2°, 24.2±0.2° and 27.5±0.2°.

[0028] Preferably, the XRPD pattern further has characteristic peaks at at least one of 2-theta values 13.5±0.2°, 16.9±0.2°, 27.0±0.2° and 28.0±0.2°.

[0029] More preferably, the XRPD pattern further has characteristic peaks at at least one of 2-theta values 7.4±0.2°, 8.8±0.2°, 15.1±0.2°, 18.0±0.2°, 19.6±0.2°, 22.6±0.2° and 25.2±0.2°.

[0030] Further preferably, the XRPD pattern is substantially as shown in Figure 5 .

[0031] Further, the thermogravimetric analysis (TGA) pattern of the compound of Formula 1 having the crystalline Form B has a weight loss of 13.3%±2% at 120±5°C.

[0032] Preferably, the TGA pattern is substantially as shown in Figure 6as shown.

[0033] The compound of Formula 1 having Form C has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 2Θ values of 5.3±0.2°, 6.6±0.2° and 8.9±0.2°.

[0034] Preferably, the XRPD pattern further has characteristic peaks at at least one of 2Θ values of 7.8±0.2°, 12.8±0.2°, 21.6±0.2° and 25.3±0.2°.

[0035] More preferably, the XRPD pattern further has characteristic peaks at at least one of 2Θ values of 8.2±0.2°, 13.1±0.2°, 24.6±0.2°, 25.5±0.2° and 26.1±0.2°.

[0036] Further preferably, the XRPD pattern is substantially as shown. Figure 8

[0037] Further, the compound of Formula 1 having Form C has a thermogravimetric analysis (TGA) pattern with a weight loss of 12.7%±2% at 120±5°C.

[0038] Preferably, the TGA pattern is substantially as shown. Figure 9

[0039] In a fourth aspect, the present application provides a method for preparing the compound of Formula 1 or the compound of Formula 2, which comprises the reaction of compound 1-5 or a salt thereof and compound 1-6 or a salt thereof:

[0040]

[0041] Preferably, the above reaction is carried out in the presence of a base;

[0042] Preferably, the base is selected from an inorganic base or an organic base;

[0043] The inorganic base is selected from an alkali metal carbonate (preferably sodium carbonate or potassium carbonate), an alkali metal bicarbonate (preferably sodium bicarbonate and potassium bicarbonate) or an alkali metal hydroxide (preferably sodium hydroxide or potassium hydroxide);

[0044] The organic base is selected from triethylamine, pyridine, N,N-diisopropylethylamine (DIEA), dimethylaminopyridine (DMAP) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the like;

[0045] The above base can be used alone or in combination of two or more.

[0046] Preferably, the temperature of the above reaction is room temperature to 150°C. ​​

[0047] Preferably, the reaction time is 1-30 hours.

[0048] Preferably, the preparation method further comprises a post-treatment step.

[0049] The post-treatment step of the compound of formula 1 comprises the following steps: after the reaction, beating, solid-liquid separation, adding water to the solid, adjusting the pH to weak alkaline with hydrochloric acid, solid-liquid separation, and purification, to obtain the compound of formula 1.

[0050] The post-treatment step of the compound of formula 2 comprises the following steps: after the reaction, beating, solid-liquid separation, adding water to the solid, adjusting the pH to weak alkaline with sulfuric acid, solid-liquid separation, and purification, to obtain the compound of formula 2.

[0051] In a fifth aspect, the present application provides a preparation method of the compound of formula 1 having crystal form A, crystal form B or crystal form C.

[0052] The preparation method of the compound of formula 1 having crystal form A comprises the following steps: mixing the compound of formula 1, a solvent and hydrochloric acid, heating, stirring, and cooling, to obtain the compound of formula 1.

[0053] Preferably, the solvent is a combination of one or more of water, methanol, ethanol, dimethyl sulfoxide and tetrahydrofuran.

[0054] Preferably, the amount of the solvent and hydrochloric acid used satisfies the following conditions: the concentration of hydrochloric acid is 0.2-12M, preferably 0.2-0.5M, and more preferably 0.36±0.04M.

[0055] Preferably, the heating temperature is 40-80℃, and more preferably 40-50℃.

[0056] Preferably, the stirring time is 5-24 hours.

[0057] Preferably, the cooling temperature is 25±5℃.

[0058] Preferably, the stirring continues after cooling.

[0059] Preferably, the stirring continues after cooling for 12-48 hours.

[0060] Preferably, the preparation method further comprises a post-treatment step, and the post-treatment step comprises solid-liquid separation and drying.

[0061] Preferably, the solid-liquid separation is filtration or centrifugation.

[0062] Preferably, the drying is oven drying or reduced-pressure drying.

[0063] Preferably, the drying temperature is 40-55℃.

[0064] The preparation method of the compound of Formula 1 having the crystal form B comprises the following steps: mixing the compound of Formula 1 and a solvent, and stirring to obtain.

[0065] Preferably, the solvent is a combination of water and methanol, preferably a combination of water and methanol in a volume ratio of 1:1.

[0066] Preferably, the amount of the solvent satisfies the following condition: the amount of the solvent is 20 mL / g based on the weight of the compound of Formula 1.

[0067] Preferably, the stirring is performed at room temperature.

[0068] Preferably, the stirring time is 24 hours.

[0069] Preferably, the preparation method further comprises a post-treatment step, and the post-treatment step comprises solid-liquid separation and drying.

[0070] Preferably, the solid-liquid separation is filtration or centrifugation.

[0071] Preferably, the drying is oven drying or reduced pressure drying.

[0072] Preferably, the drying temperature is room temperature.

[0073] The preparation method of the compound of Formula 1 having the crystal form C comprises the following steps: mixing the compound of Formula 1 and a solvent, and stirring to obtain.

[0074] Preferably, the solvent is a combination of water and ethanol, preferably a combination of water and ethanol in a volume ratio of 1:1.

[0075] Preferably, the amount of the solvent satisfies the following condition: the amount of the solvent is 200 mL / g based on the weight of the compound of Formula 1.

[0076] Preferably, the stirring is performed at 4°C.

[0077] Preferably, the stirring time is 12 hours.

[0078] Preferably, the preparation method further comprises a post-treatment step, and the post-treatment step comprises solid-liquid separation and drying.

[0079] Preferably, the solid-liquid separation is filtration or centrifugation.

[0080] Preferably, the drying is oven drying or reduced pressure drying.

[0081] Preferably, the drying temperature is room temperature.

[0082] In a sixth aspect, the present application provides a pharmaceutical composition comprising at least one of the above-mentioned pharmaceutically acceptable salts or compounds, and at least one pharmaceutically acceptable carrier.

[0083] In a seventh aspect, the present application provides use of the above-mentioned pharmaceutically acceptable salts or compounds or the above-mentioned pharmaceutical composition in the manufacture of a medicament for preventing, ameliorating and / or treating a disease or disorder associated with abnormal SHP2 activity.

[0084] In an eighth aspect, the present application provides a method for preventing, ameliorating and / or treating a disease or disorder associated with abnormal SHP2 activity, the method comprising administering a prophylactically, amelioratively and / or therapeutically effective amount of the above-mentioned pharmaceutically acceptable salts or compounds or the above-mentioned pharmaceutical composition to an individual in need thereof.

[0085] In a ninth aspect, the present application provides the above-mentioned pharmaceutically acceptable salts or compounds or the above-mentioned pharmaceutical composition for use as a SHP2 inhibitor or for use in preventing, ameliorating and / or treating a disease or disorder associated with abnormal SHP2 activity.

[0086] Preferably, in the above-mentioned medical uses, the disease or disorder associated with abnormal SHP2 activity is selected from Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, lung cancer, colon cancer, head and neck tumor, gastric cancer, anaplastic large cell lymphoma and glioblastoma, preferably non-small cell lung cancer, esophageal cancer and head and neck tumor.

[0087] The effects of the invention

[0088] The pharmaceutically acceptable salt (especially the trihydrochloride salt or the sulfate salt with a salt formation ratio of 1:1.5) of the heterocyclic compound provided by the present application has strong crystallinity, good solubility and high stability, and is easy to be formulated, and has high suitability as a pharmaceutical product. The preparation method of the pharmaceutically acceptable salt or the crystal thereof has the advantages of simple preparation process, low cost and high yield, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0089] Figure 1 XRPD pattern of Compound 1 with crystal form A prepared in Example 6.

[0090] Figure 2 DSC pattern of Compound 1 with crystal form A prepared in Example 6.

[0091] Figure 3 TGA pattern of Compound 1 with crystal form A prepared in Example 6.

[0092] Figure 4 IR pattern of Compound 1 prepared in Example 5.

[0093] Figure 5 XRPD pattern of Compound 1 having Form B prepared for Example 10.

[0094] Figure 6 TGA pattern of Compound 1 having Form B prepared for Example 10.

[0095] Figure 7 XRPD pattern of Compound 1 having Form C prepared for Example 11. 1 H-NMR pattern.

[0096] Figure 8 XRPD pattern of Compound 1 having Form C prepared for Example 11.

[0097] Figure 9 TGA pattern of Compound 1 having Form C prepared for Example 11.

[0098] Figure 10 XRPD pattern of Compound 1 having Form C prepared for Example 11. 1 H-NMR pattern. DETAILED DESCRIPTION

[0099] Terminology Definition

[0100] As used herein, the term "substantially as depicted in the XRPD pattern" with respect to an XRPD pattern means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the XRPD pattern of a certain crystal form of Compound 1 are shown in the given XRPD pattern. Variations in representative peak positions (2 theta) and relative peak intensities are taken into account. Peak positions can show some variation between different instruments and different samples, typically up to 0.1 to 0.2°. In addition, relative peak intensities can also vary between instruments and also depending on the degree of crystallinity, preferred orientation, the sample prepared, and other factors known to those skilled in the art.

[0101] As used herein, "substantially as depicted in the DSC or TGA pattern" is also intended to encompass variations known to those skilled in the art relating to these analytical techniques. For well-defined peaks in a DSC pattern, there is typically a variation of up to ± 0.2 °C, and even greater for broad peaks (up to ± 1 °C, or up to ± 5 °C). For mass loss in a TGA pattern, depending on many factors such as sample preparation and the instrument, there is typically a variation of up to ± 1 %, or up to ± 2 % in the mass loss detected by different instruments and different samples.

[0102] As used herein, the term "room temperature" means 25 ± 5 °C.

[0103] As used herein, "hydrochloride salt" or "sulfate salt" means a salt of hydrochloric acid or sulfuric acid, respectively, in any salt-forming ratio, e.g., a hydrochloride salt of a compound of Formula III can be a monohydrochloride salt, a dihydrochloride salt, or a trihydrochloride salt of a compound of Formula III, etc.

[0104] Compounds of Formula 1 and Formula 2

[0105] The "compound of Formula 1", "compound of Formula 1" or "Compound 1" in the present application refers to a compound having the following structure:

[0106]

[0107] The chemical name of which is (S)-N-(3-(3-amino-5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)pyrazin-2-ylsulfanyl)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-3-carboxamide monohydrate, the molecular formula of which is C 31 H 35 Cl4N9O3S, and the molecular weight of which is 755.54.

[0108] The "compound of Formula 2", "compound of Formula 2" or "Compound 2" in the present application refers to a compound having the following structure:

[0109]

[0110] The chemical name of which is (S)-N-(3-(3-amino-5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)pyrazin-2-ylsulfanyl)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-3-carboxamide monohydrate, the molecular formula of which is C 31 H 35 ClN9O9S 2.5 , and the molecular weight of which is 793.28.

[0111] In the process of previous research, the inventors carried out salt formation and crystallization research on (S)-N-(3-(3-amino-5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)pyrazin-2-ylsulfanyl)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide by using various pharmaceutically acceptable acids, and found through a large number of screening tests that the hydrochloride salt (especially the tris-hydrochloride salt) or the sulfate salt (especially the sulfate salt with a salt formation ratio of 1:1.5) has better crystallinity, and through optimization of the preparation method, the tris-hydrochloride salt or the sulfate salt with a salt formation ratio of 1:1.5 can be prepared into crystals at low cost and high efficiency.

[0112] Synthesis of compound 1 or compound 2

[0113] The preparation method of the compound of formula 1 or the compound of formula 2 comprises the reaction of compound 1-5 or a salt thereof and compound 1-6 or a salt thereof:

[0114]

[0115] In some embodiments, the above reaction is carried out in the presence of a base;

[0116] In some embodiments, the base is selected from an inorganic base or an organic base;

[0117] The inorganic base is selected from an alkali metal carbonate (preferably sodium carbonate or potassium carbonate), an alkali metal bicarbonate (preferably sodium bicarbonate or potassium bicarbonate), or an alkali metal hydroxide (preferably sodium hydroxide or potassium hydroxide);

[0118] The organic base is selected from triethylamine, pyridine, N,N-diisopropylethylamine (DIEA), dimethylaminopyridine (DMAP), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like common organic bases;

[0119] The above base can be used alone or in combination of two or more.

[0120] In some embodiments, the temperature of the above reaction is room temperature to 150°C.

[0121] In some embodiments, the time of the above reaction is 1-30 hours.

[0122] In some embodiments, the above preparation method further comprises a post-treatment step.

[0123] The post-treatment step of the compound of formula 1 comprises: after the reaction is completed, beating, solid-liquid separation, adding water to the solid, adjusting the pH to weak alkalinity with hydrochloric acid, solid-liquid separation, and purification, to obtain the compound of formula 1.

[0124] The post-treatment step of the compound of formula 2 includes: after the reaction is completed, beating, solid-liquid separation, adding water to the solid, adjusting the pH to weak alkaline with sulfuric acid, solid-liquid separation, and purification to obtain the compound of formula 2.

[0125] The above-mentioned compound 1-5 or a salt thereof and the compound 1-6 or a salt thereof can be prepared by a conventional method or a disclosed method.

[0126] In some embodiments, the compound of formula 1 of the present application can be prepared by a synthetic method as shown below, which can reach a preparation scale of hundreds of grams and is suitable for commercial scale-up production.

[0127]

[0128] Crystals of Formula 1 compounds

[0129] The compound of formula 1 of the present application can exist in a crystalline form, for example, the compound of formula 1 having crystal form A, the compound of formula 1 having crystal form B, and the compound of formula 1 having crystal form C, which can be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and the like. The above-mentioned methods can use the parameter settings in the conventional operation in the art, and can be adjusted or changed as appropriate according to the specific physicochemical properties of the substance to be tested.

[0130] In some embodiments, the XRPD pattern of the compound of formula 1 having crystal form A has characteristic peaks at 2θ values of 6.5±0.2°, 24.2±0.2°, and 27.6±0.2°.

[0131] In some preferred embodiments, the XRPD pattern of the compound of formula 1 having crystal form A has characteristic peaks at at least one of 2θ values of 7.3±0.2°, 13.5±0.2°, 16.9±0.2°, 26.9±0.2°, and 27.9°±0.2°.

[0132] In some more preferred embodiments, the XRPD pattern of the compound of formula 1 having crystal form A has characteristic peaks at at least one of 2θ values of 12.9°±0.2°, 15.1°±0.2°, 18.0°±0.2°, 19.6°±0.2°, 20.6°±0.2°, 22.8°±0.2°, 23.4°±0.2°, and 25.2°±0.2°.

[0133] In some most preferred embodiments, the XRPD pattern of the compound of formula 1 having crystal form A is substantially as shown in Figure 1

[0134] ​In some embodiments, the DSC pattern of the compound of Formula 1 having crystalline Form A has an endotherm peak at 192.5±5°C and 226.1±5°C, and an exotherm peak at 207.0±5°C.

[0135] In some preferred embodiments, the DSC pattern of the compound of Formula 1 having crystalline Form A is substantially as shown in Figure 2

[0136] In some embodiments, the TGA pattern of the compound of Formula 1 having crystalline Form A has a weight loss of 16.1%±2% at 265±5°C.

[0137] In some preferred embodiments, the TGA pattern of the compound of Formula 1 having crystalline Form A is substantially as shown in Figure 3

[0138] In some embodiments, the XRPD pattern of the compound of Formula 1 having crystalline Form B has characteristic peaks at 2Θ values of 6.5±0.2°, 24.2±0.2°, and 27.5±0.2°.

[0139] In some preferred embodiments, the XRPD pattern of the compound of Formula 1 having crystalline Form B has characteristic peaks at 2Θ values of 13.5±0.2°, 16.9±0.2°, 27.0±0.2°, and 28.0±0.2°.

[0140] In some more preferred embodiments, the XRPD pattern of the compound of Formula 1 having crystalline Form B has characteristic peaks at 2Θ values of 7.4±0.2°, 8.8±0.2°, 15.1±0.2°, 18.0±0.2°, 19.6±0.2°, 22.6±0.2°, and 25.2±0.2°.

[0141] In some most preferred embodiments, the XRPD pattern of the compound of Formula 1 having crystalline Form B is substantially as shown in Figure 5

[0142] In some embodiments, the TGA pattern of the compound of Formula 1 having crystalline Form B has a weight loss of 13.3%±2% at 120±5°C.

[0143] In some preferred embodiments, the TGA pattern of the compound of Formula 1 having crystalline Form B is substantially as shown in Figure 6

[0144] In some embodiments, the XRPD pattern of the compound of Formula 1 having crystalline Form C has characteristic peaks at 2Θ values of 5.3±0.2°, 6.6±0.2°, and 8.9±0.2°.

[0145] ​​​​In some preferred embodiments, the XRPD pattern of the compound of Formula 1 having Form C further has characteristic peaks at at least one of the following 2Θ values: 7.8 ± 0.2°, 12.8 ± 0.2°, 21.6 ± 0.2°, and 25.3 ± 0.2°.

[0146] In some more preferred embodiments, the XRPD pattern of the compound of Formula 1 having Form C further has characteristic peaks at at least one of the following 2Θ values: 8.2 ± 0.2°, 13.1 ± 0.2°, 24.6 ± 0.2°, 25.5 ± 0.2°, and 26.1 ± 0.2°.

[0147] In some most preferred embodiments, the XRPD pattern of the compound of Formula 1 having Form C is substantially as shown in FIG. 1. Figure 8

[0148] In some embodiments, the TGA pattern of the compound of Formula 1 having Form C has a weight loss of 12.7% ± 2% at 120 ± 5 °C.

[0149] In some preferred embodiments, the TGA pattern of the compound of Formula 1 having Form C is substantially as shown in FIG. 2. Figure 9

[0150] Preparation method of compound crystal of Formula 1

[0151] The method for preparing the compound of Formula 1 having Form A of the present application comprises the following steps: mixing the compound of Formula 1, a solvent, and hydrochloric acid, heating, stirring, cooling, and obtaining.

[0152] In some embodiments, the solvent is a combination of one or more of water, methanol, ethanol, dimethyl sulfoxide, and acetone.

[0153] In some embodiments, the solvent and hydrochloric acid are used in amounts that satisfy the following conditions: the concentration of hydrochloric acid is 0.2-12 M, preferably 0.2-0.5 M, and more preferably 0.36 ± 0.04 M.

[0154] In some embodiments, the heating temperature is 40-80 °C, and more preferably 40-50 °C.

[0155] In some embodiments, the stirring time is 5-24 hours.

[0156] In some embodiments, the cooling temperature is 25 ± 5 °C.

[0157] In some embodiments, the stirring continues after cooling.

[0158] In some embodiments, the stirring continues after cooling for 12-48 hours. ​​

[0159] In some embodiments, the preparation method further comprises a post-treatment step, which comprises solid-liquid separation and drying.

[0160] In some embodiments, the solid-liquid separation is filtration or centrifugation.

[0161] In some embodiments, the drying is oven drying or reduced pressure drying.

[0162] In some embodiments, the drying temperature is 40-55°C.

[0163] The preparation method of the compound of formula 1 with crystal form B of the present application comprises the following steps: mixing the compound of formula 1 above and a solvent, and stirring to obtain.

[0164] In some embodiments, the solvent is a combination of water and methanol, preferably a combination of water and methanol in a volume ratio of 1:1.

[0165] In some embodiments, the amount of solvent used needs to meet the following condition: the amount of solvent used is 20 mL / g based on the weight of the compound of formula 1.

[0166] In some embodiments, the stirring is carried out at room temperature.

[0167] In some embodiments, the stirring time is 24 hours.

[0168] In some embodiments, the preparation method further comprises a post-treatment step, which comprises solid-liquid separation and drying.

[0169] In some embodiments, the solid-liquid separation is filtration or centrifugation.

[0170] In some embodiments, the drying is oven drying or reduced pressure drying.

[0171] In some embodiments, the drying temperature is room temperature.

[0172] The preparation method of the compound of formula 1 with crystal form C comprises the following steps: mixing the compound of formula 1 above and a solvent, and stirring to obtain.

[0173] In some embodiments, the solvent is a combination of water and ethanol, preferably a combination of water and ethanol in a volume ratio of 1:1.

[0174] In some embodiments, the amount of solvent used needs to meet the following condition: the amount of solvent used is 200 mL / g based on the weight of the compound of formula 1.

[0175] In some embodiments, the stirring is carried out at 4°C.

[0176] In some embodiments, the time of stirring is 12 hours.

[0177] In some embodiments, the preparation method further comprises a step of post-treatment, the step of post-treatment comprising solid-liquid separation and drying.

[0178] In some embodiments, the solid-liquid separation is filtration or centrifugation.

[0179] In some embodiments, the drying is oven drying or reduced pressure drying.

[0180] In some embodiments, the temperature of drying is room temperature.

[0181] The preparation method of the crystal of the compound of Formula 1 is not limited to the method provided by the present application, and the crystal form of the compound of Formula 1 obtained by any process in the art is included in the present application as long as it is consistent with the crystal form provided by the present application, for example, using a compound of Formula 1 with different purity, different crystal form or using other organic solvents to crystallize by similar method to prepare the compound of Formula 1 with crystal form A, crystal form B or crystal form C.

[0182] Pharmaceutical Composition

[0183] The compound of the present application can be administered in a pharmaceutical composition. The term "pharmaceutical composition" refers to a composition that can be used as a medicine, which comprises a pharmaceutically active ingredient (API) (e.g. a compound of Formula 1, a crystal of the compound of Formula 1 or a compound of Formula 2 of the present application) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient that is compatible with the pharmaceutically active ingredient and is harmless to the subject, including (but not limited to) diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickening agents, glidants, flavoring agents, odorants, preservatives, antioxidants, pH adjusters, solvents, co-solvents, surfactants, etc.

[0184] In some embodiments, a pharmaceutical composition can comprise at least one pharmaceutically acceptable salt or compound described in the present application.

[0185] In some preferred embodiments, the above-mentioned pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0186] Medical Use

[0187] Whether it is the above-mentioned pharmaceutically acceptable salt or compound, or the above-mentioned pharmaceutical composition, it can be used to combat diseases or disorders associated with abnormal SHP2 activity.

[0188] In some embodiments, the present application provides use of the above-mentioned pharmaceutically acceptable salt or compound or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing, ameliorating and / or treating a disease or disorder associated with abnormal SHP2 activity.

[0189] In some embodiments, the present application also provides a method for preventing, ameliorating and / or treating a disease or disorder associated with abnormal SHP2 activity, which comprises administering a prophylactically, amelioratively and / or therapeutically effective amount of the above-mentioned pharmaceutically acceptable salt or compound or the above-mentioned pharmaceutical composition to an individual in need thereof.

[0190] In some embodiments, the present application also provides the above-mentioned pharmaceutically acceptable salt or compound or the above-mentioned pharmaceutical composition for use as a SHP2 inhibitor or for use in preventing, ameliorating and / or treating a disease or disorder associated with abnormal SHP2 activity.

[0191] In some embodiments, the above-mentioned disease or disorder associated with abnormal SHP2 activity can be selected from Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, lung cancer, colon cancer, head and neck tumor, gastric cancer, anaplastic large cell lymphoma, glioblastoma, etc., preferably non-small cell lung cancer, esophageal cancer and head and neck tumor.

[0192] The technical solutions of the present application will be described below in conjunction with specific examples. Those skilled in the art can understand that the following examples are only for further detailed description of the present application, and do not limit the scope of the present application. Unless otherwise defined, the drugs, reagents, materials, instruments and the like used in the following examples can be obtained by conventional commercial means, and the intermediates can be prepared by conventional methods or published methods.

[0193] The abbreviations appearing in the present application and their meanings are as follows:

[0194] abbreviation meaning Xantphos 4,5-Bis(diphenylphosphine)-9,9-dimethyloxanthracene [Pd2(dba)3] Tris(dibenzylacetone)dipalladium DIEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide NMP N-Methylpyrrolidone

[0195] Example 1: Synthesis of compound 1-2

[0196]

[0197] In a 10 L reaction flask, compound 1-1 (800 g), 1,4-dioxane (4 L), DIEA (1.5 kg), Xantphos (44.9 g) and Pd2(dba)3(35.54 g) were added in sequence, and 3- mercaptopropionic acid methyl ester (560 g) was added in a constant pressure dropping funnel. The reaction solution was heated to 110°C under argon protection, and 3- mercaptopropionic acid methyl ester was added dropwise. The addition was completed in 6 hours, and the solution was stirred under reflux for 7 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate until the washing solution had no UV absorption. The washing solution was added to water, stirred, and separated into layers. The organic phase was collected. The aqueous phase was extracted with ethyl acetate twice, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to column chromatography using n-heptane: ethyl acetate = 1:0 to 1:1 to obtain compound 1-2 (1007 g, yield 105%).

[0198] MS m / z 246.2 (M+H) + .

[0199] 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.01 (t, J = 8.0 Hz, 1 H), 6.64 (dd, J = 2.4, 8.0 Hz, 1 H), 6.54 (dd, J = 2.4, 8.0 Hz, 1 H), 5.54 (br s, 2 H), 3.62 (s, 3 H), 3.14 (t, J = 7.2 Hz, 2 H), 2.67 (t, J = 7.2 Hz, 2 H).

[0200] Example 2: Synthesis of compound 1-3

[0201]

[0202] A reaction kettle was charged with tetrahydrofuran (1750 mL) and compound 1-2 (350.0 g) at room temperature. After stirring until uniform, the temperature was controlled at 0°C, and potassium tert-butoxide (191.8 g) was added to the reaction solution, which was then stirred for 2 hours. Water and ethyl acetate were added to the reaction solution, which was stirred and separated into layers. The aqueous phase was retained, and the organic phase was extracted twice with 5% sodium hydroxide solution. The aqueous phases were combined, washed once with ethyl acetate, and separated into layers. The pH of the aqueous phase was adjusted to 5-6 with 1 M hydrochloric acid, and a solid was precipitated. The solid was extracted twice with ethyl acetate, and the organic phases were combined and washed once with saturated brine. After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to obtain compound 1-3 (235 g, yield 103.0%).

[0203] MS m / z 160.1 (M+H) + .

[0204] 1H NMR (400 MHz, DMSO-d6) δ ppm 6.91 (t, J=8.0 Hz, 1 H), 7.01 (t, J=8.0 Hz, 1 H), 6.73 (dd, J=2.4, 8.0 Hz, 1 H), 6.55 (dd, J=2.4, 8.0 Hz, 1 H).

[0205] Example 3: Synthesis of compound 1-4

[0206]

[0207] To a reaction flask was added compound 1-3 (125.0 g), 3-bromo-6-chloropyrazin-2- amine (163.0 g), Pd2(dba)3(7.17 g), Xantphos (9.06 g), DIEA (121.8 g), 1,4-dioxane (1250 mL), stirred to dissolve and warmed to 60 °C under argon protection, stirred and warmed for 3 hours. Stirred to cool to room temperature, filtered, the filter cake was rinsed with 1,4-dioxane until the rinse solution had no UV absorbance; the filtrate was concentrated to no solvent drops, water was added and concentrated to a small volume, water was added and filtered under suction, the filter cake was rinsed with water. The filter cake was transferred to a single neck flask, 1,4-dioxane was added and concentrated under reduced pressure to no liquid drops, heated to reflux and 1,4-dioxane was added to dissolve the solids, heating was stopped, cooled to room temperature and filtered under suction, the filter cake was washed with 1,4-dioxane, the filter cake was dried to give compound 1-4 (130.5 g, 58% yield).

[0208] MS m / z 287.1 (M+H) + .

[0209] 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.70 (s, 1 H), 7.01 - 6.97 (m, 3 H), 6.79 (dd, J=2.4, 8.0 Hz, 1 H), 6.49 (dd, J=2.4, 8.0 Hz, 1 H).

[0210] Example 4: Synthesis of compound 1-5

[0211]

[0212] Into a reaction flask was placed compound 1-4 (120 g), 2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-3-carboxylic acid ethyl ester (129.6 g) and DMF (360 mL) under argon protection, and heated to 125 °C; and kept for 3 hours. When the reaction was cooled to room temperature, dichloromethane was added to the reaction mixture, stirred, filtered, washed with dichloromethane twice, and dried under reduced pressure to give compound 1-5 (168 g, yield 83.9%).

[0213] MS m / z 479.1 (M+H) + .

[0214] 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.26 (s, 1H), 8.35 (d, J=3.6 Hz, 1H), 7.73 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.13-7.09 (m, 3H), 3.85 (t, J=5.6 Hz, 2H), 2.88 (dd, J=2.4, 6.4 Hz, 2H), 1.92-1.90 (m, 2H), 1.87-1.85 (m, 2H).

[0215] Example 5: Synthesis of compound 1

[0216]

[0217] Into a reaction flask was placed compound 1-5 (165 g), (S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-amine hydrochloride (128.9 g), sodium carbonate (183 g) and N-methyl pyrrolidone NMP (1650 mL) under argon protection, and heated to 100 °C for 9 hours. Into the reaction mixture was added methyl tert-butyl ether, stirred, filtered, the filter cake was added water, and the pH was adjusted to weak alkaline with 1M hydrochloric acid, filtered, washed with water twice, and filtered to give the crude compound. The crude compound was dissolved with concentrated hydrochloric acid, and prepared by preparative high performance liquid chromatography (mobile phase: 0.1% hydrochloric acid / acetonitrile), and the prepared liquid was concentrated under reduced pressure to give a large amount of solid, which was filtered and dried to give compound 1 (158 g).

[0218] The content of chloride ion in compound 1 was detected by ion chromatography. The chromatographic column was an anion exchange chromatographic column, Dionex Ionpac AS19, the guard column was Dionex IonPac AG, the detector was a conductivity detector, the detection mode was suppressed conductivity detection, the potassium hydroxide solution was used as the eluent, the column temperature was 30 °C, and the injection volume was 10 μL.

[0219] Accurately measure the test solution (0.2 mg / mL aqueous solution of compound 1) and the reference solution (sodium chloride solution with a chloride ion concentration of 28 μg / mL), inject them into the ion chromatograph, and record the chromatograms.

[0220] The chloride ion content in the test sample is calculated based on the peak area using the external standard method.

[0221] Calculation formula:

[0222]

[0223] Where: m s The sample weight of sodium chloride reference standard is in mg.

[0224] A i The peak area of ​​chloride ions in the chromatogram of the test sample solution;

[0225] m i The sample weight, in mg (calculated as anhydrous).

[0226] A s This represents the average area of ​​the chloride ion peak in the chromatogram of the reference solution.

[0227] P s The content of the reference standard is expressed as a percentage (%).

[0228] 0.607 is the conversion factor for sodium chloride to chloride ions.

[0229] The test results showed that the free chloride ion content was 16.16%, proving that compound 1 contains three free chloride ions and is a trihydrochloride. The theoretical content of free chloride ions in compound 1 is 14.1%. Since there may be a small amount of hydrochloric acid in the acidic environment, the actual chloride ion content is higher than normal.

[0230] MS m / z 646.3(M+H) + .

[0231] 1H NMR (400 MHz, DMSO-d6) δ ppm 12.23 (s, 1 H), 9.00 (s, 3 H), 8.76 (d, J = 4.8 Hz, 1 H), 8.55 (d, J = 8.0 Hz, 1 H), 8.13 (dd, J = 1.2, 8.0 Hz, 1 H), 7.77 (dd, J = 6.4, 7.6 Hz, 1 H), 7.72 (s, 1 H), 7.25 (t, J = 8.0 Hz, 1 H), 6.48 (dd, J = 1.2, 8.0 Hz, 1 H), 4.61 - 4.59 (m, 1 H), 4.35 - 4.32 (m, 1 H), 4.25 - 4.21 (m, 1 H), 3.88 - 3.85 (m, 2 H), 3.73 - 3.52 (m, 2 H), 3.32 - 3.15 (m, 2 H), 2.88 (t, J = 6.4 Hz, 2 H), 1.94 - 1.90 (m, 4 H), 1.88 - 1.84 (m, 4 H).

[0232] Ultraviolet absorption spectrum (UV)

[0233] Instrument: Shimadzu UV-2600 spectrometer.

[0234] Solvent: water.

[0235] Test solution: 34 mg of sample was accurately weighed and dissolved in water.

[0236] Determination wavelength: 190-800 nm.

[0237] Analysis and conclusion: In aqueous solution, the maximum absorption of the sample was 213.0 nm, 274.0 nm, 357.5 nm, and the results are shown in Table 1. The UV spectrum test results are consistent with those of compound 1.

[0238] Table 1. UV determination results

[0239]

[0240] Infrared absorption spectroscopy (IR)

[0241] Instrument: Thermo NICOLET iS10 infrared spectrometer.

[0242] Instrument calibration: The instrument wave number was calibrated using the infrared spectrum absorption peak of polystyrene film.

[0243] Method: KBr tabletting method.

[0244] Analysis and conclusion: The infrared absorption spectrum of the sample is shown in Figure 4 , and the analysis results are shown in Table 2. 3381 cm -1 , 2826 cm -1: N-H stretching vibration; 1577 cm -1 , 1528 cm -1 : N-H bending vibration; 1275 cm -1 : C-N stretching vibration, indicating that the product contains amino group in its structure. 1701 cm -1 , 1637 cm -1 : C=0 stretching vibration, indicating that the product contains carbonyl group in its structure. 1039 cm -1 : Ar-Cl stretching vibration, indicating that the product contains chlorine in its structure. From the infrared spectrum, it can be seen that the product contains amino group, carbonyl group and chlorine, etc. The IR data is consistent with the structure of the sample of compound 1.

[0245] Table 2. IR determination results

[0246]

[0247] High-resolution mass spectrometry (HRMS)

[0248] Instrument: Waters Xevo G2-Xs QTof. Ionization mode: ESI (+).

[0249] Analysis and conclusion: The high-resolution mass spectrometry determination results are shown in Table 3. The mass-to-charge ratio of the [M+H] + peak of the product determined by high-resolution mass spectrometry is 646.2122, which is consistent with the theoretical calculated value of 646.2116 of C 31 H 33 ClN9O3S, with a relative error of 0.9 ppm, indicating that it is consistent with the structure of compound 1.

[0250] Table 3. HRMS determination results

[0251]

[0252] Example 6: Preparation and detection of the crystal (crystal form A) of compound 1

[0253] Compound 1 (45 g) was added to water (300 mL) and hydrochloric acid (50 mL), heated to 50°C, stirred for 5 hours, then stirred at room temperature for 16 hours, filtered, and dried at 45°C to obtain compound 1 (42 g, yield 93%) in the form of a crystal. The crystal was characterized by XRPD, DSC, TGA, etc., and the corresponding crystal form was recorded as crystal form A.

[0254] X-ray powder diffraction (XRPD)

[0255] The XRPD spectrum of crystal form A is shown in Figure 1 , and the 2θ values and relative peak intensities of the diffraction peaks are shown in Table 4.

[0256] Table 4. XRPD data for crystal form A

[0257] Serial Number 2θ(°) Peak intensity (%) Serial Number 2θ(°) Peak intensity (%) 1 6.496 100.0 17 22.816 7.4 2 7.319 15.5 18 23.448 7.2 3 9.296 2.3 19 24.218 26.5 4 12.873 7.2 20 25.155 8.0 5 13.452 17.2 21 25.862 1.4 6 14.140 3.4 22 26.666 5.4 7 15.088 7.4 23 26.928 11.1 8 15.703 5.5 24 27.558 22.5 9 16.856 14.1 25 27.915 14.1 10 17.952 10.4 26 29.394 3.2 11 18.568 3.1 27 30.207 4.1 12 19.309 4.0 28 31.456 4.0 13 19.637 7.9 29 33.310 2.6 14 20.572 8.1 30 34.887 1.7 15 21.830 3.3 31 37.106 1.5 16 22.484 6.2 32 37.948 1.8

[0258] Differential scanning calorimetry (DSC)

[0259] The DSC spectrum of crystal form A is as follows Figure 2 As shown, two endothermic peaks and one exothermic peak were observed in the sample within the test temperature range: the first endothermic peak had an initial temperature of 176.9℃, a peak temperature of 192.5℃, and an ending temperature of 195.8℃; the second endothermic peak had an initial temperature of 212.2℃, a peak temperature of 226.1℃, and an ending temperature of 381.5℃; the endothermic peak had an initial temperature of 201.3℃, a peak temperature of 207.0℃, and an ending temperature of 211.3℃.

[0260] Thermogravimetric analysis (TGA)

[0261] The TGA spectrum of crystal form A is as follows: Figure 3 As shown, the sample lost 16.1% of its weight within the temperature range of 40.8℃ to 265℃. It is speculated that the sample lost some hydrochloric acid during dehydration, and eventually all the hydrochloric acid was lost as the water disappeared. The weight loss accelerated after 265℃, suggesting that the sample began to decompose more rapidly.

[0262] Solubility determination

[0263] The solubility of crystal form A in different solvents was determined, and the results are shown in Table 5. Crystal form A has good solubility.

[0264] Table 5. Solubility determination results of crystal form A

[0265] solvent Solubility (mg / ml) Dimethyl sulfoxide 2.5～5 water 1～2.5 Acetonitrile Less than 1 methanol 1～2.5 Trifluoroethanol 1～2.5

[0266] Stability Study

[0267] After placing crystal form A under accelerated testing conditions (40℃±2℃ / 75%RH±5%) for 3 months, relevant physicochemical properties were tested, and the results are shown in Table 6. The results show that all test items were within the standard range, proving that crystal form A has strong stability.

[0268] Table 6. Stability test results of crystal form A

[0269]

[0270] Example 7

[0271] Compound 1 was added to methanol, then hydrochloric acid was added to a hydrochloric acid concentration of 1 M, heated to 40 °C, stirred for 12 hours, then stirred at room temperature for 12 hours, filtered, and dried at 45 °C to obtain crystalline Form A.

[0272] Example 8

[0273] Compound 1 was added to dimethyl sulfoxide, then hydrochloric acid was added to a hydrochloric acid concentration of 0.36 ± 0.04 M, heated to 40 °C, stirred for 8 hours, then stirred at room temperature for 24 hours, filtered, and dried at 40 °C to obtain crystalline Form A.

[0274] Example 9

[0275] Compound 1 was added to tetrahydrofuran, then hydrochloric acid was added to a hydrochloric acid concentration of 8 M, heated to 60 °C, stirred for 10 hours, then stirred at room temperature for 30 hours, filtered, and dried at 45 °C to obtain crystalline Form A.

[0276] Example 10: Preparation and detection of crystalline compound 1 (Form B)

[0277] About 100 mg of Form A was added to 1.0 mL / 1.0 mL of a methanol / water mixed solvent, stirred at room temperature for 1 day, the obtained slurry was centrifuged, and the obtained solid was vacuum dried at room temperature overnight to obtain compound 1 in a crystalline form, and the corresponding crystal form was recorded as Form B. The XRPD pattern of Form B is shown in Figure 5 , and the 2θ values and relative peak intensities of the diffraction peaks are shown in Table 7. The salt formation ratio was 1:3 by ion chromatography detection; the DVS / isothermal adsorption curve characterization was performed under the condition of 40% RH-80% RH, and the hygroscopicity was 2.1%; the TGA pattern is shown in Figure 6 , and the weight loss before 120 °C was 13.3%, and the decomposition temperature was 185 °C; 1 The H-NMR pattern is shown in Figure 7 .

[0278] Table 7. XRPD data of Form B

[0279] Serial Number 2θ(°) Peak intensity (%) Serial Number 2θ(°) Peak intensity (%) 1 6.467 100.0 12 22.868 14.8 2 7.357 20.2 13 24.213 63.7 3 8.769 21.5 14 25.165 15.2 4 13.458 29.6 15 26.958 37.7 5 15.079 18.4 16 27.543 54.3 6 16.871 29.6 17 28.002 26.0 7 17.960 23.8 18 29.930 13.0 8 19.621 17.9 19 30.343 13.9 9 20.626 14.8 20 33.402 10.8 10 21.885 11.7 21 35.074 11.2 11 22.551 15.7

[0280] Example 11: Preparation and detection of crystalline compound 1 (Form C)

[0281] About 100 mg of Form A was added to 10.0 mL / 10.0 mL of an ethanol / water mixed solvent, stirred at 4 °C overnight, the obtained slurry was centrifuged, and the obtained solid was vacuum dried at room temperature overnight to obtain compound 1 in a crystalline form, and the corresponding crystal form was recorded as Form C. The XRPD pattern of Form C is shown in Figure 8The 2θ values and relative peak intensities of the diffraction peaks are shown in Table 8. The salt formation ratio was 1:3 by ion chromatography detection; the TGA graph is shown in Figure 9 As shown, the weight loss before 120°C was 12.7%, and the decomposition temperature was 200°C. 1 The H-NMR graph is shown in Figure 10

[0282] Table 8. XRPD data of Form C

[0283] Serial Number 2θ(°) Peak intensity (%) Serial Number 2θ(°) Peak intensity (%) 1 5.306 100.0 9 21.561 38.5 2 6.584 62.2 10 21.876 23.1 3 7.805 42.7 11 24.644 25.2 4 8.227 32.9 12 25.278 42.0 5 8.866 47.6 13 25.518 29.4 6 12.758 42.7 14 26.055 37.8 7 13.137 27.3 15 27.844 21.7 8 17.593 21.7 16 31.732 20.3

[0284] Example 12: Preparation of the compound shown in Formula 2

[0285] The preparation of the compound shown in Formula 2 can refer to the preparation method of the compound shown in Formula 1 in Example 5.

[0286]

[0287] Under argon protection, compound 1-5 (8.3 g), (S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-amine hydrochloride (6.5 g), sodium carbonate (9.2 g) and N-methyl pyrrolidone NMP (83 mL) were added to a reaction bottle, heated to 100°C for 9 hours. Methyl tert-butyl ether was added to the reaction solution, and the slurry was stirred and filtered. The filter cake was added with water, and the pH was adjusted to weak alkalinity with 1M sulfuric acid. Filtration, water washing twice, filtration, and the crude compound was obtained. The crude product was dissolved with dilute sulfuric acid (1M), and preparative high performance liquid chromatography was used for preparation separation (the mobile phase was 0.1% H2SO4 / acetonitrile). The preparation liquid was concentrated under reduced pressure, and a large amount of solid was precipitated. Filtration, and drying under reduced pressure, compound 2 (8.0 g) was obtained.

[0288] The [M+H] of the product was measured by high resolution mass spectrometry. + The mass-to-charge ratio of the peak was 646.3.

[0289] The sulfate ion content in compound 2 was detected by ion chromatography. The content of sulfate ions in the test sample was calculated by peak area according to the external standard method. The salt formation ratio was 1:1.5 by detection.​

Claims

1. The compound shown in Formula 1: 。 2. The compound of formula 1 as claimed in claim 1, characterized in that, It has crystal form A, and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.5±0.2°, 24.2±0.2° and 27.6±0.2°.

3. The compound of formula 1 as described in claim 2, characterized in that, The X-ray powder diffraction pattern also has a characteristic peak at at least one of the following 2θ values: 7.3±0.2°, 13.5±0.2°, 16.9±0.2°, 26.9±0.2°, and 27.9±0.2°.

4. The compound of formula 1 as described in claim 3, characterized in that, The X-ray powder diffraction pattern also has a characteristic peak at at least one of the following 2θ values: 12.9±0.2°, 15.1±0.2°, 18.0±0.2°, 19.6±0.2°, 20.6±0.2°, 22.8±0.2°, 23.4±0.2°, and 25.2±0.2°.

5. The compound of formula 1 as claimed in claim 4, characterized in that, The X-ray powder diffraction pattern is basically as shown in Figure 1.

6. The compound of formula 1 as claimed in claim 1, characterized in that, It has crystal form B, and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.5±0.2°, 24.2±0.2° and 27.5±0.2°.

7. The compound of formula 1 as claimed in claim 6, characterized in that, The X-ray powder diffraction pattern also has a characteristic peak at at least one of the following 2θ values: 13.5±0.2°, 16.9±0.2°, 27.0±0.2°, and 28.0±0.2°.

8. The compound of formula 1 as claimed in claim 7, characterized in that, The X-ray powder diffraction pattern also has a characteristic peak at at least one of the following 2θ values: 7.4±0.2°, 8.8±0.2°, 15.1±0.2°, 18.0±0.2°, 19.6±0.2°, 22.6±0.2°, and 25.2±0.2°.

9. The compound of formula 1 as claimed in claim 8, characterized in that, The X-ray powder diffraction pattern is basically as shown in Figure 5.

10. The compound of formula 1 as claimed in claim 1, characterized in that, It has crystal form C, and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.3±0.2°, 6.6±0.2° and 8.9±0.2°.

11. The compound of formula 1 as claimed in claim 10, characterized in that, The X-ray powder diffraction pattern also has a characteristic peak at at least one of the following 2θ values: 7.8±0.2°, 12.8±0.2°, 21.6±0.2°, and 25.3±0.2°.

12. The compound of formula 1 as claimed in claim 11, characterized in that, The X-ray powder diffraction pattern also has a characteristic peak at at least one of the following 2θ values: 8.2±0.2°, 13.1±0.2°, 24.6±0.2°, 25.5±0.2°, and 26.1±0.2°.

13. The compound of Formula 1 as claimed in claim 12, characterized in that, The X-ray powder diffraction pattern is basically as shown in Figure 8.

14. A pharmaceutical composition comprising at least one compound according to any one of claims 1-13, and at least one pharmaceutically acceptable carrier.

15. Use of the compound according to any one of claims 1-13 or the pharmaceutical composition according to claim 14 in the preparation of a medicament for the prevention, improvement and / or treatment of diseases or conditions associated with abnormal SHP2 activity.

16. The use according to claim 15, characterized in that, The diseases or conditions associated with abnormal SHP2 activity are selected from Noonan syndrome, Leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, lung cancer, colon cancer, head and neck tumors, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.

17. The use according to claim 16, characterized in that, The diseases or conditions associated with abnormal SHP2 activity are selected from non-small cell lung cancer, esophageal cancer, and head and neck tumors.

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