WO2023109761A1 - 吡唑并嘧啶酮类化合物及其盐的结晶 - Google Patents

吡唑并嘧啶酮类化合物及其盐的结晶 Download PDF

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WO2023109761A1
WO2023109761A1 PCT/CN2022/138399 CN2022138399W WO2023109761A1 WO 2023109761 A1 WO2023109761 A1 WO 2023109761A1 CN 2022138399 W CN2022138399 W CN 2022138399W WO 2023109761 A1 WO2023109761 A1 WO 2023109761A1
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formula
compound
crystal form
salt form
ray powder
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French (fr)
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付邦
陈亮
唐健
赵新涛
任伟
李因龙
吴文茂
孙中心
李玲
刘湘永
吴颢
丁列明
王家炳
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贝达药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of biomedicine, and mainly relates to crystal forms of pyrazolopyrimidinone compounds, various salt forms and crystal forms thereof, preparation methods of the crystal forms, pharmaceutical compositions and related uses.
  • Src homology region 2-containing protein tyrosine phosphatase 2 is a non-receptor protein tyrosine phosphatase encoded by PTPN11 gene
  • PTPN11 is the first The discovered proto-oncogene encoding tyrosine phosphatase (Chan R J et al.PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase.Blood,2007,109:862-867)
  • the encoded SHP2 protein Contains N-terminal SHP2 domain (N-SHP2), C-terminal SHP2 domain (C-SHP2), protein phosphatase catalytic domain (PTP), two C-terminal tyrosine residues (Y542 and Y580) and a rich Motifs containing proline (Pro).
  • SOS as a guanine nucleotide exchange factor (GEF)
  • GEF guanine nucleotide exchange factor
  • Ras-GTP further connects with the downstream signaling system, activates Ser/Thr kinase Raf1, etc., and then activates ERK under the action of regulatory kinase MEK. After activation, ERK directly acts on target molecules in the cytoplasm or transfers to the nucleus to regulate genes Transcription, cell proliferation or differentiation. This process may also be affected by SHP2 binding protein and substrate (SHP substrate-1, SHPS-1), Ras-GTPase activating protein (Ras-GAP) and other Src members.
  • SHP2 binding protein and substrate SHP substrate-1, SHPS-1
  • Ras-GTPase activating protein Ras-GTPase activating protein
  • SHP2 protein not only regulates the Ras/ERK signaling pathway, but it is also reported that it also regulates multiple signaling pathways such as JAK-STAT3, NF- ⁇ B, PI3K/Akt, RHO and NFAT, and then regulates cell proliferation, differentiation, migration, apoptosis and other physiological Function.
  • SHP2 has been proven to be associated with a variety of diseases, Tartaglia et al. (Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet, 2001, 29:465-468) found that about 50% of Noonan syndrome patients with missense mutations in PTPN11. In addition, studies have found that PTPN11 mutations are an important cause of JMMLL and various leukemias (Tartaglia M et al. Nat Genet, 2003, 34:148-150; Loh ML et al. et al.
  • PCT International Application PCT/CN2021/099275 describes a class of pyrazolopyrimidinone derivatives used as SHP2 protease inhibitors, and most of these compounds can effectively inhibit SHP2.
  • SHP2 protease inhibitors there are still unmet needs in terms of treatment options for SHP2-mediated diseases.
  • the present invention relates to compound (S)-6-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-3-(1-benzene) shown in formula I Crystal form and salt form of 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one.
  • the preparation method and structure of the compound represented by the structural formula I have been specifically described and recorded in the PCT patent application PCT/CN2021/099275.
  • an acid and a compound of formula I can form corresponding salts in corresponding systems, and these salt-type compounds can exist in various physical forms. For example, it may be in solution, suspension or solid form. In certain embodiments, salt-form compounds are in solid form. When in solid form, the compound may be amorphous, crystalline or mixtures thereof.
  • the salt form of the compound of formula I is a salt formed by the compound of formula I with the following acids: methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, L-lactic acid, L-tartaric acid, fumaric acid, L-malic acid and hydrochloride; more preferably, the acid is methanesulfonic acid.
  • various salts of the compound of formula I may exist in the form of crystal forms.
  • the X-ray powder diffraction pattern of the mesylate salt crystal form A has characteristic peaks with diffraction angles 2 ⁇ of 7.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 14.5° ⁇ 0.2°, and 23.5° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the mesylate salt crystal form A has a diffraction angle 2 ⁇ of 7.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 14.5° ⁇ 0.2°, 16.9° ⁇ 0.2°, 23.5° ⁇ 0.2 ° characteristic peak;
  • the X-ray powder diffraction pattern of the mesylate salt crystal form A has a diffraction angle 2 ⁇ of 5.6° ⁇ 0.2°, 7.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 14.5° ⁇ 0.2°, 16.9° ⁇ 0.2 °, 19.8° ⁇ 0.2°, 20.6° ⁇ 0.2°, 22.5° ⁇ 0.2°, 23.5° ⁇ 0.2° characteristic peaks;
  • the mesylate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 1;
  • mesylate salt form A has a differential scanning calorimetry (DSC) spectrum substantially as shown in Figure 2;
  • the mesylate salt form A has a thermogravimetric analysis (TGA) spectrum substantially as shown in Figure 3;
  • mesylate salt form A has a 1 H-NMR spectrum substantially as shown in Figure 4;
  • the crystal form A of the mesylate salt is an anhydrous crystal.
  • the X-ray powder diffraction pattern of the mesylate salt crystal form D has a diffraction angle 2 ⁇ of 5.7° ⁇ 0.2°, 16.4° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.1° ⁇ 0.2°, 22.9° ⁇ 0.2° 0.2° characteristic peak;
  • the X-ray powder diffraction pattern of the mesylate salt form D has a diffraction angle 2 ⁇ of 5.7° ⁇ 0.2°, 11.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.3° ⁇ 0.2°, 19.3° Characteristic peaks of ⁇ 0.2°, 20.1° ⁇ 0.2°, 22.9° ⁇ 0.2°, 26.1° ⁇ 0.2°;
  • the mesylate salt form D has an X-ray powder diffraction pattern substantially as shown in Figure 6;
  • the mesylate salt form D has a differential scanning calorimetry spectrum and a thermogravimetric analysis spectrum substantially as shown in FIG. 7 ;
  • the mesylate salt form D has a 1 H-NMR spectrum substantially as shown in FIG. 8 .
  • the single crystal data of the mesylate salt form D is shown in Table 9, the three-dimensional structure diagram of its asymmetric unit is shown in Figure 5, and its unit cell packing diagram is shown in Figure 5-1;
  • mesylate salt crystal form D is an anhydrous crystal.
  • the X-ray powder diffraction pattern of the benzenesulfonate crystal form A has a diffraction angle 2 ⁇ of 8.4° ⁇ 0.2°, 11.0° ⁇ 0.2°, 14.2° ⁇ 0.2°, 16.8° ⁇ 0.2°, 17.4° ⁇ 0.2° 0.2°, 18.8° ⁇ 0.2°, 25.6° ⁇ 0.2° characteristic peaks;
  • the X-ray powder diffraction pattern of the besylate salt crystal form A has a diffraction angle 2 ⁇ of 6.2° ⁇ 0.2°, 8.4° ⁇ 0.2°, 11.0° ⁇ 0.2°, 11.8° ⁇ 0.2°, 13.8° Characteristic peaks of ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 17.4° ⁇ 0.2°, 18.8° ⁇ 0.2°, 25.6° ⁇ 0.2°;
  • the crystal form A of the besylate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 9;
  • the crystal form A of the besylate salt has a differential scanning calorimetry spectrum and a thermogravimetric analysis spectrum substantially as shown in FIG. 10 ;
  • the crystalline form A of the besylate salt has a 1 H-NMR spectrum substantially as shown in FIG. 11 .
  • the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystal form A has a diffraction angle 2 ⁇ of 6.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 14.2° ⁇ 0.2°, 18.7° ⁇ 0.2°, 22.3° Characteristic peaks of ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystal form A has a diffraction angle 2 ⁇ of 6.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 11.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 13.0 ° ⁇ 0.2°, 14.2° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.7° ⁇ 0.2°, 22.3° ⁇ 0.2° characteristic peaks;
  • the p-toluenesulfonate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 12;
  • the p-toluenesulfonate salt form A has a differential scanning calorimetry spectrum and a thermogravimetric analysis spectrum substantially as shown in Figure 13;
  • the p-toluenesulfonate salt form A has a 1 H-NMR spectrum substantially as shown in FIG. 14 .
  • the X-ray powder diffraction pattern of the L-lactate salt form A has a diffraction angle 2 ⁇ of 6.2° ⁇ 0.2°, 6.7° ⁇ 0.2°, 12.2° ⁇ 0.2°, 13.9° ⁇ 0.2°, 18.5° Characteristic peaks of ⁇ 0.2°, 21.0° ⁇ 0.2°, 25.6° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the L-lactate salt form A has a diffraction angle 2 ⁇ of 6.2° ⁇ 0.2°, 6.7° ⁇ 0.2°, 12.2° ⁇ 0.2°, 13.9° ⁇ 0.2°, 17.2° ° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.5° ⁇ 0.2°, 21.0° ⁇ 0.2°, 25.1° ⁇ 0.2°, 25.6° ⁇ 0.2° characteristic peaks;
  • the L-lactate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 15;
  • the L-lactate salt form A has a differential scanning calorimetry spectrum and a thermogravimetric analysis spectrum substantially as shown in FIG. 16 ;
  • the L-lactate salt form A has a 1 H-NMR spectrum substantially as shown in FIG. 17 .
  • the X-ray powder diffraction pattern of the L-tartrate crystal form A has a diffraction angle 2 ⁇ of 5.9° ⁇ 0.2°, 12.6° ⁇ 0.2°, 15.8° ⁇ 0.2°, 18.9° ⁇ 0.2°, 24.6° ⁇ 0.2° 0.2° characteristic peak;
  • the X-ray powder diffraction pattern of the L-tartrate crystal form A has a diffraction angle 2 ⁇ of 5.9° ⁇ 0.2°, 10.8° ⁇ 0.2°, 12.6° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.8° Characteristic peaks of ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.4° ⁇ 0.2°, 24.6° ⁇ 0.2°, 25.3° ⁇ 0.2°;
  • the L-tartrate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 18;
  • L-tartrate crystal form A has a thermogravimetric analysis spectrum substantially as shown in Figure 19;
  • the L-tartrate crystal form A has a 1 H-NMR spectrum substantially as shown in FIG. 20 .
  • the X-ray powder diffraction pattern of the fumarate crystal form A has a diffraction angle 2 ⁇ of 7.5° ⁇ 0.2°, 15.0° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.3° ⁇ 0.2°, 22.8° ⁇ 0.2° 0.2°, 28.7° ⁇ 0.2° characteristic peak;
  • the X-ray powder diffraction pattern of the fumarate salt form A has a diffraction angle 2 ⁇ of 7.5° ⁇ 0.2°, 15.0° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.3° ⁇ 0.2°, 22.8° Characteristic peaks of ⁇ 0.2°, 28.7° ⁇ 0.2°, 29.3° ⁇ 0.2°;
  • the fumarate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 21;
  • the fumarate salt form A has a thermogravimetric analysis spectrum substantially as shown in Figure 22;
  • the fumarate salt form A has a 1 H-NMR spectrum substantially as shown in FIG. 23 .
  • the X-ray powder diffraction pattern of the L-malate crystal form A has a diffraction angle 2 ⁇ of 5.1° ⁇ 0.2°, 10.2° ⁇ 0.2°, 17.2° ⁇ 0.2°, 20.6° ⁇ 0.2°, 23.0° Characteristic peaks of ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the L-malate crystal form A has a diffraction angle 2 ⁇ of 5.1° ⁇ 0.2°, 6.1° ⁇ 0.2°, 10.2° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.2° ° ⁇ 0.2°, 20.6° ⁇ 0.2°, 23.0° ⁇ 0.2° characteristic peaks;
  • the L-malate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 24;
  • the L-malate crystal form A has a differential scanning calorimetry map and a thermogravimetric analysis map basically as shown in Figure 25;
  • the L-malate crystal form A has a 1 H-NMR spectrum substantially as shown in FIG. 26 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form A has a diffraction angle 2 ⁇ of 6.9° ⁇ 0.2°, 10.4° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.9° ⁇ 0.2°, 18.1° ⁇ 0.2° °, characteristic peaks at 18.6° ⁇ 0.2°, 19.5° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the hydrochloride salt form A has a diffraction angle 2 ⁇ of 6.9° ⁇ 0.2°, 10.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.5° ⁇ 0.2° 0.2°, 16.2° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.5° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 27;
  • hydrochloride salt form A has a differential scanning calorimetry map and a thermogravimetric analysis map basically as shown in FIG. 28 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form B has a diffraction angle 2 ⁇ of 7.3° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.5° ⁇ 0.2°, 16.0° ⁇ 0.2°, 18.7° ⁇ 0.2 °, the characteristic peak of 20.8° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the hydrochloride salt form B has a diffraction angle 2 ⁇ of 7.3° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.6° ⁇ 0.2°, 16.0° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.8° ⁇ 0.2°, 22.8° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form B has an X-ray powder diffraction pattern substantially as shown in Figure 29;
  • hydrochloride salt form B has a differential scanning calorimetry map and a thermogravimetric analysis map substantially as shown in FIG. 30 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form D has a diffraction angle 2 ⁇ of 7.6° ⁇ 0.2°, 9.1° ⁇ 0.2°, 10.7° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.8° ⁇ 0.2° ° characteristic peak;
  • the X-ray powder diffraction pattern of the hydrochloride salt form D has a diffraction angle 2 ⁇ of 7.6° ⁇ 0.2°, 9.1° ⁇ 0.2°, 10.7° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.8° ⁇ 0.2° 0.2°, 19.2° ⁇ 0.2°, 19.5° ⁇ 0.2°, 19.9° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form D has an X-ray powder diffraction pattern substantially as shown in Figure 31;
  • hydrochloride crystalline form D has a differential scanning calorimetry pattern and a thermogravimetric analysis pattern substantially as shown in Figure 32.
  • the X-ray powder diffraction pattern of the hydrochloride salt form E has a diffraction angle 2 ⁇ of 10.7° ⁇ 0.2°, 12.3° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.6° ⁇ 0.2°, 19.8° ⁇ 0.2° °, 20.6° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.7° ⁇ 0.2° characteristic peaks;
  • the X-ray powder diffraction pattern of the hydrochloride salt form E has a diffraction angle 2 ⁇ of 8.3° ⁇ 0.2°, 10.7° ⁇ 0.2°, 12.3° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.6° ⁇ 0.2° 0.2°, 17.3° ⁇ 0.2°, 19.3° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.7° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form E has an X-ray powder diffraction pattern substantially as shown in Figure 33;
  • hydrochloride salt form E has a thermogravimetric analysis diagram substantially as shown in FIG. 34 .
  • the X-ray powder diffraction pattern of the hydrochloride salt form F has a diffraction angle 2 ⁇ of 6.9° ⁇ 0.2°, 7.6° ⁇ 0.2°, 12.8° ⁇ 0.2°, 15.3° ⁇ 0.2°, 20.0° ⁇ 0.2 ° characteristic peak;
  • the hydrochloride salt form F has an X-ray powder diffraction pattern substantially as shown in FIG. 35 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form G has a diffraction angle 2 ⁇ of 7.2° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.1° ⁇ 0.2°, 15.5° ⁇ 0.2°, 18.8° ⁇ 0.2° °, 19.3° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2°, 21.7° ⁇ 0.2°, 22.2° ⁇ 0.2° characteristic peaks;
  • the X-ray powder diffraction pattern of the hydrochloride salt form G has a diffraction angle 2 ⁇ of 7.2° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.1° ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.0° ⁇ 0.2° 0.2°, 15.5° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2°, 21.7° ⁇ 0.2°, 22.2° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form G has an X-ray powder diffraction pattern substantially as shown in Figure 36;
  • hydrochloride salt form G has a differential scanning calorimetry map and a thermogravimetric analysis map basically as shown in FIG. 37 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form H has a diffraction angle 2 ⁇ of 7.1° ⁇ 0.2°, 9.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.1° ⁇ 0.2°, 15.6° ⁇ 0.2° °, 18.8° ⁇ 0.2°, 20.3° ⁇ 0.2°, 22.4° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form H has an X-ray powder diffraction pattern substantially as shown in Figure 38;
  • hydrochloride salt form H has a differential scanning calorimetry map and a thermogravimetric analysis map substantially as shown in Figure 39.
  • the X-ray powder diffraction pattern of the hydrochloride crystal form I has a diffraction angle 2 ⁇ of 7.5° ⁇ 0.2°, 11.8° ⁇ 0.2°, 16.7° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.9° ⁇ 0.2 °, the characteristic peak of 21.8° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the hydrochloride salt form I has a diffraction angle 2 ⁇ of 7.5° ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.8° ⁇ 0.2°, 16.7° ⁇ 0.2°, 18.6° ⁇ 0.2° 0.2°, 18.9° ⁇ 0.2°, 21.8° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 40;
  • hydrochloride salt form I has a differential scanning calorimetry map and a thermogravimetric analysis map substantially as shown in FIG. 41 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form J has a diffraction angle 2 ⁇ of 7.0° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.1° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.0° ⁇ 0.2 °, 24.9° ⁇ 0.2°, 26.1° ⁇ 0.2° characteristic peaks;
  • the X-ray powder diffraction pattern of the hydrochloride crystal form J has a diffraction angle 2 ⁇ of 7.0° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.1° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.0° ⁇ 0.2° 0.2°, 21.4° ⁇ 0.2°, 24.9° ⁇ 0.2°, 26.1° ⁇ 0.2°, 28.2° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form J has an X-ray powder diffraction pattern substantially as shown in Figure 42;
  • hydrochloride salt form J has a differential scanning calorimetry map and a thermogravimetric analysis map basically as shown in FIG. 43 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form K has a diffraction angle 2 ⁇ of 6.9° ⁇ 0.2°, 7.6° ⁇ 0.2°, 11.4° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.8° ⁇ 0.2 °, the characteristic peak of 19.6° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the hydrochloride crystal form K has a diffraction angle 2 ⁇ of 6.9° ⁇ 0.2°, 7.6° ⁇ 0.2°, 11.4° ⁇ 0.2°, 12.9° ⁇ 0.2°, 14.5° ⁇ 0.2° 0.2°, 16.0° ⁇ 0.2°, 17.6° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.6° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form K has an X-ray powder diffraction pattern substantially as shown in Figure 44;
  • hydrochloride salt form K has a differential scanning calorimetry pattern and a thermogravimetric analysis pattern substantially as shown in FIG. 45 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form L has a diffraction angle 2 ⁇ of 6.1° ⁇ 0.2°, 11.4° ⁇ 0.2°, 15.0° ⁇ 0.2°, 15.4° ⁇ 0.2°, 18.9° ⁇ 0.2 ° characteristic peak;
  • the X-ray powder diffraction pattern of the hydrochloride salt form L has a diffraction angle 2 ⁇ of 6.1° ⁇ 0.2°, 11.4° ⁇ 0.2°, 15.0° ⁇ 0.2°, 15.4° ⁇ 0.2°, 18.9° ⁇ 0.2° 0.2°, 21.4° ⁇ 0.2°, 22.3° ⁇ 0.2°, 23.0° ⁇ 0.2°, 23.8° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form L has an X-ray powder diffraction pattern substantially as shown in Figure 46;
  • hydrochloride salt form L has a thermogravimetric analysis diagram substantially as shown in FIG. 47 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form M has a diffraction angle 2 ⁇ of 7.1° ⁇ 0.2°, 9.7° ⁇ 0.2°, 10.4° ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.4° ⁇ 0.2° °, 19.4° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2°, 22.1° ⁇ 0.2° characteristic peaks;
  • the X-ray powder diffraction pattern of the hydrochloride crystal form M has a diffraction angle 2 ⁇ of 7.1° ⁇ 0.2°, 9.7° ⁇ 0.2°, 10.4° ⁇ 0.2°, 11.0° ⁇ 0.2°, 14.2° ⁇ 0.2° 0.2°, 15.4° ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2°, 22.1° ⁇ 0.2°, 26.6° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form M has an X-ray powder diffraction pattern substantially as shown in Figure 48;
  • hydrochloride salt form M has a differential scanning calorimetry map and a thermogravimetric analysis map basically as shown in FIG. 49 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form N has a diffraction angle 2 ⁇ of 6.4° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.8° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.2° ⁇ 0.2° °, 16.6° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.7° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.1° ⁇ 0.2°, 23.9° ⁇ 0.2° characteristic peaks;
  • the X-ray powder diffraction pattern of the hydrochloride crystal form N has a diffraction angle 2 ⁇ of 6.4° ⁇ 0.2°, 11.1° ⁇ 0.2°, 11.4° ⁇ 0.2°, 11.9° ⁇ 0.2°, 12.8° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 20.7° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.1° ⁇ 0.2 °, the characteristic peak of 23.9° ⁇ 0.2°;
  • the hydrochloride salt form N has an X-ray powder diffraction pattern substantially as shown in Figure 50;
  • hydrochloride salt form N has a differential scanning calorimetry map and a thermogravimetric analysis map basically as shown in FIG. 51 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form O has a diffraction angle 2 ⁇ of 8.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.3° ⁇ 0.2°, 14.8° ⁇ 0.2 °, 15.5° ⁇ 0.2°, 16.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.5° ⁇ 0.2°, 22.5° ⁇ 0.2°, 23.9° ⁇ 0.2° characteristic peaks;
  • the X-ray powder diffraction pattern of the hydrochloride salt form O has a diffraction angle 2 ⁇ of 8.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.3° ⁇ 0.2°, 13.6° ⁇ 0.2° 0.2°, 14.8° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.5° ⁇ 0.2°, 21.3° ⁇ 0.2°, 22.5° ⁇ 0.2°, 23.9° ⁇ 0.2° , the characteristic peak of 25.9° ⁇ 0.2°;
  • the hydrochloride salt form O has an X-ray powder diffraction pattern substantially as shown in Figure 52;
  • hydrochloride salt form O has a differential scanning calorimetry map and a thermogravimetric analysis map basically as shown in FIG. 53 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form P has a diffraction angle 2 ⁇ of 7.3° ⁇ 0.2°, 9.1° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.6° ⁇ 0.2°, 19.3° ⁇ 0.2° °, the characteristic peak of 21.4° ⁇ 0.2°;
  • the hydrochloride salt form P has an X-ray powder diffraction pattern substantially as shown in Figure 54;
  • hydrochloride salt form P has a differential scanning calorimetry map and a thermogravimetric analysis map basically as shown in FIG. 55 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form Q has a diffraction angle 2 ⁇ of 8.5° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.4° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.9° ⁇ 0.2 °, 19.6° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.9° ⁇ 0.2°, 24.0° ⁇ 0.2° characteristic peaks;
  • the X-ray powder diffraction pattern of the hydrochloride crystal form Q has a diffraction angle 2 ⁇ of 8.5° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.4° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.9° ⁇ 0.2° 0.2°, 16.6° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.9° ⁇ 0.2° , the characteristic peak of 24.0° ⁇ 0.2°;
  • the hydrochloride salt form Q has an X-ray powder diffraction pattern substantially as shown in Figure 56;
  • hydrochloride salt form Q has a differential scanning calorimetry map and a thermogravimetric analysis map substantially as shown in FIG. 57 .
  • the X-ray powder diffraction pattern of the hydrochloride crystal form R has a diffraction angle 2 ⁇ of 6.7° ⁇ 0.2°, 7.8° ⁇ 0.2°, 12.9° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.8° ⁇ 0.2° °, the characteristic peak of 19.1° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the hydrochloride salt form R has a diffraction angle 2 ⁇ of 6.7° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.9° ⁇ 0.2° 0.2°, 15.7° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.2° ⁇ 0.2° characteristic peaks;
  • the hydrochloride salt form R has an X-ray powder diffraction pattern substantially as shown in FIG. 58 .
  • the X-ray powder diffraction pattern of the crystal form A of the compound of formula I has a diffraction angle 2 ⁇ of 6.4° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.3° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.7° ⁇ 0.2 °, the characteristic peak of 23.5° ⁇ 0.2°;
  • the crystalline form A of the compound of formula I has an X-ray powder diffraction pattern substantially as shown in Figure 59;
  • the crystalline form A of the compound of formula I has a differential scanning calorimetry pattern and a thermogravimetric analysis pattern substantially as shown in FIG. 60 .
  • the X-ray powder diffraction pattern of the crystal form B of the compound of formula I has a diffraction angle 2 ⁇ of 5.3° ⁇ 0.2°, 6.5° ⁇ 0.2°, 7.7° ⁇ 0.2°, 13.3° ⁇ 0.2°, 14.9° ⁇ 0.2 °, 16.2° ⁇ 0.2°, 19.9° ⁇ 0.2°, 26.1° ⁇ 0.2°, 29.4° ⁇ 0.2° characteristic peaks;
  • the crystalline form B of the compound of formula I has an X-ray powder diffraction pattern substantially as shown in Figure 61;
  • the crystalline form B of the compound of formula I has a differential scanning calorimetry pattern and a thermogravimetric analysis pattern substantially as shown in FIG. 62 .
  • the X-ray powder diffraction pattern of the crystal form C of the compound of formula I has a diffraction angle 2 ⁇ of 5.9° ⁇ 0.2°, 6.7° ⁇ 0.2°, 14.1° ⁇ 0.2°, 15.1° ⁇ 0.2°, 17.5° ⁇ 0.2 °, characteristic peaks at 18.0° ⁇ 0.2°, 20.5° ⁇ 0.2°;
  • the crystalline form C of the compound of formula I has an X-ray powder diffraction pattern substantially as shown in Figure 63;
  • the crystalline form C of the compound of formula I has a differential scanning calorimetry pattern and a thermogravimetric analysis pattern substantially as shown in FIG. 64 .
  • the X-ray powder diffraction pattern of the crystal form D of the compound of formula I has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.4° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.5° ⁇ 0.2 °, the characteristic peak of 21.7° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the crystal form D of the compound of formula I has a diffraction angle 2 ⁇ of 5.5° ⁇ 0.2°, 8.0° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.4° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.7° ⁇ 0.2° characteristic peaks;
  • the crystal form D of the compound of formula I has an X-ray powder diffraction pattern substantially as shown in Figure 65;
  • the crystalline form D of the compound of formula I has a thermogravimetric analysis diagram substantially as shown in FIG. 66 .
  • the X-ray powder diffraction pattern of the crystal form E of the compound of formula I has a diffraction angle 2 ⁇ of 5.3° ⁇ 0.2°, 7.4° ⁇ 0.2°, 8.9° ⁇ 0.2°, 12.9° ⁇ 0.2°, 14.7° ⁇ 0.2 °, 17.2° ⁇ 0.2°, 17.9° ⁇ 0.2°, 21.3° ⁇ 0.2°, 21.8° ⁇ 0.2° characteristic peaks;
  • the crystalline form E of the compound of formula I has an X-ray powder diffraction pattern substantially as shown in FIG. 67;
  • the crystalline form E of the compound of formula I has a differential scanning calorimetry diagram and a thermogravimetric analysis diagram substantially as shown in FIG. 68 .
  • the X-ray powder diffraction pattern of the crystal form F of the compound of formula I has a diffraction angle 2 ⁇ of 6.6° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.7° ⁇ 0.2°, 21.6° ⁇ 0.2° °, 23.4° ⁇ 0.2°, 29.5° ⁇ 0.2° characteristic peaks;
  • the crystalline form F of the compound of formula I has an X-ray powder diffraction pattern substantially as shown in Figure 69;
  • the crystalline form F of the compound of formula I has a differential scanning calorimetry diagram and a thermogravimetric analysis diagram substantially as shown in FIG. 70 .
  • the X-ray powder diffraction pattern of the crystal form G of the compound of formula I has a diffraction angle 2 ⁇ of 5.8° ⁇ 0.2°, 8.0° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2 °, 17.2° ⁇ 0.2°, 17.9° ⁇ 0.2° characteristic peak;
  • the crystalline form G of the compound of formula I has an X-ray powder diffraction pattern substantially as shown in Figure 71;
  • the crystalline form G of the compound of formula I has a thermogravimetric analysis diagram substantially as shown in FIG. 72 .
  • the X-ray powder diffraction pattern of the crystal form H of the compound of formula I has a diffraction angle 2 ⁇ of 5.8° ⁇ 0.2°, 13.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.8° ⁇ 0.2°, 16.3° ⁇ 0.2 °, 17.3° ⁇ 0.2°, 17.9° ⁇ 0.2°, 21.9° ⁇ 0.2° characteristic peaks;
  • the X-ray powder diffraction pattern of the crystalline form H of the compound of formula I has a diffraction angle 2 ⁇ of 5.8° ⁇ 0.2°, 7.4° ⁇ 0.2°, 13.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.8° ⁇ 0.2° 0.2°, 16.3° ⁇ 0.2°, 17.3° ⁇ 0.2°, 17.9° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.5° ⁇ 0.2° characteristic peaks;
  • the crystalline form H of the compound of formula I has an X-ray powder diffraction pattern substantially as shown in Figure 73;
  • the crystalline form H of the compound of formula I has a differential scanning calorimetry pattern and a thermogravimetric analysis pattern substantially as shown in FIG. 74 .
  • the X-ray powder diffraction pattern of the crystal form I of the compound of formula I has a diffraction angle 2 ⁇ of 4.0° ⁇ 0.2°, 7.5° ⁇ 0.2°, 10.1° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.1° ⁇ 0.2 °, characteristic peaks at 17.8° ⁇ 0.2°, 18.9° ⁇ 0.2°;
  • the crystalline form I of the compound of formula I has an X-ray powder diffraction pattern substantially as shown in Figure 75;
  • the crystalline form I of the compound of formula I has a thermogravimetric analysis diagram substantially as shown in FIG. 76 .
  • the X-ray powder diffraction pattern of the crystal form J of the compound of formula I has a diffraction angle 2 ⁇ of 6.4° ⁇ 0.2°, 8.0° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.0° ⁇ 0.2°, 17.5° ⁇ 0.2 °, the characteristic peak of 22.4° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the crystal form J of the compound of formula I has a diffraction angle 2 ⁇ of 6.4° ⁇ 0.2°, 8.0° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.0° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.5° ⁇ 0.2°, 20.5° ⁇ 0.2°, 22.4° ⁇ 0.2° characteristic peaks;
  • the crystal form J of the compound of formula I has an X-ray powder diffraction pattern substantially as shown in Figure 77;
  • the crystalline form J of the compound of formula I has a differential scanning calorimetry pattern and a thermogravimetric analysis pattern substantially as shown in FIG. 78 .
  • the present invention further provides an amorphous compound of formula I, whose X-ray powder diffraction pattern has no obvious sharp diffraction peak;
  • its X-ray powder diffraction pattern is substantially as shown in FIG. 79 .
  • the present invention further provides intermediates of compound S2 or S3 or S21 or S22:
  • the present invention further provides a method for preparing compound S2 or S3 or S21 or S22 or a compound of formula I or a compound of formula I mesylate crystal form A, comprising the following steps:
  • Compound S2 is prepared from compound S1;
  • Compound S1 is prepared under the action of potassium acetate, water and acetic acid to obtain compound S2; and/or
  • Compound S3 is prepared from compound S2;
  • Compound S2 is prepared to obtain compound S3 under the action of the oxidizing agent potassium hydrogen peroxosulfate compound salt;
  • compound S2 is first dissolved in 1,4-dioxane solution and then reacted with potassium hydrogen peroxosulfate compound salt;
  • the compound salt of potassium hydrogen peroxosulfate participates in the reaction in the form of a mixed solution
  • the mixed solution of potassium hydrogen peroxosulfate compound salt is prepared by adding potassium peroxo hydrogen sulfate compound salt into water;
  • Compound S21 is prepared from compound S3;
  • Compound S21 is prepared from compound S3 and DHP in the presence of tetrahydrofuran and p-toluenesulfonic acid; and/or
  • Compound S22 is prepared from compound S21;
  • the compound of formula I is prepared from compound S22;
  • Compound S22 is first prepared under the action of hydrogen chloride-1,4-dioxane solution, and then under the action of sodium bicarbonate aqueous solution to obtain the compound of formula I;
  • step 1 is reacted in the presence of dichloromethane and methanol
  • step 2 is reacted in the presence of methanol; and/or
  • Form A of mesylate salt of compound of formula I is prepared from compound of formula I:
  • volume ratio of THF/water is 10-30:1; preferably, the volume ratio is 15-25:1; more preferably, the volume ratio is 19:1;
  • the temperature is 45-55°C; more preferably, the temperature is 50°C;
  • the material molar ratio of the compound of formula I and methanesulfonic acid 0.8-1.2: preferably, the material molar ratio is 0.9-1.1; more preferably, the material molar ratio is 1-1;
  • the compound of formula I is firstly added to the solvent and then stirred to dissolve, and then methanesulfonic acid is added; the stirring and dissolve is carried out at 40-60°C.
  • the present invention further provides a method for preparing the crystal form D of mesylate salt of the compound of formula I, which is prepared from the compound of formula I:
  • the compound of formula I and methanesulfonic acid were reacted at a temperature of 20 to 60° C. for 0.5-3 hours, filtered and dried to obtain the crystal form D of the mesylate salt of the compound of formula I;
  • volume ratio of ethanol/water is 10-30:1; preferably, the volume ratio is 15-25:1; more preferably, the volume ratio is 19:1;
  • the temperature is 30-50°C; more preferably, the temperature is 40°C;
  • the material molar ratio of the compound of formula I and methanesulfonic acid 0.8-1.2; preferably, the material molar ratio is 0.9-1.1; more preferably, the material molar ratio is 1-1;
  • the stirring time is 1-24 hours, and the stirring temperature is 15-30° C.; preferably, the stirring time is 4 hours, and the stirring temperature is room temperature.
  • the present invention further provides another preparation method of the mesylate salt crystal form A of the compound of formula I, which is prepared by the following method:
  • the volume ratio of THF/water is 10-30:1; preferably, the volume ratio is 15-25:1; more preferably, the volume ratio is 19:1.
  • the stirring temperature is 45 to 55°C; more preferably, the temperature is 50°C.
  • step 1 the feeding amount of methanesulfonic acid is 0.1-0.3 equivalent relative to the compound of formula I; in step 2, the feeding amount of methanesulfonic acid is 0.7-0.9 equivalent relative to the compound of formula I;
  • the solvent is ethyl acetate and water; preferably, the volume ratio of ethyl acetate and water in the solvent is 10-20:1; more preferably, ethyl acetate in the solvent The volume ratio to water is 13-18:1; more preferably, the order of adding the solvent is adding ethyl acetate first, and then adding water.
  • the crystalline form of the compound of formula I and its salt form preferably have a crystal purity greater than 50%, such as 85% or more, 95% or more, 99% or more or 99.5% or more.
  • the present invention further provides a pharmaceutical composition, which contains a therapeutically effective amount of the crystal form of the compound of formula I described in the present invention, each salt form or its corresponding crystal form, and a pharmaceutically acceptable adjuvant, adjuvant or carrier.
  • a pharmaceutical composition which contains a therapeutically effective amount of the crystal form of the compound of formula I described in the present invention, each salt form or its corresponding crystal form, and a pharmaceutically acceptable adjuvant, adjuvant or carrier.
  • the weight ratio of the crystal form of the compound of formula I, each salt form or its corresponding crystal form and the auxiliary material, auxiliary agent or carrier is in the range of 0.0001-10.
  • the present invention also provides preferred embodiments of the above pharmaceutical composition.
  • the above pharmaceutical composition contains a therapeutically effective amount of the crystal form, each salt form or the corresponding crystal form of the compound of formula I described in the present invention, combined with at least one other active ingredient.
  • the pharmaceutical composition is for oral administration.
  • the pharmaceutical composition is used in tablets or capsules.
  • the pharmaceutical composition contains 0.01% by weight to 99% by weight of the crystal form, each salt form or the corresponding crystal form of the compound of formula I described in the present invention.
  • the pharmaceutical composition contains 0.05% by weight to 50% by weight of the crystal form, each salt form or the corresponding crystal form of the compound of formula I described in the present invention.
  • the pharmaceutical composition contains 0.1% by weight to 30% by weight of the crystal form, each salt form or the corresponding crystal form of the compound of formula I described in the present invention.
  • the present invention further provides the application of the crystal form of the compound of formula I, each salt form or its corresponding crystal form or pharmaceutical composition in the preparation of medicine.
  • the present invention further provides the preferred technical scheme of said application:
  • the application is treating, preventing, delaying or arresting the occurrence or progression of cancer or cancer metastasis.
  • the application is the preparation of medicines for treating or preventing diseases mediated by SHP2.
  • said disease is cancer.
  • the cancer is selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, squamous cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, Cancer of the esophagus, lung, colon, head, stomach, lymphoma, glioblastoma, and/or pancreatic cancer.
  • the application is as a SHP2 inhibitor.
  • the present invention also provides a method of administering a therapeutically effective amount of at least any crystal form of the compound of formula I described in the present invention, each salt form or its corresponding crystal form or pharmaceutical composition to treat and/or prevent Methods for diseases mediated by SHP2.
  • the disease mediated by SHP2 is cancer.
  • the cancer is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, squamous cell carcinoma of the head and neck, acute myeloid Leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, and/or pancreatic cancer.
  • the present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any crystal form, each salt form, or its corresponding crystal form or pharmaceutical composition of the compound of formula I described in the present invention to the subject , the cancer is selected from the group consisting of Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, squamous cell carcinoma of the head and neck, acute myelogenous leukemia, breast cancer, esophageal cancer , lung, colon, head, stomach, lymphoma, glioblastoma, and/or pancreatic cancer.
  • the treatment object is human.
  • the terms "about” and “substantially” used in "having an X-ray powder diffraction pattern approximately as shown in Figure 1" or “its X-ray powder diffraction pattern substantially as shown in Figure 1” mean The precise positions of peaks in the figures should not be interpreted as absolute values. Because those skilled in the art know, the 2 ⁇ value of X-ray powder diffraction pattern may produce error because of different measurement conditions (as used equipment and instrument) and different samples, the measurement error of the diffraction angle of X-ray powder diffraction pattern 5% or less, generally, a difference of ⁇ 0.2° from the given value would be considered appropriate.
  • the relative intensities of the peaks may fluctuate with experimental conditions and sample preparation such as the preferred orientation of the particles in the sample.
  • sample preparation such as the preferred orientation of the particles in the sample.
  • the use of automatic or fixed divergence slits will also affect the relative intensity calculations.
  • the intensities shown in the X-ray powder diffraction patterns included here are exemplary only and cannot be used as absolute comparisons.
  • Figure 1 X-ray powder diffraction pattern of the mesylate salt crystal form A of the compound of formula I;
  • Figure 5 The three-dimensional structure diagram of the asymmetric unit of the mesylate salt crystal form D of the compound of formula I;
  • Figure 5-1 The unit cell packing diagram of the mesylate salt crystal form D of the compound of formula I;
  • Figure 9 X-ray powder diffraction pattern of the crystalline form A of the besylate salt of the compound of formula I;
  • Figure 10 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the besylate salt crystal form A of the compound of formula I;
  • Figure 12 X-ray powder diffraction pattern of the p-toluenesulfonate salt crystal form A of the compound of formula I;
  • Figure 15 X-ray powder diffraction pattern of compound L-lactate salt form A of formula I;
  • Figure 16 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of compound L-lactate crystal form A of formula I;
  • Figure 18 X-ray powder diffraction pattern of formula I compound L-tartrate crystal form A
  • Figure 21 X-ray powder diffraction pattern of formula I compound fumarate crystal form A
  • Figure 24 X-ray powder diffraction pattern of formula I compound L-malate crystal form A
  • Figure 25 Overlay of differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of compound L-malate crystal form A of formula I;
  • Figure 27 X-ray powder diffraction pattern of formula I compound hydrochloride crystal form A
  • Figure 28 Overlay of differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of compound hydrochloride salt form A of formula I;
  • Figure 29 X-ray powder diffraction pattern of formula I compound hydrochloride crystal form B;
  • Figure 30 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the hydrochloride salt form B of the compound of formula I;
  • Figure 31 X-ray powder diffraction pattern of the hydrochloride salt form D of the compound of formula I;
  • Figure 32 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the hydrochloride salt form D of the compound of formula I;
  • Figure 33 X-ray powder diffraction pattern of the hydrochloride salt form E of the compound of formula I;
  • Figure 35 X-ray powder diffraction pattern of Formula I compound hydrochloride crystal form F;
  • Figure 36 X-ray powder diffraction pattern of the hydrochloride salt form G of the compound of formula I;
  • Figure 37 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the hydrochloride salt form G of the compound of formula I;
  • Figure 38 X-ray powder diffraction pattern of the hydrochloride salt form H of the compound of formula I;
  • Figure 40 X-ray powder diffraction pattern of formula I compound hydrochloride crystal form I;
  • Figure 41 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the hydrochloride salt form I of the compound of formula I;
  • Figure 42 X-ray powder diffraction pattern of the hydrochloride salt form J of the compound of formula I;
  • Figure 44 X-ray powder diffraction pattern of the hydrochloride salt form K of the compound of formula I;
  • Figure 45 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the hydrochloride salt crystal form K of the compound of formula I;
  • Figure 46 X-ray powder diffraction pattern of compound hydrochloride salt form L of formula I;
  • Figure 48 X-ray powder diffraction pattern of the hydrochloride salt form M of the compound of formula I;
  • Figure 50 X-ray powder diffraction pattern of formula I compound hydrochloride crystal form N;
  • Figure 51 Overlay of differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of compound hydrochloride crystal form N of formula I;
  • Figure 52 X-ray powder diffraction pattern of the hydrochloride salt form O of the compound of formula I;
  • Figure 53 Overlay of differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of compound hydrochloride crystal form O of formula I;
  • Figure 54 X-ray powder diffraction pattern of compound hydrochloride crystal form P of formula I;
  • Figure 55 Overlay of differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of compound hydrochloride crystal form P of formula I;
  • Figure 56 X-ray powder diffraction pattern of the hydrochloride salt form Q of the compound of formula I;
  • Figure 58 X-ray powder diffraction pattern of the hydrochloride salt form R of the compound of formula I;
  • Figure 59 X-ray powder diffraction pattern of the compound of formula I, crystal form A;
  • Figure 60 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the crystal form A of the compound of formula I;
  • Figure 61 X-ray powder diffraction pattern of the compound of formula I, crystal form B;
  • Figure 62 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the crystal form B of the compound of formula I;
  • Figure 63 X-ray powder diffraction pattern of the compound of formula I, Form C;
  • Figure 64 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the crystal form C of the compound of formula I;
  • Figure 65 X-ray powder diffraction pattern of the compound of formula I, crystal form D;
  • Figure 67 X-ray powder diffraction pattern of the compound of formula I, crystal form E;
  • Figure 68 Overlay of the differential scanning calorimetry and thermogravimetric analysis spectra of the crystal form E of the compound of formula I;
  • Figure 69 X-ray powder diffraction pattern of the compound of formula I, Form F;
  • Figure 70 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the crystal form F of the compound of formula I;
  • Figure 71 X-ray powder diffraction pattern of the compound of formula I, Form G;
  • Figure 73 X-ray powder diffraction pattern of the compound of formula I, crystal form H;
  • Figure 74 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the crystal form H of the compound of formula I;
  • Figure 75 X-ray powder diffraction pattern of the compound of formula I, crystal form I;
  • Fig. 77 X-ray powder diffraction pattern of the crystal form J of the compound of formula I;
  • Figure 78 Overlay of the differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the crystal form J of the compound of formula I;
  • Figure 79 X-ray powder diffraction pattern of the amorphous compound of formula I.
  • TGA Thermogravimetric Analyzer
  • TGA 550 sample tray Platinum crucible + aluminum crucible Protective gas Nitrogen Gas flow rate (sample purge) 40mL/min Gas flow rate (balance) 60mL/min Heating rate 10°C/min
  • DSC Differential Scanning Calorimetry
  • DIPEA N,N-Diisopropylethylamine
  • DMSO dimethyl sulfoxide
  • DSC Differential Scanning Calorimetry
  • DVS dynamic vapor adsorption instrument
  • NMP N-methylpyrrolidone
  • PK pharmacokinetics.
  • the temperature of the system was lowered to 50° C., and the reaction solution was added into purified water (36.00 L) with stirring, stirred for 30 minutes, filtered, and the filter cake was rinsed with purified water (1.00 L).
  • the filter cake was transferred to a reaction kettle, and purified water (10.00 L) was added to make slurry at room temperature for 0.5 hours, filtered, and the filter cake was rinsed with purified water (2.00 L).
  • the filter cake was naturally dried at room temperature for 48 hours to obtain crude product S2, which was beaten with ethyl acetate (2.00 L) for 1 hour, filtered, and the filter cake was rinsed with ethyl acetate (0.30 L).
  • the filter cake was naturally dried at room temperature for 4 hours to obtain 701.35 g of S2 solid, yield: 92.91%.
  • Ethyl acetate (5.70 L) was added into a 10 L reaction kettle, stirred, and the temperature was raised to 50°C. Then add the above sample (350.52g), suspend and stir, then add 0.35L of purified water, stir evenly, then add 7.10g of mesylate crystal form A. Keep the reaction at 50°C, XRPD detects that all the solids are converted into mesylate salt crystal form A, cool down to 20°C, mature for 1 hour, then filter with suction, rinse the filter cake with ethyl acetate (0.35L), and vacuum the filter cake at 50°C Drying for 14 hours yielded 352.16 g of solid. As determined by XRPD, TGA, DSC and 1 H-NMR, the final product is the crystal form A of the mesylate salt of the compound of formula I.
  • Embodiment 4 Preparation of formula I compound p-toluenesulfonate crystal form A
  • Embodiment 5 Preparation of Formula I Compound L-Lactate Form A
  • hydrochloric acid diluent 87 mg of concentrated HCl solution dissolved in 4 mL of H 2 O
  • suspend and stir at room temperature for 24 h then centrifuge, and dry the solid under vacuum at room temperature for 4 hours, and test for XRPD, TGA and DSC Determination, the final product is hydrochloride crystal form A.
  • hydrochloric acid diluent 87 mg of concentrated HCl solution dissolved in 5 mL of acetone/water (19:1, volume ratio)
  • hydrochloric acid diluent 87 mg of concentrated HCl solution dissolved in 5 mL of THF/H 2 O (19:1, v/v)
  • suspend and stir at room temperature for 48 h and centrifuge to separate the solid Vacuum drying at room temperature for 4 hours, determined by XRPD, TGA and DSC, the final product is hydrochloride crystal form D.
  • hydrochloric acid diluent 87 mg of concentrated HCl solution dissolved in 4 mL of THF/H 2 O (19:1, v/v)
  • the final product is hydrochloride crystal form F.
  • hydrochloric acid diluent 163 mg of concentrated HCl solution dissolved in 5 mL of THF/H 2 O (19:1, v/v)
  • suspend and stir at room temperature for 24 h centrifuge, and solidify at room temperature Vacuum dried for 4 hours, and determined by XRPD, TGA and DSC, the final product was hydrochloride crystal form G.
  • Embodiment 16 Preparation of formula I compound hydrochloride crystal form I
  • hydrochloride crystal form B sample weigh about 20 mg of hydrochloride crystal form B sample, add 0.4 mL of acetonitrile/water (19:1, v/v) mixed solution, suspend and stir at room temperature for 5 days, then centrifuge, and dry the solid in vacuum at room temperature for 4 hours.
  • XRPD, TGA and As determined by DSC, the final product is hydrochloride crystal form I.
  • hydrochloride form B sample weigh about 20 mg of hydrochloride form B sample, add 0.4 mL of water, suspend and stir at room temperature for 5 days, then centrifuge, and dry the solid under vacuum at room temperature for 4 hours.
  • the final product is hydrochloride form J as determined by XRPD, TGA and DSC.
  • hydrochloride form E sample was picked about 100 mg hydrochloride form E sample and place it in a 60°C forced air drying oven for 10 days.
  • the final product is hydrochloride form L as determined by XRPD and TGA.
  • hydrochloride salt form M The final product is hydrochloride salt form M.
  • hydrochloride crystal form D sample weigh about 500 mg of hydrochloride crystal form D sample, add 10 mL of ethyl acetate, suspend and stir at 60°C overnight, then filter with suction, and dry the solid in vacuum at 45°C for 2 hours.
  • the final product is hydrochloride crystal form R as determined by XRPD.
  • Embodiment 36 Ion Chromatography Determination
  • Table 9 shows the mesylate crystal form D single crystal data, the three-dimensional structure diagram of its asymmetric unit is shown in Figure 5, and its unit cell packing diagram is shown in Figure 5-1.
  • mesylate salt form A and mesylate salt form D have an unexpected purification effect, that is, they can be prepared with higher purity. It can be seen that the mesylate salt form A and the mesylate salt form D are suitable for preparing more stable high-quality drugs.
  • the stability of the crystalline forms of the invention was determined.
  • Mesylate salt form A, mesylate salt form D, besylate salt form A, p-toluenesulfonate form A, L-lactate form A, L-tartrate form A , fumarate crystal form A and L-malate crystal form A were placed in 4500Lux light environment, 60°C high temperature environment and 90%RH ⁇ 5%RH high humidity environment respectively for stability test. Samples were taken on the 5th day, 10th day and 30th day, and the appearance properties, moisture content, and total related substances of the samples were recorded, and compared with the initial data.
  • mesylate salt crystal form A mesylate salt crystal form D
  • besylate salt crystal form A p-toluenesulfonate salt crystal form A
  • L-lactate crystal form A L-tartrate salt Form A
  • fumarate form A and L-malate form A have good stability, especially mesylate form A and mesylate form D have better stability .
  • the mesylate crystal form D has a weight change of 0.11% in the range of 0%RH to 80%RH, has no or almost no hygroscopicity, and has outstanding advantages in hygroscopicity; and compared with other crystals In terms of hygroscopicity data, the mesylate salt form A also has obvious advantages.
  • Embodiment 43 in vivo pharmacokinetics (PK) comparative experiment
  • SHP2 is allosterically activated by the binding of a bis-tyrosyl-phosphorylated peptide to its Src homology 2 (SH2) domain. This latter activation step results in the release of the autoinhibitory interface of SHP2, which in turn makes the SHP2 protein tyrosine phosphatase (PTP) active and available for substrate recognition and reaction catalysis.
  • PTP protein tyrosine phosphatase
  • SHP2 enzyme activity assays were performed at room temperature in 96-well black polystyrene plates (flat bottom, low flange, non-binding surface) (Perki Elmer, Cat# 6005270) using a final reaction volume of 50 ⁇ L and the following assay buffer conditions: 60 mM HEPES, 75mM NaCl, 75mM KCl, 0.05% BRIJ-35, 1mM EDTA, 5mM DTT.
  • Inhibition rate% [1-(Conversion_ sample -Conversion_ min )/(Conversion_ max -Conversion_ min )] ⁇ 100%
  • Conversion_sample is the conversion rate reading of the sample
  • Conversion_min is the average value of the blank control well, representing the conversion rate reading of the well without enzyme activity
  • Conversion_max is the average ratio of the positive control well, representing the conversion rate reading of the well without compound inhibition.
  • the dose-effect curve was fitted using the log(inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism, and the IC 50 value of the compound on the enzyme activity was calculated. After determination, the IC 50 of the compound of formula I in the present invention to SHP2 is 0.9nM.
  • the effect of the compound of the present invention on the proliferation of leukemia cell MV-4-11 and lung cancer cell NCI-H358 was evaluated using an in vitro cell assay.
  • the detection method used in the test is CELL TITER-GLO (CTG) luminescence method, which can detect the number of living cells by quantitatively measuring ATP. Because ATP participates in various enzymatic reactions in the body, it is an indicator of the metabolism of living cells. Its content directly reflects the number and state of cells. The value is directly proportional to the amount of ATP, and ATP is positively correlated with the number of living cells, so the cell viability can be inspected by detecting the ATP content.
  • CCG CELL TITER-GLO
  • the final concentration of the compound from high to low is 1000nM, 333.3nM, 111.1nM, 37.04nM, 12.35nM, 4.115nM, 1.372nM, 0.4572nM, 0.1524nM, OnM, and the well plate is placed Incubate in a 37°C, 5% CO 2 incubator for 120 hours.
  • the wells that only added culture medium but no cells were set as the blank group; the group with the compound concentration of 0 nM was set as the zero-adjusted group.
  • NCI-H358 cells were cultured for 96 hours, 50 ⁇ L of Luminescent Cell Viability Assay solution, shake gently for 2 minutes, and incubate at room temperature for 10 minutes. The cell reaction system was transferred to a white-bottomed 96-well plate. Read the detection value of each well on a multifunctional microplate reader.
  • MV-4-11 cells were cultured for 120hrs, 50 ⁇ L of Luminescent Cell Viability Assay solution, shake gently for 2 minutes, continue to incubate at room temperature for 10 minutes, and read the detection value of each well on a multifunctional microplate reader.
  • Inhibition rate% (1-(administration group value-blank group value)/(zeroing group value-blank group value) ⁇ 100
  • GraphPad Prism's log(inhibitor) vs. response-Variable slope fits the dose-effect curve and calculates the IC 50 of the compound inhibiting cell proliferation.
  • the IC 50 value of the compound of formula I in the present invention on MV - 4-11 cells and NCI-H358 cells are both less than 20nM.
  • test sample diluent Dilute the test sample diluent in sequence with extracellular fluid to prepare test solutions with final concentrations of 0.3 ⁇ M, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M and 30 ⁇ M. Visually inspect the solubility of the samples to be tested.
  • the cell line was derived from HEK293 cells and cultured in a 37°C, 5% CO 2 incubator. In order to prevent cell senescence caused by contact inhibition, when the confluence of cell culture should not exceed 80%, subculture once every 3/4 days, and the seeding density of each T175 bottle is 2*10 6 cells. Pre-wash with phosphate buffered saline (PBS), then digest the cells with trypsin/EDTA for 2-3 minutes, add cell culture medium to stop the digestion, and transfer to a new culture bottle.
  • PBS phosphate buffered saline
  • HEK293 cells overexpressing the hERG potassium ion channel were cultured overnight at a cell density below 50%.
  • the experimental cells were transferred to a cell bath embedded in an inverted microscope platform (Diaphot, Nikon) and perfused with extracellular fluid.
  • the extracellular fluid contains 137mM NaCl, 4mM KCl, 1.8mM CaCl 2 , 1mM MgCl 2 , 10mM glucose and 10mM HEPES (pH 7.4 with NaOH), and the perfusion rate is 4ml/min.
  • the inner tube solution contains 130mM KCl, 1mM MgCl 2 , 5mM EGTA, 5mM MgATP and 10mM HEPES (pH 7.2 with KOH).
  • Membrane currents were recorded using a HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany). All experiments were done at room temperature (22-23°
  • the electrode (BF150-86-10) was straightened using a P-97 microelectrode puller (Sutter Instrument Company, One Digital Drive, Novato, CA 94949) in the experiment.
  • the inner diameter of the electrode is 1-1.5mm, and the water resistance after being filled with inner liquid is 2-4M ⁇ .
  • Electrophysiological Stimulation Protocol
  • the extracellular fluid containing the drug to be tested is perfused.
  • the same procedure was repeated 3-5 times to expose each cell to 4-6 compounds at increasing concentrations. The progress of blocking and unblocking of hERG during compound exposure and washout was continuously recorded.
  • the cell membrane voltage is clamped at -80mV, and the depolarization is carried out for 2 seconds every 12 seconds.
  • the clamping voltage is depolarized from -80mV to -50mV, and the tail current is measured under the 5-second repolarization pulse of -50mv. peak.
  • Peak hERG tail currents were measured under a 5 s repolarization pulse of -50 mV. Each drug concentration was plotted against the current inhibition rate as a function of the logarithm of the compound concentration. The following Hill equation was used to fit the concentration-response curve, and the IC 50 was fitted.
  • the hERG IC 50 value of the compound of formula I in the present invention is 9.5 ⁇ M.
  • liver microsomes (concentration: 20 mg/mL)
  • reaction termination solution Take 50 ⁇ L samples from the above reaction solution at 0, 5, 15, and 45 minutes respectively, and add 400 ⁇ L of reaction termination solution to terminate the reaction
  • C protein is the concentration of liver microsomes.
  • Table 14 shows the metabolic stability results of liver microsomes of the compound of formula I in humans and rats.

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Abstract

本发明涉及式I所示化合物的晶型、各种盐型及其盐型晶型，本发明还涉及式I所示化合物的晶型、各种盐型及其盐型晶型的制备方法，含有所述晶型、各种盐型及其盐型晶型的药物组合物,以及它们在制备治疗疾病、病症或病状的药物中的应用或用于治疗疾病、病症或病状的治疗方法。

Description

吡唑并嘧啶酮类化合物及其盐的结晶 技术领域
本发明属于生物医药领域，主要涉及吡唑并嘧啶酮类化合物的晶型、各种盐型及其晶型以及晶型的制备方法、药物组合物以及相关用途。
背景技术
含Src同源区2蛋白质酪氨酸磷酸酶2(Src homologyregion 2-containing protein tyrosine phosphatase 2,SHP2)是由一种由PTPN11基因编码的非受体型蛋白质酪氨酸磷酸酶，PTPN11是首个被发现的编码酪氨酸磷激酶的原癌基因(Chan R J et al.PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase.Blood,2007,109:862-867)，其编码的SHP2蛋白包含N端的SHP2结构域(N-SHP2)、C端SHP2结构域(C-SHP2)、蛋白质磷酸酶催化结构域(PTP)，两个C端的酪氨酸残基(Y542和Y580)以及一个富含脯氨酸(Pro)的模体。
近年研究主要认为Ras/ERK通路是SHP2发挥作用最重要的一条信号转导通路，其机制(Dance M et al.The molecular functions of Shp2 in the RAS/mitogen-activated protein kinase(ERK1/2)pathway.Cell Signal,2008,20:453-459)大致为：生长因子受体活化后，其酪氨酸残基发生自体磷酸化，为Grb2和SHP2(含有SH2结构域的衔接蛋白)磷酸酪氨酸结合区域SH2提供停靠位点。Grb2与磷酸化的生长因子受体的结合导致SOS蛋白在胞膜的聚集。SOS作为一种鸟嘌呤核苷酸交换因子(guanine nucleotide exchange factor,GEF)，可以催化膜结合蛋白Ras从无活性的Ras-GDP转换为有活性的Ras-GTP。Ras-GTP再进一步与下游的信号系统发生联系，激活Ser/Thr激酶Raf1等，进而在调节激酶MEK的作用下使ERK活化，ERK活化后直接作用于细胞质的靶分子或转移到细胞核内调节基因转录，使细胞增殖或分化。这一过程可能还受到SHP2结合蛋白和底物(SHP substrate-1,SHPS-1)、Ras-GTP酶活化蛋白(Ras-GAP)以及其他Src成员的影响。
SHP2蛋白不仅调节Ras/ERK信号通路，另有报道其还调节JAK-STAT3、NF-κB、PI3K/Akt、RHO和NFAT等多条信号通路，进而调节细胞增殖、分化、迁移、凋亡等生理学功能。
SHP2被证明与多种疾病相关，Tartaglia等(Tartaglia M et al.Mutations in PTPN11,encoding the protein tyrosine phosphatase SHP-2,cause Noonan sydrome.Nat Genet,2001, 29:465-468)发现大约50％的努南综合征患者伴有PTPN11的错义突变。另外，研究发现PTPN11突变是JMMLL以及多种白血病发病的重要原因(Tartaglia M et al.Nat Genet,2003,34:148-150；Loh ML et al.Blood,2004,103:2325-2331；Tartaglia M et al.Br J Haematol,2005,129:333-339；Xu R et al.Blood,2005,106:3142-3149.)。随着对PTPN11/SHP2研究的深入，发现其与肺癌、胃癌、结肠癌、黑色素瘤、甲状腺癌等多种癌症的发生均有关系(唐春兰等.中国肺癌杂志，2010,13:98-101；Higuchi M et al.Cancer Sci,2004,95:442-447；Bentires-Al j M et al.Cancer Res,2004,64:8816-8820；Martinelli S et al.Cancer Genet Cytogenet,2006,166:124-129.)。
PCT国际申请PCT/CN2021/099275描述了一类用作SHP2蛋白酶抑制剂的吡唑并嘧啶酮类衍生物，这些化合物中的大部分能够有效地抑制SHP2。然而在SHP2介导疾病的治疗选择方面仍有未满足的需求，在此我们进一步筛选吡唑并嘧啶酮类衍生物的晶型以及盐型以满足患者的医疗需求。
发明内容
本发明涉及式I所示化合物(S)-6-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-3-(1-苯基环丙基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的晶型以及盐型。所述结构式I所示的化合物的制备方法和结构均已在PCT专利申请PCT/CN2021/099275中予以具体描述记载。
Figure PCTCN2022138399-appb-000001
式I化合物的盐型
在一些实施方案中，一种酸和式I化合物可在相应体系中形成相应的盐，这些盐型化合物可以以各种物理形式存在。例如，可以是溶液、悬浮液或固体形式。在某些实施方式中，盐型化合物为固体形式。为固体形式时，所述化合物可以是无定型物，结晶物或其混合物。优选地，式I化合物的盐型为式I化合物与以下酸所形成的盐：甲磺酸、苯磺酸、对甲苯磺酸、L-乳酸、L-酒石酸、富马酸、L-苹果酸和盐酸盐；更优选地，所述酸为甲磺酸。进一步地，式I化合物的各种盐可以晶型的形式存在。
式I化合物各种盐的不同晶型示范性举例如下：
式I化合物甲磺酸盐晶型A；
作为优选，该甲磺酸盐晶型A的X射线粉末衍射图具有衍射角2θ为7.2°±0.2°， 10.0°±0.2°，14.5°±0.2°，23.5°±0.2°的特征峰；
作为优选，该甲磺酸盐晶型A的X射线粉末衍射图具有衍射角2θ为7.2°±0.2°，10.0°±0.2°，14.5°±0.2°，16.9°±0.2°，23.5°±0.2°的特征峰；
作为优选，该甲磺酸盐晶型A的X射线粉末衍射图具有衍射角2θ为5.6°±0.2°，7.2°±0.2°，10.0°±0.2°，14.5°±0.2°，16.9°±0.2°，19.8°±0.2°，20.6°±0.2°，22.5°±0.2°，23.5°±0.2°的特征峰；
更优选地，该甲磺酸盐晶型A的X射线粉末衍射图的主要数据如表1所示；
表1
Figure PCTCN2022138399-appb-000002
作为优选，该甲磺酸盐晶型A具有基本上如图1所示的X射线粉末衍射图；
进一步地，该甲磺酸盐晶型A具有基本上如图2所示的差示扫描量热(DSC)图谱；
进一步地，该甲磺酸盐晶型A具有基本上如图3所示的热重分析(TGA)图谱；
进一步地，该甲磺酸盐晶型A具有基本上如图4所示的 1H-NMR图谱；
进一步地，该甲磺酸盐晶型A为无水晶型。
式I化合物甲磺酸盐晶型D；
作为优选，所述甲磺酸盐晶型D的X射线粉末衍射图具有衍射角2θ为5.7°±0.2°，16.4°±0.2°，19.3°±0.2°，20.1°±0.2°，22.9°±0.2°的特征峰；
更优选地，所述甲磺酸盐晶型D的X射线粉末衍射图具有衍射角2θ为5.7°±0.2°，11.9°±0.2°，16.4°±0.2°，17.3°±0.2°，19.3°±0.2°，20.1°±0.2°，22.9°±0.2°，26.1°±0.2°的特 征峰；
作为优选，所述甲磺酸盐晶型D具有基本上如图6所示的X射线粉末衍射图；
进一步地，所述甲磺酸盐晶型D具有基本上如图7所示的差示扫描量热图谱和热重分析图谱；
进一步地，所述甲磺酸盐晶型D具有基本上如图8所示的 1H-NMR图谱。
进一步地，该甲磺酸盐晶型D的单晶数据如表9所示，其不对称单位的立体结构图如图5所示，其晶胞堆积图如图5-1所示；
进一步地，该甲磺酸盐晶型D为无水晶型。
式I化合物苯磺酸盐晶型A；
作为优选，所述苯磺酸盐晶型A的X射线粉末衍射图具有衍射角2θ为8.4°±0.2°，11.0°±0.2°，14.2°±0.2°，16.8°±0.2°，17.4°±0.2°，18.8°±0.2°，25.6°±0.2°的特征峰；
更优选地，所述苯磺酸盐晶型A的X射线粉末衍射图具有衍射角2θ为6.2°±0.2°，8.4°±0.2°，11.0°±0.2°，11.8°±0.2°，13.8°±0.2°，14.2°±0.2°，15.9°±0.2°，16.8°±0.2°，17.4°±0.2°，18.8°±0.2°，25.6°±0.2°的特征峰；
作为优选，所述苯磺酸盐晶型A具有基本上如图9所示的X射线粉末衍射图；
进一步地，所述苯磺酸盐晶型A具有基本上如图10所示的差示扫描量热图谱和热重分析图谱；
进一步地，所述苯磺酸盐晶型A具有基本上如图11所示的 1H-NMR图谱。
式I化合物对甲苯磺酸盐晶型A；
作为优选，所述对甲苯磺酸盐晶型A的X射线粉末衍射图具有衍射角2θ为6.0°±0.2°，10.4°±0.2°，14.2°±0.2°，18.7°±0.2°，22.3°±0.2°的特征峰；
更优选地，所述对甲苯磺酸盐晶型A的X射线粉末衍射图具有衍射角2θ为6.0°±0.2°，10.4°±0.2°，11.2°±0.2°，12.4°±0.2°，13.0°±0.2°，14.2°±0.2°，18.3°±0.2°，18.7°±0.2°，22.3°±0.2°的特征峰；
作为优选，所述对甲苯磺酸盐晶型A具有基本上如图12所示的X射线粉末衍射图；
进一步地，所述对甲苯磺酸盐晶型A具有基本上如图13所示的差示扫描量热图谱和热重分析图谱；
进一步地，所述对甲苯磺酸盐晶型A具有基本上如图14所示的 1H-NMR图谱。
式I化合物L-乳酸盐晶型A；
作为优选，所述L-乳酸盐晶型A的X射线粉末衍射图具有衍射角2θ为6.2°±0.2°， 6.7°±0.2°，12.2°±0.2°，13.9°±0.2°，18.5°±0.2°，21.0°±0.2°，25.6°±0.2°的特征峰；
更优选地，所述L-乳酸盐晶型A的X射线粉末衍射图具有衍射角2θ为6.2°±0.2°，6.7°±0.2°，12.2°±0.2°，13.9°±0.2°，17.2°±0.2°，17.9°±0.2°，18.5°±0.2°，21.0°±0.2°，25.1°±0.2°，25.6°±0.2°的特征峰；
作为优选，所述L-乳酸盐晶型A具有基本上如图15所示的X射线粉末衍射图；
进一步地，所述L-乳酸盐晶型A具有基本上如图16所示的差示扫描量热图谱和热重分析图谱；
进一步地，所述L-乳酸盐晶型A具有基本上如图17所示的 1H-NMR图谱。
式I化合物L-酒石酸盐晶型A；
作为优选，所述L-酒石酸盐晶型A的X射线粉末衍射图具有衍射角2θ为5.9°±0.2°，12.6°±0.2°，15.8°±0.2°，18.9°±0.2°，24.6°±0.2°的特征峰；
更优选地，所述L-酒石酸盐晶型A的X射线粉末衍射图具有衍射角2θ为5.9°±0.2°，10.8°±0.2°，12.6°±0.2°，15.1°±0.2°，15.8°±0.2°，17.9°±0.2°，18.6°±0.2°，18.9°±0.2°，19.4°±0.2°，24.6°±0.2°，25.3°±0.2°的特征峰；
作为优选，所述L-酒石酸盐晶型A具有基本上如图18所示的X射线粉末衍射图；
进一步地，所述L-酒石酸盐晶型A具有基本上如图19所示的热重分析图谱；
进一步地，所述L-酒石酸盐晶型A具有基本上如图20所示的 1H-NMR图谱。
式I化合物富马酸盐晶型A；
作为优选，所述富马酸盐晶型A的X射线粉末衍射图具有衍射角2θ为7.5°±0.2°，15.0°±0.2°，16.2°±0.2°，17.3°±0.2°，22.8°±0.2°，28.7°±0.2°的特征峰；
更优选地，所述富马酸盐晶型A的X射线粉末衍射图具有衍射角2θ为7.5°±0.2°，15.0°±0.2°，16.2°±0.2°，17.3°±0.2°，22.8°±0.2°，28.7°±0.2°，29.3°±0.2°的特征峰；
作为优选，所述富马酸盐晶型A具有基本上如图21所示的X射线粉末衍射图；
进一步地，所述富马酸盐晶型A具有基本上如图22所示的热重分析图谱；
进一步地，所述富马酸盐晶型A具有基本上如图23所示的 1H-NMR图谱。
式I化合物L-苹果酸盐晶型A；
作为优选，所述L-苹果酸盐晶型A的X射线粉末衍射图具有衍射角2θ为5.1°±0.2°，10.2°±0.2°，17.2°±0.2°，20.6°±0.2°，23.0°±0.2°的特征峰；
更优选地，所述L-苹果酸盐晶型A的X射线粉末衍射图具有衍射角2θ为5.1°±0.2°，6.1°±0.2°，10.2°±0.2°，16.2°±0.2°，17.2°±0.2°，20.6°±0.2°，23.0°±0.2°的特征峰；
作为优选，所述L-苹果酸盐晶型A具有基本上如图24所示的X射线粉末衍射图；
进一步地，所述L-苹果酸盐晶型A具有基本上如图25所示的差示扫描量热图谱和热重分析图；
进一步地，所述L-苹果酸盐晶型A具有基本上如图26所示的 1H-NMR图谱。
式I化合物盐酸盐晶型A：
作为优选，所述盐酸盐晶型A的X射线粉末衍射图具有衍射角2θ为6.9°±0.2°，10.4°±0.2°，16.2°±0.2°，16.9°±0.2°，18.1°±0.2°，18.6°±0.2°，19.5°±0.2°的特征峰；
更优选地，所述盐酸盐晶型A的X射线粉末衍射图具有衍射角2θ为6.9°±0.2°，10.4°±0.2°，13.9°±0.2°，14.2°±0.2°，15.5°±0.2°，16.2°±0.2°，16.9°±0.2°，17.5°±0.2°，18.1°±0.2°，18.6°±0.2°，19.5°±0.2°的特征峰；
作为优选，所述盐酸盐晶型A具有基本上如图27所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型A具有基本上如图28所示的差示扫描量热图谱和热重分析图。
式I化合物盐酸盐晶型B：
作为优选，所述盐酸盐晶型B的X射线粉末衍射图具有衍射角2θ为7.3°±0.2°，10.0°±0.2°，10.5°±0.2°，16.0°±0.2°，18.7°±0.2°，20.8°±0.2°的特征峰；
更优选地，所述盐酸盐晶型B的X射线粉末衍射图具有衍射角2θ为7.3°±0.2°，10.0°±0.2°，10.5°±0.2°，14.0°±0.2°，14.6°±0.2°，16.0°±0.2°，18.7°±0.2°，19.2°±0.2°，19.6°±0.2°，20.8°±0.2°，22.8°±0.2°的特征峰；
作为优选，所述盐酸盐晶型B具有基本上如图29所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型B具有基本上如图30所示的差示扫描量热图谱和热重分析图。
式I化合物盐酸盐晶型D：
作为优选，所述盐酸盐晶型D的X射线粉末衍射图具有衍射角2θ为7.6°±0.2°，9.1°±0.2°，10.7°±0.2°，17.8°±0.2°，18.8°±0.2°的特征峰；
更优选地，所述盐酸盐晶型D的X射线粉末衍射图具有衍射角2θ为7.6°±0.2°，9.1°±0.2°，10.7°±0.2°，17.8°±0.2°，18.8°±0.2°，19.2°±0.2°，19.5°±0.2°，19.9°±0.2°的特征峰；
作为优选，所述盐酸盐晶型D具有基本上如图31所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型D具有基本上如图32所示的差示扫描量热图谱和热重分 析图。
式I化合物盐酸盐晶型E：
作为优选，所述盐酸盐晶型E的X射线粉末衍射图具有衍射角2θ为10.7°±0.2°，12.3°±0.2°，15.1°±0.2°，15.6°±0.2°，19.8°±0.2°，20.6°±0.2°，21.5°±0.2°，22.7°±0.2°，23.7°±0.2°的特征峰；
更优选地，所述盐酸盐晶型E的X射线粉末衍射图具有衍射角2θ为8.3°±0.2°，10.7°±0.2°，12.3°±0.2°，15.1°±0.2°，15.6°±0.2°，17.3°±0.2°，19.3°±0.2°，19.8°±0.2°，20.6°±0.2°，21.5°±0.2°，22.7°±0.2°，23.7°±0.2°的特征峰；
作为优选，所述盐酸盐晶型E具有基本上如图33所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型E具有基本上如图34所示的热重分析图。
式I化合物盐酸盐晶型F：
作为优选，所述盐酸盐晶型F的X射线粉末衍射图具有衍射角2θ为6.9°±0.2°，7.6°±0.2°，12.8°±0.2°，15.3°±0.2°，20.0°±0.2°的特征峰；
作为优选，所述盐酸盐晶型F具有基本上如图35所示的X射线粉末衍射图。
式I化合物盐酸盐晶型G：
作为优选，所述盐酸盐晶型G的X射线粉末衍射图具有衍射角2θ为7.2°±0.2°，9.6°±0.2°，10.1°±0.2°，15.5°±0.2°，18.8°±0.2°，19.3°±0.2°，20.1°±0.2°，21.4°±0.2°，21.7°±0.2°，22.2°±0.2°的特征峰；
更优选地，所述盐酸盐晶型G的X射线粉末衍射图具有衍射角2θ为7.2°±0.2°，9.6°±0.2°，10.1°±0.2°，10.7°±0.2°，11.0°±0.2°，15.5°±0.2°，18.8°±0.2°，19.3°±0.2°，20.1°±0.2°，21.4°±0.2°，21.7°±0.2°，22.2°±0.2°的特征峰；
作为优选，所述盐酸盐晶型G具有基本上如图36所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型G具有基本上如图37所示的差示扫描量热图谱和热重分析图。
式I化合物盐酸盐晶型H：
作为优选，所述盐酸盐晶型H的X射线粉末衍射图具有衍射角2θ为7.1°±0.2°，9.8°±0.2°，10.5°±0.2°，11.1°±0.2°，15.6°±0.2°，18.8°±0.2°，20.3°±0.2°，22.4°±0.2°的特征峰；
作为优选，所述盐酸盐晶型H具有基本上如图38所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型H具有基本上如图39所示的差示扫描量热图谱和热重分 析图。
式I化合物盐酸盐晶型I：
作为优选，所述盐酸盐晶型I的X射线粉末衍射图具有衍射角2θ为7.5°±0.2°，11.8°±0.2°，16.7°±0.2°，18.6°±0.2°，18.9°±0.2°，21.8°±0.2°的特征峰；
更优选地，所述盐酸盐晶型I的X射线粉末衍射图具有衍射角2θ为7.5°±0.2°，10.7°±0.2°，11.8°±0.2°，16.7°±0.2°，18.6°±0.2°，18.9°±0.2°，21.8°±0.2°的特征峰；
作为优选，所述盐酸盐晶型I具有基本上如图40所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型I具有基本上如图41所示的差示扫描量热图谱和热重分析图。
式I化合物盐酸盐晶型J：
作为优选，所述盐酸盐晶型J的X射线粉末衍射图具有衍射角2θ为7.0°±0.2°，10.5°±0.2°，14.1°±0.2°，17.6°±0.2°，19.0°±0.2°，24.9°±0.2°，26.1°±0.2°的特征峰；
更优选地，所述盐酸盐晶型J的X射线粉末衍射图具有衍射角2θ为7.0°±0.2°，10.5°±0.2°，14.1°±0.2°，17.6°±0.2°，19.0°±0.2°，21.4°±0.2°，24.9°±0.2°，26.1°±0.2°，28.2°±0.2°的特征峰；
作为优选，所述盐酸盐晶型J具有基本上如图42所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型J具有基本上如图43所示的差示扫描量热图谱和热重分析图。
式I化合物盐酸盐晶型K：
作为优选，所述盐酸盐晶型K的X射线粉末衍射图具有衍射角2θ为6.9°±0.2°，7.6°±0.2°，11.4°±0.2°，17.9°±0.2°，18.8°±0.2°，19.6°±0.2°的特征峰；
更优选地，所述盐酸盐晶型K的X射线粉末衍射图具有衍射角2θ为6.9°±0.2°，7.6°±0.2°，11.4°±0.2°，12.9°±0.2°，14.5°±0.2°，16.0°±0.2°，17.6°±0.2°，17.9°±0.2°，18.8°±0.2°，19.6°±0.2°的特征峰；
作为优选，所述盐酸盐晶型K具有基本上如图44所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型K具有基本上如图45所示的差示扫描量热图谱和热重分析图。
式I化合物盐酸盐晶型L：
作为优选，所述盐酸盐晶型L的X射线粉末衍射图具有衍射角2θ为6.1°±0.2°，11.4°±0.2°，15.0°±0.2°，15.4°±0.2°，18.9°±0.2°的特征峰；
更优选地，所述盐酸盐晶型L的X射线粉末衍射图具有衍射角2θ为6.1°±0.2°，11.4°±0.2°，15.0°±0.2°，15.4°±0.2°，18.9°±0.2°，21.4°±0.2°，22.3°±0.2°，23.0°±0.2°，23.8°±0.2°的特征峰；
作为优选，所述盐酸盐晶型L具有基本上如图46所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型L具有基本上如图47所示的热重分析图。
式I化合物盐酸盐晶型M：
作为优选，所述盐酸盐晶型M的X射线粉末衍射图具有衍射角2θ为7.1°±0.2°，9.7°±0.2°，10.4°±0.2°，14.2°±0.2°，15.4°±0.2°，19.4°±0.2°，20.1°±0.2°，21.4°±0.2°，22.1°±0.2°的特征峰；
更优选地，所述盐酸盐晶型M的X射线粉末衍射图具有衍射角2θ为7.1°±0.2°，9.7°±0.2°，10.4°±0.2°，11.0°±0.2°，14.2°±0.2°，15.4°±0.2°，19.4°±0.2°，20.1°±0.2°，21.4°±0.2°，22.1°±0.2°，26.6°±0.2°的特征峰；
作为优选，所述盐酸盐晶型M具有基本上如图48所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型M具有基本上如图49所示的差示扫描量热图谱和热重分析图。
式I化合物盐酸盐晶型N：
作为优选，所述盐酸盐晶型N的X射线粉末衍射图具有衍射角2θ为6.4°±0.2°，11.1°±0.2°，12.8°±0.2°，15.7°±0.2°，16.2°±0.2°，16.6°±0.2°，18.7°±0.2°，20.7°±0.2°，22.1°±0.2°，23.1°±0.2°，23.9°±0.2°的特征峰；
更优选地，所述盐酸盐晶型N的X射线粉末衍射图具有衍射角2θ为6.4°±0.2°，11.1°±0.2°，，11.4°±0.2°，11.9°±0.2°，12.8°±0.2°，15.7°±0.2°，16.2°±0.2°，16.6°±0.2°，18.7°±0.2°，19.2°±0.2°，20.7°±0.2°，22.1°±0.2°，23.1°±0.2°，23.9°±0.2°的特征峰；
作为优选，所述盐酸盐晶型N具有基本上如图50所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型N具有基本上如图51所示的差示扫描量热图谱和热重分析图。
式I化合物盐酸盐晶型O：
作为优选，所述盐酸盐晶型O的X射线粉末衍射图具有衍射角2θ为8.0°±0.2°，10.6°±0.2°，12.1°±0.2°，12.3°±0.2°，14.8°±0.2°，15.5°±0.2°，16.6°±0.2°，19.3°±0.2°，20.5°±0.2°，22.5°±0.2°，23.9°±0.2°的特征峰；
更优选地，所述盐酸盐晶型O的X射线粉末衍射图具有衍射角2θ为8.0°±0.2°， 10.6°±0.2°，12.1°±0.2°，12.3°±0.2°，13.6°±0.2°，14.8°±0.2°，15.5°±0.2°，16.6°±0.2°，19.3°±0.2°，20.5°±0.2°，21.3°±0.2°，22.5°±0.2°，23.9°±0.2°，25.9°±0.2°的特征峰；
作为优选，所述盐酸盐晶型O具有基本上如图52所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型O具有基本上如图53所示的差示扫描量热图谱和热重分析图。
式I化合物盐酸盐晶型P：
作为优选，所述盐酸盐晶型P的X射线粉末衍射图具有衍射角2θ为7.3°±0.2°，9.1°±0.2°，14.7°±0.2°，15.6°±0.2°，19.3°±0.2°，21.4°±0.2°的特征峰；
作为优选，所述盐酸盐晶型P具有基本上如图54所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型P具有基本上如图55所示的差示扫描量热图谱和热重分析图。
式I化合物盐酸盐晶型Q：
作为优选，所述盐酸盐晶型Q的X射线粉末衍射图具有衍射角2θ为8.5°±0.2°，10.9°±0.2°，12.4°±0.2°，15.3°±0.2°，15.9°±0.2°，19.6°±0.2°，20.1°±0.2°，20.6°±0.2°，21.6°±0.2°，22.9°±0.2°，24.0°±0.2°的特征峰；
更优选地，所述盐酸盐晶型Q的X射线粉末衍射图具有衍射角2θ为8.5°±0.2°，10.9°±0.2°，12.4°±0.2°，15.3°±0.2°，15.9°±0.2°，16.6°±0.2°，17.6°±0.2°，18.6°±0.2°，19.6°±0.2°，20.1°±0.2°，20.6°±0.2°，21.6°±0.2°，22.9°±0.2°，24.0°±0.2°的特征峰；
作为优选，所述盐酸盐晶型Q具有基本上如图56所示的X射线粉末衍射图；
进一步地，所述盐酸盐晶型Q具有基本上如图57所示的差示扫描量热图谱和热重分析图。
式I化合物盐酸盐晶型R：
作为优选，所述盐酸盐晶型R的X射线粉末衍射图具有衍射角2θ为6.7°±0.2°，7.8°±0.2°，12.9°±0.2°，15.7°±0.2°，18.8°±0.2°，19.1°±0.2°的特征峰；
更优选地，所述盐酸盐晶型R的X射线粉末衍射图具有衍射角2θ为6.7°±0.2°，7.8°±0.2°，9.6°±0.2°，10.9°±0.2°，12.9°±0.2°，15.7°±0.2°，18.8°±0.2°，19.1°±0.2°，19.5°±0.2°，20.2°±0.2°的特征峰；
作为优选，所述盐酸盐晶型R具有基本上如图58所示的X射线粉末衍射图。
式I化合物的不同晶型示范性举例如下：
式I化合物晶型A：
作为优选，所述式I化合物晶型A的X射线粉末衍射图具有衍射角2θ为6.4°±0.2°，15.5°±0.2°，16.3°±0.2°，18.0°±0.2°，18.7°±0.2°，23.5°±0.2°的特征峰；
作为优选，所述式I化合物晶型A具有基本上如图59所示的X射线粉末衍射图；
进一步地，所述式I化合物晶型A具有基本上如图60所示的差示扫描量热图谱和热重分析图。
式I化合物晶型B：
作为优选，所述式I化合物晶型B的X射线粉末衍射图具有衍射角2θ为5.3°±0.2°，6.5°±0.2°，7.7°±0.2°，13.3°±0.2°，14.9°±0.2°，16.2°±0.2°，19.9°±0.2°，26.1°±0.2°，29.4°±0.2°的特征峰；
作为优选，所述式I化合物晶型B具有基本上如图61所示的X射线粉末衍射图；
进一步地，所述式I化合物晶型B具有基本上如图62所示的差示扫描量热图谱和热重分析图。
式I化合物晶型C：
作为优选，所述式I化合物晶型C的X射线粉末衍射图具有衍射角2θ为5.9°±0.2°，6.7°±0.2°，14.1°±0.2°，15.1°±0.2°，17.5°±0.2°，18.0°±0.2°，20.5°±0.2°的特征峰；
作为优选，所述式I化合物晶型C具有基本上如图63所示的X射线粉末衍射图；
进一步地，所述式I化合物晶型C具有基本上如图64所示的差示扫描量热图谱和热重分析图。
式I化合物晶型D：
作为优选，所述式I化合物晶型D的X射线粉末衍射图具有衍射角2θ为5.5°±0.2°，14.7°±0.2°，15.4°±0.2°，16.5°±0.2°，17.5°±0.2°，21.7°±0.2°的特征峰；
更优选地，所述式I化合物晶型D的X射线粉末衍射图具有衍射角2θ为5.5°±0.2°，8.0°±0.2°，14.2°±0.2°，14.7°±0.2°，15.4°±0.2°，16.5°±0.2°，17.5°±0.2°，18.0°±0.2°，19.7°±0.2°，21.7°±0.2°的特征峰；
作为优选，所述式I化合物晶型D具有基本上如图65所示的X射线粉末衍射图；
进一步地，所述式I化合物晶型D具有基本上如图66所示的热重分析图。
式I化合物晶型E：
作为优选，所述式I化合物晶型E的X射线粉末衍射图具有衍射角2θ为5.3°±0.2°，7.4°±0.2°，8.9°±0.2°，12.9°±0.2°，14.7°±0.2°，17.2°±0.2°，17.9°±0.2°，21.3°±0.2°，21.8°±0.2°的特征峰；
作为优选，所述式I化合物晶型E具有基本上如图67所示的X射线粉末衍射图；
进一步地，所述式I化合物晶型E具有基本上如图68所示的差示扫描量热图谱和热重分析图。
式I化合物晶型F：
作为优选，所述式I化合物晶型F的X射线粉末衍射图具有衍射角2θ为6.6°±0.2°，15.9°±0.2°，16.2°±0.2°，17.7°±0.2°，21.6°±0.2°，23.4°±0.2°，29.5°±0.2°的特征峰；
作为优选，所述式I化合物晶型F具有基本上如图69所示的X射线粉末衍射图；
进一步地，所述式I化合物晶型F具有基本上如图70所示的差示扫描量热图谱和热重分析图。
式I化合物晶型G：
作为优选，所述式I化合物晶型G的X射线粉末衍射图具有衍射角2θ为5.8°±0.2°，8.0°±0.2°，14.6°±0.2°，15.2°±0.2°，15.9°±0.2°，17.2°±0.2°，17.9°±0.2°的特征峰；
作为优选，所述式I化合物晶型G具有基本上如图71所示的X射线粉末衍射图；
进一步地，所述式I化合物晶型G具有基本上如图72所示的热重分析图。
式I化合物晶型H：
作为优选，所述式I化合物晶型H的X射线粉末衍射图具有衍射角2θ为5.8°±0.2°，13.0°±0.2°，14.3°±0.2°，14.8°±0.2°，16.3°±0.2°，17.3°±0.2°，17.9°±0.2°，21.9°±0.2°的特征峰；
更优选地，所述式I化合物晶型H的X射线粉末衍射图具有衍射角2θ为5.8°±0.2°，7.4°±0.2°，13.0°±0.2°，14.3°±0.2°，14.8°±0.2°，16.3°±0.2°，17.3°±0.2°，17.9°±0.2°，21.9°±0.2°，22.5°±0.2°的特征峰；
作为优选，所述式I化合物晶型H具有基本上如图73所示的X射线粉末衍射图；
进一步地，所述式I化合物晶型H具有基本上如图74所示的差示扫描量热图谱和热重分析图。
式I化合物晶型I：
作为优选，所述式I化合物晶型I的X射线粉末衍射图具有衍射角2θ为4.0°±0.2°，7.5°±0.2°，10.1°±0.2°，14.7°±0.2°，15.1°±0.2°，17.8°±0.2°，18.9°±0.2°的特征峰；
作为优选，所述式I化合物晶型I具有基本上如图75所示的X射线粉末衍射图；
进一步地，所述式I化合物晶型I具有基本上如图76所示的热重分析图。
式I化合物晶型J：
作为优选，所述式I化合物晶型J的X射线粉末衍射图具有衍射角2θ为6.4°±0.2°，8.0°±0.2°，14.7°±0.2°，16.0°±0.2°，17.5°±0.2°，22.4°±0.2°的特征峰；
更优选地，所述式I化合物晶型J的X射线粉末衍射图具有衍射角2θ为6.4°±0.2°，8.0°±0.2°，14.7°±0.2°，16.0°±0.2°，16.7°±0.2°，17.5°±0.2°，20.5°±0.2°，22.4°±0.2°的特征峰；
作为优选，所述式I化合物晶型J具有基本上如图77所示的X射线粉末衍射图；
进一步地，所述式I化合物晶型J具有基本上如图78所示的差示扫描量热图谱和热重分析图。
本发明进一步提供了式I化合物的无定型物，其X射线粉末衍射图谱无明显的尖锐衍射峰；
作为优选，其X射线粉末衍射图基本上如图79所示。
本发明进一步提供了化合物S2或S3或S21或S22的中间体：
Figure PCTCN2022138399-appb-000003
本发明进一步提供了化合物S2或S3或S21或S22或式I化合物或式I化合物甲磺酸盐晶型A的制备方法，包括如下步骤：
化合物S2由化合物S1制备得到；
Figure PCTCN2022138399-appb-000004
化合物S1在醋酸钾、水和醋酸的作用下，制备得到化合物S2；和/或
化合物S3由化合物S2制备得到；
Figure PCTCN2022138399-appb-000005
化合物S2在氧化剂过氧硫酸氢钾复合盐的作用下，制备得到化合物S3；
进一步地，化合物S2先溶解在1,4-二氧六环溶液中再与过氧硫酸氢钾复合盐反应；
进一步地，过氧硫酸氢钾复合盐以混合液的形式参与反应；
进一步地，过氧硫酸氢钾复合盐的混合液通过如下方式制备：将过氧硫酸氢钾复合盐加入水中制得；和/或
化合物S21由化合物S3制备得到；
Figure PCTCN2022138399-appb-000006
以化合物S3和DHP为原料，在四氢呋喃和对甲苯磺酸的存在下，制备得到化合物S21；和/或
化合物S22由化合物S21制备得到；
Figure PCTCN2022138399-appb-000007
以化合物S21和化合物S04为原料，在乙腈和DIPEA的存在下，反应制得化合物S22；和/或
式I化合物由化合物S22制备得到；
Figure PCTCN2022138399-appb-000008
化合物S22先在氯化氢-1,4-二氧六环溶液的作用下，然后再在碳酸氢钠水溶液作用下制备得到式I化合物；
进一步地，所述步骤1在二氯甲烷和甲醇的存在下进行反应；
进一步地，所述步骤2在甲醇的存在下进行反应；和/或
式I化合物甲磺酸盐晶型A由式I化合物制备得到：
Figure PCTCN2022138399-appb-000009
以四氢呋喃/水为溶剂，式I化合物和甲磺酸在40至80℃温度下搅拌8-24个小时，经过滤、干燥，制备得到式I化合物甲磺酸盐晶型A；
进一步地，四氢呋喃/水的体积比为10-30:1；优选地，所述体积比为15-25:1；更优选地，所述体积比为19:1；
进一步地，温度为45-55℃；更优选地，温度为50℃；
进一步地，式I化合物和甲磺酸的物料摩尔比：0.8-1.2:优选地，所述物料摩尔比为0.9-1.1；更优选地，所述物料摩尔比为1-1；
进一步地，先在溶剂中加入式I化合物后搅拌溶清，再加入甲磺酸；所述搅拌溶清在40-60℃下进行。
本发明进一步提供了式I化合物甲磺酸盐晶型D的制备方法，其由式I化合物制备得到：
Figure PCTCN2022138399-appb-000010
以乙醇/水为溶剂，式I化合物和甲磺酸在20至60℃温度下反应0.5-3小时，经过滤、干燥，制备得到式I化合物甲磺酸盐晶型D；
进一步地，乙醇/水的体积比为10-30:1；优选地，所述体积比为15-25:1；更优选地，所述体积比为19:1；
进一步地，温度为30-50℃；更优选地，温度为40℃；
进一步地，式I化合物和甲磺酸的物料摩尔比：0.8-1.2；优选地，所述物料摩尔比为 0.9-1.1；更优选地，所述物料摩尔比为1-1；
进一步地，式I化合物和甲磺酸反应后搅拌，搅拌时间为1-24小时，搅拌温度在15-30℃下进行；优选地，所述搅拌时间为4小时，搅拌温度为室温。
本发明进一步提供了式I化合物甲磺酸盐晶型A的另一种制备方法，其由如下方法制备得到：
Figure PCTCN2022138399-appb-000011
①以四氢呋喃/水为溶剂，式I化合物在40至80℃温度下搅拌溶清，加入相对于式I化合物当量为0.1-0.3的甲磺酸；
②在保持反应温度下，加入前述制备得到的甲磺酸晶型D的晶种，继续加入相对于式I化合物当量为0.7-0.9的甲磺酸，降温，反应1-12小时，过滤，得到晶型D；
③将得到的晶型D和溶剂在40至80℃下混合，再加入前述制备得到的晶型A的晶种，保温反应至固体全部转化为晶型A；降温，过滤制备得到晶型A。
进一步地，步骤①中，四氢呋喃/水的体积比为10-30:1；优选地，所述体积比为15-25:1；更优选地，所述体积比为19:1。
进一步地，步骤①中，搅拌温度为45至55℃；更优选地，温度为50℃。
进一步地，步骤①中，甲磺酸的投料量为相对于式I化合物的0.1-0.3当量；步骤②中，甲磺酸的投料量为相对于式I化合物的0.7-0.9当量；
进一步地，步骤③中，所述溶剂为乙酸乙酯和水；优选地，所述溶剂中乙酸乙酯和水的体积比为10-20：1；更优选地，所述溶剂中乙酸乙酯和水的体积比为13-18：1；更优选地，所述溶剂的加入顺序为先加入乙酸乙酯，再加入水。
根据本发明，所述式I化合物的晶型以及其盐型晶型的晶体纯度优选大于50％，例如85％以上、95％以上、99％以上或99.5％以上。
本发明进一步提供了一种药物组合物，其含有治疗有效量的本发明所述的式I化合物的晶型、各盐型或其相应的晶型，和药学上可接受的辅料、辅助剂或载体。在上述药物组合物中，所述式I化合物的晶型、各盐型或其相应的晶型和所述辅料、辅助剂或载体的重量比范围是0.0001～10。
其次，本发明还提供了上述药物组合物的优选实施方式。
作为优选，上述药物组合物含有治疗有效量的本发明所述的式I化合物的晶型、各盐型或其相应的晶型，联用至少一种其他的活性成分。
作为优选，所述药物组合物用于口服给药。
作为优选，所述药物组合物用于片剂或胶囊。
作为优选，所述药物组合物含有0.01重量％-99重量％的本发明所述的式I化合物的晶型、各盐型或其相应的晶型。
作为优选，所述药物组合物含有0.05重量％-50重量％的本发明所述的式I化合物的晶型、各盐型或其相应的晶型。
作为优选，所述药物组合物含有0.1重量％-30重量％的本发明所述的式I化合物的晶型、各盐型或其相应的晶型。
本发明进一步提供了所述的式I化合物的晶型、各盐型或其相应的晶型或药物组合物在制备药物中的应用。
本发明进一步提供了所述应用的优选技术方案：
作为优选，所述应用为治疗、预防、延迟或阻止癌症或癌症转移的发生或进展。
作为优选，所述应用为制备治疗或预防由SHP2介导的疾病的药物。
作为优选，所述疾病是癌症。
作为优选，所述癌症选自Noonan综合征、豹斑综合征、少年骨髓单核细胞白血病、神经母细胞瘤、黑素瘤、头颈部鳞状细胞癌、急性髓细胞性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、胃癌、淋巴瘤、成胶质细胞瘤和/或胰腺癌。
作为优选，所述应用为用作SHP2抑制剂。
本发明还提供了一种在治疗对象上施用治疗有效量的至少任意一种本发明所述的式I化合物的晶型、各盐型或其相应的晶型或药物组合物治疗和/或预防由SHP2介导的疾病的方法。
作为优选，在上述方法中，所述由SHP2介导的疾病是癌症。
作为优选，在上述方法中，所述癌症选自Noonan综合征、豹斑综合征、少年骨髓单核细胞白血病、神经母细胞瘤、黑素瘤、头颈部鳞状细胞癌、急性髓细胞性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、胃癌、淋巴瘤、成胶质细胞瘤和/或胰腺癌。
本发明还提供了一种治疗癌症的方法，包括向治疗对象施用治疗有效量的至少任意一种本发明所述的式I化合物的晶型、各盐型或其相应的晶型或药物组合物，所述癌症选自Noonan综合征、豹斑综合征、少年骨髓单核细胞白血病、神经母细胞瘤、黑素瘤、头颈 部鳞状细胞癌、急性髓细胞性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、胃癌、淋巴瘤、成胶质细胞瘤和/或胰腺癌。
作为优选，在上述方法中，所述的治疗对象为人类。
本发明中，“具有约如图1所示的X射线粉末衍射图”或“其X射线粉末衍射图基本上如图1所示”中所使用的术语“约”和“基本上”是表示附图中的峰的精确位置不应当被解释为绝对值。因为本领域技术人员可知，X射线粉末衍射图的2θ值可能会由于不同的测量条件(如所使用的设备和仪器)和不同的样品而产生误差，X射线粉末衍射图的衍射角的测量误差为5％或更小，通常，给定的值的±0.2°的差别会被认为是恰当的。还应理解，峰值的相对强度可能随实验条件和样品制备诸如颗粒在样品中的优选的取向而波动。自动或固定的发散狭缝的使用也将会影响相对强度的计算。在这里所包括的X射线粉末衍射图所示强度只是示例性的，不能被用作绝对比较。
本领域的技术人员应理解，由于样品纯度、样品制备以及测量条件(例如加热速率)的变化，由DSC测量的数据可能会发生小的变化。应当理解，通过其它种类的仪器或通过使用不同于那些在下文中描述的条件，可能会给出可替换的熔点的读数。因此，本申请所引用的吸热图并不作为绝对值，且当解释DSC数据时将考虑这样的测量误差。
附图说明
图1：式I化合物甲磺酸盐晶型A的X射线粉末衍射图；
图2：式I化合物甲磺酸盐晶型A的差示扫描量热图谱；
图3：式I化合物甲磺酸盐晶型A的热重分析图谱；
图4：式I化合物甲磺酸盐晶型A的 1H-NMR图谱；
图5：式I化合物甲磺酸盐晶型D的不对称单位的立体结构图；
图5-1：式I化合物甲磺酸盐晶型D的晶胞堆积图；
图6：式I化合物甲磺酸盐晶型D的X射线粉末衍射图；
图7：式I化合物甲磺酸盐晶型D的差示扫描量热图谱和热重分析图谱的叠图；
图8：式I化合物甲磺酸盐晶型D的 1H-NMR图谱；
图9：式I化合物苯磺酸盐晶型A的X射线粉末衍射图；
图10：式I化合物苯磺酸盐晶型A的差示扫描量热图谱和热重分析图谱的叠图；
图11：式I化合物苯磺酸盐晶型A的 1H-NMR图谱；
图12：式I化合物对甲苯磺酸盐晶型A的X射线粉末衍射图；
图13：式I化合物对甲苯磺酸盐晶型A的差示扫描量热图谱和热重分析图谱的叠图；
图14：式I化合物对甲苯磺酸盐晶型A的 1H-NMR图谱；
图15：式I化合物L-乳酸盐晶型A的X射线粉末衍射图；
图16：式I化合物L-乳酸盐晶型A的差示扫描量热图谱和热重分析图谱的叠图；
图17：式I化合物L-乳酸盐晶型A的 1H-NMR图谱；
图18：式I化合物L-酒石酸盐晶型A的X射线粉末衍射图；
图19：式I化合物L-酒石酸盐晶型A的热重分析图谱；
图20：式I化合物L-酒石酸盐晶型A的 1H-NMR图谱；
图21：式I化合物富马酸盐晶型A的X射线粉末衍射图；
图22：式I化合物富马酸盐晶型A的热重分析图谱；
图23：式I化合物富马酸盐晶型A的 1H-NMR图谱；
图24：式I化合物L-苹果酸盐晶型A的X射线粉末衍射图；
图25：式I化合物L-苹果酸盐晶型A的差示扫描量热图谱和热重分析图谱的叠图；
图26：式I化合物L苹果酸盐晶型A的 1H-NMR图谱；
图27：式I化合物盐酸盐晶型A的X射线粉末衍射图；
图28：式I化合物盐酸盐晶型A的差示扫描量热图谱和热重分析图谱的叠图；
图29：式I化合物盐酸盐晶型B的X射线粉末衍射图；
图30：式I化合物盐酸盐晶型B的差示扫描量热图谱和热重分析图谱的叠图；
图31：式I化合物盐酸盐晶型D的X射线粉末衍射图；
图32：式I化合物盐酸盐晶型D的差示扫描量热图谱和热重分析图谱的叠图；
图33：式I化合物盐酸盐晶型E的X射线粉末衍射图；
图34：式I化合物盐酸盐晶型E的热重分析图谱；
图35：式I化合物盐酸盐晶型F的X射线粉末衍射图；
图36：式I化合物盐酸盐晶型G的X射线粉末衍射图；
图37：式I化合物盐酸盐晶型G的差示扫描量热图谱和热重分析图谱的叠图；
图38：式I化合物盐酸盐晶型H的X射线粉末衍射图；
图39：式I化合物盐酸盐晶型H的差示扫描量热图谱和热重分析图谱的叠图；
图40：式I化合物盐酸盐晶型I的X射线粉末衍射图；
图41：式I化合物盐酸盐晶型I的差示扫描量热图谱和热重分析图谱的叠图；
图42：式I化合物盐酸盐晶型J的X射线粉末衍射图；
图43：式I化合物盐酸盐晶型J的差示扫描量热图谱和热重分析图谱的叠图；
图44：式I化合物盐酸盐晶型K的X射线粉末衍射图；
图45：式I化合物盐酸盐晶型K的差示扫描量热图谱和热重分析图谱的叠图；
图46：式I化合物盐酸盐晶型L的X射线粉末衍射图；
图47：式I化合物盐酸盐晶型L的热重分析图谱；
图48：式I化合物盐酸盐晶型M的X射线粉末衍射图；
图49：式I化合物盐酸盐晶型M的差示扫描量热图谱和热重分析图谱的叠图；
图50：式I化合物盐酸盐晶型N的X射线粉末衍射图；
图51：式I化合物盐酸盐晶型N的差示扫描量热图谱和热重分析图谱的叠图；
图52：式I化合物盐酸盐晶型O的X射线粉末衍射图；
图53：式I化合物盐酸盐晶型O的差示扫描量热图谱和热重分析图谱的叠图；
图54：式I化合物盐酸盐晶型P的X射线粉末衍射图；
图55：式I化合物盐酸盐晶型P的差示扫描量热图谱和热重分析图谱的叠图；
图56：式I化合物盐酸盐晶型Q的X射线粉末衍射图；
图57：式I化合物盐酸盐晶型Q的差示扫描量热图谱和热重分析图谱的叠图；
图58：式I化合物盐酸盐晶型R的X射线粉末衍射图；
图59：式I化合物晶型A的X射线粉末衍射图；
图60：式I化合物晶型A的差示扫描量热图谱和热重分析图谱的叠图；
图61：式I化合物晶型B的X射线粉末衍射图；
图62：式I化合物晶型B的差示扫描量热图谱和热重分析图谱的叠图；
图63：式I化合物晶型C的X射线粉末衍射图；
图64：式I化合物晶型C的差示扫描量热图谱和热重分析图谱的叠图；
图65：式I化合物晶型D的X射线粉末衍射图；
图66：式I化合物晶型D的热重分析图谱；
图67：式I化合物晶型E的X射线粉末衍射图；
图68：式I化合物晶型E的差示扫描量热图谱和热重分析图谱的叠图；
图69：式I化合物晶型F的X射线粉末衍射图；
图70：式I化合物晶型F的差示扫描量热图谱和热重分析图谱的叠图；
图71：式I化合物晶型G的X射线粉末衍射图；
图72：式I化合物晶型G的热重分析图谱；
图73：式I化合物晶型H的X射线粉末衍射图；
图74：式I化合物晶型H的差示扫描量热图谱和热重分析图谱的叠图；
图75：式I化合物晶型I的X射线粉末衍射图；
图76：式I化合物晶型I的热重分析图谱；
图77：式I化合物晶型J的X射线粉末衍射图；
图78：式I化合物晶型J的差示扫描量热图谱和热重分析图谱的叠图；
图79：式I化合物无定型物的X射线粉末衍射图。
除非另有说明，本发明所用到的检测仪器信息和检测方法参数如表2-表5所示：
表2
Figure PCTCN2022138399-appb-000012
表3
设备名称 热重分析仪(TGA)
设备型号 Discovery TGA 550
样品盘 铂金坩埚+铝坩埚
保护气体 氮气
气体流速(样品吹扫) 40mL/min
气体流速(天平) 60mL/min
升温速率 10℃/min
表4
设备名称 差示扫描量热仪(DSC)
设备型号 Discovery DSC 2500
样品盘 铝坩埚
保护气体 氮气
气体流速 50mL/min
升温速率 10℃/min
表5
Figure PCTCN2022138399-appb-000013
具体实施方式
下面通过给出的各实施例和实验例对本发明作出进一步说明，但所述实施例和实验例并不能对本发明要求保护的范围构成任何限制。在本发明的具体实施例中，除非特别说明，所述技术或方法为本领域的常规技术或方法等。
缩略语：
DHP：3,4-二氢-2H-吡喃；
DIPEA：N,N-二异丙基乙胺；
DMSO：二甲基亚砜；
DSC：差示扫描量热；
DVS：动态蒸汽吸附仪；
EtOAc或EA：乙酸乙酯；
h：小时；
min：分钟；
MsOH：甲磺酸；
NMP：N-甲基吡咯烷酮；
XRPD：X射线粉末衍射；
1H-NMR：核磁共振氢谱；
TGA：热重分析；
PK：药代动力学。
实施例1式I化合物无定型物的制备方法
Figure PCTCN2022138399-appb-000014
步骤一：化合物S2的制备
Figure PCTCN2022138399-appb-000015
20L反应釜中加入801.11g化合物S1、2492.50g醋酸钾、80g纯化水和8L醋酸，搅拌升温至110±5℃，反应3小时，HPLC检测反应至结束。
体系降温至50℃，搅拌下将反应液加入纯化水(36.00L)中，搅拌30分钟，过滤，滤饼用纯化水(1.00L)淋洗。滤饼转入反应釜中，加入纯化水(10.00L)室温打浆0.5小时，过滤，滤饼用纯化水(2.00L)淋洗。滤饼室温自然干燥48小时得S2粗品，粗品用乙酸乙酯(2.00L)打浆1小时，过滤，滤饼用乙酸乙酯(0.30L)淋洗。滤饼室温自然干燥4小时，得S2固体701.35g，收率：92.91％。
步骤二：化合物S3的制备
Figure PCTCN2022138399-appb-000016
50L反应釜中加入701.23g S2和11.20L 1,4-二氧六环，搅拌降温；将1185.75g过氧硫酸氢钾复合盐加入2.80L水中，搅拌5分钟，备用。反应体系温度降至12℃，分批加入过氧硫酸氢钾复合盐混合液，过程控制温度不大于20℃。加入完毕保持温度10-20℃反应4小时，HPLC检测反应至结束。
停止反应，向反应釜中加入纯化水(7.50L)和二氯甲烷(7.50L)，搅拌10分钟，静止分层。分液，水相用二氯甲烷(4.00L)萃取一遍。合并有机相，依次用0.5M硫代硫酸钠水溶液(1.00L)、纯化水(7.00L)、纯化水(7.00L)、饱和氯化钠水溶液(7.00L)洗涤，然后用无水硫酸钠和无水硫酸镁干燥。过滤，滤液浓缩，得到S3的粗品。粗品用四氢呋喃(2.20L)打浆18小时，过滤，滤饼用四氢呋喃(1.00L)淋洗。滤饼真空25℃干燥3小时，得S3固体472.31g，收率：63.93％。
步骤三：化合物S21的制备
Figure PCTCN2022138399-appb-000017
10L反应釜中依次加入4.72L四氢呋喃、472.31g S3、252.69g DHP和25.86g对甲苯磺酸，搅拌升温至70℃，保温反应3小时，HPLC检测至反应结束。
体系降温至32℃，浓缩至干。然后加入二氯甲烷(4.50L)，搅拌溶解。有机相依次用纯化水(3.00L)和饱和氯化钠水溶液(4.00L)洗涤，无水硫酸钠干燥。过滤，滤液浓缩至干得S21粗品。
步骤四：化合物S22的制备
Figure PCTCN2022138399-appb-000018
搅拌下，依次向20L反应釜中加入6L乙腈、598.52g S21、552.38g S04和129.24g DIPEA，然后升温至80℃，保持温度反应21小时，HPLC检测至反应结束。
降温至60℃，浓缩。蒸出约3.00L乙腈，然后加入3.00L NMP。搅拌下，将混合液 倒入纯化水(28.00L)中。搅拌20分钟，过滤。滤饼用纯化水(1.00L)淋洗。滤饼转入反应釜中，加入纯化水(8.00L)室温打浆0.5小时，过滤，滤饼用纯化水(2.00L)淋洗。滤饼室温自然干燥72小时，得S22粗品。粗品加入四氢呋喃(2.00L)打浆18小时，过滤，滤饼用正庚烷(1.00L)淋洗。滤饼室温自然干燥得S22固体726.40g。
步骤五：式I化合物无定型物的制备
Figure PCTCN2022138399-appb-000019
搅拌下，向20L反应釜中加入724.31g S22和5.79L二氯甲烷，待体系溶清后过滤，滤液转移回20L反应釜中。搅拌，加入1.45L甲醇。滴加氯化氢-1,4-二氧六环溶液(1.13L)，控制温度不大于25℃。搅拌反应2小时，HPLC检测至反应结束。
浓缩至干，然后加入甲醇(0.70L)，将固体全部溶解。搅拌下，将上述混合液滴加入二氯甲烷(36.00L)中。加入完毕，搅拌20分钟。过滤，滤饼用二氯甲烷(2.00L)淋洗。滤饼室温自然干燥15小时，得固体570.39g。
向50L反应釜中加入甲醇(5.70L)，然后加入上述固体(570.39g)，搅拌溶解，过滤。滤液转移回20L反应釜中；搅拌，加入纯化水(1.00L)。分批加入1M碳酸氢钠水溶液(5.56L)，再加入纯化水(7.00L)稀释，搅拌30分钟。过滤，纯化水(1.00L)淋洗。滤饼转入反应釜中，加入纯化水(7.00L)室温打浆20分钟，过滤，纯化水(2.00L)淋洗。滤饼室温自然干燥48小时，得式I化合物固体426.22g。经XRPD测定，终产品为无定型物。
实施例2-1式I化合物甲磺酸盐晶型A的制备
Figure PCTCN2022138399-appb-000020
向500mL反应瓶中加入300mL四氢呋喃/水(19:1，v/v)混合溶剂，再加入10g式I化合物无定型物，升温到50℃搅拌溶清。加入2.33g甲磺酸，50℃搅拌过夜，过滤得到固体，并于40℃下真空干燥4小时，经XRPD、TGA、DSC以及 1H-NMR测定，终产品为式I化合物甲磺酸盐晶型A。同样的方法制备更多的甲磺酸盐晶型A备用。
实施例2-2式I化合物甲磺酸晶型D的制备
Figure PCTCN2022138399-appb-000021
称取1.00g式I化合物无定型物和242mg甲磺酸，加入到10mL乙醇/水(19:1，v/v)混合溶剂中，置于40℃温度下反应1小时，室温搅拌4小时，过滤得到固体，并于40℃下真空干燥4小时，经XRPD、TGA、DSC、 1H-NMR和单晶衍射测定，终产品为式I化合物甲磺酸盐晶型D。同样的方法制备更多的甲磺酸盐晶型D备用。
实施例2-3式I化合物甲磺酸盐晶型A的制备
Figure PCTCN2022138399-appb-000022
向10L反应釜中，加入四氢呋喃(4.47L)和水(0.24L)，开启搅拌，升温至50℃。然后加入375.50g式I化合物无定型物。搅拌溶清，趁热过滤，将滤液转移到10L反应釜中。称取16.04g甲磺酸溶于四氢呋喃(0.94L)中，滴加到反应液中，约30分钟滴加完毕。
称取7.51g甲磺酸盐晶型D加入，析出白色浑浊，保持反应液50℃。再将72.10g甲磺酸溶于四氢呋喃(3.76L)中，滴加到反应液中，约3小时滴加完毕。降温至20℃左右反应2小时，过滤。滤饼用四氢呋喃(0.40L)淋洗。滤饼50℃真空干燥14小时得到甲磺酸盐晶型D 353.24g。
向10L反应釜中，加入乙酸乙酯(5.70L)，搅拌，升温至50℃。然后加入上述样品(350.52g)，悬浮搅拌，再加入0.35L的纯化水，搅拌均匀后，再加入7.10g甲磺酸盐晶型A。保持50℃反应，XRPD检测至固体全部转化为甲磺酸盐晶型A，降温至20℃，熟化1小时后抽滤，滤饼用乙酸乙酯(0.35L)淋洗，滤饼50℃真空干燥14小时得到固体352.16g。经XRPD、TGA、DSC以及 1H-NMR测定，终产品为式I化合物甲磺酸盐晶型A。
实施例3式I化合物苯磺酸盐晶型A的制备
称取约300mg的式I化合物无定型物和230mg苯磺酸，加入6mL乙醇/水(19:1,v/v)溶剂，置于50℃温度下，磁力搅拌过夜后，过滤得到固体，并于40℃下真空干燥2小 时，再室温干燥过夜，经XRPD、TGA、DSC以及 1H-NMR测定，终产品为苯磺酸盐晶型A。
实施例4式I化合物对甲苯磺酸盐晶型A的制备
称取约200mg的式I化合物无定型物和168.13mg对甲苯磺酸，加入3mL乙醇溶剂，置于室温下，磁力搅拌过夜后升温至35℃搅拌过夜，离心得到固体，并于50℃下真空干燥4小时，经XRPD、TGA、DSC以及 1H-NMR测定，终产品为对甲苯磺酸盐晶型A。
实施例5式I化合物L-乳酸盐晶型A的制备
称取约300mg的式I化合物无定型物和123mg L-乳酸，加入6mL乙醇溶剂，置于50℃下，磁力搅拌过夜后，置于0℃冷却，再室温搅拌析出固体，离心分离得到固体，并于40℃下真空干燥3小时，经XRPD、TGA、DSC以及 1H-NMR测定，终产品为L-乳酸盐晶型A。
实施例6式I化合物L-酒石酸盐晶型A的制备
称取约200mg的式I化合物无定型物和144.37mg L-酒石酸，加入4mL乙醇溶剂，置于室温下，磁力搅拌过夜后，升温至35℃搅拌过夜，离心得到固体，并于50℃下真空干燥4小时，经XRPD、TGA、DSC以及 1H-NMR测定，终产品为L-酒石酸盐晶型A。
实施例7式I化合物富马酸盐晶型A的制备
称取约200mg的式I化合物无定型物和109.41mg富马酸，加入4mL乙酸乙酯溶剂，置于室温下，磁力搅拌过夜后，升温至35℃搅拌过夜，离心得到固体，并于50℃下真空干燥4小时，经XRPD、TGA、DSC以及 1H-NMR测定，终产品为富马酸盐晶型A。
实施例8式I化合物L-苹果酸盐晶型A的制备
称取约200mg的式I化合物无定型物和126.30mg L-酒石酸，加入3mL乙酸乙酯溶剂，置于室温下，磁力搅拌过夜后，升温至35℃搅拌过夜，离心得到固体，并于50℃下真空干燥4小时，经XRPD、TGA、DSC以及 1H-NMR测定，终产品为L-苹果酸盐晶型A。
实施例9式I化合物盐酸盐晶型A的制备
称取约100mg式I化合物无定型物，加入2mL盐酸稀释液(87mg浓HCl溶液溶于4mL H 2O)，室温悬浮搅拌24h后离心分离，固体室温真空干燥4小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型A。
实施例10式I化合物盐酸盐晶型B的制备
称取约20mg式I化合物无定型物，加入0.5mL盐酸稀释液(87mg浓HCl溶液溶于5mL丙酮/水(19:1，体积比))，室温悬浮搅拌48h后离心分离，固体室温真空干燥4小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型B。
实施例11式I化合物盐酸盐晶型D的制备
称取约20mg式I化合物无定型物，加入0.5mL盐酸稀释液(87mg浓HCl溶液溶于5mL THF/H 2O(19:1,v/v))，室温悬浮搅拌48h后离心分离，固体室温真空干燥4小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型D。
实施例12式I化合物盐酸盐晶型E的制备
称取约100mg式I化合物无定型物，加入2mL盐酸稀释液(182mg浓HCl溶液溶于4mL EtOH/H 2O(19:1,v/v))，室温悬浮搅拌2天后离心分离，固体室温真空干燥4小时，经XRPD和TGA测定，终产品为盐酸盐晶型E。
实施例13式I化合物盐酸盐晶型F的制备
称取约100mg式I化合物无定型物，加入2mL盐酸稀释液(87mg浓HCl溶液溶于4mL THF/H 2O(19:1,v/v))，室温悬浮搅拌24h后离心分离，经XRPD测定，终产品为盐酸盐晶型F。
实施例14式I化合物盐酸盐晶型G的制备
称取约50mg式I化合物无定型物，加入1mL盐酸稀释液(163mg浓HCl溶液溶于5mL THF/H 2O(19:1,v/v))，室温悬浮搅拌24h后离心分离，固体室温真空干燥4小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型G。
实施例15式I化合物盐酸盐晶型H的制备
称取约25mg式I化合物无定型物，加入0.5mL MEK，再加入50μL 4M的盐酸甲醇溶液，室温悬浮搅拌48h后离心分离，固体室温真空干燥4小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型H。
实施例16式I化合物盐酸盐晶型I的制备
称取约20mg盐酸盐晶型B样品，加入0.4mL乙腈/水(19:1,v/v)混合溶液，室温悬浮搅拌5天后离心分离，固体室温真空干燥4小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型I。
实施例17式I化合物盐酸盐晶型J的制备
称取约20mg盐酸盐晶型B样品，加入0.4mL水，室温悬浮搅拌5天后离心分离， 固体室温真空干燥4小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型J。
实施例18式I化合物盐酸盐晶型K的制备
称取约25mg式I化合物无定型物，加入0.5mL IPA，再加入50μL 4M的盐酸甲醇溶液，室温悬浮搅拌48h后离心分离，固体室温真空干燥4小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型K。
实施例19式I化合物盐酸盐晶型L的制备
称取约100mg盐酸盐晶型E样品置于60℃鼓风干燥箱中敞口放置10天，经XRPD和TGA测定，终产品为盐酸盐晶型L。
实施例20式I化合物盐酸盐晶型M的制备
称取约15mg盐酸盐晶型G样品，溶于0.2mL甲醇，缓慢滴加到0.8mL乙酸乙酯中，得到浑浊液离心分离，固体室温真空干燥4小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型M。
实施例21式I化合物盐酸盐晶型N的制备
称取约25mg盐酸盐晶型E样品，加入0.4mL MIBK溶液，50℃悬浮搅拌7天后离心分离，固体室温真空干燥3小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型N。
实施例22式I化合物盐酸盐晶型O的制备
称取约25mg盐酸盐晶型E样品，加入0.4mL异丙醇溶液，50℃悬浮搅拌7天后离心分离，固体室温真空干燥3小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型O。
实施例23式I化合物盐酸盐晶型P的制备
称取约25mg盐酸盐晶型E样品，加入0.4mL环己烷溶液，50℃悬浮搅拌7天后离心分离，固体室温真空干燥3小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型P。
实施例24式I化合物盐酸盐晶型Q的制备
称取约25mg盐酸盐晶型E样品，加入0.4mL甲醇溶液，50℃悬浮搅拌7天后离心分离，固体室温真空干燥3小时，经XRPD、TGA和DSC测定，终产品为盐酸盐晶型Q。
实施例25式I化合物盐酸盐晶型R的制备
称取约500mg盐酸盐晶型D样品，加入10mL乙酸乙酯，60℃悬浮搅拌过夜后抽 滤，固体45℃真空干燥2小时，经XRPD测定，终产品为盐酸盐晶型R。
实施例26式I化合物晶型A的制备
称取约15mg式I化合物无定型物，加入到0.3mL甲醇中室温搅拌4小时后离心分离，干燥，经XRPD、TGA和DSC测定，终产品为式I化合物晶型A。
实施例27式I化合物晶型B的制备
称取约15mg式I化合物无定型物，加入到0.3mL乙醇中室温搅拌4小时后离心分离，干燥，经XRPD、TGA和DSC测定，终产品为式I化合物晶型B。
实施例28式I化合物晶型C的制备
称取约15mg式I化合物无定型物，加入到0.3mL丙酮中室温搅拌4小时后离心分离，干燥，经XRPD、TGA和DSC测定，终产品为式I化合物晶型C。
实施例29式I化合物晶型D的制备
称取约15mg式I化合物无定型物，加入到0.3mL丁酮中室温搅拌4小时后离心分离，干燥，经XRPD和TGA测定，终产品为式I化合物晶型D。
实施例30式I化合物晶型E的制备
称取约15mg式I化合物无定型物，加入到0.3mL乙酸乙酯中室温搅拌4小时后离心分离，干燥，经XRPD、TGA和DSC测定，终产品为式I化合物晶型E。
实施例31式I化合物晶型F的制备
称取约15mg式I化合物无定型物，加入到0.3mL四氢呋喃中室温搅拌4小时后离心分离，干燥，经XRPD、TGA和DSC测定，终产品为式I化合物晶型F。
实施例32式I化合物晶型G的制备
称取约15mg式I化合物无定型物，加入到0.3mL乙腈中室温搅拌4小时后离心分离，干燥，经XRPD和TGA测定，终产品为式I化合物晶型G。
实施例33式I化合物晶型H的制备
称取约15mg式I化合物无定型物，加入到0.3mL乙腈/水(19:1,v/v)中室温搅拌4小时后离心分离，干燥，经XRPD、TGA和DSC测定，终产品为式I化合物晶型H。
实施例34式I化合物晶型I的制备
称取约15mg式I化合物无定型物，加入到0.3mL乙醇/水(19:1,v/v)中室温搅拌4小时后离心分离，干燥，经XRPD和TGA测定，终产品为式I化合物晶型I。
实施例35式I化合物晶型J的制备
称取约15mg式I化合物无定型物，加热到220℃，经XRPD、TGA和DSC测定， 终产品为式I化合物晶型J。
实施例36离子色谱测定
取约20mg甲磺酸盐晶型A配成浓度为0.1mg/mL的溶液，以无甲磺酸钠为对照品，通过离子色谱测定甲磺酸盐晶型A中甲磺酸的含量，结果如表6所示。
表6
Figure PCTCN2022138399-appb-000023
结果表明，甲磺酸盐中甲磺酸的理论含量与甲磺酸盐晶型A中甲磺酸的实际测得含量的比为1:1.05，证明甲磺酸盐晶型A为单甲磺酸盐。
实施例37单晶衍射实验
照《中国药典》2020年版四部通则0451第一法测定，测试条件：CuKα辐射，
Figure PCTCN2022138399-appb-000024
扫描。单晶衍射仪器设备信息如表8所示。
单晶衍射实验结果：甲磺酸盐晶型D单晶数据如表9所示，其不对称单位的立体结构图如图5所示，其晶胞堆积图如图5-1所示。
表7单晶衍射仪器设备信息
Figure PCTCN2022138399-appb-000025
表8式I化合物甲磺酸盐晶型D的单晶数据
Figure PCTCN2022138399-appb-000026
实施例38式I化合物甲磺酸盐晶型A/D转化关系
称取一定量的甲磺酸盐晶型A样品，分别加入四氢呋喃和乙腈，悬浮搅拌过夜，过滤得到饱和溶液。分别向饱和溶液中加入5mg晶型A和5mg晶型D样品，置于5℃/25℃/60℃下搅拌，取样检测XRPD，结果如表9所示。
表9
Figure PCTCN2022138399-appb-000027
结果显示：在5℃-60℃之间，甲磺酸盐晶型A较甲磺酸盐晶型D热力学稳定。
实施例39纯度测定
取实施例2-1、2-2、实施例3至实施例8方法制得的晶型化合物，经由HPLC测定纯度。结果如下：
化合物晶型 供试品 纯度(％)
甲磺酸盐晶型A 实施例2-1 99.58
甲磺酸盐晶型D 实施例2-2 99.92
苯磺酸盐晶型A 实施例3 97.96
对甲苯磺酸盐晶型A 实施例4 97.84
L-乳酸盐晶型A 实施例5 98.66
L-酒石酸盐晶型A 实施例6 98.44
富马酸盐晶型A 实施例7 93.21
L-苹果酸盐晶型A 实施例8 97.64
令人惊讶地，相比其他晶型，甲磺酸盐晶型A和甲磺酸盐晶型D获得了意料不到的提纯效果，即可以更高纯度被制得。可见，甲磺酸盐晶型A和甲磺酸盐晶型D适宜用以制备更加稳定的高质量药物。
实施例40稳定性的测定
测定本发明的晶型的稳定性。将甲磺酸盐晶型A、甲磺酸盐晶型D、苯磺酸盐晶型A、对甲苯磺酸盐晶型A、L-乳酸盐晶型A、L-酒石酸盐晶型A、富马酸盐晶型A和L-苹果 酸盐晶型A分别置于4500Lux光照环境、60℃高温环境和90％RH±5％RH高湿环境下进行稳定性测试，于第0天、第5天、第10天和第30天取样，所取样品记录外观性状、水分含量、总相关物质，并与初始数据比较。比较结果发现，甲磺酸盐晶型A、甲磺酸盐晶型D、苯磺酸盐晶型A、对甲苯磺酸盐晶型A、L-乳酸盐晶型A、L-酒石酸盐晶型A、富马酸盐晶型A和L-苹果酸盐晶型A具有较好的稳定性，尤其是甲磺酸盐晶型A、甲磺酸盐晶型D具有更好的稳定性。
实施例41溶解度的测定
分别称取约10mg式I化合物的甲磺酸盐晶型A、苯磺酸盐晶型A、对甲苯磺酸盐晶型A、L-酒石酸盐晶型A、富马酸盐晶型A、L-苹果酸盐晶型A和盐酸盐晶型N，加入0.8mL人工胃液或纯化水，悬浮液置37℃恒温摇床中振摇24h，取母液检测浓度。结果见表10。
表10不同晶型的溶解度测定结果
Figure PCTCN2022138399-appb-000028
实施例42动态水分吸附(DVS)的测定
本发明的动态吸附仪检测设备和方法如表11所示，动态水分吸附测定结果如表12所示。
表11动态水分吸附仪检测设备和方法数据
设备名称 动态蒸汽吸附仪
厂家 Surface Measurement Systems
设备型号 DVS Resolution
样品盘 铝坩埚
检测样品量 30-50mg
保护气体 氮气
气体流速 200sccm
表12动态水分吸附测定结果
Figure PCTCN2022138399-appb-000029
由检测结果可知，甲磺酸盐晶型D在0％RH至80％RH范围内重量变化为0.11％，为无或几乎无引湿性，在吸湿性方面具有突出的优势；且相较其他晶型的吸湿性数据而言，甲磺酸盐晶型A也具有明显优势。
实施例43体内药代动力学(PK)对比实验
实验方法：使用雄性大鼠15只，分为五组，每组3只，分别单次灌胃10mg/kg式(I)化合物的甲磺酸盐晶型A、对甲苯磺酸盐晶型A、L-乳酸盐晶型A、L-酒石酸盐晶型A、L-苹果酸盐晶型A和盐酸盐晶型J，分别在指定的时间点(15min、30min、1h、2h、4h、7h和24h)通过眼底静脉丛采血，分离血浆，放入-80℃冰箱保存。
取30或50μL血浆加到200uL含内标乙腈中沉淀，离心，取上清液100μL，加水100μL混匀，取10μL至LC-MS/MS检测，试验数据如表13所示：
表13体内药代动力学对比实验结果
化合物 剂量(mg/kg) C max(ng/mL) AUC last(h*ng/mL)
甲磺酸盐晶型A 10 1177 5489
对甲苯磺酸盐晶型A 10 1255 5613
L-乳酸盐晶型A 10 1613 7916
L-酒石酸盐晶型A 10 979 5328
L-苹果酸盐晶型A 10 1887 9387
盐酸盐晶型J 10 2277 9317
结果发现，上述晶型在体内的生物利用度高，满足药物开发的需要。
药理实验
实施例A：SHP2变构抑制酶活测定
SHP2通过双-酪氨酰-磷酰化的肽与其Src同源2(SH2)结构域的结合而变构活化。该在后的活化步骤导致SHP2的自动抑制界面的释放，这又使该SHP2蛋白酪氨酸磷酸酶(PTP)活化并可用于底物识别和反应催化。在迅速荧光测定版式中使用替代物DiFMUP监测SHP2的催化活性。
试验步骤：
(1)化合物配制：
用100％DMSO将本发明化合物(10mM储液)稀释成合适倍数，本发明化合物最终测试浓度为1μM,0.333μM,0.111μM,0.0370μM,0.0124μM,0.00412μM,0.00137μM,0.00046μM,0.00015μM,0.00μM；
(2)准备酶反应工作液：
在室温下在96孔黑色聚苯乙烯板(平底、低凸缘、非结合表面)(Perki Elmer,Cat#6005270)中，使用50μL的最终反应体积和以下测定缓冲条件进行SHP2酶活检测：60mM HEPES，75mM NaCl，75mM KCl，0.05％BRIJ-35，1mM EDTA，5mM DTT。
(3)酶催化反应及数据监测：
取本发明化合物加到对应的96孔板中，设置不加化合物和酶只加缓冲液的做为空白试验孔。将SHP2Activating Peptide(IRS1_pY1172(dPEG8)pY1222)置于冰上融化，每孔加入0.5μM，然后取0.2ng SHP2蛋白样品加到对应孔板中，室温孵育1小时。加入底物DiFMUP(Invitrogen，Cat#D6567)加入反应，室温反应1小时后。采用分别使用340nM和450nM的激发波长和发射波长的酶标仪(Envision，Perki Elmer)监测荧光信号。
(4)数据分析：
计算公式：
抑制率％＝[1-(Conversion_ sample-Conversion_ min)/(Conversion_ max-Conversion_ min)]×100％
其中：Conversion_sample是样品的转化率读数；Conversion_min是空白对照孔均值，代表没有酶活孔的转化率读数；Conversion_max是阳性对照孔比值均值，代表没有化合物抑制孔的转化率读数。
采用分析软件GraphPad Prism的log(inhibitor)vs.response-Variable slope拟合量效曲线，并计算化合物对酶活性的IC 50值。经测定，本发明中式I化合物对SHP2的IC 50为0.9nM。
实施例B：细胞增殖试验
使用体外细胞试验评估本发明的化合物对白血病细胞MV-4-11和肺癌细胞NCI-H358增 殖的影响。试验中所用的检测方法是CELL TITER-GLO(CTG)发光法，该法可通过对ATP进行定量测定来检测活细胞数目。因为ATP参与生物体内多种酶促反应，是活细胞新陈代谢的一个指标，其含量直接反应了细胞的数量及细胞状态，实验过程中向细胞培养基加入CellTiter-Glo TM试剂，测量发光值，发光值与ATP量成正比，而ATP又和活细胞数正相关，因此可通过检测ATP含量考察细胞活力。
试验步骤：
(1)细胞铺板：
取一瓶对数生长期的MV-4-11细胞，离心重悬细胞后计数，调整细胞密度后接种到96孔板(Corning#3917)中，每孔接种4000个细胞，孔板置于37℃、5％CO 2的培养箱中培养24小时后加入本发明化合物进行处理；
取一瓶对数生长期的NCI-H358细胞，消化重悬细胞后计数，调整细胞密度后接种到96孔透明超低吸附细胞培养板(Corning#3474)中，每孔接种2000个细胞，孔板置于37℃、5％CO 2的培养箱中培养24小时后加入本发明化合物进行处理；
(2)细胞化合物处理：
配取适量本发明化合物进行细胞处理，化合物终浓度从高至低依次为1000nM、333.3nM、111.1nM、37.04nM、12.35nM、4.115nM、1.372nM、0.4572nM、0.1524nM、0nM，孔板放入37℃，5％CO 2培养箱培养120小时。只加培养基不加细胞孔设为空白组；化合物浓度为0nM组为调零组。
(3)CTG检测：
NCI-H358细胞培养96小时后每孔加入50μL的
Figure PCTCN2022138399-appb-000030
Luminescent Cell Viability Assay溶液，轻轻震荡2分钟，室温继续孵育10分钟。细胞反应体系转移至白底96孔板中。在多功能酶标仪上读取各孔的检测数值。
MV-4-11细胞培养120hrs后每孔加入50μL的
Figure PCTCN2022138399-appb-000031
Luminescent Cell Viability Assay溶液，轻轻震荡2分钟，室温继续孵育10分钟，在多功能酶标仪上读取各孔的检测数值。
(4)数据分析：
根据发光值读数计算抑制率，
抑制率％＝(1-(给药组值-空白组值)/(调零组值-空白组值)×100
GraphPad Prism的log(inhibitor)vs.response-Variable slope拟合量效曲线并计算化合物抑制细胞增殖的IC 50。本发明中式I化合物对MV-4-11细胞IC 50值和对NCI-H358细胞IC 50值均 小于20nM。
实施例C膜片钳实验评估化合物对hERG离子通道的作用
测试溶液配方：
用细胞外液将供试品稀释液依次稀释，配成终浓度0.3μM、1μΜ、3μΜ、10μΜ和30μΜ的检测液。目测待测样品的溶解性。
细胞培养与铺板：
细胞株来源于HEK293细胞，培养于在37℃、5％CO 2培养箱中。为防止接触抑制导致细胞衰老，细胞培养融合度应不超80％时，每3/4天传代一次，每T175瓶接种密度为2*10 6个细胞。先用磷酸盐缓冲液(PBS)预清洗，然后用胰蛋白酶/EDTA消化细胞2-3分钟，加入细胞培养基终止消化，转移至新培养瓶子。
过表达hERG钾离子通道HEK293细胞，细胞密度低于50％，培养过夜。将实验用细胞转移到一个嵌于倒置显微镜平台(Diaphot,Nikon)的细胞浴槽中，灌流细胞外液。细胞外液含有137mM NaCl,4mM KCl,1.8mM CaCl 2,1mM MgCl 2,10mM glucose and 10mM HEPES(pH 7.4 with NaOH)，灌流速度为4ml/分钟。内管液含有130mM KCl,1mM MgCl 2,5mM EGTA,5mM MgATP and 10mM HEPES(pH 7.2 with KOH)。采用HEKA EPC-10膜片钳放大器和PATCHMASTER采集系统记录膜电流(HEKA Instruments Inc.,D-67466 Lambrecht，Pfalz，Germany)。所有实验均在室温(22-23℃)下完成。
实验中使用P-97微电极拉制仪(Sutter Instrument Company，One DigitalDrive，Novato，CA 94949)拉直电极(BF150-86-10)。电极内径为1-1.5mm，充满内液后的入水电阻为2-4MΩ。
电生理刺激方案：
当形成全细胞封接后，等待电流稳定2分钟(5分钟内电流衰减小于5％，尾电流值大于500pA)，此时尾电流峰值即为对照电流值。接着灌流含待测药物的细胞外液。同样的程序重复3～5次，使每个细胞暴露于4～6个浓度递增的化合物中。连续记录化合物暴露和冲洗过程中阻断和解除hERG的过程。
当形成全细胞封接后细胞膜电压钳制于-80mV，每12秒进行2秒的去极化，钳制电压由-80mV除极至-50mV，在-50mv的5秒复极化脉冲下测量尾电流峰值。
参数分析：
在-50mv的5秒复极化脉冲下测量hERG尾电流峰值。将每一个药物浓度于电流抑 制率绘制成化合物浓度对数的函数。用以下Hill方程拟合浓度响应曲线，拟合IC 50。
Figure PCTCN2022138399-appb-000032
Y：测试数值；Bottom：最低测试值(0)；Top：最高测试值(1)；Hillcoefficient：曲线斜率的最大绝对值。
数据分析与统计
实验数据使用PATCHMASTER(HEKA Instruments Inc.,D-67466 Lambrecht，Pfalz，Germany)采集，并采用Origin(OriginLab Corporation，Northampton，MA)进行分析和统计。
数据以平均值±标准差的方式呈现。采用t-Test检验，与对照组相比是否具有显著性差异，当p<0.05，认为具有显著性差异。
经测定，本发明中式I化合物的hERG IC 50值为9.5μM。
实施例D：人和大鼠肝微粒体的体外代谢稳定性
测试缓冲液配制:
将1900mg MgCl 2溶解到400mL的超纯水中。
分别将17.42g K 2HPO 4和13.65g KH 2PO 4溶解到1000mL的超纯水中。将一定比例的K 2HPO 4和KH 2PO 4混合，调节pH值为7.30±0.10。
反应终止液配制：
配制含10ng/mL拉贝洛尔和10ng/mL格列本脲的乙腈溶液，并储存于4℃。
化合物工作液配制：
用DMSO配制10mM维拉帕米(阳性对照)和供试品储备液。然后用MeOH/ACN/H 2O溶液(体积比为1:1:2)，分别稀释成50μM和200μM的工作液。
试验步骤：
1)将40μL MgCl 2和306μL PBS加入96个板孔中(同时设置空白对照组、阳性对照组、待测化合物样品组、阴性对照组)
2)向每孔中加入4μL化合物工作液(空白组对应加入4μL PBS缓冲液)(注：DMSO体积在体系中的终浓度≤0.5％)
3)每孔中加入10μL肝微粒体(浓度：20mg/mL)，混匀，于37℃条件下预孵育10分钟。
4)向每孔中添加40μL 10mM NADPH工作溶液以开始反应(空白对照组和阴性对照组分别加入等体积的PBS缓冲液)，总反应体积为400μL。
5)分别在0、5、15、45分钟时从上述反应溶液中取出50μL样品，并加入400μL反应终止液终止反应
6)将终止反应后的样品于振荡器上振荡5分钟。
7)将样品于3200rcf条件下离心10分钟，离心完成后，取50μL上清液转移至200μL H 2O中稀释，用于LC-MS/MS分析。
数据分析
使用一阶动力学方程式进行t 1/2和CL int的计算：
k＝-slope
t 1/2＝0.693/k
CL int＝k/C protein
式中，k表示消除常数，由剩余百分比与时间的对数线性图计算得出。t 1/2代表半衰期。C protein是肝微粒体的浓度。式I化合物在人、大鼠上的肝微粒体代谢稳定性结果见表14。
表14式I化合物在人、大鼠上的肝微粒体代谢稳定性数据
Figure PCTCN2022138399-appb-000033

Claims (68)

  1. 一种式I所示化合物的盐型：
    Figure PCTCN2022138399-appb-100001
  2. 权利要求1所述的式I所示化合物的盐型，其特征在于，所述盐型为甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、L-乳酸盐、L-酒石酸盐、富马酸盐、L-苹果酸盐和盐酸盐。
  3. 权利要求1或2所述的式I所示化合物的盐型，其特征在于，所述盐型为甲磺酸盐。
  4. 权利要求1-3中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为晶型。
  5. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为甲磺酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为7.2°±0.2°，10.0°±0.2°，14.5°±0.2°，23.5°±0.2°的特征峰。
  6. 权利要求1-5中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为甲磺酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为7.2°±0.2°，10.0°±0.2°，14.5°±0.2°，16.9°±0.2°，23.5°±0.2°的特征峰。
  7. 权利要求1-6中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为甲磺酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为5.6°±0.2°，7.2°±0.2°，10.0°±0.2°，14.5°±0.2°，16.9°±0.2°，19.8°±0.2°，20.6°±0.2°，22.5°±0.2°，23.5°±0.2°的特征峰。
  8. 权利要求1-7中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为甲磺酸盐晶型A，其X射线粉末衍射图基本上如表1所示。
  9. 权利要求1-8中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为甲磺酸盐晶型A，其X射线粉末衍射图基本上如图1所示。
  10. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为甲磺酸盐晶型D，其X射线粉末衍射图具有衍射角2θ为5.7°±0.2°，16.4°±0.2°，19.3°±0.2°，20.1°±0.2°，22.9°±0.2°的特征峰。
  11. 权利要求1-4或10中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为甲磺酸盐晶型D，其X射线粉末衍射图具有衍射角2θ为5.7°±0.2°，11.9°±0.2°， 16.4°±0.2°，17.3°±0.2°，19.3°±0.2°，20.1°±0.2°，22.9°±0.2°，26.1°±0.2°的特征峰。
  12. 权利要求1-4或10-11中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为甲磺酸盐晶型D，其X射线粉末衍射图基本上如图6所示。
  13. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为苯磺酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为8.4°±0.2°，11.0°±0.2°，14.2°±0.2°，16.8°±0.2°，17.4°±0.2°，18.8°±0.2°，25.6°±0.2°的特征峰。
  14. 权利要求1-4或13中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为苯磺酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为6.2°±0.2°，8.4°±0.2°，11.0°±0.2°，11.8°±0.2°，13.8°±0.2°，14.2°±0.2°，15.9°±0.2°，16.8°±0.2°，17.4°±0.2°，18.8°±0.2°，25.6°±0.2°的特征峰。
  15. 权利要求1-4或13-14中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为苯磺酸盐晶型A，其X射线粉末衍射图基本上如图9所示。
  16. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为对甲苯磺酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为6.0°±0.2°，10.4°±0.2°，14.2°±0.2°，18.7°±0.2°，22.3°±0.2°的特征峰。
  17. 权利要求1-4或16中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为对甲苯磺酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为6.0°±0.2°，10.4°±0.2°，11.2°±0.2°，12.4°±0.2°，13.0°±0.2°，14.2°±0.2°，18.3°±0.2°，18.7°±0.2°，22.3°±0.2°的特征峰。
  18. 权利要求1-4或16-17中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为对甲苯磺酸盐晶型A，其X射线粉末衍射图基本上如图12所示。
  19. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为L-乳酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为6.2°±0.2°，6.7°±0.2°，12.2°±0.2°，13.9°±0.2°，18.5°±0.2°，21.0°±0.2°，25.6°±0.2°的特征峰。
  20. 权利要求1-4或19中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为L-乳酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为6.2°±0.2°，6.7°±0.2°，12.2°±0.2°，13.9°±0.2°，17.2°±0.2°，17.9°±0.2°，18.5°±0.2°，21.0°±0.2°，25.1°±0.2°，25.6°±0.2°的特征峰。
  21. 权利要求1-4或19-20中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为L-乳酸盐晶型A，其X射线粉末衍射图基本上如图15所示。
  22. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为L-酒石酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为5.9°±0.2°，12.6°±0.2°，15.8°±0.2°，18.9°±0.2°，24.6°±0.2°的特征峰。
  23. 权利要求1-4或22中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为L-酒石酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为5.9°±0.2°，10.8°±0.2°，12.6°±0.2°，15.1°±0.2°，15.8°±0.2°，17.9°±0.2°，18.6°±0.2°，18.9°±0.2°，19.4°±0.2°，24.6°±0.2°，25.3°±0.2°的特征峰。
  24. 权利要求1-4或22-23中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为L-酒石酸盐晶型A，其X射线粉末衍射图基本上如图18所示。
  25. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为富马酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为7.5°±0.2°，15.0°±0.2°，16.2°±0.2°，17.3°±0.2°，22.8°±0.2°，28.7°±0.2°的特征峰。
  26. 权利要求1-4或25中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为富马酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为7.5°±0.2°，15.0°±0.2°，16.2°±0.2°，17.3°±0.2°，22.8°±0.2°，28.7°±0.2°，29.3°±0.2°的特征峰。
  27. 权利要求1-4或25-26中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为富马酸盐晶型A，其X射线粉末衍射图基本上如图21所示。
  28. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为L-苹果酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为5.1°±0.2°，10.2°±0.2°，17.2°±0.2°，20.6°±0.2°，23.0°±0.2°的特征峰。
  29. 权利要求1-4或28中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为L-苹果酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为5.1°±0.2°，6.1°±0.2°，10.2°±0.2°，16.2°±0.2°，17.2°±0.2°，20.6°±0.2°，23.0°±0.2°的特征峰。
  30. 权利要求1-4或28-29中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为L-苹果酸盐晶型A，其X射线粉末衍射图基本上如图24所示。
  31. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为6.9°±0.2°，10.4°±0.2°，16.2°±0.2°，16.9°±0.2°，18.1°±0.2°，18.6°±0.2°，19.5°±0.2°的特征峰。
  32. 权利要求1-4或31中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型A，其X射线粉末衍射图具有衍射角2θ为6.9°±0.2°，10.4°±0.2°， 13.9°±0.2°，14.2°±0.2°，15.5°±0.2°，16.2°±0.2°，16.9°±0.2°，17.5°±0.2°，18.1°±0.2°，18.6°±0.2°，19.5°±0.2°的特征峰。
  33. 权利要求1-4或31-32中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型A，其X射线粉末衍射图基本上如图27所示。
  34. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型I，其X射线粉末衍射图具有衍射角2θ为7.5°±0.2°，11.8°±0.2°，16.7°±0.2°，18.6°±0.2°，18.9°±0.2°，21.8°±0.2°的特征峰。
  35. 权利要求1-4或34中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型I，其X射线粉末衍射图具有衍射角2θ为7.5°±0.2°，10.7°±0.2°，11.8°±0.2°，16.7°±0.2°，18.6°±0.2°，18.9°±0.2°，21.8°±0.2°的特征峰。
  36. 权利要求1-4或34-35中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型I，其X射线粉末衍射图基本上如图40所示。
  37. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型J，其X射线粉末衍射图具有衍射角2θ为7.0°±0.2°，10.5°±0.2°，14.1°±0.2°，17.6°±0.2°，19.0°±0.2°，24.9°±0.2°，26.1°±0.2°的特征峰。
  38. 权利要求1-4或37中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型J，其X射线粉末衍射图具有衍射角2θ为7.0°±0.2°，10.5°±0.2°，14.1°±0.2°，17.6°±0.2°，19.0°±0.2°，21.4°±0.2°，24.9°±0.2°，26.1°±0.2°，28.2°±0.2°的特征峰。
  39. 权利要求1-4或37-38中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型J，其X射线粉末衍射图基本上如图42所示。
  40. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型L，其X射线粉末衍射图具有衍射角2θ为6.1°±0.2°，11.4°±0.2°，15.0°±0.2°，15.4°±0.2°，18.9°±0.2°的特征峰。
  41. 权利要求1-4或40中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型L，其X射线粉末衍射图具有衍射角2θ为6.1°±0.2°，11.4°±0.2°，15.0°±0.2°，15.4°±0.2°，18.9°±0.2°，21.4°±0.2°，22.3°±0.2°，23.0°±0.2°，23.8°±0.2°的特征峰。
  42. 权利要求1-4或40-41中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型L，其X射线粉末衍射图基本上如图46所示。
  43. 权利要求1-4中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型N，其X射线粉末衍射图具有衍射角2θ为6.4°±0.2°，11.1°±0.2°，12.8°±0.2°，15.7°±0.2°，16.2°±0.2°，16.6°±0.2°，18.7°±0.2°，20.7°±0.2°，22.1°±0.2°，23.1°±0.2°，23.9°±0.2°的特征峰。
  44. 权利要求1-4或43中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型N，其X射线粉末衍射图具有衍射角2θ为6.4°±0.2°，11.1°±0.2°，，11.4°±0.2°，11.9°±0.2°，12.8°±0.2°，15.7°±0.2°，16.2°±0.2°，16.6°±0.2°，18.7°±0.2°，19.2°±0.2°，20.7°±0.2°，22.1°±0.2°，23.1°±0.2°，23.9°±0.2°的特征峰。
  45. 权利要求1-4或43-44中任意一项所述的式I所示化合物的盐型，其特征在于，所述盐型为盐酸盐晶型N，其X射线粉末衍射图基本上如图50所示。
  46. 一种式I所示化合物的晶型：
    Figure PCTCN2022138399-appb-100002
  47. 权利要求46中所述的式I所示化合物的晶型，其特征在于，所述晶型为晶型D，其X射线粉末衍射图具有衍射角2θ为5.5°±0.2°，14.7°±0.2°，15.4°±0.2°，16.5°±0.2°，17.5°±0.2°，21.7°±0.2°的特征峰。
  48. 权利要求46或47所述的式I所示化合物的晶型，其特征在于，所述晶型为晶型D，其X射线粉末衍射图具有衍射角2θ为5.5°±0.2°，8.0°±0.2°，14.2°±0.2°，14.7°±0.2°，15.4°±0.2°，16.5°±0.2°，17.5°±0.2°，18.0°±0.2°，19.7°±0.2°，21.7°±0.2°的特征峰。
  49. 权利要求46-48中任意一项所述的式I所示化合物的晶型，其特征在于，所述晶型为晶型D，其X射线粉末衍射图基本上如图65所示。
  50. 权利要求46中所述的式I所示化合物的晶型，其特征在于，所述晶型为晶型H，其X射线粉末衍射图具有衍射角2θ为5.8°±0.2°，13.0°±0.2°，14.3°±0.2°，14.8°±0.2°，16.3°±0.2°，17.3°±0.2°，17.9°±0.2°，21.9°±0.2°的特征峰。
  51. 权利要求46或50所述的式I所示化合物的晶型，其特征在于，所述晶型为晶型H，其X射线粉末衍射图具有衍射角2θ为5.8°±0.2°，7.4°±0.2°，13.0°±0.2°，14.3°±0.2°，14.8°±0.2°，16.3°±0.2°，17.3°±0.2°，17.9°±0.2°，21.9°±0.2°，22.5°±0.2°的特征峰。
  52. 权利要求46、50或51中任意一项所述的式I所示化合物的晶型，其特征在于， 所述晶型为晶型H，其X射线粉末衍射图基本上如图73所示。
  53. 一种式I所示化合物的无定型物：其特征在于，所述X-射线粉末衍射图谱无明显的尖锐衍射峰；作为优选，其X射线粉末衍射图基本上如图79所示。
  54. 一种式I化合物的制备方法，其特征在于，由以下步骤制得：
    Figure PCTCN2022138399-appb-100003
    步骤1：化合物S1在醋酸钾、水和醋酸的作用下，制备得到化合物S2；
    步骤2：化合物S2在氧化剂过氧硫酸氢钾复合盐的作用下，制备得到化合物S3；
    步骤3：以化合物S3和DHP为原料，在四氢呋喃和对甲苯磺酸的存在下，制备得到化合物S21；
    步骤4：以化合物S21和化合物S04为原料，在乙腈和DIPEA的存在下，反应制得化合物S22；
    步骤5：化合物S22先在氯化氢-1,4-二氧六环溶液的作用下，然后再在碳酸氢钠水溶液作用下制备得到式I化合物。
  55. 权利要求5-9中任意一项所述的甲磺酸盐晶型A的制备方法，其特征在于，由以下步骤制得：
    Figure PCTCN2022138399-appb-100004
    以四氢呋喃/水为溶剂，式I化合物和甲磺酸在40至80℃温度下搅拌8-24个小时，经过滤、干燥，制备得到式I化合物甲磺酸盐晶型A。
  56. 权利要求10-12中任意一项所述的甲磺酸盐晶型D的制备方法，其特征在于，由以下步骤制得：
    Figure PCTCN2022138399-appb-100005
    以乙醇/水为溶剂，式I化合物和甲磺酸在20至60℃温度下反应0.5-3小时，经过滤、干燥，制备得到式I化合物甲磺酸盐晶型D。
  57. 权利要求5-9中任意一项所述的甲磺酸盐晶型A的制备方法，其特征在于，由以下步骤制得：
    Figure PCTCN2022138399-appb-100006
    ①以四氢呋喃/水为溶剂，式I化合物在40至80℃温度下搅拌溶清，加入相对于式I化合物当量为0.1-0.3的甲磺酸；
    ②在保持反应温度下，加入权利要求10-12任意一项所述的甲磺酸盐晶型D的晶种，继续加入相对于式I化合物当量为0.7-0.9的甲磺酸，降温，反应1-12小时，过滤，得到晶型D；
    ③将得到的甲磺酸盐晶型D和溶剂在40至80℃下混合，再加入权利要求5-9任意一项所述的甲磺酸盐晶型A的晶种，保温反应至固体全部转化为甲磺酸盐晶型A，降温，过滤制备得到甲磺酸盐晶型A。
  58. 一种药物组合物，其包含权利要求1-45中任一项所述的式I所示化合物的盐型或权利要求46-52中任一项所述的式I所示化合物的晶型或权利要求53所述的式I所示化合物的无定型物，以及至少一种药学上可接受的载体或赋形剂。
  59. 权利要求1-45中任一项所述的式I所示化合物的盐型或权利要求46-52中任一项所述的式I所示化合物的晶型或权利要求53所述的式I所示化合物的无定型物或权利要求58所述的药物组合物在制备药物中的用途。
  60. 权利要求59的用途，其特征在于，所述药物用于治疗、预防、延迟或预防癌症、癌症转移、心血管疾病、免疫疾病、纤维化或眼病。
  61. 权利要求59的用途，其特征在于，所述药物用于治疗由SHP2介导的疾病。
  62. 权利要求61所述的用途，其特征在于，所述疾病是癌症。
  63. 权利要求62所述的用途，其特征在于，所述癌症是Noonan综合征、豹斑综合征、少年骨髓单核细胞白血病、神经母细胞瘤、黑素瘤、头颈部鳞状细胞癌、急性髓细胞性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、胃癌、淋巴瘤、成胶质细胞瘤和/或胰腺癌。
  64. 权利要求1-45中任一项所述的式I所示化合物的盐型或权利要求46-52中任一项所述的式I所示化合物的晶型或权利要求53所述的式I所示化合物的无定型物或权利要求58所述的药物组合物在制备SHP2抑制剂中的用途。
  65. 一种用于治疗和/或预防由SHP2介导的疾病的方法，所述方法向有需要的患者施用1-45中任一项所述的式I所示化合物的盐型或权利要求45-52中任一项所述的式I所示化合物的晶型或权利要求53所述的式I所示化合物的无定型物或权利要求58所述的药物组合物。
  66. 权利要求65所述的方法，其特征在于，所述疾病是癌症。
  67. 一种治疗癌症的方法，所述方法为向有需要的患者施用权利要求1-45中任一项所述的式I所示化合物的盐型或权利要求46-52中任一项所述的式I所示化合物的晶型或权利要求53所述的式I所示化合物的无定型物或权利要求58所述的药物组合物。
  68. 权利要求66或67所述的方法，其特征在于，所述癌症是Noonan综合征、豹斑综合征、少年骨髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓细胞性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、胃癌、淋巴瘤、成胶质细胞瘤和/或胰腺癌。
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