WO2020043078A1 - 新型氮杂三环类化合物的盐型、晶型及其用途 - Google Patents

新型氮杂三环类化合物的盐型、晶型及其用途 Download PDF

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WO2020043078A1
WO2020043078A1 PCT/CN2019/102720 CN2019102720W WO2020043078A1 WO 2020043078 A1 WO2020043078 A1 WO 2020043078A1 CN 2019102720 W CN2019102720 W CN 2019102720W WO 2020043078 A1 WO2020043078 A1 WO 2020043078A1
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crystal form
cancer
salt
ray powder
powder diffraction
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PCT/CN2019/102720
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English (en)
French (fr)
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徐晓峰
王家炳
丁列明
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贝达药业股份有限公司
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Priority to EP19855166.5A priority Critical patent/EP3845534A4/en
Priority to KR1020217008050A priority patent/KR20210050530A/ko
Priority to CN201980055280.7A priority patent/CN112654623B/zh
Priority to US17/271,410 priority patent/US20210340142A1/en
Priority to JP2021510717A priority patent/JP2021535143A/ja
Publication of WO2020043078A1 publication Critical patent/WO2020043078A1/zh

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    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to 6- (2-chloro-3,5-dimethoxyphenyl) -N- (4- (4-morpholinylpiperidin-1-yl) phenyl)-[1,2,4 ] Triazolo [4 ′, 3 ′: 1,6] pyrido [2,3-d] pyrimidin-2-amine salt form, crystal form, preparation method of crystal form, and medicine containing said crystal form Compositions, use of said crystalline forms and pharmaceutical compositions as FGFR inhibitors, and methods of treating FGFR-mediated diseases.
  • Protein kinases are enzymes that catalyze the phosphorylation of proteins. In most cases, this phosphorylation occurs on ser, thr, and tyr residues of proteins. Many aspects of the cell's life course, such as cell growth, differentiation, proliferation, cell cycle, and survival, depend on the activity of protein kinases. Moreover, many diseases such as cancer and inflammation are associated with abnormalities in protein kinase activity.
  • PTK Protein Tyrosine Kinase
  • Fibroblast growth factor receptor belongs to the Receptor Tyrosine Kinase (RTK) superfamily, and has become one of the targets for the development of new anti-tumor drugs by global pharmaceutical companies.
  • FGFR is involved in the regulation of cell proliferation, apoptosis, migration, and neoangiogenesis. Due to its wide range of functions, FGFR and other RTKs are strictly regulated under normal circumstances.
  • tumors such as breast cancer, bladder cancer, and prostate cancer (currently developed indications)
  • FGFR activation mutations or ligand / receptor overexpression lead to continuous activation, which is not only closely related to tumor occurrence, development, and poor prognosis.
  • FGFR is recognized as an important target for anti-tumor, and the development of FGFR small molecule inhibitors has gradually received more and more attention.
  • Fibroblast growth factor (FGFs) signal activation and transmission FGFs can trigger autophosphorylation of FGFRs on tyrosine residues on key activation loops in the tyrosine kinase structure, leading to the tyrosine kinase domain from The non-activated state is transformed into an activated state (Bae, J, Schlessinger, J. Molecules and Cells, 2010, 29 (5): 443-448).
  • the activated tyrosine kinase domain in FGFRs gradually phosphorylates other tyrosine residues at the substrate binding site along the adaptor molecules bound by FGFRs.
  • Phosphorylation of tyrosine residues in the C-terminal region of FGFRs can absorb and activate phosphatase C ⁇ (PLC ⁇ ), thereby catalyzing the conversion of phosphatidylinositol diphosphate (PIP2) to diglyceride (DAG) and triphosphate Alcohol (IP3) (Dailey L, Ambrostti D, Mansukhani A, et al. Cytokine & Growth Factor Reviews, 2005, 16 (2), 233-247).
  • PLC ⁇ phosphatase C ⁇
  • PIP3 triphosphate Alcohol
  • FSS2 Activated FGFR phosphorylation substrate 2
  • GRB2 growth factor receptor binding protein 2
  • FGFs signals can be transmitted to Ras mitogen-activated protein kinase (Ras-MAPK) or PI3 kinase-protein kinase B (PI3K-AKT) signal pathway through FRS2 and GRB2, and transmitted to protein kinase C (PKC) or protein through PLC ⁇ and DAG.
  • Ras mitogen-activated protein kinase Ras mitogen-activated protein kinase
  • PI3K-AKT PI3 kinase-protein kinase B
  • PLC protein kinase C
  • the kinase D (PKD) signaling pathway is transmitted to the calcium ion release cascade via PLC ⁇ and IP3.
  • FGFs-induced Ras-MAPK activation is involved in cell proliferation, while FGFs-induced PI3K-AKT activation is involved in cell survival.
  • FGFs signals are involved in various aspects of tumor biology, such as anti-apoptosis, angiogenesis, epithelial to mesenchymal transition (EMT) or invasion
  • targeted therapy of FGFRs has become the field of clinical oncology
  • a hotspot, small molecule compounds designed and developed to fit the ATP-binding pocket in the tyrosine kinase domain have been used in cancer treatment.
  • FGFs signaling can inhibit angiogenesis while reducing the load on cancer cells
  • FGFR inhibitors can enhance cancer cells' resistance to conventional anticancer drugs such as 5-fluorouracil, Irinotecan, paclitaxel, etc.).
  • Polymorphs of specific organic drug compounds have different physical properties, such as solubility, hygroscopicity, and stability, due to their unique three-dimensional structures. However, it is often impossible to predict whether a particular organic drug compound will form a different crystalline form, and it is even more impossible to predict the structure and properties of the crystal form itself. Exploring new or polymorphic forms of pharmaceutically acceptable compounds offers opportunities to improve the overall performance of pharmaceutical products, while expanding the variety of materials available to formulation scientist designs. It is clearly advantageous to expand the variety of materials for formulation design as new crystal forms of useful compounds are discovered.
  • the present invention relates to compound 6- (2-chloro-3,5-dimethoxyphenyl) -N- (4- (4-morpholinylpiperidin-1-yl) phenyl)-[
  • the salt forms of 1,2,4] triazolo [4 ', 3': 1,6] pyrido [2,3-d] pyrimidin-2-amine and each salt form are substantially pure crystalline forms.
  • an acid and Compound I form the corresponding salts.
  • These salt-type compounds can exist in various physical forms. For example, it can be in solution, suspension or solid form.
  • the salt-type compound is in a solid form. When in solid form, the compound can be an amorphous, crystalline or mixture thereof.
  • the following exemplifies the salt forms formed by Compound I and nine acids.
  • the nine acids are maleic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, phosphoric acid, L-tartaric acid, L-malic acid, citric acid and fumaric acid.
  • the present invention provides a preferred crystal form of the maleate salt of the compound represented by the structural formula I.
  • the X-ray powder diffraction pattern of the crystal form has a diffraction angle 2 ⁇ of 5.6 ° ⁇ 0.2 °, 8.4 ° ⁇ 0.2 °, 11.2 ° ⁇ 0.2 °, 22.6 ° ⁇ 0.2 ° and 28.3 ° ⁇ 0.2 °.
  • the present invention is referred to as maleate crystal form 1.
  • the present invention provides another preferred crystal form of the maleate salt of the compound represented by the structural formula I.
  • the X-ray powder diffraction pattern of the crystal form has a characteristic peak with a diffraction angle 2 ⁇ of 5.9 ° ⁇ 0.2 °.
  • the present invention is referred to as maleate crystal form 2.
  • the present invention provides a preferred crystal form of the mesylate salt of the compound represented by the structural formula I.
  • the crystal form X-ray powder diffraction pattern has a diffraction angle 2 ⁇ of 4.7 ° ⁇ 0.2 °, 9.4 ° ⁇ 0.2 °, and 14.1 ° ⁇ 0.2. ° Characteristic peak.
  • the present invention is referred to as mesylate crystal form 1.
  • the present invention provides another preferred crystal form of the mesylate salt of the compound represented by the structural formula I.
  • the X-ray powder diffraction pattern of the crystal form has a diffraction angle 2 ⁇ of 3.9 ° ⁇ 0.2 °, 15.7 ° ⁇ 0.2 °, and 20.4 ° ⁇ 0.2 ° characteristic peak.
  • this invention is referred to as mesylate crystal form 2.
  • the present invention provides a preferred crystal form of the benzenesulfonate of the compound represented by the structural formula I.
  • the crystal form X-ray powder diffraction pattern has a diffraction angle 2 ⁇ of 4.5 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 °, 20.4 ° ⁇ 0.2 ° and 21.5 ° ⁇ 0.2 ° characteristic peaks.
  • the present invention is referred to as benzenesulfonate crystal form 1.
  • the present invention provides another preferred crystal form of the besylate salt of the compound represented by the structural formula I.
  • the crystal form X-ray powder diffraction pattern has a diffraction angle 2 ⁇ of 4.0 ° ⁇ 0.2 °, 4.9 ° ⁇ 0.2 °, 6.9 ° ⁇ Characteristic peaks of 0.2 ° and 18.4 ° ⁇ 0.2 °.
  • the present invention is referred to as benzenesulfonate crystal form 2.
  • the present invention provides a preferred crystal form of the hydrochloride salt of the compound represented by structural formula I.
  • the crystal form X-ray powder diffraction pattern has a diffraction angle 2 ⁇ of 4.2 ° ⁇ 0.2 °, 4.7 ° ⁇ 0.2 °, and 6.9 ° ⁇ 0.2 ° Characteristic peak.
  • the present invention is referred to as hydrochloride crystal form 1.
  • the present invention provides a preferred crystal form of the phosphate of the compound represented by the structural formula I.
  • the X-ray powder diffraction pattern of the crystal form has a diffraction angle 2 ⁇ of 7.5 ° ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, 16.4 ° ⁇ 0.2 °, Characteristic peaks of 18.9 ° ⁇ 0.2 ° and 26.8 ° ⁇ 0.2 °.
  • the present invention is referred to as phosphate crystal form 1.
  • the present invention provides a crystalline form of L-tartrate of a compound represented by structural formula I.
  • the X-ray powder diffraction pattern of the crystalline form has a diffraction angle 2 ⁇ of 7.6 ° ⁇ 0.2 °, 18.8 ° ⁇ 0.2 °, and 27.3 ° ⁇ 0.2 ° Characteristic peak.
  • the present invention is referred to as L-tartrate crystal form 1.
  • the present invention provides a preferred crystal form of the L-malate salt of the compound represented by the structural formula I.
  • the crystal form X-ray powder diffraction pattern has a diffraction angle 2 ⁇ of 3.6 ° ⁇ 0.2 °, 7.4 ° ⁇ 0.2 °, and 18.8 ° ⁇ 0.2 ° characteristic peak.
  • the present invention is referred to as L-malate crystal form 1.
  • the present invention provides a crystalline form of a citrate salt of a compound represented by structural formula I.
  • the X-ray powder diffraction pattern of the crystalline form has a diffraction angle 2 ⁇ of 3.5 ° ⁇ 0.2 °, 7.3 ° ⁇ 0.2 °, and 18.7 ° ⁇ 0.2 °. Characteristic peaks.
  • the present invention is referred to as citrate crystal form 1.
  • the present invention provides a preferred crystal form of the fumarate salt of the compound represented by the structural formula I.
  • the crystal form X-ray powder diffraction pattern has a diffraction angle 2 ⁇ of 5.5 ° ⁇ 0.2 °, 5.7 ° ⁇ 0.2 °, and 19.3 ° ⁇ 0.2. ° Characteristic peak.
  • the present invention is referred to as fumarate crystal form 1.
  • the present invention provides another preferred crystal form of the fumarate salt of the compound represented by the structural formula I.
  • the crystal form X-ray powder diffraction pattern has a characteristic peak with a diffraction angle 2 ⁇ of 4.5 ° ⁇ 0.2 °.
  • the present invention is referred to as fumarate crystal form 2.
  • the X-ray powder diffraction patterns were all measured using a K ⁇ line of a Cu target.
  • the present invention further provides a preferred embodiment of the maleate crystal form 1:
  • the X-ray powder diffraction pattern of the maleate crystal form 1 has a diffraction angle 2 ⁇ of 5.6 ° ⁇ 0.2 °, 8.4 ° ⁇ 0.2 °, 11.2 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 19.7 ⁇ 0.2 ° , 22.6 ° ⁇ 0.2 °, 25.4 ⁇ 0.2 °, 28.3 ° ⁇ 0.2 ° characteristic peaks.
  • the X-ray powder diffraction pattern of the maleate crystal form 1 has a diffraction angle 2 ⁇ of 5.6 ° ⁇ 0.2 °, 8.4 ° ⁇ 0.2 °, 11.2 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 19.7 ⁇ 0.2 ° , 22.6 ° ⁇ 0.2 °, 23.3 ° ⁇ 0.2 °, 25.4 ⁇ 0.2 °, 28.3 ° ⁇ 0.2 ° are the characteristic peaks.
  • the X-ray powder diffraction pattern of the maleate crystal form 1 has a diffraction angle 2 ⁇ of 5.6 ° ⁇ 0.2 °, 8.4 ° ⁇ 0.2 °, 11.2 ° ⁇ 0.2 °, 14.0 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 19.7 ⁇ 0.2 °, 22.6 ° ⁇ 0.2 °, 23.3 ° ⁇ 0.2 °, 25.4 ⁇ 0.2 °, 28.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the maleate crystal form 1 has a diffraction angle 2 ⁇ of 5.6 ° ⁇ 0.2 °, 8.4 ° ⁇ 0.2 °, 11.2 ° ⁇ 0.2 °, 15.3 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 17.5 ° ⁇ 0.2 °, 18.5 ° ⁇ 0.2 °, 19.7 ° ⁇ 0.2 °, 22.6 ° ⁇ 0.2 °, 23.3 ° ⁇ 0.2 °, 25.4 ° ⁇ 0.2 °, 26.3 ° ⁇ 0.2 °, Characteristic peaks of 27.5 ° ⁇ 0.2 ° and 28.3 ° ⁇ 0.2 °.
  • the main data of the X-ray powder diffraction pattern of the maleate crystal form 1 is shown in Table 1.
  • the maleate crystal form 1 has an X-ray powder diffraction pattern as shown in FIG. 1.
  • the maleate crystal form 1 has an X-ray powder diffraction pattern as shown in FIG. 2.
  • the maleate crystal form 1 has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 4.
  • the onset temperature of the besylate salt Form 1 is about 216 ° C, and the peak temperature is about 221 ° C.
  • the maleate crystal form 1 has a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 5. Further, the maleate crystal form 1 has a 1 H-NMR spectrum substantially as shown in FIG. 6.
  • the present invention further provides a preferred embodiment of the maleate crystal form 2:
  • the X-ray powder diffraction pattern of the maleate crystal form 2 has a diffraction angle 2 ⁇ of 5.9 ° ⁇ 0.2 °, 11.7 ° ⁇ 0.2 °, 17.6 ° ⁇ 0.2 °, 20.6 ° ⁇ 0.2 °, and 23.5 ° ⁇ 0.2 ° characteristic peak.
  • the main data of the X-ray powder diffraction pattern of maleate crystal form 2 are shown in Table 2.
  • the maleate crystal form 2 has an X-ray powder diffraction pattern as shown in FIG. 7.
  • the maleate crystal form 2 has a differential scanning calorimetry (DSC) pattern substantially as shown in FIG. 8.
  • DSC differential scanning calorimetry
  • the maleate crystal form 2 has a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 9.
  • TGA thermogravimetric analysis
  • the present invention further provides an amorphous form of the maleate salt of the compound represented by the structural formula I.
  • the amorphous form has an X-ray powder diffraction pattern as shown in FIG. 10, and it can be seen that no diffraction peak is seen. After heating up to 160 ° C, a diffraction peak of maleate crystal form 1 appeared, as shown in FIG. 11.
  • the present invention further provides a preferred embodiment of the mesylate salt form 1:
  • the X-ray powder diffraction pattern of the mesylate salt form 1 has a diffraction angle 2 ⁇ of 4.7 ° ⁇ 0.2 °, 9.4 ° ⁇ 0.2 °, 10.7 ° ⁇ 0.2 °, 12.1 ° ⁇ 0.2 °, 14.1 ° ⁇ Characteristic peaks of 0.2 ° and 19.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the mesylate salt form 1 has a diffraction angle 2 ⁇ of 4.7 ° ⁇ 0.2 °, 9.4 ° ⁇ 0.2 °, 10.7 ° ⁇ 0.2 °, 12.1 ° ⁇ 0.2 °, 14.1 ° ⁇
  • the characteristic peaks are 0.2 °, 16.3 ° ⁇ 0.2 °, 16.8 ° ⁇ 0.2 ° and 19.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the mesylate salt form 1 has a diffraction angle 2 ⁇ of 4.7 ° ⁇ 0.2 °, 9.4 ° ⁇ 0.2 °, 10.7 ° ⁇ 0.2 °, 12.1 ° ⁇ 0.2 °, 14.1 ° ⁇
  • the characteristic peaks are 0.2 °, 16.3 ° ⁇ 0.2 °, 16.8 ° ⁇ 0.2 °, 19.0 ° ⁇ 0.2 °, 21.1 ° ⁇ 0.2 °, 21.4 ° ⁇ 0.2 °, 23.9 ° ⁇ 0.2 °, and 28.2 ° ⁇ 0.2 °.
  • the main data of the X-ray powder diffraction pattern of the mesylate salt Form 1 is shown in Table 3.
  • the mesylate salt form 1 has an X-ray powder diffraction pattern as shown in FIG. 12.
  • solubility of the mesylate salt Form 1 in water at 25 ° C. is about 1.0 mg / mL.
  • the mesylate salt Form 1 has a hot stage XRD pattern substantially as shown in FIG. 13. Wherein, the mesylate salt crystal form 1 is heated to 100 ° C, and the crystal form remains unchanged.
  • the mesylate salt Form 1 has a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 14.
  • TGA thermogravimetric analysis
  • the mesylate salt form 1 has a differential scanning calorimetry (DSC) substantially as shown in FIG. 15.
  • DSC differential scanning calorimetry
  • the mesylate salt Form 1 has a 1 H-NMR spectrum substantially as shown in FIG. 16.
  • the present invention further provides a preferred embodiment of the mesylate salt crystal form 2:
  • the X-ray powder diffraction pattern of the mesylate salt form 2 has a diffraction angle 2 ⁇ of 3.9 ° ⁇ 0.2 °, 4.8 ° ⁇ 0.2 °, 6.5 ° ⁇ 0.2 °, 13.0 ° ⁇ 0.2 °, 13.9 ° ⁇
  • the characteristic peaks are 0.2 °, 15.7 ° ⁇ 0.2 ° and 20.4 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the mesylate salt form 2 has a diffraction angle 2 ⁇ of 3.9 ° ⁇ 0.2 °, 4.8 ° ⁇ 0.2 °, 6.5 ° ⁇ 0.2 °, 8.0 ° ⁇ 0.2 °, 11.9 ° ⁇ 0.2 °, 12.4 ° ⁇ 0.2 °, 13.0 ° ⁇ 0.2 °, 13.9 ° ⁇ 0.2 °, 15.7 ° ⁇ 0.2 °, 16.4 ° ⁇ 0.2 °, 18.7 ° ⁇ 0.2 °, 19.6 ° ⁇ 0.2 °, 19.8 ° ⁇ 0.2 ° , 20.4 ° ⁇ 0.2 °, 21.6 ° ⁇ 0.2 °, 22.4 ° ⁇ 0.2 °, 23.7 ° ⁇ 0.2 ° and 24.6 ° ⁇ 0.2 ° are the characteristic peaks.
  • the main data of the X-ray powder diffraction pattern of the mesylate salt crystal form 2 are shown in Table 4.
  • the mesylate salt form 2 has an X-ray powder diffraction pattern as shown in FIG. 17.
  • the mesylate salt form 2 has a solubility of about 5.0 mg / mL in water at 25 ° C.
  • the mesylate salt crystal form 2 has a hot stage XRD pattern substantially as shown in FIG. 18. Wherein, the mesylate salt crystal form 2 is heated to 100 ° C, and the crystal form is not significantly changed.
  • the mesylate salt Form 2 has a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 19.
  • TGA thermogravimetric analysis
  • the mesylate salt crystal form 2 has a differential scanning calorimetry (DSC) substantially as shown in FIG. 20.
  • the mesylate salt Form 2 has a 1 H-NMR spectrum substantially as shown in FIG. 21.
  • the present invention further provides a preferred embodiment of the besylate salt crystal form 1:
  • the X-ray powder diffraction pattern of the besylate salt form 1 has a diffraction angle 2 ⁇ of 4.5 ° ⁇ 0.2 °, 7.9 ° ⁇ 0.2 °, 12.5 ° ⁇ 0.2 °, 12.9 ° ⁇ 0.2 °, 18.1 ° ⁇
  • the characteristic peaks are 0.2 °, 20.4 ° ⁇ 0.2 ° and 21.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the besylate salt form 1 has a diffraction angle 2 ⁇ of 4.5 ° ⁇ 0.2 °, 6.3 ° ⁇ 0.2 °, 7.9 ° ⁇ 0.2 °, 9.0 ° ⁇ 0.2 °, 12.5 ° ⁇ 0.2 °, 12.9 ° ⁇ 0.2 °, 13.9 ° ⁇ 0.2 °, 15.7 ° ⁇ 0.2 °, 16.3 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 °, 18.9 ° ⁇ 0.2 °, 19.3 ° ⁇ 0.2 °, 20.4 ° ⁇ 0.2 ° , 21.5 ° ⁇ 0.2 °, 24.3 ° ⁇ 0.2 ° and 26.2 ° ⁇ 0.2 °.
  • the main data of the X-ray powder diffraction pattern of the besylate salt crystal form 1 are shown in Table 5.
  • the besylate salt form 1 has an X-ray powder diffraction pattern as shown in FIG. 22.
  • solubility of the besylate salt Form 1 in water at 25 ° C. is about 0.08 mg / mL.
  • the endothermic peak starting temperature of the benzenesulfonate crystal form 1 is about 224 ° C, and the peak temperature is about 234 ° C.
  • thermogravimetric analysis showed that the benzenesulfonate crystal form 1 lost about 3.8% before 120 ° C.
  • besylate salt Form 1 has a 1 H-NMR spectrum substantially as shown in FIG. 23.
  • the present invention further provides a preferred embodiment of the besylate salt crystal form 2:
  • the X-ray powder diffraction pattern of the besylate salt crystal form 2 has a diffraction angle 2 ⁇ of 4.0 ° ⁇ 0.2 °, 4.5 ° ⁇ 0.2 °, 4.9 ° ⁇ 0.2 °, 6.9 ° ⁇ 0.2 °, 14.4 ° ⁇
  • the characteristic peaks are 0.2 °, 14.7 ° ⁇ 0.2 °, 18.4 ° ⁇ 0.2 ° and 24.1 ° ⁇ 0.2 °.
  • the main data of the X-ray powder diffraction pattern of the besylate salt crystal form 2 are shown in Table 6.
  • the besylate salt crystal form 2 has an X-ray powder diffraction pattern as shown in FIG. 24.
  • solubility of the besylate salt crystal form 2 in water at 25 ° C. is about 1.0 mg / mL.
  • thermogravimetric analysis showed that the besylate salt Form 2 lost about 7.8% before 120 ° C.
  • besylate salt crystal form 2 has a differential scanning calorimetry (DSC) substantially as shown in FIG. 25.
  • besylate salt crystal form 2 has a 1 H-NMR spectrum shown in FIG. 26.
  • the present invention further provides a preferred embodiment of the hydrochloride crystal form 1:
  • the X-ray powder diffraction pattern of the hydrochloride crystal form 1 has a diffraction angle 2 ⁇ of 4.2 ° ⁇ 0.2 °, 4.7 ° ⁇ 0.2 °, 6.9 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 12.1 ° ⁇ 0.2 °, 14.0 ° ⁇ 0.2 °, 14.6 ° ⁇ 0.2 °, 15.6 ° ⁇ 0.2 ° and 19.7 ° ⁇ 0.2 °.
  • the hydrochloride crystal form 1 has an X-ray powder diffraction pattern as shown in FIG. 27.
  • hydrochloride crystal form 1 has a solubility of about 1.25 mg / mL in water at 25 ° C.
  • thermogravimetric analysis showed that the hydrochloride crystal form 1 lost about 8.8% before 120 ° C.
  • the present invention further provides a preferred embodiment of the phosphate crystal form 1:
  • the X-ray powder diffraction pattern of the phosphate crystal form 1 has a diffraction angle 2 ⁇ of 7.5 ° ⁇ 0.2 °, 12.6 ° ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, 16.4 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 ° , 18.3 ° ⁇ 0.2 °, 18.9 ° ⁇ 0.2 °, 19.4 ° ⁇ 0.2 °, 21.4 ° ⁇ 0.2 °, 22.2 ° ⁇ 0.2 ° and 26.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the phosphate crystal form 1 has a diffraction angle 2 ⁇ of 7.5 ° ⁇ 0.2 °, 9.2 ° ⁇ 0.2 °, 9.5 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 12.6 ° ⁇ 0.2 ° , 13.0 ° ⁇ 0.2 °, 13.8 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, 16.4 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 °, 18.3 ° ⁇ 0.2 °, 18.9 ° ⁇ 0.2 °, 19.4 ° ⁇ 0.2 °, 20.1 ° ⁇ 0.2 °, 21.4 ° ⁇ 0.2 °, 22.2 ° ⁇ 0.2 °, 23.3 ° ⁇ 0.2 °, 23.6 ° ⁇ 0.2 °, 25.3 ° ⁇ 0.2 °,
  • the main data of the X-ray powder diffraction pattern of the phosphate crystal form 1 are shown in Table 8.
  • the phosphate crystal form 1 has an X-ray powder diffraction pattern as shown in FIG. 28.
  • solubility of the phosphate crystal form 1 in water at 25 ° C. is about 0.1 mg / mL.
  • thermogravimetric analysis showed that the phosphate crystal form 1 lost about 4.0% before 120 ° C.
  • the phosphate crystal form 1 has a differential scanning calorimetry (DSC) pattern substantially as shown in FIG. 29.
  • DSC differential scanning calorimetry
  • the present invention further provides a preferred embodiment of the L-tartrate salt crystal form 1:
  • the X-ray powder diffraction pattern of the L-tartrate salt crystal form 1 has a diffraction angle 2 ⁇ of 3.6 ° ⁇ 0.2 °, 7.1 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 18.8 ° ⁇ 0.2 °, 19.4 ° ⁇ Characteristic peaks of 0.2 ° and 27.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the L-tartrate salt Form 1 has a diffraction angle 2 ⁇ of 3.6 ° ⁇ 0.2 °, 7.1 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.0 ° ⁇ 0.2 °, 13.1 ° ⁇ 0.2 °, 14.6 ° ⁇ 0.2 °, 15.2 ° ⁇ 0.2 °, 18.8 ° ⁇ 0.2 °, 19.4 ° ⁇ 0.2 °, 20.9 ° ⁇ 0.2 °, 21.4 ° ⁇ 0.2 °, 22.1 ° ⁇ 0.2 °, 23.6 ° ⁇ 0.2 ° And 27.3 ° ⁇ 0.2 ° characteristic peaks.
  • the main data of the X-ray powder diffraction pattern of the L-tartrate salt Form 1 is shown in Table 9.
  • the L-tartrate salt Form 1 has an X-ray powder diffraction pattern as shown in FIG. 30.
  • solubility of the L-tartrate crystal form 1 in water at 25 ° C. is about 0.08 mg / mL.
  • thermogravimetric analysis showed that the L-tartrate salt of Form 1 lost about 2.7% before 120 ° C.
  • L-tartrate salt Form 1 has a 1 H-NMR spectrum substantially as shown in FIG. 31.
  • the present invention further provides a preferred embodiment of the L-malate crystal form 1:
  • the X-ray powder diffraction pattern of the L-malate crystal form 1 has characteristic peaks with diffraction angles 2 ⁇ of 3.6 ° ⁇ 0.2 °, 7.4 ° ⁇ 0.2 °, 18.8 ° ⁇ 0.2 °, and 27.2 ° ⁇ 0.2 °. .
  • the X-ray powder diffraction pattern of the L-malate crystal form 1 has a diffraction angle 2 ⁇ of 3.6 ° ⁇ 0.2 °, 7.4 ° ⁇ 0.2 °, 9.0 ° ⁇ 0.2 °, 10.5 ° ⁇ 0.2 °, 13.0 °
  • the characteristic peaks are ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, 18.8 ° ⁇ 0.2 ° and 27.2 ° ⁇ 0.2 °.
  • the main data of the X-ray powder diffraction pattern of the L-malate crystal form 1 is shown in Table 10.
  • the L-malate crystal form 1 has an X-ray powder diffraction pattern as shown in FIG. 32.
  • solubility of the L-malate crystal form 1 in water at 25 ° C. is about 0.25 mg / mL.
  • thermogravimetric analysis showed that the L-malate crystal form 1 was at 3.3%.
  • the L-malate crystal form 1 has a differential scanning calorimetry (DSC) substantially as shown in FIG. 33.
  • DSC differential scanning calorimetry
  • the L-malate crystal form 1 has a 1 H-NMR spectrum substantially as shown in FIG. 34.
  • the present invention further provides a preferred embodiment of the citrate crystal form 1:
  • the X-ray powder diffraction pattern of the citrate crystal form 1 has a diffraction angle 2 ⁇ of 3.5 ° ⁇ 0.2 °, 7.3 ° ⁇ 0.2 °, 12.5 ° ⁇ 0.2 °, 14.9 ° ⁇ 0.2 °, 18.7 ° ⁇ 0.2 °, 21.0 ° ⁇ 0.2 ° and 26.8 ° ⁇ 0.2 °.
  • the main data of the X-ray powder diffraction pattern of the citrate crystal form 1 is shown in Table 11.
  • the citrate crystal form 1 has an X-ray powder diffraction pattern as shown in FIG. 35.
  • solubility of the citrate crystal form 1 in water at 25 ° C. is about 0.08 mg / mL.
  • thermogravimetric analysis showed that the citrate crystal form 1 lost about 2.2% before 120 ° C.
  • citrate crystal form 1 has a 1 H-NMR spectrum substantially as shown in FIG. 36.
  • the present invention further provides a preferred embodiment of the fumarate crystal form 1:
  • the X-ray powder diffraction pattern of the fumarate crystal form 1 has a diffraction angle 2 ⁇ of 5.5 ° ⁇ 0.2 °, 5.7 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 19.3 ° ⁇ 0.2 °, and 22.2 ° ⁇ 0.2 ° characteristic peak.
  • the X-ray powder diffraction pattern of the fumarate crystal form 1 has a diffraction angle 2 ⁇ of 5.5 ° ⁇ 0.2 °, 5.7 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 19.3 ° ⁇ 0.2 °, 22.2 ° ⁇
  • the characteristic peaks are 0.2 °, 23.5 ° ⁇ 0.2 ° and 27.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the fumarate crystal form 1 has a diffraction angle 2 ⁇ of 5.5 ° ⁇ 0.2 °, 5.7 ° ⁇ 0.2 °, 10.8 ° ⁇ 0.2 °, 13.6 ° ⁇ 0.2 °, 16.1 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 18.2 ° ⁇ 0.2 °, 19.3 ° ⁇ 0.2 °, 20.3 ° ⁇ 0.2 °, 22.2 ° ⁇ 0.2 °, 23.5 ° ⁇ 0.2 °, 24.9 ° ⁇ 0.2 °, and 27.0 ° ⁇ 0.2 ° Characteristic peak.
  • the main data of the X-ray powder diffraction pattern of the fumarate crystal form 1 is shown in Table 12.
  • the fumarate crystal form 1 has an X-ray powder diffraction pattern as shown in FIG. 37.
  • the present invention further provides a preferred embodiment of the fumarate crystal form 2:
  • the X-ray powder diffraction pattern of the fumarate crystal form 2 has characteristic peaks having diffraction angles 2 ⁇ of 4.5 ° ⁇ 0.2 °, 9.0 ° ⁇ 0.2 °, and 13.4 ° ⁇ 0.2 °.
  • the main data of the X-ray powder diffraction pattern of the fumarate crystal form 2 is shown in Table 13.
  • the fumarate crystal form 2 has an X-ray powder diffraction pattern as shown in FIG. 38.
  • the fumarate crystal form 2 has a solubility of less than 0.05 mg / mL in water at 25 ° C.
  • thermogravimetric analysis showed that the fumarate crystal form 1 lost about 3.2% before 120 ° C.
  • the fumarate crystal form 2 has a 1 H-NMR spectrum substantially as shown in FIG. 39.
  • the maleate crystalline form 1 maleate crystalline form 2, mesylate crystalline form 1, mesylate crystalline form 2, benzene sulfonate crystalline form 1, and benzene sulfonate Form 2, Hydrochloride Form 1, Phosphate Form 1, L-Tartrate Form 1, L-malate Form 1, Citrate Form 1, Fumarate Form 1, and Rich
  • the purity of the maleate crystal form 2 is preferably greater than 50%, such as 85% or more, 99% or more, or 99.5% or more.
  • the invention further provides the preparation of the compound represented by structural formula I and its maleate crystal form 1, maleate crystal form 2, maleate amorphous form, mesylate salt form 1, and mesylate salt form.
  • benzene sulfonate crystal form 1, benzene sulfonate crystal form 2
  • hydrochloride crystal form 1, phosphate crystal form 1, L-tartrate salt crystal form 1, L-malate salt crystal form 1, citric acid Method for salt crystal form 1, fumarate crystal form 1 and fumarate crystal form 2.
  • the compound represented by the structural formula I can be prepared by the following route:
  • the method for preparing maleate crystal form 1 is as follows:
  • the method for preparing maleate crystal form 2 is as follows:
  • maleate crystal form 1 to dimethyl sulfoxide, and place it in a tetrahydrofuran system at room temperature to diffuse and stand to precipitate the crystals to obtain maleate crystal form 2; or,
  • maleate crystal form 1 to dimethyl sulfoxide / tetrahydrofuran, stir to dissolve at 60 ° C, filter, stir the filtrate, precipitate a yellow solid, and centrifuge and dry at room temperature under vacuum to obtain maleate crystal form 2.
  • the amorphous preparation method is as follows:
  • Lactate crystal form 1 is amorphous.
  • the method for preparing mesylate salt form 1 is as follows:
  • the method for preparing mesylate salt form 2 is as follows:
  • the method for preparing the benzenesulfonate crystal form 2 is as follows:
  • the method for preparing hydrochloride crystal form 1 is as follows:
  • the method for preparing phosphate crystal form 1 is as follows:
  • the method for preparing L-tartrate crystal form 1 is as follows:
  • the method for preparing L-malate crystal form 1 is as follows:
  • the method for preparing citrate crystal form 1 is as follows:
  • the method for preparing fumarate crystal form 1 is as follows:
  • the method for preparing fumarate crystal form 2 is as follows:
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the salt form or crystal form of the present invention, and a pharmaceutically acceptable excipient, adjuvant or carrier.
  • the weight ratio of the salt form or crystal form and the auxiliary material, adjuvant or carrier ranges from 0.0001 to 10.
  • the present invention also provides a preferred embodiment of the above pharmaceutical composition.
  • the above-mentioned pharmaceutical composition contains a therapeutically effective amount of the salt form or crystal form of the present invention in combination with at least one other active ingredient.
  • the pharmaceutical composition is for oral administration.
  • the pharmaceutical composition is used in a tablet or capsule.
  • the pharmaceutical composition contains 0.01 to 99% by weight of the crystalline form of the present invention.
  • the pharmaceutical composition contains 0.05% to 50% by weight of the crystalline form of the present invention.
  • the pharmaceutical composition contains 0.1% to 30% by weight of the crystalline form of the present invention.
  • the invention further provides the application of the crystalline form or pharmaceutical composition in the preparation of a medicament.
  • said application is to treat, prevent, delay or prevent the occurrence or progression of cancer or cancer metastasis.
  • the application is to prepare a medicament for treating a disease mediated by FGFR.
  • the disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic lung cancer, ovarian cancer, and esophagus Cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumor, intracranial tumor, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, Squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • said use is as a FGFR inhibitor.
  • the FGFR includes FGFR1, FGFR2, FGFR3, or FGFR4.
  • the invention also provides a method of administering a therapeutically effective amount of at least any one crystalline form or pharmaceutical composition to a subject to treat and / or prevent a disease mediated by FGFR.
  • the FGFR includes FGFR1, FGFR2, FGFR3, or FGFR4.
  • the FGFR-mediated disease is cancer.
  • the cancer is selected from the group consisting of breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, and pleomorphic lung cancer.
  • Ovarian cancer Ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumor, intracranial tumor, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Xu Mast cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.
  • the present invention also provides a method for treating cancer, which comprises administering to a subject a therapeutically effective amount of at least any one crystal form or a pharmaceutical composition.
  • the cancer is breast cancer, multiple myeloma, bladder cancer, endometrium. Cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, intracranial tumor, Hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, Testicular cancer or liposarcoma.
  • the subject to be treated is a human.
  • substantially pure means that the content of said crystal form is not less than 85% by weight, preferably not less than 95%, and more preferably not less than 99%.
  • the terms "about” and “substantially” used in "having an X-ray powder diffraction pattern substantially as shown in Fig. 1" or "the X-ray powder diffraction pattern thereof is substantially as shown in Fig. 1" mean The exact positions of the peaks in the drawings should not be interpreted as absolute values. Because those skilled in the art know that the 2 ⁇ value of the X-ray powder diffraction pattern may have errors due to different measurement conditions (such as equipment and instruments used) and different samples. The measurement error of the diffraction angle of the X-ray powder diffraction pattern is 5% or less, in general, a difference of ⁇ 0.2 ° of a given value is considered appropriate.
  • the relative intensity of the peaks may fluctuate depending on experimental conditions and sample preparation, such as the preferred orientation of particles in the sample.
  • the use of automatic or fixed divergence slits will also affect the calculation of relative strength.
  • the intensity shown in the XRD curve included here is only exemplary and cannot be used as an absolute comparison.
  • terapéuticaally effective amount means that when a compound is administered to a subject to treat at least one clinical symptom of a disease, or a disease or disorder, it is sufficient to affect such treatment of the disease, disorder, or symptom. the amount.
  • a “therapeutically effective amount” may vary with the compound, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the patient being treated, and / or the Changes in patient's weight, etc. In any particular case, a suitable amount may be apparent to those skilled in the art, or it may be determined by routine experimentation.
  • therapeuticically effective amount refers to the total amount of a combination subject effective to treat a disease, disorder, or condition.
  • the salt form or crystal form according to the present invention can be used in combination as an active ingredient and mixed with a drug carrier to form a pharmaceutical composition.
  • the pharmaceutical carrier can take a variety of forms, depending on the mode of administration desired, for example, oral or injection (including intravenous). Therefore, the pharmaceutical composition of the present invention may be in the form of a separate unit suitable for oral administration. Such as capsules, cachets or tablets containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may be in the form of a powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion or water-in-oil emulsion.
  • the salt or crystal forms of the present invention can also be administered by controlled release and / or delivery devices.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with a carrier that constitutes one or more of the necessary components. Generally, the pharmaceutical composition is prepared by uniformly and intimately mixing an active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. In addition, the product can be easily prepared into a desired appearance.
  • “Pharmaceutically acceptable carrier” refers to a conventional pharmaceutical carrier suitable for the desired pharmaceutical formulation, for example: diluents, excipients such as water, various organic solvents, etc .; such as starch, pregelatinized starch, sucrose, Fillers for dextrin, mannitol, lactose, spray-dried lactose, microcrystalline cellulose, silicified microcrystalline cellulose, inorganic salts, etc .; such as starch syrup, dextrin, sugar powder, syrup, glue, polyethylene glycol , Cellulose derivatives, alginates, gelatin, hydroxypropyl cellulose, copovidone and polyvinylpyrrolidone (PVP), etc .; wetting agents such as distilled water, ethanol, and glycerol; such as dry starch, low substitution Disintegrants of hydroxypropyl cellulose, hydroxypropyl starch, agar, calcium carbonate, sodium bicarbonate, crospovidone, croscar
  • excipients can be added to the pharmaceutical composition, such as antioxidants, colorants, preservatives, pH adjusters, hardeners, emulsifiers, propellants, dispersants, stabilizers, thickeners. , Complexing agents, buffers, penetration enhancers, polymers, fragrances, sweeteners and dyes. It is preferred to use excipients suitable for the desired dosage form and the desired mode of administration.
  • disease or “disorder” or “condition” refers to any disease, discomfort, disease, symptom, or indication.
  • FIG. 1 X-ray powder diffraction pattern of maleate crystal form 1 of a compound represented by structural formula I.
  • FIG. (Maleic acid crystal form 1 prepared from the sample of batch number 20180227-2)
  • FIG. 2 X-ray powder diffraction pattern of maleate crystal form 1 of the compound represented by structural formula I.
  • FIG. (Malay salt crystal form 1 prepared from the sample of batch number 20180123)
  • FIG. 4 Differential scanning calorimetry of maleate crystal form 1 of the compound represented by structural formula I.
  • Figure 5 Thermogravimetric analysis pattern of maleate crystal form 1 of the compound represented by structural formula I.
  • FIG. 6 1 H-NMR chart of maleate crystal form 1 of the compound represented by structural formula I.
  • Figure 7 X-ray powder diffraction pattern of maleate crystal form 2 of the compound represented by structural formula I.
  • Figure 8 Differential scanning calorimetry of maleate crystal form 2 of the compound represented by structural formula I.
  • Figure 9 Thermogravimetric analysis pattern of maleate crystal form 2 of the compound represented by structural formula I.
  • Fig. 10 Amorphous X-ray powder diffraction pattern of the compound represented by Structural Formula I.
  • FIG. 11 Amorphous hot-stage X-ray powder diffraction pattern of the compound represented by structural formula I.
  • FIG. 12 X-ray powder diffraction pattern of the mesylate salt form 1 of the compound represented by the structural formula I.
  • FIG. 13 A hot table X-ray powder diffraction pattern of the mesylate salt form 1 of the compound represented by the structural formula I.
  • FIG. 13 A hot table X-ray powder diffraction pattern of the mesylate salt form 1 of the compound represented by the structural formula I.
  • FIG. 14 Thermogravimetric spectrum of mesylate salt Form 1 of the compound represented by Structural Formula I.
  • FIG. 15 Differential scanning calorimetry of mesylate salt Form 1 of the compound represented by Structural Formula I.
  • FIG. 17 X-ray powder diffraction pattern of the mesylate salt Form 2 of the compound represented by the structural formula I.
  • FIG. 18 A hot table X-ray powder diffraction pattern of the mesylate salt Form 2 of the compound represented by the structural formula I.
  • FIG. 18 A hot table X-ray powder diffraction pattern of the mesylate salt Form 2 of the compound represented by the structural formula I.
  • FIG. 20 Differential scanning calorimetry of mesylate salt Form 2 of the compound represented by Structural Formula I.
  • FIG. 31 1 H-NMR chart of mesylate salt Form 2 of the compound represented by Structural Formula I.
  • FIG. 22 X-ray powder diffraction pattern of besylate salt form 1 of the compound represented by structural formula I.
  • FIG. 23 1 H-NMR chart of besylate salt Form 1 of the compound represented by Structural Formula I.
  • Figure 24 X-ray powder diffraction pattern of besylate salt Form 2 of the compound represented by Structural Formula I.
  • FIG. 25 Differential scanning calorimetry of besylate salt Form 2 of the compound represented by Structural Formula I.
  • FIG. 26 1 H-NMR chart of besylate salt Form 2 of the compound represented by Structural Formula I.
  • Fig. 27 X-ray powder diffraction pattern of hydrochloride crystal form 1 of the compound represented by structural formula I.
  • Fig. 28 X-ray powder diffraction pattern of phosphate crystal form 1 of the compound represented by structural formula I.
  • FIG. 29 Differential scanning calorimetry of phosphate crystal form 1 of the compound represented by structural formula I.
  • FIG. 29 Differential scanning calorimetry of phosphate crystal form 1 of the compound represented by structural formula I.
  • FIG. 30 X-ray powder diffraction pattern of L-tartrate crystal form 1 of the compound represented by structural formula I.
  • FIG. 31 1 H-NMR chart of L-tartrate salt Form 1 of the compound represented by Structural Formula I.
  • Fig. 32 X-ray powder diffraction pattern of L-malate crystal form 1 of the compound represented by structural formula I.
  • Figure 33 Differential scanning calorimetry of L-malate crystal form 1 of the compound represented by structural formula I.
  • FIG. 34 1 H-NMR chart of L-malate crystal form 1 of the compound represented by structural formula I.
  • Fig. 35 X-ray powder diffraction pattern of citrate crystal form 1 of the compound represented by structural formula I.
  • FIG. 36 1 H-NMR chart of citrate crystal form 1 of the compound represented by structural formula I.
  • Fig. 37 X-ray powder diffraction pattern of fumarate crystal form 1 of the compound represented by structural formula I.
  • Fig. 38 X-ray powder diffraction pattern of the fumarate crystal form 2 of the compound represented by the structural formula I.
  • FIG. 39 1 H-NMR chart of fumarate crystal form 2 of the compound represented by structural formula I.
  • Figure 40 Isothermal adsorption curve of maleate crystal form 1 of the compound represented by structural formula I.
  • Figure 41 Isothermal adsorption curve of mesylate salt Form 1 of the compound represented by structural formula I.
  • Figure 43 Isothermal adsorption curve of besylate salt Form 1 of the compound represented by Structural Formula I.
  • Figure 44 Isothermal adsorption curve of benzenesulfonate crystal form 2 of the compound represented by structural formula I.
  • Figure 45 Isothermal adsorption curve of hydrochloride crystal form 1 of the compound represented by structural formula I.
  • Fig. 46 X-ray powder diffraction pattern of an influencing factor experiment of maleate crystal form 1 of the compound represented by structural formula I.
  • Fig. 47 X-ray powder diffraction pattern of an influencing factor experiment of the mesylate salt form 1 of the compound represented by the structural formula I.
  • Fig. 48 X-ray powder diffraction pattern of an influencing factor experiment of a compound represented by structural formula I.
  • Figure 50 Thermogravimetric analysis of the influencing factors of the mesylate salt Form 1 of the compound represented by the structural formula I.
  • Fig. 51 X-ray powder diffraction pattern of the maleate crystal form 2 of the compound represented by the structural formula I after drying at room temperature for 1 day.
  • Fig. 52 Hot stage X-ray powder diffraction pattern of maleate crystal form 2 of the compound represented by structural formula I.
  • Figure 53 Antitumor activity of the compound represented by Formula I in a NCI-H1581 xenograft nude mouse model.
  • Figure 54 Antitumor activity of a compound of formula I in a SNU-16 xenograft nude mouse model.
  • Figure 55 The plasma concentration-time curve of the compound represented by Structural Formula I and its maleate crystal form 1 (administration dose: 10 mg / kg).
  • DSC Differential Thermal Analysis Scanner
  • TA Instruments Q200DSC controlling software Thermal Advantage Analyzing Software Universal Analysis Sample tray Aluminum crucible (covered without perforation)
  • Sample detection amount 0.5-5mg Protective gas Nitrogen Gas flow rate 40mL / min
  • Common detection methods Equilibrate at 25 °C; Ramp at 10 °C / min to 300 °C
  • API API
  • DMSO dimethyl sulfoxide
  • m-CPBA m-chloroperoxybenzoic acid
  • RH relative humidity
  • RRT relative retention time
  • TFA trifluoroacetic acid
  • XRD X-ray powder diffraction.
  • Step 4 Preparation of the compound a-5
  • the cake was sampled for UPLC purity testing. Take the filter cake, add anhydrous methanol (1077 mL), DCM (5385 mL) and TFA (179 mL), stir to clear, and filter. 428.10 g of anhydrous potassium carbonate was dissolved in 4200 mL of water, added dropwise to the filtrate, stirred, adjusted to pH to alkaline, allowed to stand, and separated. The organic phase was concentrated under reduced pressure, and the obtained solid was added to 898 mL of anhydrous methanol to be slurried for 1 h, and then filtered. The filter cake was dried under vacuum at 45 ° C. for 12 h to obtain 105.36 g of the compound represented by Formula I in a yield of 91.3%.
  • Example 2 Method 1 for preparing maleate crystal form 1 of a compound represented by structural formula I
  • Example 3 Method 2 for preparing maleate crystal form 1 of a compound represented by structural formula I
  • Example 4 Method 1 for preparing maleate crystal form 2 of a compound represented by structural formula I
  • maleate crystal form 1 About 10 mg was taken, added to 0.1 mL of dimethyl sulfoxide, and placed in a tetrahydrofuran system at room temperature to diffuse and crystallize to obtain maleate crystal form 2.
  • Example 5 Method 2 for preparing maleate crystal form 2 of the compound represented by structural formula I
  • maleate crystal form 2 Take about 10 mg of maleate crystal form 1, add 0.1 mL of dimethyl sulfoxide and 5.0 mL of tetrahydrofuran successively, stir to dissolve at 60 ° C, filter, and filter the filtrate in an ice-salt bath to precipitate a yellow solid, centrifuge and dry at room temperature under vacuum , To obtain maleate crystal form 2.
  • Example 8 Preparation method of besylate salt form 1 of a compound represented by structural formula I
  • Example 1 of the present invention With reference to the preparation method provided in Example 1 of the present invention, two batches of samples of the compound of structural formula I in different batches (batch numbers: 20180227-2 and 20180123) were obtained, and then two batches of different batches were obtained according to the preparation method of Example 2. Form 1 of maleate and characterize them separately.
  • the XRD spectra are shown in Figures 1 to 3, and the analysis data of the spectra are shown in Table 24 and Table 25, respectively.
  • Table 24 Analytical data of maleic acid crystal form 1XRD prepared from the sample of batch number 20180227-2
  • Table 25 Analytical data of maleic acid crystal form 1XRD prepared from the sample of batch number 20180123
  • the analysis data table of two batches of maleate crystal form 1 and the relative peaks of the individual peaks recorded in the XRD spectrum Intensity can be changed by many factors (such as crystal orientation in X-ray beam and purity of analytical substance, etc.), the peak position can also be slightly shifted due to changes in sample weight and other factors, but the crystal form of the two batches is essentially The above is the same.
  • the XRD pattern of the maleic acid crystal form 1 of the compound represented by the structural formula I provided by the present invention is not limited to the X-ray powder diffraction pattern shown in FIG. 1 or FIG. 2, and is substantially the same as that shown in FIG. 1 or FIG. 2. The crystals of the X-ray powder diffraction pattern all fall within the scope of the invention.
  • a dynamic moisture absorber (DVS) was used to measure the hygroscopicity of the samples (the samples are the multiple crystal forms shown in Table 26).
  • the samples were subjected to changes in moisture absorption and weight gain in the range of 0% RH (relative humidity) to 80% RH.
  • the test results are shown in Figure 40-45 and the test results are shown in Table 26.
  • the maleate crystal form 1 has outstanding advantages in terms of hygroscopicity. Compared with the compound of the structural formula I, the maleate crystal form 1 has greatly reduced hygroscopicity.
  • the mesylate salt form 1 also has obvious advantages, and the other forms have relatively high hygroscopicity.
  • Example 19 Determination of the crystal form stability of the compound represented by structural formula I and its maleate crystal form 1 and mesylate salt form 1.
  • Samples and experimental preparations Take an appropriate amount of the maleate salt form 1, the mesylate salt form 1 and the compound of the structural formula I and place them in a watch glass, and spread a thin layer of about 3-5 mm in thickness.
  • the experimental conditions were: conventional (25 ° C, protected from light), high temperature (60 ° C, protected from light), high temperature and humidity (40 ° C / 75% RH, open, protected from light), light (25 ° C, 4500lux ⁇ 500lux, open) and Place in an oxidized (closed container at 40 ° C, urea hydrogen peroxide, protected from light) for 14 days.
  • Test items Samples were taken on day 0 and day 14, respectively. XRD, TGA and HPLC were compared. The test results on day 14 are shown in Table 27.
  • TGA test showed that the maleate crystal form 1 had no significant change in weight loss after being left for 14 days under normal, high temperature, high temperature and high humidity, light and oxidation conditions, and the weight loss was less than 1% before 120 ° C.
  • Form 1 of mesylate salt under the oxidizing condition has a slight increase in weight loss for 14 days.
  • the specific TGA chart is shown in Figure 49-50.
  • Example 20 Determination of the stability of maleate crystal form 2 of the compound represented by structural formula I
  • the stability of the maleate crystal form 2 after being left at room temperature for 1 day and heated to 120 ° C. was tested by XRD. The specific test results are shown in FIG. 51 and FIG. 52.
  • Stop solution 100mM HEPES (pH 7.5); 0.015% Brij-35; 0.2% CoatingReagent # 3; 50mM EDTA
  • Method 1 Use CellTiter AQ ueous one Solution cell proliferation test kit method, to observe the growth inhibitory effect of the compound represented by structural formula I on human tumor cells NCl-H1581 cultured in vitro.
  • Detection method Add 180 ⁇ L of cell suspension to a 96-well plate and place in a CO 2 incubator overnight. The test compound was dissolved in DMSO and diluted 3 times to a total of 10 concentrations. Transfer 20 ⁇ L of the test compound or DMSO-containing medium to the corresponding cell wells, respectively. Incubate at 37 ° C, 5% CO 2 for 144 hrs. Add 40 ⁇ L CellTiter The AQ ueous one Solution cell proliferation test reagent was placed in a detection plate, and incubated at 37 ° C and 5% CO 2 for 2 hrs. The VICTOR TM X5 instrument was used to record the light absorption value (OD490) at 490 nm and the IC 50 value was calculated.
  • OD490 light absorption value
  • Method 2 CellTiter and Gloassay methods were used to observe the growth inhibitory effect of the compound represented by the structural formula I of the present invention on human tumor cells NCI-H1581 and SNU-16 cultured in vitro.
  • Detection method add an appropriate volume of whole medium and suspend the cells. Add 100 ⁇ L of cell suspension to a 96-well plate and place in a CO2 incubator overnight. The test compound was dissolved in DMSO and diluted 3 times to a total of 10 concentrations. The compound of formula I or DMSO control was transferred to a well containing 100 ⁇ L of culture medium, respectively. Incubate at 37 ° C, 5% CO 2 for 96 hrs. Add 100 ⁇ L CellTiter-Glo reagent to the detection plate and incubate at room temperature for 10 min to stabilize the luminescence signal. RIC (relative luminescence unit) values were recorded using a VICTOR TM X5 instrument and IC 50 values were calculated.
  • Example C Xenograft tumor model test 1
  • Reagents DMSO, polyethylene glycol-15-hydroxystearate (Solutol), physiological saline.
  • mice SPF-grade animals, weighing 18-22 g, females, provided by Weitong Lihua Experimental Animal Technology Co., Ltd., fed with SPF-grade feed, and freely drinking distilled water.
  • Human cancer cell line NCI-H1581 human non-small cell lung cancer cell line, provided by Shanghai Ruizhi Chemical Research Co., Ltd.
  • NCI-H1581 cell line was used to inoculate BALB / C nude mice subcutaneously in the right armpit of NLB-C nude mice with 1 ⁇ 10 7 cells / 100 ⁇ L / head under aseptic operation in a clean bench, and the tumors would develop after 10 days.
  • the animals were randomly divided into groups of 6 animals in each group and weighed.
  • the experimental group was given the compound of formula I by intragastric administration once a day. Nude mice are kept at a room temperature of 20-22 ° C and a relative humidity of 40-60%, and the shielding system is supplemented by a clean laminar flow cabinet environment.
  • Example D Xenograft tumor model test 2
  • Reagents DMSO, polyethylene glycol-15-hydroxystearate (Solutol), physiological saline.
  • mice SPF animals, weighing 18-22g, females, provided by Nanjing University-Nanjing Institute of Biomedicine, fed with SPF feed, and freely drinking distilled water.
  • Human cancer cell line SNU-16 human gastric cancer cell line, purchased from ATCC under the trade number CRL-5974 TM .
  • Tumor transplantation test method SNU-16 cell line was used to inoculate 0.2LB (3 ⁇ 10 6 + Matrigel) per mouse into the right back of nude mice with SNU-16 cells under sterile operation in a clean bench, waiting for tumor Group administration was started when the average volume reached 151 mm 3 . Animals were randomly divided into groups of 6 animals and weighed. The positive drug group was given JNJ42756493 once a day by intragastric administration. The experimental group was given the compound of formula I by intragastric administration once a day. Nude mice are kept at a room temperature of 20-22 ° C and a relative humidity of 40-60%, and the shielding system is supplemented by a clean laminar flow cabinet environment.
  • Subcutaneous tumor volume was measured with a caliper twice a week after the start of the experiment, and the tumor growth curve was plotted to calculate the tumor suppression rate.
  • the calculation results were statistically analyzed using GraphPad Prism5 software. The experimental data are shown in Figure 54.
  • Drugs and reagents 6- (2-chloro-3,5-dimethoxyphenyl) -N- (4- (4-morpholinylpiperidin-1-yl) phenyl)- [1,2,4] triazolo [4 ', 3': 1,6] pyrido [2,3-d] pyrimidin-2amine (compound of formula I), horse of compound of formula I Lactate Form 1 is ground into fine particles. The content (purity) of the material is not less than 99.0%.
  • Test animals SD rats were randomly divided into the compound group represented by the structural formula I and the maleate crystal form group 1 of the compound represented by the structural formula I, and each group included 3 male rats.
  • Drug preparation Each compound is formulated into a clear solution in 10% DMSO / 10% Solutol / 80% Water solution, and the final concentration of each compound is 1 mg / mL.
  • Each suspension was orally administered to fasted SD rats at a dose volume of 10 mL / kg at a dose of 10 mg / kg.
  • Blood samples were collected in pre-anticoagulated tubes of EDTA-K before (0h) and 0.25h, 0.5h, 1h, 2h, 4h, 7h, and 24h after dosing. Centrifuge at 4 ° C for 10 min at 4 ° C to separate plasma from the sample. Plasma samples were collected and stored at -80 ° C for analysis.
  • the samples were analyzed by AB4000API LC / MS combined with HPLC. Under liquid chromatography conditions, a phenomenex C18 2.6u (50 ⁇ 2.1mm) column was used as the stationary phase, and acetonitrile-water and 0.1% formic acid were used as the mobile phase. The injection volume was 10 ⁇ L.
  • the PK data of the compound represented by the formula I and the maleate crystal form 1 of the compound represented by the formula I are shown in Table 29 and FIG. 55. The absorption value of the maleate crystal form 1 of the compound represented by the structural formula I is higher than that of the compound represented by the structural formula I.
  • Drugs and reagents 6- (2-chloro-3,5-dimethoxyphenyl) -N- (4- (4-morpholinylpiperidin-1-yl) phenyl)- [1,2,4] triazolo [4 ', 3': 1,6] pyrido [2,3-d] pyrimidin-2amine (compound of formula I), apple of compound of formula I Crystal Forms, Tartrate Forms, Phosphate Forms, Mesylate Forms, Hydrochloride Forms, Fumarate Forms, Citrate Forms, Besylate Forms, and Sulfates The crystal form is ground into fine particles. The content (purity) of the material is not less than 99.0%.
  • Test animals SD rats were randomly divided into the compound group represented by the structural formula I and each crystal group of the compound represented by the structural formula I, and each group included 3 male rats.
  • Drug formulation Each compound is formulated in a solution of purified water, in which the mesylate crystal form, hydrochloride crystal form and benzenesulfonate crystal form are formulated as clear solutions, malate crystal form, tartrate crystal form, Phosphate crystal form, fumarate crystal form, citrate crystal form and sulfate crystal form were formulated as a suspension solution, and the final compound concentration was 0.5 mg / mL.
  • Each suspension was orally administered to fasted SD rats at a dose volume of 10 mL / kg and a dose of 5 mg / kg.
  • Blood samples were collected in pre-anticoagulation tubes of EDTA-K before (0h) and 0.5h, 1h, 2h, 4h, 7h, and 24h after dosing. Centrifuge at 4 ° C for 10 min at 4 ° C to separate plasma from the sample. Plasma samples were collected and stored at -80 ° C for analysis.
  • Example 24 Method 1 for preparing capsules
  • the API described herein refers specifically to the maleate crystal form 1 of the compound represented by Structural Formula I.
  • the preparation process of the capsule is as follows:
  • the sieved API, mannitol and crospovidone are weighed and transferred to a square cone mixer for mixing.
  • This product is packaged in an oral solid medicinal high-density polyethylene bottle and an oral solid medicinal polypropylene / low-density polyethylene moisture-proof combined lid.
  • the packaged product is stored at room temperature.
  • the API described herein refers specifically to the maleate crystal form 1 of the compound represented by Structural Formula I.
  • the preparation process of the capsule is as follows:
  • the sieved API, microcrystalline cellulose, spray-dried lactose and crospovidone are weighed and transferred to a square cone mixer for mixing.
  • This product is packaged in an oral solid medicinal high-density polyethylene bottle and an oral solid medicinal polypropylene / low-density polyethylene moisture-proof combined lid.
  • the packaged product is stored at room temperature.

Abstract

结构式I所示化合物的马来酸盐、甲磺酸盐、苯磺酸盐、盐酸盐、磷酸盐、L-酒石酸盐、L-苹果酸盐、柠檬酸盐和富马酸盐，及各盐型的多种晶型，其制备方法及其应用。 (I)

Description

新型氮杂三环类化合物的盐型、晶型及其用途 技术领域
本发明涉及6-(2-氯-3，5-二甲氧基苯基)-N-(4-(4-吗啉基哌啶-1-基)苯基)-[1，2，4]三氮唑并[4′，3′：1，6]吡啶并[2，3-d]嘧啶-2-胺的盐型、晶型、晶型的制备方法、含所述晶型的药物组合物，所述晶型和药物组合物作为FGFR抑制剂的用途以及治疗FGFR介导的疾病的方法。
背景技术
蛋白激酶是催化蛋白质磷酸化反应的酶，在大多数情况下，这一磷酸化反应发生在蛋白质的丝氨酸(ser)、苏氨酸(thr)和酪氨酸(tyr)残基上。细胞生命历程的很多方面(例如细胞生长、分化、增殖、细胞周期和存活)均依赖于蛋白激酶的活性。而且，许多疾病(例如癌症和炎症)与蛋白激酶活性的异常有关。
目前发现酪氨酸蛋白激酶(Protein Tyrosine Kinase，PTK)有100多个家族成员，其在调节细胞的分化、生长和增殖中起重要作用。根据PTK的结构，可分为受体型和非受体型PTK两大类，前者又称跨膜PTK，后者又称细胞内PTK。
成纤维细胞生长因子受体(FGFR)属于受体型酪氨酸蛋白激酶(Receptor Tyrosine Kinase，RTK)超家族的一员，已成为全球制药公司开发新型抗肿瘤药物的靶标之一。FGFR参与调节细胞增殖，凋亡、迁移、新生血管生成等多个过程。由于作用广泛，FGFR及其它RTK在正常情况下受到严格调控。在肿瘤中，如乳腺癌、膀胱癌、***癌(目前开发的适应症)等，FGFR激活突变或者配体/受体过表达导致其持续激活，不仅与肿瘤的发生、发展、不良预后等密切相关，并且在肿瘤新生血管生成、肿瘤的侵袭与转移等过程中也发挥重要作用。因此，FGFR被公认为是抗肿瘤的重要靶点，FGFR小分子抑制剂的研发逐步受到越来越多的关注。
成纤维细胞生长因子(FGFs)信号的激活和传导：FGFs能够在酪氨酸激酶结构中的关键活化环的酪氨酸残基上引发FGFRs的自身磷酸化，从而导致酪氨酸激酶结构域从非活化状态转变为活化状态(Bae J H，Schlessinger J.Molecules  and Cells，2010，29(5)：443-448)。FGFRs中活化的酪氨酸激酶结构域在底物结合位点沿着FGFRs结合的衔接分子逐步磷酸化其它酪氨酸残基。FGFRs的C-末端区的酪氨酸残基磷酸化能够使磷酸酯酶Cγ(PLCγ)吸纳并激活，从而催化磷脂酰肌醇二磷酸(PIP2)转化为甘油二酯(DAG)和三磷酸肌醇(IP3)(Dailey L，Ambrostti D，Mansukhani A，et al.Cytokine&Growth Factor Reviews，2005，16(2)，233-247)。活化的FGFR磷酸化底物2(FRS2)能够吸纳生长因子受体结合蛋白2(GRB2)适配分子。
FGFs信号可以通过FRS2和GRB2传导到Ras促***原活化蛋白激酶(Ras-MAPK)或PI3激酶-蛋白激酶B(PI3K-AKT)信号通路，通过PLCγ和DAG传导到蛋白激酶C(PKC)或蛋白激酶D(PKD)信号通路，通过PLCγ和IP3传导到钙离子释放级联通路。FGFs诱导的Ras-MAPK活化参与细胞增殖，而FGFs诱导的PI3K-AKT活化参与细胞存活。
由于FGFs信号参与肿瘤生物学的各个方面，如抗凋亡、血管生成、上皮细胞向***的转变(Epithelial to Mesenchymal Transition，EMT)或侵袭等，FGFRs的靶向治疗已成为临床肿瘤学领域的热点，拟合于酪氨酸激酶结构域中ATP结合口袋而设计开发的小分子化合物已经用于癌症治疗。
FGFRs异常激活而获得抗凋亡潜能的人类癌细胞中，抑制FGFs信号能够在抑制血管新生的同时降低癌细胞的负荷，并且FGFR抑制剂能够增强癌细胞对常规抗癌药物(如5-氟尿嘧啶、伊立替康、紫杉醇等)的敏感性。随着科研人员对FGFs信号网络的深入了解，以及对FGFs和FGFRs作用机制的深入研究，特异性强、治疗效果好的FGFR抑制剂将会被开发出来，采用FGFRs靶向抗癌药物***将会具有非常广阔的前景。
特定有机药物化合物的多晶型物，由于各自的独特的三维结构，而具有不同的物理性质，如溶解性、吸湿性及稳定性等。但是，通常无法预测特定有机药物化合物是否会形成不同的结晶形式，更不可能预测晶型本身的结构和性质。探索可药用化合物的新晶型或多晶型物提供了提高医药产品的整体性能的机会，同时扩大了制剂科学家设计时可用的材料品种。由于发现有用化合物的新晶型而扩大了制剂设计的材料品种，这显然是有利的。
发明内容
本发明涉及结构式I所示化合物6-(2-氯-3，5-二甲氧基苯基)-N-(4-(4-吗啉基哌啶-1-基)苯基)-[1，2，4]三氮唑并[4′，3′：1，6]吡啶并[2，3-d]嘧啶-2-胺的盐型及各个盐型基本上纯的晶型。
Figure PCTCN2019102720-appb-000001
结构式I所示化合物的盐型
在一些实施方案中，一种酸和化合物I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形物，结晶物或其混合物。下面示范性列举了化合物I与九种酸所形成的盐型。所述的九种酸分别是马来酸、甲磺酸、苯磺酸、盐酸、磷酸、L-酒石酸、L-苹果酸、柠檬酸和富马酸。
结构式I所示化合物各盐型的晶型示范性例举如下：
本发明提供了结构式I所示化合物的马来酸盐的一种优选晶型，该晶型X射线粉末衍射图具有衍射角2θ为5.6°±0.2°，8.4°±0.2°，11.2°±0.2°，22.6°±0.2°和28.3°±0.2°的特征峰。为方便，本发明称之为马来酸盐晶型1。
本发明提供了结构式I所示化合物的马来酸盐的另一种优选晶型，该晶型X射线粉末衍射图具有衍射角2θ为5.9°±0.2°的特征峰。为方便，本发明称之为马来酸盐晶型2。
本发明提供了结构式I所示化合物的甲磺酸盐的一种优选晶型，该晶型X射线粉末衍射图具有衍射角2θ为4.7°±0.2°，9.4°±0.2°和14.1°±0.2°的特征峰。为方便，本发明称之为甲磺酸盐晶型1。
本发明提供了结构式I所示化合物的甲磺酸盐的另一种优选晶型，该晶型X射线粉末衍射图具有衍射角2θ为3.9°±0.2°，15.7°±0.2°和20.4°±0.2°的特征峰。为 方便，本发明称之为甲磺酸盐晶型2。
本发明提供了结构式I所示化合物的苯磺酸盐的一种优选晶型，该晶型X射线粉末衍射图具有衍射角2θ为4.5°±0.2°，18.1°±0.2°，20.4°±0.2°和21.5°±0.2°的特征峰。为方便，本发明称之为苯磺酸盐晶型1。
本发明提供了结构式I所示化合物的苯磺酸盐的另一种优选晶型，该晶型X射线粉末衍射图具有衍射角2θ为4.0°±0.2°，4.9°±0.2°，6.9°±0.2°和18.4°±0.2°的特征峰。为方便，本发明称之为苯磺酸盐晶型2。
本发明提供了结构式I所示化合物的盐酸盐的一种优选晶型，该晶型X射线粉末衍射图具有衍射角2θ为4.2°±0.2°，4.7°±0.2°和6.9°±0.2°的特征峰。为方便，本发明称之为盐酸盐晶型1。
本发明提供了结构式I所示化合物的磷酸盐的一种优选晶型，该晶型X射线粉末衍射图具有衍射角2θ为7.5°±0.2°，15.1°±0.2°，16.4°±0.2°，18.9°±0.2°和26.8°±0.2°的特征峰。为方便，本发明称之为磷酸盐晶型1。
本发明提供了结构式I所示化合物的L-酒石酸盐的一种晶型，该晶型X射线粉末衍射图具有衍射角2θ为7.6°±0.2°，18.8°±0.2°和27.3°±0.2°的特征峰。为方便，本发明称之为L-酒石酸盐晶型1。
本发明提供了结构式I所示化合物的L-苹果酸盐的一种优选晶型，该晶型X射线粉末衍射图具有衍射角2θ为3.6°±0.2°，7.4°±0.2°和18.8°±0.2°的特征峰。为方便，本发明称之为L-苹果酸盐晶型1。
本发明提供了结构式I所示化合物的柠檬酸盐的一种晶型，该晶型X射线粉末衍射图具有衍射角2θ为3.5°±0.2°，7.3°±0.2°和18.7°±0.2°的特征峰。为方便，本发明称之为柠檬酸盐晶型1。
本发明提供了结构式I所示化合物的富马酸盐的一种优选晶型，该晶型X射线粉末衍射图具有衍射角2θ为5.5°±0.2°，5.7°±0.2°和19.3°±0.2°的特征峰。为方便，本发明称之为富马酸盐晶型1。
本发明提供了结构式I所示化合物的富马酸盐的另一种优选晶型，该晶型X射线粉末衍射图具有衍射角2θ为4.5°±0.2°的特征峰。为方便，本发明称之为富马酸盐晶型2。
所述X射线粉末衍射图均使用Cu靶的Kα谱线测得。
本发明进一步提供了所述马来酸盐晶型1的优选实施方式：
作为优选，该马来酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.6°±0.2°，8.4°±0.2°，11.2°±0.2°，17.0°±0.2°，19.7±0.2°，22.6°±0.2°，25.4±0.2°，28.3°±0.2°的特征峰。
作为优选，该马来酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.6°±0.2°，8.4°±0.2°，11.2°±0.2°，17.0°±0.2°，19.7±0.2°，22.6°±0.2°，23.3°±0.2°，25.4±0.2°，28.3°±0.2°的特征峰。
作为优选，该马来酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.6°±0.2°，8.4°±0.2°，11.2°±0.2°，14.0°±0.2°，17.0°±0.2°，19.7±0.2°，22.6°±0.2°，23.3°±0.2°，25.4±0.2°，28.3°±0.2°的特征峰。
作为优选，该马来酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.6°±0.2°，8.4°±0.2°，11.2°±0.2°，15.3°±0.2°，15.9°±0.2°，17.0°±0.2°，17.5°±0.2°，18.5°±0.2°，19.7°±0.2°，22.6°±0.2°，23.3°±0.2°，25.4°±0.2°，26.3°±0.2°，27.5°±0.2°和28.3°±0.2°的特征峰。
更优选地，所述马来酸盐晶型1的X射线粉末衍射图的主要数据如表1所示。
表1
Figure PCTCN2019102720-appb-000002
Figure PCTCN2019102720-appb-000003
作为优选，所述马来酸盐晶型1具有约如图1所示的X射线粉末衍射图。
作为优选，所述马来酸盐晶型1具有约如图2所示的X射线粉末衍射图。
进一步地，所述马来酸盐晶型1具有基本上如图4所示的差式扫描量热(DSC)图谱。所述苯磺酸盐晶型1吸热峰起始温度(onset temperature)约为216℃，以及峰值温度约为221℃。
进一步地，所述马来酸盐晶型1具有基本上如图5所示的热重分析(TGA)图谱。进一步地，所述马来酸盐晶型1具有基本上如图6所示的 1H-NMR图谱。
本发明进一步提供了所述马来酸盐晶型2的优选实施方式：
作为优选，所述马来酸盐晶型2的X射线粉末衍射图具有衍射角2θ为5.9°±0.2°，11.7°±0.2°，17.6°±0.2°，20.6°±0.2°和23.5°±0.2°的特征峰。
更优选地，马来酸盐晶型2的X射线粉末衍射图的主要数据如表2所示。
表2
Figure PCTCN2019102720-appb-000004
作为优选，所述马来酸盐晶型2具有约如图7所示的X射线粉末衍射图谱。
进一步地，所述马来酸盐晶型2具有基本上如图8所示的差式扫描量热(DSC)图谱。
进一步地，所述马来酸盐晶型2具有基本上如图9所示的热重分析(TGA)图谱。
本发明进一步提供了结构式I所示化合物马来酸盐的无定型物，该无定型物具有如图10所示的X射线粉末衍射图，可知未见衍射峰。升温至160℃后出现了马来酸盐晶型1的衍射峰，如图11所示。
本发明进一步提供了所述甲磺酸盐晶型1的优选实施方式：
作为优选，所述甲磺酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.7°±0.2°，9.4°±0.2°，10.7°±0.2°，12.1°±0.2°，14.1°±0.2°和19.0°±0.2°的特征峰。
作为优选，所述甲磺酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.7°±0.2°，9.4°±0.2°，10.7°±0.2°，12.1°±0.2°，14.1°±0.2°，16.3°±0.2°，16.8°±0.2°和19.0°±0.2°的特征峰。
作为优选，所述甲磺酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.7°±0.2°，9.4°±0.2°，10.7°±0.2°，12.1°±0.2°，14.1°±0.2°，16.3°±0.2°，16.8°±0.2°，19.0°±0.2°，21.1°±0.2°，21.4°±0.2°，23.9°±0.2°和28.2°±0.2°的特征峰。
更优选地，所述甲磺酸盐晶型1的X射线粉末衍射图的主要数据如表3所示。
表3
Figure PCTCN2019102720-appb-000005
Figure PCTCN2019102720-appb-000006
作为优选，所述甲磺酸盐晶型1具有约如图12所示的X射线粉末衍射图。
进一步地，所述甲磺酸盐晶型1在25℃水中溶解度约为1.0mg/mL。
进一步地，所述甲磺酸盐晶型1具有基本上如图13所示的热台XRD图谱。其中，所述甲磺酸盐晶型1升温至100℃，晶型未变。
进一步地，所述甲磺酸盐晶型1具有基本上如图14所示的热重分析(TGA)图谱。
进一步地，所述甲磺酸盐晶型1具有基本上如图15所示的差式扫描量热图(DSC)。
进一步地，所述甲磺酸盐晶型1具有基本上如图16所示的 1H-NMR图谱。
本发明进一步提供了所述甲磺酸盐晶型2的优选实施方式：
作为优选，所述甲磺酸盐晶型2的X射线粉末衍射图具有衍射角2θ为3.9°±0.2°，4.8°±0.2°，6.5°±0.2°，13.0°±0.2°，13.9°±0.2°，15.7°±0.2°和20.4°±0.2° 的特征峰。
作为优选，所述甲磺酸盐晶型2的X射线粉末衍射图具有衍射角2θ为3.9°±0.2°，4.8°±0.2°，6.5°±0.2°，8.0°±0.2°，11.9°±0.2°，12.4°±0.2°，13.0°±0.2°，13.9°±0.2°，15.7°±0.2°，16.4°±0.2°，18.7°±0.2°，19.6°±0.2°，19.8°±0.2°，20.4°±0.2°，21.6°±0.2°，22.4°±0.2°，23.7°±0.2°和24.6°±0.2°的特征峰。
更优选地，所述甲磺酸盐晶型2的X射线粉末衍射图的主要数据如表4所示。
表4
Figure PCTCN2019102720-appb-000007
作为优选，所述甲磺酸盐晶型2具有约如图17所示的X射线粉末衍射图。
进一步地，所述甲磺酸盐晶型2在25℃水中溶解度约为5.0mg/mL。
进一步地，所述甲磺酸盐晶型2具有基本上如图18所示的热台XRD图谱。其中，所述甲磺酸盐晶型2升温至100℃，晶型未明显改变。
进一步地，所述甲磺酸盐晶型2具有基本上如图19所示的热重分析(TGA)图谱。
进一步地，所述甲磺酸盐晶型2具有基本上如图20所示的差式扫描量热图(DSC)。
进一步地，所述甲磺酸盐晶型2具有基本上如图21所示的 1H-NMR图谱
本发明进一步提供了所述苯磺酸盐晶型1的优选实施方式：
作为优选，所述苯磺酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.5°±0.2°，7.9°±0.2°，12.5°±0.2°，12.9°±0.2°，18.1°±0.2°，20.4°±0.2°和21.5°±0.2°的特征峰。
作为优选，所述苯磺酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.5°±0.2°，6.3°±0.2°，7.9°±0.2°，9.0°±0.2°，12.5°±0.2°，12.9°±0.2°，13.9°±0.2°，15.7°±0.2°，16.3°±0.2°，18.1°±0.2°，18.9°±0.2°，19.3°±0.2°，20.4°±0.2°，21.5°±0.2°，24.3°±0.2°和26.2°±0.2°的特征峰。
更优选地，所述苯磺酸盐晶型1的X射线粉末衍射图的主要数据如表5所示。
表5
Figure PCTCN2019102720-appb-000008
作为优选，所述苯磺酸盐晶型1具有约如图22所示的X射线粉末衍射图。
进一步地，所述苯磺酸盐晶型1在25℃水中溶解度约为0.08mg/mL。
进一步地，对所述苯磺酸盐晶型1进行差示扫描量热法分析，所述苯磺酸盐晶型1吸热峰起始温度约为224℃，以及峰值温度约为234℃。
进一步地，对所述苯磺酸盐晶型1进行热重分析，热重分析显示所述苯磺酸盐晶型1在120℃之前失重约3.8％。
进一步地，所述苯磺酸盐晶型1具有基本上如图23所示的 1H-NMR图谱。
本发明进一步提供了所述苯磺酸盐晶型2的优选实施方式：
作为优选，所述苯磺酸盐晶型2的X射线粉末衍射图具有衍射角2θ为4.0°±0.2°，4.5°±0.2°，4.9°±0.2°，6.9°±0.2°，14.4°±0.2°，14.7°±0.2°，18.4°±0.2°和24.1°±0.2°的特征峰。
更优选地，所述苯磺酸盐晶型2的X射线粉末衍射图的主要数据如表6所示。
表6
Figure PCTCN2019102720-appb-000009
Figure PCTCN2019102720-appb-000010
作为优选，所述苯磺酸盐晶型2具有约如图24所示的X射线粉末衍射图。
进一步地，所述苯磺酸盐晶型2在25℃水中溶解度约为1.0mg/mL。
进一步地，热重分析显示所述苯磺酸盐晶型2在120℃之前失重约7.8％。
进一步地，所述苯磺酸盐晶型2具有基本上如图25所示的差式扫描量热图(DSC)。
进一步地，所述苯磺酸盐晶型2具有如图26所示的 1H-NMR图谱。
本发明进一步提供了所述盐酸盐晶型1的优选实施方式：
作为优选，所述盐酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.2°±0.2°，4.7°±0.2°，6.9°±0.2°，9.3°±0.2°，12.1°±0.2°，14.0°±0.2°，14.6°±0.2°，15.6°±0.2°和19.7°±0.2°的特征峰。
更优选地，所述盐酸盐晶型1的X射线粉末衍射图的主要数据如表7所示。
表7
Figure PCTCN2019102720-appb-000011
Figure PCTCN2019102720-appb-000012
作为优选，所述盐酸盐晶型1具有约如图27所示的X射线粉末衍射图。
进一步地，所述盐酸盐晶型1在25℃水中溶解度约为1.25mg/mL。
进一步地，差示扫描量热法分析显示，所述盐酸盐晶型1吸热峰起始温度约为216℃，以及峰值温度约为223℃。
进一步地，热重分析显示所述盐酸盐晶型1在120℃之前失重约8.8％。
本发明进一步提供了所述磷酸盐晶型1的优选实施方式：
作为优选，所述磷酸盐晶型1的X射线粉末衍射图具有衍射角2θ为7.5°±0.2°，12.6°±0.2°，15.1°±0.2°，16.4°±0.2°，18.1°±0.2°，18.3°±0.2°，18.9°±0.2°，19.4°±0.2°，21.4°±0.2°，22.2°±0.2°和26.8°±0.2°的特征峰。
作为优选，所述磷酸盐晶型1的X射线粉末衍射图具有衍射角2θ为7.5°±0.2°，9.2°±0.2°，9.5°±0.2°，10.4°±0.2°，12.6°±0.2°，13.0°±0.2°，13.8°±0.2°，14.5°±0.2°，15.1°±0.2°，16.4°±0.2°，18.1°±0.2°，18.3°±0.2°，18.9°±0.2°，19.4°±0.2°，20.1°±0.2°，21.4°±0.2°，22.2°±0.2°，23.3°±0.2°，23.6°±0.2°，25.3°±0.2°，25.6°±0.2°，26.0°±0.2°，26.8°±0.2°和28.1°±0.2°的特征峰。
更优选地，所述磷酸盐晶型1的X射线粉末衍射图的主要数据如表8所示。
表8
Figure PCTCN2019102720-appb-000013
Figure PCTCN2019102720-appb-000014
作为优选，所述磷酸盐晶型1具有约如图28所示的X射线粉末衍射图。
进一步地，所述磷酸盐晶型1在25℃水中溶解度约为0.1mg/mL。
进一步地，热重分析显示所述磷酸盐晶型1在120℃之前失重约4.0％。
进一步地，所述磷酸盐晶型1具有基本上如图29所示的差式扫描量热分析(DSC)图谱。
本发明进一步提供了所述L-酒石酸盐晶型1的优选实施方式：
作为优选，所述L-酒石酸盐晶型1的X射线粉末衍射图具有衍射角2θ为3.6°±0.2°，7.1°±0.2°，7.6°±0.2°，18.8°±0.2°，19.4°±0.2°和27.3°±0.2°的特征峰。
作为优选，所述L-酒石酸盐晶型1的X射线粉末衍射图具有衍射角2θ为3.6°±0.2°，7.1°±0.2°，7.6°±0.2°，9.0°±0.2°，13.1°±0.2°，14.6°±0.2°，15.2°±0.2°，18.8°±0.2°，19.4°±0.2°，20.9°±0.2°，21.4°±0.2°，22.1°±0.2°，23.6°±0.2°和27.3°±0.2°的特征峰。
更优选地，所述L-酒石酸盐晶型1的X射线粉末衍射图的主要数据如表9所示。
表9
Figure PCTCN2019102720-appb-000015
Figure PCTCN2019102720-appb-000016
作为优选，所述L-酒石酸盐晶型1具有约如图30所示的X射线粉末衍射图。
进一步地，所述L-酒石酸盐晶型1在25℃水中溶解度约为0.08mg/mL。
进一步地，差示扫描量热法分析显示，所述L-酒石酸盐晶型1吸热峰起始温度约为201℃，以及峰值温度约为213℃。
进一步第，热重分析显示所述L-酒石酸盐晶型1在120℃之前失重约2.7％。
进一步地，所述L-酒石酸盐晶型1具有基本上如图31所示的 1H-NMR图谱。
本发明进一步提供了所述L-苹果酸盐晶型1的优选实施方式：
作为优选，所述L-苹果酸盐晶型1的X射线粉末衍射图具有衍射角2θ为3.6°±0.2°，7.4°±0.2°，18.8°±0.2°和27.2°±0.2°的特征峰。
作为优选，所述L-苹果酸盐晶型1的X射线粉末衍射图具有衍射角2θ为3.6°±0.2°，7.4°±0.2°，9.0°±0.2°，10.5°±0.2°，13.0°±0.2°，15.1°±0.2°，18.8°±0.2°和27.2°±0.2°的特征峰。
更优选地，所述L-苹果酸盐晶型1的X射线粉末衍射图的主要数据如表10所示。
表10
Figure PCTCN2019102720-appb-000017
Figure PCTCN2019102720-appb-000018
作为优选，所述L-苹果酸盐晶型1具有约如图32所示的X射线粉末衍射图。
进一步地，所述L-苹果酸盐晶型1在25℃水中溶解度约为0.25mg/mL。
进一步地，热重分析显示所述L-苹果酸盐晶型1在3.3％。
进一步地，所述L-苹果酸盐晶型1具有基本上如图33所示的差式扫描量热图(DSC)。
进一步地，所述L-苹果酸盐晶型1具有基本上如图34所示的 1H-NMR图谱。
本发明进一步提供了所述柠檬酸盐晶型1的优选实施方式：
作为优选，所述柠檬酸盐晶型1的X射线粉末衍射图具有衍射角2θ为3.5°±0.2°，7.3°±0.2°，12.5°±0.2°，14.9°±0.2°，18.7°±0.2°，21.0°±0.2°和26.8°±0.2°的特征峰。
更优选地，所述柠檬酸盐晶型1的X射线粉末衍射图的主要数据如表11所示。
表11
Figure PCTCN2019102720-appb-000019
作为优选，所述柠檬酸盐晶型1具有约如图35所示的X射线粉末衍射图。
进一步地，所述柠檬酸盐晶型1在25℃水中溶解度约为0.08mg/mL。
进一步地，差示扫描量热法分析显示，所述柠檬酸盐晶型1吸热峰起始温度约为164℃，以及峰值温度约为188℃。
进一步地，热重分析显示所述柠檬酸盐晶型1在120℃之前失重约2.2％。
进一步地，所述柠檬酸盐晶型1具有基本上如图36所示的 1H-NMR图谱。
本发明进一步提供了所述富马酸盐晶型1的优选实施方式：
作为优选，所述富马酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.5°±0.2°，5.7°±0.2°，17.0°±0.2°，19.3°±0.2°和22.2°±0.2°的特征峰。
作为优选，所述富马酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.5°±0.2°，5.7°±0.2°，17.0°±0.2°，19.3°±0.2°，22.2°±0.2°，23.5°±0.2°和27.0°±0.2°的特征峰。
作为优选，所述富马酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.5°±0.2°，5.7°±0.2°，10.8°±0.2°，13.6°±0.2°，16.1°±0.2°，17.0°±0.2°，18.2°±0.2°，19.3°±0.2°，20.3°±0.2°，22.2°±0.2°，23.5°±0.2°，24.9°±0.2°和27.0°±0.2°的特征峰。
更优选地，所述富马酸盐晶型1的X射线粉末衍射图的主要数据如表12所示。
表12
Figure PCTCN2019102720-appb-000020
Figure PCTCN2019102720-appb-000021
作为优选，所述富马酸盐晶型1具有约如图37所示的X射线粉末衍射图。
本发明进一步提供了所述富马酸盐晶型2的优选实施方式：
作为优选，所述富马酸盐晶型2的X射线粉末衍射图具有衍射角2θ为4.5°±0.2°，9.0°±0.2°和13.4°±0.2°的特征峰。
更优选地，所述富马酸盐晶型2的X射线粉末衍射图的主要数据如表13所示。
表13
Figure PCTCN2019102720-appb-000022
作为优选，所述富马酸盐晶型2具有约如图38所示的X射线粉末衍射图。
进一步地，所述富马酸盐晶型2在25℃水中溶解度小于0.05mg/mL。
进一步地，差示扫描量热法分析显示，所述富马酸盐晶型2吸热峰起始温度约为182℃，以及峰值温度约为194℃。
进一步地，热重分析显示所述富马酸盐晶型1在120℃之前失重约3.2％。
进一步地，所述富马酸盐晶型2具有基本上如图39所示的 1H-NMR图谱。
根据本发明，所述马来酸盐晶型1、马来酸盐晶型2、甲磺酸盐晶型1、甲磺酸盐晶型2、苯磺酸盐晶型1、苯磺酸盐晶型2、盐酸盐晶型1、磷酸盐晶型1、L-酒石酸盐晶型1、L-苹果酸盐晶型1、柠檬酸盐晶型1、富马酸盐晶型1和富马酸盐晶型2的纯度优选大于50％，例如85％以上、99％以上或99.5％以上。
本发明进一步提供了制备结构式I所示化合物及其马来酸盐晶型1、马来酸盐晶型2、马来酸盐无定型、甲磺酸盐晶型1、甲磺酸盐晶型2、苯磺酸盐晶型1、苯磺酸盐晶型2、盐酸盐晶型1、磷酸盐晶型1、L-酒石酸盐晶型1、L-苹果酸盐 晶型1、柠檬酸盐晶型1、富马酸盐晶型1和富马酸盐晶型2的方法。
其中，结构式I所示化合物可通过下述路线制备：
Figure PCTCN2019102720-appb-000023
其中，马来酸盐晶型1的制备方法如下：
将结构式I所示的化合物加入丙酮/水中，60℃搅拌，体系不溶清，将马来酸溶于水后逐滴加入到上述悬浊体系，搅拌溶清，继续搅拌约2分钟至固体析出，60℃下继续搅拌30分钟，自然降至室温后搅拌4天，减压抽滤，所得固体室温真空干燥24小时，制得马来酸盐晶型1；或者，
将马来酸盐晶型1无定型加入二甲亚砜/乙醇、二甲亚砜/丙酮、二甲亚砜/丁酮、二甲亚砜/乙酸乙酯、二甲亚砜/乙腈、三氟乙醇/丁酮、三氟乙醇/甲基叔丁基醚、三氟乙醇/乙酸异丙酯、三氟乙醇/乙腈、水/甲醇、水/乙醇、水/异丙醇、水/丙酮或水/乙腈后，升温至60℃溶清，过滤后置于冰盐浴下搅拌，析出固体后，立即离心制得马来酸盐晶型1；若未析出固体，于4℃搅拌过夜或转室温挥发，析出固体制得马来酸盐晶型1。
其中，马来酸盐晶型2的制备方法如下：
将马来酸盐晶型1加入二甲亚砜中，室温下置于四氢呋喃体系中扩散静置析出晶体，制得马来酸盐晶型2；或者，
将马来酸盐晶型1加入二甲亚砜/四氢呋喃中，60℃搅拌溶清，过滤，滤液搅拌，析出黄色固体，离心室温真空干燥，制得马来酸盐晶型2。
其中，无定型的制备方法如下：
将马来酸盐晶型1加入三氟乙醇/二氯甲烷中，60℃水浴搅拌10分钟，体系不溶清，将悬浊液在40℃下减压浓缩干，得到深黄色固体，制得马来酸盐晶型1 无定型。
其中，甲磺酸盐晶型1的制备方法如下：
将结构式I所示化合物依次加入丙酮和水中，60℃水浴搅拌，未溶清，取甲磺酸溶于水中，滴加到上述悬浊体系中，体系溶清，取出置于室温下搅拌30分钟，无析出，滴加丙酮，析出大量固体，室温继续搅拌3天，减压抽滤，室温真空干燥24小时，制得甲磺酸盐晶型1。
其中，甲磺酸盐晶型2的制备方法如下：
将结构式I所示化合物加入丙酮和水中，60℃水浴搅拌溶清，取甲磺酸溶于丙酮中，滴加到上述澄清体系中，无析出，继续60℃下搅拌30分钟，无析出，自然降至室温，搅拌2天，减压抽滤，室温真空干燥24小时，制得甲磺酸盐晶型2。
其中，苯磺酸盐晶型1的制备方法如下：
取结构式I所示化合物加入丙酮，60℃水浴搅拌，未溶清，取苯磺酸溶于水中，室温下滴加到上述悬浊体系中，体系不溶清，室温下继续搅拌5天，减压抽滤，室温真空干燥24小时，得到苯磺酸盐晶型1。
其中，苯磺酸盐晶型2的制备方法如下：
取结构式I所示化合物依次加入丙酮和水，60℃水浴搅拌溶清，取苯磺酸溶于丙酮中，滴加到上述澄清体系中，无析出，继续60℃下搅拌30分钟，无析出，自然降至室温，搅拌2天析出，减压抽滤，室温真空干燥24小时，得到苯磺酸盐晶型2。
其中，盐酸盐晶型1的制备方法如下：
取结构式I所示化合物加入丙酮分散，50℃水浴搅拌10分钟，再加入水，大部分溶清，取浓盐酸溶于水中，滴加到上述悬浊体系中，析出大量白色沉淀，继续搅拌30分钟后，自然降至室温，搅拌过夜，继续搅拌1天，减压抽滤，45℃真空干燥3小时，得到盐酸盐晶型1。
其中，磷酸盐晶型1的制备方法如下：
取结构式I所示化合物加入丙酮，60℃水浴搅拌，未溶清，取85％的磷酸，溶于水中，室温下滴加到上述悬浊体系中，体系不溶清，室温下继续搅拌5天，减压抽滤，室温真空干燥24小时，得到磷酸盐晶型1。
其中，L-酒石酸盐晶型1的制备方法如下：
取结构式I所示化合物加入异丙醇，60℃搅拌10分钟，体系不溶清，取L-酒石酸溶于水中，逐滴加入到上述悬浊体系中，体系搅拌溶清，继续搅拌10分钟，逐滴加入到异丙醇，无析出，继续搅拌30分钟，无析出，自然降至室温，搅拌过夜，析出固体，减压抽滤，45℃真空干燥3小时，得到L-酒石酸盐晶型1。
其中，L-苹果酸盐晶型1的制备方法如下：
取结构式I所示化合物加入异丙醇分散，60℃搅拌10分钟，未溶清，取L-苹果酸溶于水中，逐滴加入到上述悬浊体系中，体系搅拌溶清，继续搅拌10分钟，逐滴加入异丙醇，无析出，继续搅拌30分钟，无析出，自然降至室温，搅拌过夜，析出固体，减压抽滤，滤饼分别用异丙醇和甲基叔丁基醚淋洗3次，45℃真空干燥3小时，得到L-苹果酸盐晶型1。
其中，柠檬酸盐晶型1的制备方法如下：
取结构式I所示化合物加入异丙醇分散，60℃搅拌10分钟，未溶清，取柠檬酸溶于水中，逐滴加入到上述悬浊体系中，体系搅拌溶清，继续搅拌10分钟，逐滴加入异丙醇，无析出，继续搅拌30分钟，无析出，自然降至室温，搅拌过夜，析出固体，减压抽滤，滤饼分别用异丙醇和甲基叔丁基醚淋洗3次，45℃真空干燥3小时，得到柠檬酸盐晶型1。
其中，富马酸盐晶型1的制备方法如下：
取结构式I所示化合物加入四氢呋喃，60℃搅拌溶清，取富马酸溶于四氢呋喃中，室温下逐滴加入到上述溶清体系中，无析出，继续室温搅拌4天，析出固体，离心，室温真空干燥4小时，得到富马酸盐晶型1。
其中，富马酸盐晶型2的制备方法如下：
取结构式I所示化合物加入异丙醇分散，60℃搅拌10分钟，体系不溶清，取富马酸溶于水中，逐滴加入到上述悬浊体系中，体系搅拌溶清，继续搅拌30分钟，无析出，自然降至室温，搅拌过夜，析出固体，继续室温搅拌1天，减压抽滤，45℃真空干燥3小时，得到富马酸盐晶型2。
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盐型或晶型，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，所述盐型或晶型和所述辅料、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的盐型或晶型，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％的本发明的晶型。
本发明进一步提供了所述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由FGFR介导的疾病的药物。
作为优选，所述疾病是癌症。
作为优选，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞癌、头颈部肿瘤、颅内肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、许旺式细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
作为优选，所述应用为用作FGFR抑制剂。
作为优选，在上述应用中，所述FGFR包括FGFR1、FGFR2、FGFR3或FGFR4。
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晶型或药物组合物治疗和/或预防由FGFR介导的疾病的方法。
作为优选，在上述方法中，所述FGFR包括FGFR1、FGFR2、FGFR3或FGFR4。
作为优选，在上述方法中，所述FGFR介导的疾病是癌症。
作为优选，在上述方法中，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞癌、头颈部肿瘤、颅内肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、 许旺式细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
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晶型或药物组合物，所述癌症是乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞癌、头颈部肿瘤、颅内肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、许旺式细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
作为优选，在上述方法中，所述的治疗对象为人类。
本发明的所有晶型都是基本上纯的。
本文所用的术语“基本上纯的”是指所述晶型的含量以重量计，不小于85％，优选不小于95％，更优选不小于99％。
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XRD曲线所示强度只是示例性的，不能被用作绝对比较。
本领域的技术人员将会理解，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。
本文所用术语“治疗有效量”是指一个化合物施用于治疗对象时对于治疗一种疾病、或一种疾病或病症的至少一种临床症状时，足以影响对疾病、病症或症 状的这种治疗的量。“治疗有效量”可以随着化合物，疾病、病症和/或疾病或病症的症状，疾病、病症和/或疾病或病症的症状的严重程度，被治疗的患者的年龄，和/或被治疗的患者的体重等变化。在任意特定的情况下，一个合适的量对那些本领域的技术人员可以是显而易见的，也可以是用常规实验确定的。在联合治疗的情况下，“治疗有效量”是指有效治疗疾病、病症或病状的联用对象的总量。
本发明所述的盐型或晶型可以合并用药作为活性组分，与药物载体混合成药物组合物。所述药物载体可以采取各种各样的形式，取决于想采用的给药方式，例如，口服或注射(包括静脉注射)。因此，本发明的药物组合物可以采用适于口服给药的独立单位的形式。如包含预先确定剂量的活性组分的胶囊剂，扁囊剂或片剂。进一步地，本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液或油包水型乳液形式。另外，除上述提到的常见的剂型，本发明所述的盐型或晶型也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下，这种方法包括使活性组分和构成一个或多个必要组分的载体缔合的步骤。一般情况下，所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过均匀的密切混合制得。另外，该产品可以方便地制备成所需要的外观。
“药学上可接受的载体”是指适合于期望药物制剂的常规的药用载体，例如：诸如水、各种有机溶剂等的稀释剂、赋形剂；诸如淀粉、预胶化淀粉、蔗糖、糊精、甘露醇、乳糖、喷雾干燥乳糖、微晶纤维素、硅化微晶纤维素、无机盐类等的填充剂；诸如淀粉浆、糊精、糖粉、糖浆、胶浆、聚乙二醇、纤维素衍生物、藻酸盐、明胶、羟丙纤维素、共聚维酮和聚乙烯吡咯烷酮(PVP)等的粘合剂；诸如蒸馏水、乙醇和甘油等的湿润剂；诸如干淀粉、低取代羟丙纤维素、羟丙基淀粉、琼脂、碳酸钙、碳酸氢钠、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠等的崩解剂；诸如季铵化合物、氨基酸乙胺衍生物、乙酰醋酸酯类、β-二羧酸酯、芳香族酸性化合物、脂肪族酸性化合物等的吸收促进剂；诸如十六烷基硫酸钠、十八烷基硫酸钠、二辛基琥珀酸磺酸钠、十二烷基磺酸钠、苯扎溴铵、苯扎氯铵、杜灭芬、卵磷脂、十六烷醇、十二烷基硫酸钠、吐温和司盘等的表面活性剂；诸如聚乙二醇、卡波姆、纤维素衍生物、甘油明胶、聚乙烯醇、可可豆 酯、合成或全合成脂肪酸甘油酯、聚乙烯醇40硬脂酸酯、凡士林、固体石蜡、液体石蜡、二甲基硅油、羊毛脂、蜂蜡和豚酯等的载药基质；诸如高岭土和膨润土等的吸收载体；诸如滑石粉、微粉硅胶、二氧化硅、氢化植物油、十二烷基硫酸镁、十二烷基硫酸钠、硬脂酸、硬脂酸钙、硬脂酸镁、硬脂富马酸钠和聚乙二醇等的润滑剂。另外还可以在药物组合物中加入其它药学上可接受的辅料，如抗氧剂、着色剂、防腐剂、pH调节剂、硬化剂、乳化剂、抛射剂、分散剂、稳定剂、增稠剂、络合剂、缓冲剂、渗透促进剂、聚合物、芳香剂、甜味剂和染料。优选使用适合期望剂型和期望给药方式的辅料。
术语“疾病”或“病症”或“病状”是指任意的疾病、不适、病、症状或者适应症。
附图说明
图1：结构式I所示化合物的马来酸盐晶型1的X射线粉末衍射图谱。(以批号为20180227-2的样品为原料制备而成的马来酸盐晶型1)
图2：结构式I所示化合物的马来酸盐晶型1的X射线粉末衍射图谱。(以批号为20180123的样品为原料制备而成的马来酸盐晶型1)
图3：图1和图2的图谱比较。
图4：结构式I所示化合物的马来酸盐晶型1的差式扫描量热图谱。
图5：结构式I所示化合物的马来酸盐晶型1的热重分析图谱。
图6：结构式I所示化合物的马来酸盐晶型1的 1H-NMR图谱。
图7：结构式I所示化合物的马来酸盐晶型2的X射线粉末衍射图谱。
图8：结构式I所示化合物的马来酸盐晶型2的差式扫描量热图谱。
图9：结构式I所示化合物的马来酸盐晶型2的热重分析图谱。
图10：结构式I所示化合物的无定型的X射线粉末衍射图谱。
图11：结构式I所示化合物的无定型的热台X射线粉末衍射图谱。
图12：结构式I所示化合物的甲磺酸盐晶型1的X射线粉末衍射图谱。
图13：结构式I所示化合物的甲磺酸盐晶型1的热台X射线粉末衍射图谱。
图14：结构式I所示化合物的甲磺酸盐晶型1的热重图谱。
图15：结构式I所示化合物的甲磺酸盐晶型1的差式扫描量热图谱。
图16：结构式I所示化合物的甲磺酸盐晶型1的 1H-NMR图谱。
图17：结构式I所示化合物的甲磺酸盐晶型2的X射线粉末衍射图谱。
图18：结构式I所示化合物的甲磺酸盐晶型2的热台X射线粉末衍射图谱。
图19：结构式I所示化合物的甲磺酸盐晶型2的热重图谱。
图20：结构式I所示化合物的甲磺酸盐晶型2的差式扫描量热图谱。
图31：结构式I所示化合物的甲磺酸盐晶型2的 1H-NMR图谱。
图22：结构式I所示化合物的苯磺酸盐晶型1的X射线粉末衍射图谱。
图23：结构式I所示化合物的苯磺酸盐晶型1的 1H-NMR图谱。
图24：结构式I所示化合物的苯磺酸盐晶型2的X射线粉末衍射图谱。
图25：结构式I所示化合物的苯磺酸盐晶型2的差式扫描量热图谱。
图26：结构式I所示化合物的苯磺酸盐晶型2的 1H-NMR图谱。
图27：结构式I所示化合物的盐酸盐晶型1的X射线粉末衍射图谱。
图28：结构式I所示化合物的磷酸盐晶型1的X射线粉末衍射图谱。
图29：结构式I所示化合物的磷酸盐晶型1的差式扫描量热图谱。
图30：结构式I所示化合物的L-酒石酸盐晶型1的X射线粉末衍射图谱。
图31：结构式I所示化合物的L-酒石酸盐晶型1的 1H-NMR图谱。
图32：结构式I所示化合物的L-苹果酸盐晶型1的X射线粉末衍射图谱。
图33：结构式I所示化合物的L-苹果酸盐晶型1的差式扫描量热图谱。
图34：结构式I所示化合物的L-苹果酸盐晶型1的 1H-NMR图谱。
图35：结构式I所示化合物的柠檬酸盐晶型1的X射线粉末衍射图谱。
图36：结构式I所示化合物的柠檬酸盐晶型1的 1H-NMR图谱。
图37：结构式I所示化合物的富马酸盐晶型1的X射线粉末衍射图谱。
图38：结构式I所示化合物的富马酸盐晶型2的X射线粉末衍射图谱。
图39：结构式I所示化合物的富马酸盐晶型2的 1H-NMR图谱。
图40：结构式I所示化合物的马来酸盐晶型1的等温吸附曲线。
图41：结构式I所示化合物的甲磺酸盐晶型1的等温吸附曲线。
图42：结构式I所示化合物的甲磺酸盐晶型2的等温吸附曲线。
图43：结构式I所示化合物的苯磺酸盐晶型1的等温吸附曲线。
图44：结构式I所示化合物的苯磺酸盐晶型2的等温吸附曲线。
图45：结构式I所示化合物的盐酸盐晶型1的等温吸附曲线。
图46：结构式I所示化合物的马来酸盐晶型1的影响因素实验的X射线粉末衍射图谱。
图47：结构式I所示化合物的甲磺酸盐晶型1的影响因素实验的X射线粉末衍射图谱。
图48：结构式I所示化合物的影响因素实验的X射线粉末衍射图谱。
图49：结构式I所示化合物的马来酸盐晶型1的影响因素实验的热重分析图谱。
图50：结构式I所示化合物的甲磺酸盐晶型1的影响因素实验的热重分析图谱。
图51：结构式I所示化合物的马来酸盐晶型2室温干燥放置1天的X射线粉末衍射图谱。
图52：结构式I所示化合物的马来酸盐晶型2的热台X射线粉末衍射图谱。
图53：结构式I所示化合物在NCI-H1581异种移植裸鼠模型上的抗肿瘤活性。
图54：结构式I所示化合物在SNU-16异种移植裸鼠模型上的抗肿瘤活性。
图55：结构式I所示化合物及其马来酸盐晶型1的血药浓度-时间曲线(给药剂量10mg/kg)。
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下：
表14
Figure PCTCN2019102720-appb-000024
Figure PCTCN2019102720-appb-000025
表15
设备名称 差热分析扫描仪(DSC)
仪器 TA Instruments Q200DSC
控制软件 Thermal Advantage
分析软件 Universal Analysis
样品盘 铝坩埚(加盖不打孔)
样品检测量 0.5-5mg
保护气体 氮气
气体流速 40mL/min
常用检测方法 Equilibrate at 25℃；Ramp 10℃/min to 300℃
表16
Figure PCTCN2019102720-appb-000026
表17
Figure PCTCN2019102720-appb-000027
Figure PCTCN2019102720-appb-000028
表18
Figure PCTCN2019102720-appb-000029
表19
Figure PCTCN2019102720-appb-000030
表20.溶解度测定
Figure PCTCN2019102720-appb-000031
表21
仪器 恒温恒湿箱
型号 SHH-250SD
生产厂家 重庆市永生实验仪器厂
温度 40℃
相对湿度 75％
具体操作方法 样品装于表面皿中，敞口避光放置
表22
仪器 高温烘箱
型号 DHG-9053A
生产厂家 上海精宏实验设备有限公司
温度设置 60℃
具体操作方法 样品装于表面皿中，敞口避光放置
表23
仪器 光照箱
型号 SHH-100GD-2
生产厂家 重庆市永生实验仪器厂
温度 25℃
照度 4500lux±500lux
具体操作方法 样品装于表面皿中，敞口避光放置
具体实施方式
下面通过给出的实施例对本发明作出进一步说明，但所述实施例并不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：
API：原料药；
ATCC：美国模式培养物集存库
DCM：二氯甲烷；
13C-NMR：13C核磁共振；
DMSO：二甲基亚砜；
h：小时；
1H-NMR：1H核磁共振；
HPLC：高效液相色谱；
LC/MS：液相色谱-质谱联用；
m-CPBA：间氯过氧苯甲酸；
min：分钟；
PO：口服；
RH：相对湿度；
RRT：相对保留时间；
TFA：三氟乙酸；
TGA：热重分析：
UPLC：超高效液相色谱；
XRD：X射线粉末衍射。
中间体M1的制备
Figure PCTCN2019102720-appb-000032
步骤1：化合物M1-2的制备
将500g化合物M1-1、651gTEA和782ml氨水(25％)溶于2.4L THF中，RT下搅拌12hrs。反应混合物用水稀释，用EA萃取，水洗，无水Na2SO4干燥，减压浓缩得到450g化合物M1-2，产率98.3％，不必纯化直接用于下一步。
LC-MS[M+H+]214。
步骤2：化合物M1-3的制备
-20℃氮气保护，将570ml LiAlH4(2.5N，悬浮于THF中)搅拌下滴加入250g化合物M1-2溶于2LTHF形成的混合液中，反应混合物在-10℃以下搅拌反应3hrs，50ml水加入反应液中终止反应，15℃以下，搅拌下加入50ml 15％NaOH溶液，再加入150ml水。混合液过滤，滤饼用EA洗涤，收集滤液，减压浓缩，得到180g化合物M1-3，产率89.7％，不必纯化，直接用于下一步反应。
LC-MS[M+H+]172.1。
步骤3：化合物M1的制备
320g M1-3、1465g MnO2和3L DCM的混合物RT下搅拌12hrs，过滤，滤饼用DCM洗涤，收集滤液，减压浓缩得261g M1，产率为82.5％，不必纯化直接用于下一步。
化合物A的合成
Figure PCTCN2019102720-appb-000033
步骤1：化合物a-2的制备
16.77g a-1、11.17g M1、27.33g K 2CO 3和150ml DMF的混合物于110℃下搅拌12hrs。反应混合液冷却至RT，倾入冰水中，过滤，滤饼用水洗，减压干燥，得到17.21g化合物a-2，黄色固体，不必纯化直接用于下一步反应。
LC-MS[M+H+]363.1。
步骤2：化合物a-3的制备
16.75g a-1溶于50ml乙酸中，RT搅拌下，分次加入15.97gNaNO 2，反应混合物于70℃下搅拌3hrs，冷却至RT，倒入冰水中，过滤，滤饼用水洗涤，减压干燥，得到15.21g化合物a-3，淡黄色固体。
LC-MS[M+H+]364.0。
步骤3：化合物a-4的制备
2.71g a-3和50ml三氯氧磷的混合物于100℃搅拌3hrs，反应液浓缩，转移 走大部分三氯氧磷，残余物用冰水终止反应。用饱和NaHCO 3调节pH至8，混合液用EA萃取，饱和氯化钠洗涤，无水Na 2SO 4干燥，减压浓缩，得到3.01g化合物a-4，白色固体，不必纯化直接用于下一步反应。
步骤4：化合物a-5的制备
500mg化合物a-4、818mg水合肼(80％)和25ml乙醇的混合物回流2hrs，减压浓缩得到520mg化合物a-5粗品，黄色固体，不必纯化直接用于下一步反应。
LC-MS[M+H+]378.1。
步骤5：化合物A的制备
520mg化合物a-5和25ml甲酸回流反应1h，反应混合液用水稀释，过滤，滤饼用水洗涤，得到310mg化合物A，浅黄色固体，产率58％。
LC-MS[M+H+]388.1。
实施例1：结构式I所示化合物的合成：
Figure PCTCN2019102720-appb-000034
步骤1：化合物B的合成
搅拌状态下，取化合物A(100.01g)、DCM(2000mL)和TFA(130mL)依次加入到10L三口瓶中，搅拌至体系溶清。反应体系降温至0℃至-5℃，将m-CPBA溶于乙酸乙酯后逐滴加入上述反应体系中，30min后滴加完毕，保持温度0℃至5℃反应1.5h。薄层色谱监测(DCM∶甲醇＝15∶1)，并取样进行LC-MS 检测反应完全。将103.98g无水亚硫酸钠溶于2600mL水中，逐滴加入反应体系，淬灭反应。10min后滴加完毕，静置、分液。有机相加入1000mL水，搅拌5min，静置，分液。有机相减压浓缩。所得残余物加入1000mL乙酸乙酯打浆1h，过滤。滤饼加入1000mL无水甲醇打浆1h，过滤。滤饼在45℃真空下干燥14h，得到78.57g浅黄色固体B，收率为75.4％。
步骤2：结构式I所示化合物的合成
搅拌状态下，取化合物B(77.52g)、仲丁醇(1550mL)、化合物C(60.21g)和TFA(39mL)依次加入10L三口瓶中，开始加热升温至回流。反应6h后，薄层色谱监测(DCM∶甲醇＝15∶1)，并取样进行LC-MS监测反应完全。冷却降温，反应体系减压浓缩，浓缩残余物加入1162mL无水甲醇中打浆30min至1h，过滤。滤饼加入775mL无水甲醇打浆10min至30min，过滤。滤饼取样进行UPLC纯度检测。取滤饼加入无水甲醇(1077mL)、DCM(5385mL)和TFA(179mL)，搅拌溶清，过滤。将428.10g无水碳酸钾溶于4200mL水中，逐滴加入滤液中，搅拌，调节PH至碱性，静置，分液。有机相减压浓缩，所得固体加入898mL无水甲醇打浆1h，过滤。滤饼在45℃真空下干燥12h，得到105.36g结构式I所示化合物，收率为91.3％。
实施例2：结构式I所示化合物的马来酸盐晶型1的制备方法一
取4.0g结构式I所示化合物，加入200mL丙酮和36mL水，60℃搅拌，体系不溶清，取2.318g马来酸，溶于4.0mL水中，逐滴加入到上述悬浊体系中，体系搅拌溶清，继续搅拌约2分钟，析出固体，继续60℃搅拌30分钟，自然降至室温，搅拌4天，减压抽滤，室温真空干燥24小时，制得5.336g结构式I所示化合物的马来酸盐晶型1。
实施例3：结构式I所示化合物的马来酸盐晶型1的制备方法二
将40.03g结构式I所示化合物加入到800mL无水甲醇中，加入400mL水，升温至50℃。将8.50g马来酸溶于40mL水中，逐滴加入上述反应体系，体系逐渐全部溶清，趁热过滤。滤液转移至5L三口瓶中，搅拌下加入1200mL无水甲醇，加热升温到50℃。将14.69g马来酸溶于60mL水中，逐滴加入反应体系中， 滴加完毕，自然降温，搅拌过夜。过滤，滤饼用无水甲醇淋洗。滤饼在60℃下真空干燥20h，制得53.27g浅黄色固体，即为结构式I所示化合物的马来酸盐晶型1，收率为96.0％。
实施例4：结构式I所示化合物的马来酸盐晶型2的制备方法一
取约10mg马来酸盐晶型1，加入0.1mL二甲亚砜中，室温下置于四氢呋喃体系中扩散静置析晶，制得马来酸盐晶型2。
实施例5：结构式I所示化合物的马来酸盐晶型2的制备方法二
取约10mg马来酸盐晶型1，先后依次加入0.1mL二甲亚砜和5.0mL四氢呋喃，60℃搅拌溶清，过滤，滤液置于冰盐浴中搅拌，析出黄色固体，离心室温真空干燥，制得马来酸盐晶型2。
实施例6：结构式I所示化合物的甲磺酸盐晶型1的制备方法
取400mg结构式I所示化合物依次加入20mL丙酮和2mL水，60℃水浴搅拌，未溶清，取70.35mg甲磺酸溶于2.0mL水中，滴加到上述悬浊体系中，体系溶清，取出置于室温下搅拌30分钟，无析出，滴加20mL丙酮，析出大量固体，室温继续搅拌3天，减压抽滤，室温真空干燥24小时，得到342mg甲磺酸盐晶型1。
实施例7：结构式I所示化合物的甲磺酸盐晶型2的制备方法
取200mg结构式I所示化合物加入10mL丙酮和2mL水，60℃水浴搅拌溶清，取96mg甲磺酸溶于0.2mL丙酮中，滴加到上述澄清体系中，无析出，继续60℃下搅拌30分钟，无析出，自然降至室温，搅拌2天，减压抽滤，室温真空干燥24小时，得到160mg甲磺酸晶型2。
实施例8：结构式I所示化合物的苯磺酸盐晶型1的制备方法
取100mg结构式I所示化合物加入20mL丙酮，60℃水浴搅拌，未溶清，取28.94mg苯磺酸溶于1.0mL水中，室温下滴加到上述悬浊体系中，体系不溶清，室温下继续搅拌5天，减压抽滤，室温真空干燥24小时，得到54mg苯磺酸盐晶型1。
实施例9：结构式I所示化合物的苯磺酸盐晶型2的制备方法
取200mg结构式I所示化合物依次加入10mL丙酮和2.0mL水，60℃水浴搅拌溶清，取158mg苯磺酸溶于0.2mL丙酮中，滴加到上述澄清体系中，无析出，继续60℃下搅拌30分钟，无析出，自然降至室温，搅拌2天析出，减压抽滤，室温真空干燥24小时，得到141mg苯磺酸盐晶型2。
实施例10：结构式I所示化合物的盐酸盐晶型1的制备方法
取200mg结构式I所示化合物加入10mL丙酮分散，50℃水浴搅拌10分钟，再加入1.8mL水，大部分溶清，取101.09mg浓盐酸溶于0.2mL水中，滴加到上述悬浊体系中，析出大量白色沉淀，继续搅拌30分钟后，自然降至室温，搅拌过夜，继续搅拌1天，减压抽滤，45℃真空干燥3小时，得到158mg盐酸盐晶型1。
实施例11：结构式I所示化合物的磷酸盐晶型1的制备方法
取100mg结构式I所示化合物加入20mL丙酮，60℃水浴搅拌，未溶清，取21.10mg 85％的磷酸，溶于1.0mL水中，室温下滴加到上述悬浊体系中，体系不溶清，室温下继续搅拌5天，减压抽滤，室温真空干燥24小时，得到51mg磷酸盐晶型1。
实施例12：结构式I所示化合物的L-酒石酸盐晶型1的制备方法
取150mg结构式I所示化合物加入2.5mL异丙醇，60℃搅拌10分钟，体系不溶清，取112mg L-酒石酸溶于2.5mL水中，逐滴加入到上述悬浊体系中，体系搅拌溶清，继续搅拌10分钟，逐滴加入到7.5mL异丙醇，无析出，继续搅拌30分钟，无析出，自然降至室温，搅拌过夜，析出固体，减压抽滤，45℃真空干燥3小时，得到120mg L-酒石酸盐晶型1。
实施例13：结构式I所示化合物的L-苹果酸盐晶型1的制备方法
取150mg结构式I所示化合物加入2.5mL异丙醇分散，60℃搅拌10分钟，未溶清，取100mg L-苹果酸溶于2.5mL水中，逐滴加入到上述悬浊体系中，体系搅拌溶清，继续搅拌10分钟，逐滴加入7.5mL异丙醇，无析出，继续搅拌30 分钟，无析出，自然降至室温，搅拌过夜，析出固体，减压抽滤，滤饼分别用异丙醇和甲基叔丁基醚淋洗3次，45℃真空干燥3小时，得到120mg L-苹果酸盐晶型1。
实施例14：结构式I所示化合物的柠檬酸盐晶型1的制备方法
取150mg结构式I所示化合物加入2.5mL异丙醇分散，60℃搅拌10分钟，未溶清，取144mg柠檬酸溶于2.5mL水中，逐滴加入到上述悬浊体系中，体系搅拌溶清，继续搅拌10分钟，逐滴加入7.5mL异丙醇，无析出，继续搅拌30分钟，无析出，自然降至室温，搅拌过夜，析出固体，减压抽滤，滤饼分别用异丙醇和甲基叔丁基醚淋洗3次，45℃真空干燥3小时，得到124mg柠檬酸盐晶型1。
实施例15：结构式I所示化合物的富马酸盐晶型1的制备方法
取20mg结构式I所示化合物加入5.0mL四氢呋喃，60℃搅拌溶清，取4.25mg富马酸溶于0.2mL四氢呋喃中，室温下逐滴加入到上述溶清体系中，无析出，继续室温搅拌4天，析出固体，离心，室温真空干燥4小时，得到富马酸盐晶型1。
实施例16：结构式I所示化合物的富马酸盐晶型2的制备方法
取150mg结构式I所示化合物加入2.5mL异丙醇分散，60℃搅拌10分钟，体系不溶清，取87mg富马酸溶于5mL水中，逐滴加入到上述悬浊体系中，体系搅拌溶清，继续搅拌30分钟，无析出，自然降至室温，搅拌过夜，析出固体，继续室温搅拌1天，减压抽滤，45℃真空干燥3小时，得到124mg富马酸盐晶型2。
实施例17结构式I所示化合物的马来酸盐晶型1XRD分析结果
参考本发明实施例1所提供的制备方法获得结构式I化合物两个批次不同批量的样品(批号为：20180227-2和20180123)，然后根据实施例2的制备方法获得两个批次不同批量的马来酸盐晶型1，并对其分别进行表征，XRD谱图分别见图1-图3，谱图分析数据分别见表24和表25。
表24 以批号为20180227-2的样品为原料制备而成的马来酸盐晶型1XRD谱图解析数据
序号 2θ±0.2(° ) 相对强度(％)
1 5.6 50.9
2 8.4 46.9
3 10.7 3.5
4 11.2 47.5
5 12.6 6.5
6 13.3 9.4
7 14.0 14.9
8 15.3 93.1
9 15.6 36.3
10 15.9 75.9
11 16.3 39.1
12 17.0 48.2
13 17.5 83.4
14 17.9 17.9
15 18.3 22.9
16 18.5 43.0
17 19.7 80.5
18 20.1 25.2
19 20.7 7.2
20 21.0 3.8
21 21.9 11.3
22 22.6 93.2
23 23.3 40.9
24 24.6 7.7
25 25.0 10.1
26 25.4 63.1
27 26.3 48.2
28 26.9 6.7
29 27.5 53.4
30 28.3 100
31 29.1 5.5
32 30.4 11.9
33 31.1 4.6
34 31.7 5.2
35 32.5 6.3
36 33.6 7.8
37 34.3 5.8
38 35.5 4.2
39 36.2 2.7
40 37.1 3.9
41 37.7 2.7
表25 以批号为20180123的样品为原料制备而成的马来酸盐晶型1XRD谱图解析数据
序号 2θ±0.2(° ) 相对强度(％)
1 5.7 42.6
2 8.5 39.2
3 11.3 29.6
4 12.6 2.2
5 13.5 3.1
6 14.1 13.9
7 15.5 3.3
8 15.7 11.4
9 16.1 2.3
10 16.4 2.5
11 16.9 54.6
12 17.6 3.0
13 18.3 1.4
14 18.6 3.2
15 19.8 73.1
16 20.1 2.5
17 20.7 2.2
18 22.0 2.2
19 22.6 100.0
20 23.4 25.3
21 24.7 4.7
22 25.0 15.4
23 25.5 59.5
24 26.1 18.1
25 27.0 2.3
26 27.5 3.1
27 28.4 44.5
28 30.3 2.4
29 30.6 1.8
30 31.3 2.4
31 31.8 2.7
32 33.6 1.4
33 34.4 3.4
34 36.3 1.7
35 36.8 1.1
36 37.1 1.7
根据所述XRD谱图分析数据和图3的对比图，本领域技术人员应了解，两个批次的马来酸盐晶型1的分析数据表和XRD谱图中所记录的各个峰的相对强度可由诸多因素(如X射线束中的晶体定向作用及分析物质纯度等)的变化而变化，峰位置亦可由于样品重量变化等因素而产生微小偏移，但两个批次的晶型实质上是相同的。应当理解，本发明提供的结构式I所示化合物马来酸盐晶型1的XRD谱图不限于图1或图2所示的X射线粉末衍射图谱，与图1或图2所示基本相同的X射线粉末衍射图的晶体都落在本发明的范围内。
实施例18结构式I所示化合物的晶型吸湿性测定
使用动态水分吸附仪(DVS)对样品(所述样品为表26所示的多种晶型)进行吸湿性测定，对样品进行0％RH(相对湿度)至80％RH范围内吸湿增重变化检测，检测结果见图40-45，检测结果见表26。
表26 样品0％RH至80％RH范围内重量变化
晶型 吸湿增重
结构式I化合物 15.3％
马来酸盐晶型1 0.97％
甲磺酸盐晶型1 5.1％
甲磺酸盐晶型2 14.7％
苯磺酸盐晶型1 7.1％
苯磺酸盐晶型2 9.9％
盐酸盐晶型1 12.3％
由所述检测结果可知，马来酸盐晶型1在吸湿性方面具有突出的优势，相比结构式I化合物而言，马来酸盐晶型1的吸湿性大大降低。甲磺酸盐晶型1也具有明显优势，其他晶型吸湿性相对较高。
实施例19：结构式I所示化合物及其马来酸盐晶型1和甲磺酸盐晶型1的晶型稳定性测定
样品及实验准备：取适量的结构式I所示化合物的马来酸盐晶型1、甲磺酸盐晶型1和结构式I化合物置表面皿内，铺成约3-5毫米厚度薄层。
实验条件为：常规(25℃避光)、高温(60℃避光)和高温高湿(40℃/75％RH，敞口避光)、光照(25℃，4500lux±500lux，敞口)与氧化(40℃，盛有过氧化氢脲的密闭容器，避光敞口)下放置14天。
检测项目：分别于第0天和第14天取样，对XRD、TGA和HPLC进行检测比较，第14天检测结果见表27。
表27 第14天稳定性测试结果
Figure PCTCN2019102720-appb-000035
由所述结果数据可知：
(1)XRD检测显示马来酸盐晶型1在常规、高温、高温高湿、光照和氧化条件下放置14天均无明显变化。甲磺酸盐晶型1在氧化条件下放置14天结晶度有所降低。而结构式I化合物晶型稳定性较低，具体XRD谱图见图46-48。
(2)TGA检测显示马来酸盐晶型1在常规、高温、高温高湿、光照和氧化条件下放置14天失重无明显变化，120℃之前失重均小于1％。甲磺酸盐晶型1在氧化条件下放置14天失重略有增加，具体TGA图见图49-50。
(3)HPLC检测结果显示马来酸盐晶型1在常规、高温、高温高湿条件下放置14天主成分纯度下降小于0.1％；在光照条件下放置14天主成分纯度下降约0.7％；在氧化条件下放置14天主成分纯度下降约5.3％；而结构式I化合物和甲磺酸盐晶型1在光照条件下主成分纯度大幅下降。
实施例20：结构式I所示化合物的马来酸盐晶型2稳定性的测定
对马来酸盐晶型2在室温状态放置1天和加热到120℃的晶型稳定性进行检测，检测方式为XRD，具体检测结果见图51和图52。
由检测结果可知，马来酸盐晶型2在室温放置1天，结晶态明显变差；在温度升至120℃后马来酸盐晶型2的结晶态发生改变，部分转晶为马来酸盐晶型1。
实施例21：结构式I所示化合物的药理试验
实施例A：激酶试验
方法：采用迁移率改变法测试结构式I所示化合物对FGFR1，FGFR2，FGFR3，FGFR4和KDR的抑制活性(ATP浓度是Km值)。
检测方法：
试剂：基础激酶缓冲液：50mM HEPES(pH 7.5)；0.0015％Brij-35
终止液：100mM HEPES(pH 7.5)；0.0015％Brij-35；0.2％Coating Reagent#3；50mM EDTA
准备化合物：利用100％DMSO将测试化合物稀释到特定的浓度
反应过程：1)准备2.5X酶溶液
将激酶加入1X基础激酶缓冲液
2)准备2.5X多肽溶液
将FAM-labeled多肽和ATP加入1X基础激酶缓冲液
3)准备分析板
转移10μL测试化合物至384孔板，加入90μL 1X基础激酶缓冲液
4)向分析板每孔加入10μL 2.5X酶溶液，室温孵育10min
5)向分析板每孔加入10μL 2.5X酶溶液，28℃孵育特定时间
6)每孔加入25μL终止液终止反应
7)利用Capiler读取数据，并计算IC 50值
表28
Figure PCTCN2019102720-appb-000036
实施例B：细胞增殖试验
方法1：采用CellTiter
Figure PCTCN2019102720-appb-000037
AQ ueous one Solution细胞增殖测试试剂盒方法，观察结构式I所示化合物对体外培养的人肿瘤细胞NCl-H1581的生长抑制作用。
检测方法：加入180μL细胞悬浮液至96孔板，置CO 2培养箱过夜。测试化合物溶于DMSO，进行3倍梯度稀释，共10个浓度。分别转移20μL含测试化合物或DMSO的培养基至对应的细胞孔中。37℃，5％CO 2孵育144hrs。加入40μL CellTiter
Figure PCTCN2019102720-appb-000038
AQ ueous one Solution细胞增殖测试试剂至检测板中，置于37℃，5％CO 2条件下孵育2hrs。使用VICTOR TM X5仪器记录490nm处的光吸收值(OD490)，计算IC 50值。
方法2：采用CellTiter Glo assay方法，观察本发明的结构式I所示化合物对体外培养的人肿瘤细胞NCI-H1581和SNU-16的生长抑制作用。
检测方法：加入适当体积的全培养基，悬浮细胞。加入100μL细胞悬浮液至96孔板，置CO2培养箱过夜。测试化合物溶于DMSO，进行3倍梯度稀释，共10个浓度。分别转移结构式I所示化合物或DMSO对照品至含有100μL培养基的孔中。37℃，5％CO 2孵育96hrs。加入100μLCellTiter-Glo试剂至检测板中，置于室温下孵育10min稳定发光信号。使用VICTOR TM X5仪器记录RLU(relative luminescence unit)值，计算IC 50值。
结果显示：结构式I所示化合物对NCI-H1581细胞的IC 50值和对SNU-16细胞的IC 50值分别为2.0nM和＜1nM。
实施例C：异种移植肿瘤模型试验一
试剂：DMSO，聚乙二醇-15-羟基硬脂酸酯(Solutol)，生理盐水。
动物：BALB/C-nude品系裸鼠：SPF级动物，体重18-22g，雌性，由维通利华实验动物技术有限公司提供，饲以SPF级饲料，自由饮用蒸馏水。
人癌细胞株：NCI-H1581人非小细胞肺癌细胞系，由上海睿智化学研究有限公司提供。
肿瘤移植试验方法：在超净台内无菌操作下用NCI-H1581细胞系以1×10 7个/100μL/只的量接种于BALB/C裸鼠右腋窝皮下，经10天待肿瘤长出并可触及时(约100-200mm 3)，将动物随机分组，每组6只，称体重标号。实验组每日灌胃1次给予结构式I所示化合物。裸鼠饲养在室温20-22℃，相对湿度40-60％条件中，并屏蔽***辅以洁净层流柜的环境内。于实验开始后每3-4日用卡尺测一次皮下肿瘤体积，绘出肿瘤生长曲线，计算抑瘤率。计算结果用GraphPad Prism5软件进行统计学分析，实验数据如图53所示。
实施例D：异种移植肿瘤模型试验二
试剂：DMSO，聚乙二醇-15-羟基硬脂酸酯(Solutol)，生理盐水。
动物：BALB/C-nude品系裸鼠：SPF级动物，体重18-22g，雌性，由南京大学-南京生物医药研究院提供，饲以SPF级饲料，自由饮用蒸馏水。
人癌细胞株：SNU-16人胃癌细胞系，购自ATCC，货号为CRL-5974 TM。
肿瘤移植试验方法：在超净台内无菌操作下用SNU-16细胞系以0.2mL(3×10 6个+Matrigel)/只的量接种于BALB/C裸鼠的右后背，待肿瘤平均体积达到151mm 3时开始分组给药。将动物随机分组，每组6只，称体重标号。阳性药组每日灌胃1次给予JNJ42756493。实验组每日灌胃1次给予结构式I所示化合物。裸鼠饲养在室温20-22℃，相对湿度40-60％条件中，并屏蔽***辅以洁净层流柜的环境内。于实验开始后一周两次用卡尺测一次皮下肿瘤体积，绘出肿瘤生长曲线，计算抑瘤率。计算结果用GraphPad Prism5软件进行统计学分析，实验数据如图54所示。
实施例22：结构式I所示化合物和其马来酸盐晶型1的药代动力学实验
药品和试剂：本研究所使用的6-(2-氯-3，5-二甲氧基苯基)-N-(4-(4-吗啉基哌啶-1-基)苯基)-[1，2，4]三氮唑并[4’，3’：1，6]吡啶并[2，3-d]嘧啶-2胺(结构式I所示化合物)、结构式I所示化合物的马来酸盐晶型1被研磨成细颗粒。材料的含量(纯度)不低于99.0％。
试验动物：SD大鼠被随机分为结构式I所示化合物组和结构式I所示化合 物的马来酸盐晶型1组，每组包括3只雄鼠。
药物配制：各化合物均在10％DMSO/10％Solutol/80％Water溶液中配制成澄清溶液，最终各化合物浓度为1mg/mL。
给药和样品收集：各悬浮液以10mL/kg的剂量体积，给药剂量为10mg/kg口服给药于禁食的SD大鼠。给药前(0h)和给药后0.25h、0.5h、1h、2h、4h、7h和24h，将血液样品采集于EDTA-K的预抗凝管中。4℃下，经每分钟4000转的转速离心10min分离出样品中的血浆。收集血浆样品并保存在-80℃条件下以备分析使用。
样品通过AB4000API LC/MS结合HPLC分析。液相色谱条件下利用phenomenex C18 2.6u(50×2.1mm)的色谱柱作为固定相，用乙腈-水和0.1％的甲酸作为流动相，进样体积为10μL。结构式I所示化合物和结构式I所示化合物的马来酸盐晶型1的PK数据如表29和图55所示。结构式I所示化合物的马来酸盐晶型1的吸收值高于结构式I所示化合物。
表29
Figure PCTCN2019102720-appb-000039
实施例23：结构式I所示化合物和其各个盐型的药代动力学实验
药品和试剂：本研究所使用的6-(2-氯-3，5-二甲氧基苯基)-N-(4-(4-吗啉基哌啶-1-基)苯基)-[1，2，4]三氮唑并[4’，3’：1，6]吡啶并[2，3-d]嘧啶-2胺(结构式I所示化合物)、结构式I所示化合物的苹果酸盐晶型、酒石酸盐晶型、磷酸盐晶型、甲磺酸盐晶型、盐酸盐晶型、富马酸盐晶型、柠檬酸盐晶型、苯磺酸盐晶型和硫酸盐晶型被研磨成细颗粒。材料的含量(纯度)不低于99.0％。
试验动物：SD大鼠被随机分为结构式I所示化合物组和结构式I所示化合物的各个晶型组，每组包括3只雄鼠。
药物配制：各化合物均在纯化水的溶液中配制，其中甲磺酸盐晶型、盐酸盐晶型和苯磺酸盐晶型配制为澄清溶液，苹果酸盐晶型、酒石酸盐晶型、磷酸盐晶型、富马酸盐晶型、柠檬酸盐晶型和硫酸盐晶型配制为混悬溶液，最终各化合物浓度为0.5mg/mL。
给药和样品收集：各悬浮液以10mL/kg的剂量体积，给药剂量5mg/kg口服给药于禁食的SD大鼠。给药前(0h)和给药后0.5h、1h、2h、4h、7h和24h，将血液样品采集于EDTA-K的预抗凝管中。4℃下，经每分钟4000转的转速离心10min分离出样品中的血浆。收集血浆样品并保存在-80℃条件下以备分析使用。
样品通过AB4000API LC/MS结合HPLC分析。液相色谱条件下利用phenomenex C18 2.6u(50×2.1mm)的色谱柱作为固定相，用乙腈-水和0.1％的甲酸作为流动相，进样体积为10μL。结构式I所示化合物和结构式I所示化合物及其各晶型的PK数据如表30所示。结构式I所示化合物的酒石酸盐晶型1的吸收值高于其他化合物。
表30
Figure PCTCN2019102720-appb-000040
1结构式I所示化合物
2结构式I所示化合物的L-苹果酸盐晶型1
3结构式I所示化合物的L-酒石酸盐晶型1
4结构式I所示化合物的磷酸盐晶型1
5结构式I所示化合物的甲磺酸盐晶型1
6结构式I所示化合物的盐酸盐晶型1
7结构式I所示化合物的富马酸盐晶型1
8结构式I所示化合物的柠檬酸盐晶型1
9结构式I所示化合物的苯磺酸盐晶型1
实施例24：胶囊的制备方法一
制剂配方如下表所示：
表31
组分 5mg强度胶囊剂 2mg强度胶囊剂 0.5mg强度胶囊剂
批量(胶囊数量) 20000 20000粒 10000粒
API 2 138.60 1 55.44 1 6.93 1
甘露醇 2681.40 1824.56 745.07
交联聚维酮 150.00 100.00 40.00
硬脂酸镁 30.00 20.00 8.00
总重 3000.00 2000.00 800.00
1已根据成盐系数对活性成分的单位含量进行调整
2此处所述API特指代为结构式I所示的化合物的马来酸盐晶型1。
所述胶囊的制备流程如下：
1)API筛分
将API加入前手动过筛，或使用配有合适目数筛网的粉碎设备过筛。
2)混合
称取过筛后的API、甘露醇和交联聚维酮转移至方锥混合机中混合。
3)总混
称取硬脂酸镁加入到方锥混合机中继续混合。
4)胶囊填充
5mg规格使用2号明胶胶囊壳填充，2mg规格使用3号明胶胶囊壳填充，0.5mg规格使用4号明胶胶囊壳填充。
5)包装
本品采用口服固体药用高密度聚乙烯瓶，口服固体药用聚丙烯/低密度聚乙烯防潮组合盖包装，将包装的产品于室温下保存。
实施例25：胶囊的制备方法二
制剂配方如下表所示：
表32
组分 5mg强度胶囊剂 2mg强度胶囊剂 0.5mg强度胶囊剂
批量(胶囊数量) 20000粒 20000粒 10000粒
API 2 138.60 1 55.44 1 6.93 1
微晶纤维素 1481.40 1024.56 425.07
喷雾干燥乳糖 1200.00 800.00 320.00
交联聚维酮 150.00 100.00 40.00
硬脂酸镁 30.00 20.00 8.00
总重 3000.00 2000.00 800.00
1已根据成盐系数对活性成分的单位含量进行调整
2此处所述API特指代为结构式I所示的化合物的马来酸盐晶型1。
所述胶囊的制备流程如下：
1)API筛分
将API加入前手动过筛，或使用配有合适目数筛网的粉碎设备过筛。
2)混合
称取过筛后的API、微晶纤维素、喷雾干燥乳糖和交联聚维酮转移至方锥混合机中混合。
3)总混
称取硬脂酸镁加入到方锥混合机中继续混合。
4)胶囊填充
5mg规格使用2号明胶胶囊壳填充，2mg规格使用3号明胶胶囊壳填充，0.5mg规格使用4号明胶胶囊壳填充。
5)包装
本品采用口服固体药用高密度聚乙烯瓶，口服固体药用聚丙烯/低密度聚乙烯防潮组合盖包装，将包装的产品于室温下保存。
以上对本发明的示例性实施方案进行了说明。但是，本发明的技术方案不拘囿于此。本领域技术人员应当理解，凡在本发明的精神和原则范围内进行的任何修改、等同替换、改进等，均应属于本发明保护的范围。

Claims (24)

  1. 结构式I所示化合物的盐型及晶型：
    Figure PCTCN2019102720-appb-100001
  2. 权利要求1所述的盐型及晶型，其特征在于，所述盐型选自马来酸盐、甲磺酸盐、苯磺酸盐、盐酸盐、磷酸盐、L-酒石酸盐、L-苹果酸盐、柠檬酸盐或富马酸盐。
  3. 权利要求1或2所述的盐型及晶型，其特征在于，所述盐型为马来酸盐，所述结构式I所示的化合物的马来酸盐为结晶型。
  4. 权利要求3所述的盐型及晶型，其特征在于，所述马来酸盐的结晶型，其X射线粉末衍射图具有衍射角2θ为5.6°±0.2°，8.4°±0.2°，11.2°±0.2°，22.6°±0.2°和28.3°±0.2°的特征峰。
  5. 权利要求3所述的盐型及晶型，其特征在于，所述马来酸盐的结晶型，其X射线粉末衍射图具有衍射角2θ为5.6°±0.2°，8.4°±0.2°，11.2°±0.2°，17.0°±0.2°，19.7±0.2°，22.6°±0.2°，25.4±0.2°，28.3°±0.2°的特征峰。
  6. 权利要求3所述的盐型及晶型，其特征在于，所述马来酸盐的结晶型，其X射线粉末衍射图具有衍射角2θ为5.6°±0.2°，8.4°±0.2°，11.2°±0.2°，17.0°±0.2°，19.7±0.2°，22.6°±0.2°，23.3°±0.2°，25.4±0.2°，28.3°±0.2°的特征峰。
  7. 权利要求3所述的盐型及晶型，其特征在于，所述马来酸盐的结晶型，其X射线粉末衍射图具有衍射角2θ为5.6°±0.2°，8.4°±0.2°，11.2°±0.2°，14.0°±0.2°，17.0°±0.2°，19.7±0.2°，22.6°±0.2°，23.3°±0.2°，25.4±0.2°，28.3°±0.2°的特征峰。
  8. 权利要求3所述的盐型及晶型，其特征在于，所述马来酸盐的结晶型，其X射线粉末衍射图基本上如图1所示。
  9. 权利要求3所述的盐型及晶型，其特征在于，所述马来酸盐的结晶型，其X射线粉末衍射图基本上如图2所示。
  10. 权利要求1或2所述的盐型及晶型，其特征在于，所述盐型为甲磺酸盐，所述结构式I所示的化合物的甲磺酸盐为结晶型，其X射线粉末衍射图具有衍 射角2θ为4.7°±0.2°，9.4°±0.2°和14.1°±0.2°的特征峰。
  11. 权利要求10所述的盐型及晶型，其特征在于，所述甲磺酸盐的结晶型，其X射线粉末衍射图具有衍射角2θ为4.7°±0.2°，9.4°±0.2°，10.7°±0.2°，12.1°±0.2°，14.1°±0.2°和19.0°±0.2°的特征峰。
  12. 权利要求10所述的盐型及晶型，其特征在于，所述甲磺酸盐的结晶型，其X射线粉末衍射图具有衍射角2θ为4.7°±0.2°，9.4°±0.2°，10.7°±0.2°，12.1°±0.2°，14.1°±0.2°，16.3°±0.2°，16.8°±0.2°和19.0°±0.2°的特征峰。
  13. 权利要求10所述的盐型及晶型，其特征在于，所述甲磺酸盐的结晶型，其X射线粉末衍射图基本上如图12所示。
  14. 一种药物组合物，其特征在于：含有治疗有效量的权利要求1-13任一项所述的盐型或晶型，和药学上可接受的辅料，辅助剂和/或载体。
  15. 如权利要求14所述的组合物，其特征在于，所述组合物用于口服给药。
  16. 权利要求1—13任一项所述的盐型和/或晶型或权利要求14或15所述的组合物在制备药物中的应用，其特征在于，所述药物用于治疗、预防、延迟或阻止癌症或癌症转移的发生或进展。
  17. 如权利要求16所述的应用，其特征在于，所述化合物在制备治疗由FGFR介导的疾病的药物中的应用。
  18. 如权利要求17所述的应用，其特征在于，所述的FGFR包括FGFR1、FGFR2、FGFR3或FGFR4。
  19. 如权利要求16所述的应用，其特征在于，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞癌、头颈部肿瘤、颅内肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、许旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
  20. 一种治疗或预防由FGFR介导的疾病的方法，其特征在于，向治疗对象施用治疗有效量的权利要求1-13任一项所述的盐型和/或晶型或权利要求14或15所述的药物组合物。
  21. 如权利要求20所述的方法，其特征在于，所述的FGFR包括FGFR1、 FGFR2、FGFR3或FGFR4。
  22. 如权利要求21所述的方法，其特征在于，所述FGFR介导的疾病是癌症。
  23. 如权利要求23所述的方法，其特征在于，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞癌、头颈部肿瘤、颅内肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、许旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
  24. 如权利要求20-23任一所述的方法，其特征在于，所述治疗对象为人类。
PCT/CN2019/102720 2018-08-27 2019-08-27 新型氮杂三环类化合物的盐型、晶型及其用途 WO2020043078A1 (zh)

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