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WO2023093859A1 - Axl激酶抑制剂的盐、其制备方法和用途 - Google Patents

Axl激酶抑制剂的盐、其制备方法和用途 Download PDF

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WO2023093859A1
WO2023093859A1 PCT/CN2022/134408 CN2022134408W WO2023093859A1 WO 2023093859 A1 WO2023093859 A1 WO 2023093859A1 CN 2022134408 W CN2022134408 W CN 2022134408W WO 2023093859 A1 WO2023093859 A1 WO 2023093859A1
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compound
formula
salt
pharmaceutically acceptable
crystal form
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PCT/CN2022/134408
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English (en)
French (fr)
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张林林
马昌友
吴有智
裴俊杰
吴舰
徐丹
朱春霞
田舟山
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南京正大天晴制药有限公司
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Priority to CN202280074029.7A priority Critical patent/CN118251400A/zh
Publication of WO2023093859A1 publication Critical patent/WO2023093859A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/42—Separation; Purification; Stabilisation; Use of additives
    • C07C303/44—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • 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 invention belongs to the technical field of medicine, and the compound is an AXL kinase inhibitor, and specifically relates to a salt of the AXL inhibitor, a preparation method and a medical application thereof.
  • RTKs Receptor tyrosine kinases
  • Ligand-receptor binding induces receptor dimerization and activation of its intracellular kinase domain, which in turn leads to the recruitment, phosphorylation and activation of multiple downstream signaling cascades (Robinson, D.R. et al., Oncogene, 19:5548-5557, 2000).
  • RTKs have been identified in the human genome that regulate a variety of cellular processes, including cell survival, growth, differentiation, proliferation, adhesion, and motility (Segaliny, A.I. et al., J. Bone Oncol, 4:1 -12, 2015).
  • AXL (also known as UFO, ARK, and Tyro7) belongs to the TAM family of receptor tyrosine kinases, which also includes Mer and Tyro3. Among them, AXL and Tyro3 have the most similar gene structure, while AXL and Mer have the most similar amino acid sequence of tyrosine kinase domain. Like other receptor tyrosine kinases (RTKs), the structure of the TAM family consists of an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The extracellular domain of AXL has a unique structure that juxtaposes immunoglobulin and type III fibronectin repeat units and is reminiscent of a neutrophil adhesion molecule.
  • TAM family members have a common ligand—growth arrest specific protein 6 (Gas6), which can bind to all TAM receptor tyrosine kinases. After AXL binds to Gas6, it will lead to receptor dimerization and AXL autophosphorylation, thereby activating multiple downstream signal transduction pathways and participating in multiple processes of tumorigenesis (Linger, R.M et al., Ther.Targets, 14(10 ), 1073-1090, 2010; Rescigno, J. et al., Oncogene, 6(10), 1909-1913, 1991).
  • Gas6 growth arrest specific protein 6
  • AXL is widely expressed in normal tissues of the human body, such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver, and kidney, among which the expression is highest in cardiac muscle and skeletal muscle, and bone marrow CD34+ cells and stromal cells also have a higher expression High expression, very low expression in normal lymphoid tissue (Wu YM, Robinson DR, Kung HJ, Cancer Res, 64(20), 7311-7320, 2004; hung BI et al., DNA Cell Biol, 22(8), 533-540 , 2003).
  • AXL gene was overexpressed or ectopically expressed in hematopoietic cells, mesenchymal cells and endothelial cells.
  • the overexpression of AXL kinase is particularly prominent.
  • Inhibition of AXL receptor tyrosine kinase can reduce the pro-survival signals of tumor cells, block the invasion ability of tumors, and increase the sensitivity of targeted drug therapy and chemotherapy. Therefore, finding effective AXL inhibitors is an important direction for the development of tumor-targeted drugs.
  • the present invention provides a pharmaceutically acceptable salt of the compound of formula I, wherein the salt is selected from organic acid salts or inorganic acid salts, wherein the organic acid salts are selected from methanesulfonate, benzenesulfonate, oxalate
  • the inorganic acid salt is selected from one of hydrochloride, hydrobromide, sulfate or phosphate, the compound of formula I
  • the structure is as follows:
  • the organic acid salt is mesylate.
  • the mesylate salt is a hydrate of the mesylate salt.
  • the mesylate salt is the dihydrate of the mesylate salt.
  • the molar ratio of the compound of formula I to the organic acid in the organic acid salt is 1:1.
  • the molar ratio of the compound of formula I to the inorganic acid in the inorganic acid salt is 1:1 or 1:2.
  • the salt of an inorganic acid is a hydrochloride.
  • the molar ratio of the compound of formula I to hydrogen chloride in the hydrochloride salt is 1:1 or 1:2.
  • the molar ratio of the compound of formula I to hydrogen chloride in the hydrochloride salt is 1:2.
  • the molar ratio of the compound of formula I to sulfuric acid in the sulfate salt is 1:1.
  • the molar ratio of the compound of formula I to hydrobromic acid in the hydrobromide salt is 1:1.
  • the molar ratio of the compound of formula I to phosphoric acid in the phosphate salt is 1:1.
  • the salt in the present invention is obtained by a salt-forming reaction between the compound of formula I and the corresponding acid.
  • the compound of formula I is converted into a cation and combined with the acid radical of the corresponding acid to form the salt. Therefore, the molar ratio of the compound of formula I to the acid in the present invention can be understood as the molar ratio of the cation of the compound of formula I to the acid group of the corresponding acid in the salt.
  • the present invention provides the mesylate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to methanesulfonic acid is 1:1, or the molar ratio of the cation of the compound of formula I to the acid group of methanesulfonic acid The ratio is 1:1.
  • the present invention provides a crystal form of a pharmaceutically acceptable salt of the compound of formula I, wherein the salt is selected from organic acid salts or inorganic acid salts, wherein the organic acid salts are selected from methanesulfonate, benzenesulfonate , oxalate, fumarate, citrate and hippurate, the inorganic acid salt is selected from hydrochloride, hydrobromide or phosphate.
  • the present invention provides a crystalline form of the mesylate salt of the compound of Formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the mesylate salt crystal is detailed in Table 1 below:
  • the present invention provides a crystalline form of the mesylate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 1 .
  • the present invention provides a crystalline form of the monohydrochloride salt of a compound of formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the monohydrochloride crystal is detailed in Table 2 below:
  • the present invention provides a crystalline form of the monohydrochloride salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 4 . In some embodiments, the present invention provides a crystalline form of the dihydrochloride salt of the compound of formula I.
  • the dihydrochloride salt is crystalline, and the 2 ⁇ of its X-ray powder diffraction pattern is detailed in Table 3 below:
  • the present invention provides a crystal form of the dihydrochloride salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 5 .
  • the present invention provides a crystalline form of the phosphate salt of a compound of formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the phosphate crystal is detailed in Table 4 below:
  • the present invention provides a crystalline form of the phosphate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 6 .
  • the present invention provides a crystalline form of a hippurate salt of a compound of Formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the hippurate crystal is detailed in Table 5 below:
  • the present invention provides a crystalline form of hippurate of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 7 .
  • the present invention provides an amorphous form of the sulfate salt of the compound of formula I.
  • the present invention provides a crystalline form of the hydrobromide salt of a compound of formula I.
  • the 2 ⁇ of the hydrobromide crystal is shown in Table 6 below in detail in its X-ray powder diffraction pattern:
  • the present invention provides a crystal form of the hydrobromide salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 9 .
  • the present invention provides a crystalline form of the besylate salt of the compound of formula I.
  • the benzenesulfonate salt is crystalline, and the 2 ⁇ of its X-ray powder diffraction pattern is detailed in Table 7 below:
  • the present invention provides a crystalline form of the besylate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 10 .
  • the present invention provides a crystalline form of the oxalate salt of the compound of formula I.
  • the oxalate salt crystals, the 2 ⁇ of its X-ray powder diffraction pattern are detailed in Table 8 below:
  • the present invention provides the crystalline form of the oxalate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 11 .
  • the present invention provides a crystalline form of the fumarate salt of the compound of formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the fumarate crystals is detailed in Table 9 below:
  • the present invention provides a crystalline form of the fumarate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 12 .
  • the present invention provides a crystalline form of the citrate salt of the compound of formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the citrate crystals is detailed in Table 10 below:
  • the present invention provides a crystalline form of the citrate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 13 .
  • the present invention provides a crystal form A of the compound of formula I, whose X-ray powder diffraction pattern is 7.6° ⁇ 0.2°, 10.2° ⁇ 0.2°, 17.6° ⁇ 0.2°, 20.3° ⁇ 0.2° at 2 ⁇ There are diffraction peaks at 20.9° ⁇ 0.2°.
  • the crystal form A has an X-ray powder diffraction pattern at 2 ⁇ of 4.1° ⁇ 0.2°, 7.6° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 17.6° There are diffraction peaks at ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.9° ⁇ 0.2° and 22.2° ⁇ 0.2°.
  • the crystal form A has an X-ray powder diffraction pattern at 2 ⁇ of 4.1° ⁇ 0.2°, 5.6° ⁇ 0.2°, 7.6° ⁇ 0.2°, 10.2° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.2° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.9° ⁇ 0.2°, 22.2° ⁇ 0.2°, 23.2° ⁇ 0.2 °, 24.6° ⁇ 0.2°, 27.0° ⁇ 0.2°, 28.8° ⁇ 0.2°, 37.0° ⁇ 0.2° and 37.7° ⁇ 0.2° have diffraction peaks.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the crystal form A is detailed in the table below:
  • the X-ray powder diffraction of the crystal form A in 2 ⁇ angle has a pattern as shown in FIG. 14 .
  • the present invention provides a method for preparing a pharmaceutically acceptable salt of the compound of formula I or a crystal form of the pharmaceutically acceptable salt thereof, which comprises the step of forming a salt of the compound of formula I with a corresponding acid.
  • the reaction solvent of the preparation method is selected from mixed solvents of alcohol solvents and alkane solvents, mixed solvents of ketone solvents and alkane solvents, mixed solvents of ester solvents and alkane solvents, nitrile solvents - A mixed solvent of an aqueous solvent and an alkane solvent, a mixed solvent of an alkylbenzene solvent and an alkane solvent, or a mixed solvent of a halogenated hydrocarbon solvent and an alkane solvent.
  • the alcohol solvent is selected from methanol, ethanol or isopropanol; the ketone solvent is selected from acetone or butanone; preferably acetone; the ester solvent is selected from ethyl acetate or butyl acetate ; Preferred ethyl acetate;
  • the nitriles-water solvent is selected from the mixed solution of nitriles-water, and the alkane solvent is selected from n-heptane.
  • the crystal form of the pharmaceutically acceptable salt is a mesylate salt crystal form
  • the mesylate salt crystal form is prepared by a method comprising the following steps:
  • step S2 stirring and reacting the compound of formula (I), methanesulfonic acid and ethyl acetate, adding the crystal form obtained in step S1 and continuing to stir;
  • the present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound of formula I.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is a solid pharmaceutical preparation suitable for oral administration, preferably a tablet or a capsule.
  • the present invention also provides a pharmaceutical composition comprising the crystal form of the pharmaceutically acceptable salt of the compound of formula I.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is a solid pharmaceutical preparation suitable for oral administration, preferably a tablet or a capsule.
  • the present invention provides a crystal form composition, wherein the pharmaceutically acceptable salt of the compound of formula I above, and the crystal form of the pharmaceutically acceptable salt of the compound of formula I account for the weight of the crystal form composition above 50.
  • the present invention also provides a pharmaceutical composition comprising the above crystal composition; the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the present invention also provides a pharmaceutically acceptable salt of the compound of formula I or its crystal form composition or its pharmaceutical composition for use as a medicine.
  • the present invention also provides a pharmaceutically acceptable salt crystal form of the compound of formula I or its crystal form composition or pharmaceutical composition thereof for use as a medicine.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering the salt of the compound of formula I of the present invention, or its crystal form, to individuals in need Composition or its pharmaceutical composition.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering the crystalline form of the salt of the compound of formula I of the present invention, Its crystal form composition or its pharmaceutical composition.
  • the present invention also provides the salt of the compound of formula I of the present invention, its crystal form composition or its pharmaceutical composition for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides the crystalline form of the salt of the compound of formula I of the present invention, its crystalline form composition or its pharmaceutical composition for preventing and/or treating AXL kinase-mediated diseases or disease states .
  • the AXL kinase-mediated disease or condition is cancer.
  • the cancer is a disease associated with hematological and solid tumors.
  • the pharmaceutically acceptable salts of the present invention also include their hydrated forms.
  • pharmaceutically acceptable carrier refers to those carriers that have no obvious stimulating effect on the body and will not impair the biological activity and performance of the active compound. Including but not limited to any diluents, disintegrants, binders, glidants, and wetting agents approved by the State Food and Drug Administration for human or animal use.
  • fumaric acid refers to fumaric acid, which has the structure:
  • alcohol solvent refers to a substance derived from one or more hydroxyl groups (OH) replacing one or more hydrogen atoms on a C1-C6 alkane
  • C1-C6 alkane refers to a substance containing 1-6 carbon atoms
  • Specific examples of linear or branched alkanes and alcohol solvents include, but are not limited to: methanol, ethanol, isopropanol or n-propanol.
  • alkane solvent refers to straight chain or branched chain or cyclic alkanes containing 5-7 carbon atoms, specific examples include but not limited to n-hexane, cyclohexane, n-heptane.
  • ester solvent refers to a chain compound containing an ester group -COOR and a carbon number of 3-10, wherein R is a C1-C6 alkyl group, and the C1-C6 alkyl group refers to a chain compound containing 1-6
  • R is a C1-C6 alkyl group
  • C1-C6 alkyl group refers to a chain compound containing 1-6
  • Specific examples of straight-chain or branched-chain alkanes with carbon atoms and ester solvents include but are not limited to methyl acetate, ethyl acetate, and propyl acetate.
  • halogenated hydrocarbon solvent refers to a substance derived from one or more halogen atoms replacing one or more hydrogen atoms on a C1-C6 alkane
  • the C1-C6 alkane refers to a substance containing 1-6 carbon atoms
  • the halogen atoms refer to fluorine, chlorine, bromine, and iodine.
  • Specific examples of halogenated hydrocarbon solvents include but are not limited to dichloromethane or chloroform.
  • ketone solvent refers to a chain or cyclic compound containing carbonyl -CO- and having 3-10 carbon atoms, specific examples include but not limited to acetone, methyl ethyl ketone or cyclohexanone.
  • benzene-based solvent means a solvent containing a phenyl group, and specific examples include toluene, xylene, cumene, or chlorobenzene.
  • equivalent refers to the equivalent amount of other raw materials required in accordance with the equivalent relationship of chemical reactions, taking the basic raw materials used in each step as 1 equivalent.
  • the "X-ray powder diffraction pattern" in the present invention is obtained by using Cu-K ⁇ radiation measurement.
  • the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystal, where the relative intensity of the bands (especially at low angles) may vary due to The effect of dominant orientation due to differences in crystallization conditions, particle size and other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic of the targeted crystals.
  • XRPD X-ray powder diffraction
  • the position of the peak can move, and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • the peak positions of their XRPD spectra are similar on the whole, and the relative intensity error may be large.
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric analysis refers to a thermal analysis technique that measures the relationship between the mass of the sample to be tested and the temperature change at a programmed temperature.
  • TGA Thermogravimetric analysis
  • IMDM (Iscove's Modified Dulbecco's Medium): Iscove (person's name) modified Dulbecco (person's name) medium.
  • Fig. 1 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound mesylate in embodiment 5;
  • Fig. 2 shows the differential scanning calorimetry (DSC) figure of formula I compound mesylate in embodiment 5;
  • Fig. 3 shows the thermogravimetric (TGA) figure of formula I compound mesylate in embodiment 5;
  • Fig. 4 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound monohydrochloride in embodiment 3;
  • Fig. 5 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound dihydrochloride in embodiment 3;
  • Fig. 6 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound phosphate in embodiment 3;
  • Fig. 7 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound hippurate in embodiment 3;
  • Fig. 8 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound sulfate in embodiment 3;
  • Fig. 9 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound hydrobromide in embodiment 3;
  • Fig. 10 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound besylate in embodiment 3;
  • Fig. 11 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound oxalate in embodiment 3;
  • Fig. 12 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound fumarate in embodiment 3;
  • Fig. 13 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound citrate in embodiment 3;
  • Figure 14 shows the X-ray powder diffraction (XRPD) spectrum of the crystal form A of the compound of formula I in Example 6.
  • test conditions of each instrument are as follows:
  • Temperature rise range room temperature - 300°C
  • Method Put the sample in an aluminum pan, then place the aluminum pan in a platinum pan, expose it in a nitrogen atmosphere, and raise the temperature from room temperature to the set temperature at a rate of 10°C/min.
  • Heating range 20-300°C
  • the sample was placed in an aluminum pan, and after capping, the temperature was raised from 20°C to the set temperature at a rate of 10°C/min in a nitrogen atmosphere.
  • the crude product was purified by reverse-phase high-performance liquid chromatography (column is YMC Actus Triart C18, 30*150mm, particle diameter 5 ⁇ m, mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60mL/ min, gradient: 20%B to 50%B, 8min, wavelength: 220nm, retention time: 6.83min, column temperature: 25°C), the title product (20.2mg) was obtained.
  • Example 1 Related compounds prepared in Example 1 carry out related enzyme activities, cells, and related activities in vivo
  • the specific structure of the positive drug 1 (BGB324) used in the activity test is as follows:
  • 1 ⁇ enzyme buffer 200 ⁇ L of Enzymatic buffer kinase 5X, 10 ⁇ L of 500 mM MgCl 2 , 10 ⁇ L of 100 mM DTT, 6.26 ⁇
  • DMSO dilute the compounds and positive drugs prepared in the examples from 10 mM to 100 ⁇ M, and titrate with a compound titrator (Tecan, D300e), and the titrator will automatically spray the required concentration into each well, the first step A concentration of 1 ⁇ M, 1/2 log gradient dilution, a total of 8 concentrations. Centrifuge at 2500rpm for 30s and incubate at room temperature for 15min.
  • ATP (Sigma, A7699) was diluted with 1 ⁇ enzyme buffer, from 10 mM to 75 ⁇ M (5 ⁇ ), and the final concentration was 15 ⁇ M; substrate TK Substrate 3-biotin (Cisbio, 61TK0BLC) was diluted with 1 ⁇ enzyme buffer solution from 500 ⁇ M to 5 ⁇ M (5 ⁇ ), and the final concentration was 1 ⁇ M; ATP was mixed with the substrate in equal volume, and 4 ⁇ L was added to each well using a BioTek automatic liquid dispenser; centrifuged at 2500 rpm for 30 s, at 25 ° C React for 45 minutes.
  • Streptavidin-XL665 (Cisbio, 610SAXLG) was diluted from 16.67 ⁇ M to 250nM (4 ⁇ ) with HTRF KinEASE detection buffer (cisbio), and the final concentration was 62.5nM;
  • TK Antibody-Cryptate (Cisbio) was diluted with HTRF KinEASE detection buffer (cisbio) was diluted from 100 ⁇ to 5 ⁇ , and the final concentration was 1 ⁇ ;
  • XL665 was mixed with Antibody in equal volume, 10 ⁇ L was added to each well using a BioTek automatic dispenser, centrifuged at 2500 rpm for 30 seconds, and reacted at 25°C for 1 hour. After the reaction, the multifunctional plate reader HTRF was used for detection.
  • MV-4-11 human myelomonocytic leukemia cell line, medium: IMDM+10% fetal bovine serum
  • IMDM+10% fetal bovine serum was purchased from Nanjing Kebai Biotechnology Co., Ltd., and placed in an incubator at 37°C and 5% CO 2 nourish.
  • Cells in the logarithmic growth phase were plated in 96-well plates at cell densities of 8000/well, 6000/well, 5000/well, 4000/well and 3000/well, and a blank control group was set at the same time.
  • Signal value of the test substance the mean value of the fluorescent signal of the cell + medium + compound group
  • Signal value of the blank group the average value of the fluorescence signal of the culture medium group (containing 0.5% DMSO);
  • Signal value of negative control group mean value of fluorescence signal of cell+medium group (containing 0.5% DMSO).
  • the IC 50 (MV4-11, nM) of the antiproliferative activity of the compound of Example 1 on MV4-11 cells was 6.97.
  • test compound The inhibitory effect of the test compound and the positive drug on the growth of human acute monocytic leukemia cell MV-4-11 xenografted tumor model in nude mice in vivo.
  • MV-4-11 cells in the logarithmic growth phase were collected, counted and resuspended, and the cell concentration was adjusted to 7.0 ⁇ 10 7 cells/mL; injected subcutaneously into the right axilla of nude mice, each animal was inoculated with 200 L (14 ⁇ 10 6 cells/monkey), the MV-4-11 xenograft tumor model was established. When the tumor volume reaches 100-300 mm 3 , tumor-bearing mice with good health and similar tumor volume are selected.
  • Solvent control group PEG400&citric acid buffer (20:80, v:v).
  • tumor volume (mm 3 ) l ⁇ w 2 /2
  • RTV relative tumor volume
  • TV initial is the tumor volume measured during group administration
  • TV t is the tumor volume at each measurement during administration.
  • TV t (T) represents the tumor volume measured each time in the treatment group
  • TV initial (T) represents the tumor volume of the treatment group when administered in groups
  • TV t (C) represents the tumor volume measured each time in the solvent control group
  • TV initial (C) represents the tumor volume of the solvent control group at the time of group administration.
  • RTV T represents the RTV of the treatment group
  • RTV C represents the RTV of the solvent control group.
  • the experimental data in the table is the relevant data obtained when the experiment ends (the end of the experiment is defined as: after 21 days or when the tumor volume of the solvent control group reaches 2000 mm 3 and the experiment ends (whichever is reached earlier)).
  • Each compound was prepared as a 10 mg/mL stock solution in DMSO.
  • mice Male ICR mice aged 6-10 weeks (source of mice: Weitong Lihua Experimental Animal Technology Co., Ltd.), 6 in each group, were fasted overnight and fed 4 hours after administration. On the day of the experiment, the mice were given 10 mg kg- 1 compound test solution by intragastric administration. At 0, 5min, 15min, 30min, 1h, 2h, 4h, 8h, and 24h after administration, about 100 ⁇ L of blood was collected from the orbit of the mice and placed in an EDTA-K 2 anticoagulant tube. Whole blood samples were centrifuged at 1500-1600 g for 10 min, and the separated plasma was stored in a -40-20°C refrigerator for biological sample analysis. LC-MS/MS method was used to determine the plasma concentration.
  • Fig. 4-13 is respectively formula I compound hydrochloride, dihydrochloride, phosphate, hippurate, sulfate, hydrobromide, benzenesulfonate, oxalate, fumarate, citric acid X-ray powder diffraction (XRPD) pattern of the salt.
  • XRPD X-ray powder diffraction
  • Embodiment 6 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7] wheel Preparation of Form A of En-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide (compound of formula I)

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Abstract

本发明提供了一种式（I）化合物的盐以及盐的晶型，及其制备方法和用途。其中所述盐选自甲磺酸盐、苯磺酸盐、草酸盐、富马酸盐、柠檬酸盐、马尿酸盐、盐酸盐、氢溴酸盐、硫酸盐或磷酸盐。

Description

AXL激酶抑制剂的盐、其制备方法和用途 技术领域
本发明属于医药技术领域，所述化合物是AXL激酶抑制剂，具体涉及AXL抑制剂的盐、其制备方法以及医药用途。
背景技术
受体酪氨酸激酶(RTK)是多域跨膜蛋白，可作为细胞外配体的传感器。配体受体结合诱导受体二聚化并激活其胞内激酶结构域，继而导致多个下游信号级联反应的募集、磷酸化和激活(Robinson,D.R.等,Oncogene,19:5548-5557,2000)。迄今为止，已在人类基因组中鉴定出58个RTK，它们可调节多种细胞过程，包括细胞存活、生长、分化、增殖、粘附和运动(Segaliny,A.I.等,J.Bone Oncol,4:1-12,2015)。
AXL(又称为UFO、ARK和Tyro7)属于受体酪氨酸激酶TAM家族，该家族成员还包括Mer和Tyro3。其中，AXL和Tyro3具有最为相似的基因结构，而AXL和Mer具有最为相似的酪氨酸激酶域氨基酸序列。与其他受体酪氨酸激酶(RTKs)一样，TAM家族的结构包含胞外域、跨膜域和保守的胞内激酶域。AXL的细胞外结构域具有独特的使免疫球蛋白和III型纤维连接蛋白重复单元并置的结构并且使人联想到中性细胞粘附分子的结构。TAM家族成员有1个共同配体—生长抑制特异性蛋白6(Gas6)，该配体能够与所有TAM受体酪氨酸激酶结合。AXL与Gas6结合后，会导致受体二聚化和AXL自磷酸化，从而激活下游多条信号转导通路，并参与肿瘤发生的多个过程(Linger,R.M等，Ther.Targets，14(10),1073-1090，2010；Rescigno,J.等，Oncogene,6(10),1909-1913，1991)。
AXL广泛表达于人体正常组织，如单核细胞、巨噬细胞、血小板、内皮细胞、小脑、心脏、骨骼肌、肝脏和肾脏等，其中心肌和骨骼肌表达最高，骨髓CD34+细胞和基质细胞也有较高的表达，正常淋巴组织表达很低(Wu YM,Robinson DR,Kung HJ,Cancer Res,64(20),7311-7320,2004；hung BI等，DNA Cell Biol,22(8)，533-540，2003)。在对许多癌细胞的研究中发现，在造血细胞、间质细胞和内皮细胞中，AXL基因都存在着超表达或异位表达。在各类白血病和多数的实体瘤中，AXL激酶的超表达现象尤为突出。通过抑制AXL受体酪氨酸激酶可以降低肿瘤细胞的促存活信号、阻滞肿瘤的侵袭能力，增加靶向药物治疗和化疗敏感度。因此寻找有效的AXL抑制剂是当前肿瘤靶向药物研发的重要方向。
发明内容
一方面，本发明提供了式I化合物的药学上可接受的盐，所述盐选自有机酸盐或无机酸盐，其中所述有机酸盐选自甲磺酸盐、苯磺酸盐、草酸盐、富马酸盐、柠檬酸盐和马尿酸盐中的一种，所述无机酸盐选自盐酸盐、氢溴酸盐、硫酸盐或磷酸盐中的一种，式I化合物结构如下：
Figure PCTCN2022134408-appb-000001
在一些实施方案中，所述有机酸盐为甲磺酸盐。
在一些实施方案中，所述甲磺酸盐为甲磺酸盐的水合物。
在一些实施方案中，所述甲磺酸盐为甲磺酸盐的二水合物。
在一些实施方案中，所述有机酸盐中式I化合物与有机酸的摩尔比为1：1。
在一些实施方案中，所述无机酸盐中式I化合物与无机酸的摩尔比为1：1或1：2。
在一些实施方案中，所述无机酸盐为盐酸盐。
在一些实施方案中，所述盐酸盐中式I化合物与氯化氢的摩尔比为1：1或1：2。
在一些实施方案中，所述盐酸盐中式I化合物与氯化氢的摩尔比为1：2。
在一些实施方案中，所述硫酸盐中式I化合物与硫酸的摩尔比为1：1。
在一些实施方案中，所述氢溴酸盐中式I化合物与氢溴酸的摩尔比为1：1。
在一些实施方案中，所述磷酸盐中式I化合物与磷酸的摩尔比为1：1。
可以理解为，本发明所说的盐是式I化合物与相应的酸通过成盐反应获得，在反应中，式I化合物转化为阳离子，与相应的酸的酸根结合，形成所述盐。因此，本发明中式I化合物与酸的摩尔比可以理解为盐中式I化合物的阳离子与相应酸的酸根的摩尔比。
在一些典型实施方案中，本发明提供了式I化合物的甲磺酸盐，其中式I化合物与甲磺酸的摩尔比为1：1，或式I化合物的阳离子与甲磺酸的酸根的摩尔比为1：1。
另一方面，本发明提供了式I化合物的药学上可接受的盐的晶型，所述盐选自有机酸盐或无机酸盐，其中有机酸盐选自甲磺酸盐、苯磺酸盐、草酸盐、富马酸盐、柠檬酸盐和马尿酸盐，所述无机酸盐选自盐酸盐、氢溴酸盐或磷酸盐。
在一些实施方案中，本发明提供了式I化合物的甲磺酸盐的结晶形式。
在一些实施方案中，所述甲磺酸盐结晶，其X射线粉末衍射图的2θ详见下表1：
表1式I化合物的甲磺酸盐晶型X射线粉末衍射图数据
2θ(°) 高度(counts) I/I 0(％)
5.300 54 17.1
7.793 46 14.5
9.174 102 32.0
10.479 60 18.9
13.271 83 26.2
15.415 318 100.0
16.067 90 28.4
17.164 89 28.1
17.693 80 25.0
18.201 41 12.8
18.959 83 26.1
20.332 212 66.7
20.853 38 11.8
21.883 99 31.0
22.519 26 8.2
23.101 117 36.9
23.484 51 16.0
24.949 34 10.6
25.792 37 11.5
26.331 28 8.7
29.544 82 25.9
33.006 26 8.2
39.463 71 22.3
。
在一些实施方案中，本发明提供了式I化合物的甲磺酸盐的晶型，其X射线粉末衍射图如图1所示。
在一些实施方案中，本发明提供了式I化合物的单盐酸盐的结晶形式。
在一些实施方案中，所述单盐酸盐结晶，其X射线粉末衍射图的2θ详见下表2：
表2式I化合物的单盐酸盐晶型X射线粉末衍射图数据
Figure PCTCN2022134408-appb-000002
Figure PCTCN2022134408-appb-000003
在一些实施方案中，本发明提供了式I化合物的单盐酸盐的晶型，其X射线粉末衍射图如图4所示。在一些实施方案中，本发明提供了式I化合物的二盐酸盐的结晶形式。
在一些实施方案中，所述二盐酸盐结晶，其X射线粉末衍射图的2θ详见下表3：
表3式I化合物的二盐酸盐晶型X射线粉末衍射图数据
Figure PCTCN2022134408-appb-000004
Figure PCTCN2022134408-appb-000005
在一些实施方案中，本发明提供了式I化合物的二盐酸盐的晶型，其X射线粉末衍射图如图5所示。
在一些实施方案中，本发明提供了式I化合物的磷酸盐的结晶形式。
在一些实施方案中，所述磷酸盐结晶，其X射线粉末衍射图的2θ详见下表4：
表4式I化合物的磷酸盐晶型X射线粉末衍射图数据
2θ(°) 高度(counts) I/I 0(％)
4.921 34 22.3
6.595 7 4.8
9.767 153 100.0
10.994 23 15.4
11.732 24 15.6
13.388 45 29.8
14.569 49 32.4
15.322 20 12.9
16.030 13 8.7
18.439 55 36.0
19.043 66 43.3
20.484 17 11.3
21.343 22 14.2
22.584 46 29.9
24.366 82 53.8
24.890 60 39.0
25.994 60 39.1
29.305 72 47.3
32.096 7 4.9
33.988 13 8.3
35.573 9 5.9
37.022 12 7.9
39.391 9 5.8
。
在一些实施方案中，本发明提供了式I化合物的磷酸盐的晶型，其X射线粉末衍射图如图6所示。
在一些实施方案中，本发明提供了式I化合物的马尿酸盐的结晶形式。
在一些实施方案中，所述马尿酸盐结晶，其X射线粉末衍射图的2θ详见下表5：
表5式I化合物的马尿酸盐晶型X射线粉末衍射图数据
Figure PCTCN2022134408-appb-000006
Figure PCTCN2022134408-appb-000007
在一些实施方案中，本发明提供了式I化合物的马尿酸盐的晶型，其X射线粉末衍射图如图7所示。
在一些实施方案中，本发明提供了式I化合物的硫酸盐的无定型。
在一些实施方案中，本发明提供了式I化合物的氢溴酸盐的结晶形式。
在一些实施方案中，所述氢溴酸盐结晶，其X射线粉末衍射图的2θ详见下表6：
表6式I化合物的氢溴酸盐晶型X射线粉末衍射图数据
2θ(°) 高度(counts) I/I 0(％)
5.671 15 6.6
8.457 56 24.2
11.318 145 62.5
12.029 69 29.9
12.920 205 88.2
13.219 110 47.4
13.753 181 78.2
14.791 42 17.9
16.779 143 61.5
18.057 112 48.3
21.010 141 61.0
21.484 121 52.1
22.056 62 26.6
22.614 98 42.2
23.270 232 100.0
24.129 181 77.9
24.907 94 40.4
25.636 148 63.7
27.155 100 43.0
28.296 57 24.7
29.464 32 13.7
33.019 32 13.6
34.699 67 28.8
。
在一些实施方案中，本发明提供了式I化合物的氢溴酸盐的晶型，其X射线粉末衍射图如图9所示。
在一些实施方案中，本发明提供了式I化合物的苯磺酸盐的结晶形式。
在一些实施方案中，所述苯磺酸盐结晶，其X射线粉末衍射图的2θ详见下表7：
表7苯磺酸盐晶型X射线粉末衍射图数据
2θ(°) 高度(counts) I/I 0(％)
10.980 25 12.3
12.144 90 43.7
13.601 60 29.5
15.200 125 60.8
17.066 116 56.6
18.536 205 100.0
19.384 99 48.5
20.160 111 54.0
21.250 73 35.7
21.975 203 99.2
24.505 154 75.0
26.759 78 38.0
27.897 47 23.1
30.580 36 17.5
32.115 18 8.6
。
在一些实施方案中，本发明提供了式I化合物的苯磺酸盐的晶型，其X射线粉末衍射图如图10所示。
在一些实施方案中，本发明提供了式I化合物的草酸盐的结晶形式。
在一些实施方案中，所述草酸盐结晶，其其X射线粉末衍射图的2θ详见下表8：
表8式I化合物的草酸盐晶型X射线粉末衍射图数据
2θ(°) 高度(counts) I/I 0(％)
5.912 94 14.6
8.834 174 26.9
10.270 114 17.7
11.760 78 12.1
14.710 646 100.0
17.656 485 75.0
18.229 72 11.2
19.318 54 8.4
19.720 60 9.4
21.564 194 30.0
25.441 103 16.0
26.590 121 18.7
27.016 100 15.5
32.375 7 1.0
34.957 29 4.5
。
在一些实施方案中，本发明提供了式I化合物的草酸盐的晶型，其X射线粉末衍射图如图11所示。
在一些实施方案中，本发明提供了式I化合物的富马酸盐的结晶形式。
在一些实施方案中，所述富马酸盐结晶，其X射线粉末衍射图的2θ详见下表9：
表9式I化合物的富马酸盐晶型X射线粉末衍射图数据
Figure PCTCN2022134408-appb-000008
Figure PCTCN2022134408-appb-000009
在一些实施方案中，本发明提供了式I化合物的富马酸盐的晶型，其X射线粉末衍射图如图12所示。
在一些实施方案中，本发明提供了式I化合物的柠檬酸盐的结晶形式。
在一些实施方案中，所述柠檬酸盐结晶，其X射线粉末衍射图的2θ详见下表10：
表10式I化合物的柠檬酸盐晶型X射线粉末衍射图数据
2θ(°) 高度(counts) I/I 0(％)
18.138 90 100.0
19.467 63 70.0
26.072 55 61.5
31.101 14 15.4
。
在一些实施方案中，本发明提供了式I化合物的柠檬酸盐的晶型，其X射线粉末衍射图如图13所示。
另一方面，本发明提供了一种式I化合物的晶型A，其X射线粉末衍射图在2θ为7.6°±0.2°、10.2°±0.2°、17.6°±0.2°、20.3°±0.2°和20.9°±0.2°处具有衍射峰。
进一步地，所述晶型A，其X射线粉末衍射图在2θ为4.1°±0.2°、7.6°±0.2°、10.2°±0.2°、12.6°±0.2°、13.0°±0.2°、17.6°±0.2°、19.7°±0.2°、20.3°±0.2°、20.9°±0.2°和22.2°±0.2°处具有衍射峰。
进一步地，所述晶型A，其X射线粉末衍射图在2θ为4.1°±0.2°、5.6°±0.2°、7.6°±0.2°、10.2°±0.2°、10.9°±0.2°、12.6°±0.2°、13.0°±0.2°、15.2°±0.2°、17.6°±0.2°、19.7°±0.2°、20.3°±0.2°、20.9°±0.2°、22.2°±0.2°、23.2°±0.2°、24.6°±0.2°、27.0°±0.2°、28.8°±0.2°、37.0°±0.2°和37.7°±0.2°处具有衍射峰。
在一些实施方案中，所述晶型A，其X射线粉末衍射图的2θ详见下表：
表11晶型A的X射线粉末衍射图数据
Figure PCTCN2022134408-appb-000010
Figure PCTCN2022134408-appb-000011
在一些实施方案中，所述晶型A以2θ角度表示的X射线粉末衍射具有如图14所示的图谱。
另一方面，本发明提供了式I化合物的药学上可接受的盐或其药学上可接受的盐的晶型的制备方法，其包括将式I化合物与相应的酸成盐的步骤。
在一些实施方案中，所述制备方法的反应溶剂选自醇类溶剂与烷烃类溶剂的混合溶剂、酮类溶剂与烷烃类溶剂的混合溶剂、酯类溶剂与烷烃类溶剂的混合溶剂、腈类-水类溶剂与烷烃类溶剂的混合溶剂、烷苯类溶剂与烷烃类溶剂的混合溶剂或卤代烃类溶剂与烷烃类溶剂的混合溶剂。
在一些实施方案中，所述醇类溶剂选自甲醇、乙醇或异丙醇；所述酮类溶剂选自丙酮或丁酮；优选丙酮；所述酯类溶剂选自乙酸乙酯或乙酸丁酯；优选乙酸乙酯；所述腈类-水类溶剂选自腈类-水的混合溶液，所述烷烃类溶剂选自正庚烷。
在一些实施方案中，所述药学上可接受的盐的晶型为甲磺酸盐晶型，所述甲磺酸盐晶型通过包括以下步骤的方法制备得到：
S1：将式I化合物、甲磺酸与甲苯搅拌得到式I化合物的甲磺酸盐晶型的晶种；
S2：将式(I)化合物、甲磺酸与乙酸乙酯搅拌反应后加入步骤S1得到的晶型继续搅拌；
S3：加入乙酸乙酯、丙酮和权利要求8所述的式I化合物的晶型，搅拌析晶得到所述甲磺酸盐晶型(或称甲磺酸盐晶型II)。
另一方面，本发明还提供了包含所述式I化合物的药学上可接受的盐的药物组合物。
在一些实施方案中，所述药物组合物进一步包含一种或多种药学上可接受的载体。
在一些实施方案中，所述药物组合物为适于口服的固体药物制剂，优选片剂或胶囊。
另一方面，本发明还提供了包含所述式I化合物的药学上可接受的盐的晶型的药物组合物。
在一些实施方案中，所述药物组合物进一步包含一种或多种药学上可接受的载体。
在一些实施方案中，所述药物组合物为适于口服的固体药物制剂，优选片剂或胶囊。
另一方面，本发明提供一种晶型组合物，其中上述式I化合物的药学上可接受的盐、上述式I化合物的药学上可接受的盐的晶型占所述晶型组合物重量的50％以上。
进一步占所述晶型组合物重量的80％以上；
进一步占所述晶型组合物重量的90％以上；
进一步占所述晶型组合物重量的95％以上。
另一方面，本发明还提供了包含上述晶型组合物的药物组合物；所述药物组合物进一步包含一种或多种药学上可接受的载体。
另一方面，本发明还提供了用作药物的式I化合物的药学上可接受的盐或其晶型组合物或其药物组合物。
另一方面，本发明还提供了用作药物的式I化合物的药学上可接受的盐的晶型或其晶型组合物或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的方法，其包括向有需要的个体给予本发明的所述式I化合物的盐、其晶型组合物或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的方法，其包括向有需要的个体给予本发明的所述式I化合物的盐的晶型、其晶型组合物或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的本发明的所述式I化合物的 盐、其晶型组合物或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的本发明的所述式I化合物的盐的晶型、其晶型组合物或其药物组合物。
在一些实施方案中，所述AXL激酶介导的疾病或疾病状态为癌症。
在一些典型的实施方案中，所述癌症为与血液肿瘤和实体瘤相关的疾病。
相关定义
除非有特定说明，下列用在说明书和权利要求书中的术语具有下述含义：
本发明的药学上可接受的盐还包括它们的水合物形式。
术语“药学上可接受的载体”是指对机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。包括但不限于国家食品药品监督管理局许可的可用于人或动物的任何稀释剂、崩解剂、粘合剂、助流剂、润湿剂。
术语“富马酸”指反丁烯二酸，具有结构：
Figure PCTCN2022134408-appb-000012
术语“醇类溶剂”是指一个或多个羟基(OH)取代C1-C6烷烃上的一个或多个氢原子所衍生的物质，所述C1-C6烷烃是指含有1-6个碳原子的直链或支链的烷烃，醇类溶剂的具体实例包括但不限于：甲醇、乙醇、异丙醇或正丙醇。
术语“烷烃类溶剂”是指含有5-7个碳原子的直链或支链或环状的烷烃，具体实例包括但不限于正己烷、环己烷、正庚烷。
术语“酯类溶剂”是指含有酯基-COOR且碳原子数为3-10个的链状化合物，其中R为C1-C6烷基，所述C1-C6烷基是指含有1-6个碳原子的直链或支链烷烃，酯类溶剂的具体实例包括但不限于乙酸甲酯、乙酸乙酯、乙酸丙酯。
术语“卤代烃类溶剂”是指一个或多个卤素原子取代C1-C6烷烃上的一个或多个氢原子所衍生的物质，所述C1-C6烷烃是指含有1-6个碳原子的直链或支链的烷烃，所述卤素原子是指氟、氯、溴、碘，卤代烃类溶剂的具体实例包括但不限于二氯甲烷或氯仿。
术语“酮类溶剂”是指含有羰基-CO-且碳原子数为3-10个的链状或环状化合物，具体实例包括但不限于丙酮、丁酮或环己酮。
术语“苯类溶剂”是指含有苯基的溶剂，具体实例包括甲苯、二甲苯、异丙苯或氯苯。
术语“当量”是指按照化学反应的当量关系，以每步骤中所用基本原料为1当量，所需要的其他原料的当量用量。
本发明中的“X射线粉末衍射图谱”为使用Cu-Kα辐射测量得到。
需要说明的是，在X射线粉末衍射光谱(XRPD)中，由结晶化合物得到的衍射谱图对于特定的结晶往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为结晶条件、粒径和其它测定条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的结晶并非是特征性的。判断是否与已知的结晶相同时，更应该注意的是峰的相对位置而不是它们的相对强度。此外，对任何给定的结晶而言，峰的位置可能存在轻微误差，这在结晶学领域中也是公知的。例如，由于分析样品时温度的变化、样品移动、或仪器的标定等，峰的位置可以移动，2θ值的测定误差有时约为±0.2°。因此，在确定每种结晶结构时，应该将此误差考虑在内。在XRPD图谱中通常用2θ角或晶面距d表示峰位置，两者之间具有简单的换算关系：d＝λ/2sinθ，其中d代表晶面距，λ代表入射X射线的波长，θ为衍射角。对于同种化合物的同种结晶，其XRPD谱的峰位置在整体上具有相似性，相对强度误差可能较大。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至一条谱带也可能对给定的结晶是特征性的。
差示扫描量热法(DSC)测定当晶体由于其晶体结构发生变化或晶体熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃之内，通常在约3℃之内。当描述某个化合物具有某一给定的DSC峰或熔点时，指的是该DSC峰或熔点±5℃。DSC提供了一种辨别不同晶型的辅助方法。不同的晶体形态可根据其不同的转变温度特征而加以识别。需要指出的是对于混合物而言，其DSC峰或熔点可能会在更大的范围内波动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。
热重分析(TGA)指的是在程序控制温度下测量待测样品的质量与温度变化之间关系的一种热分析技术。当被测物质在加热过程中有升华或汽化现象时，其分解出了气体或失去了结晶水时，引起被测物质量发生变化。这时， 热重曲线就不是直线而是有所下降。通过分析热重曲线，即可知道被测物质在什么温度下产生变化，并且根据所失重量，可计算失去了多少物质量。
在提到例如XRPD图谱、DSC图谱或TGA图谱时，术语“如……所示”包括与本文描绘的那些不一定相同，但在被本领域技术人员考虑时落入实验误差的限度内的图谱。
如无特殊说明，本发明的简称具有如下含义：
M：mol/L
mM：mmol/L
nM：nmol/L
Boc:叔丁氧羰基
1H NMR：核磁共振氢谱
MS(ESI+)：质谱
DMSO-d 6:氘代二甲基亚砜
CDCl 3：氘代氯仿
DTT：二硫苏糖醇
SEB：Supplemented Enzymatic Buffer(补充酶缓冲液)
IMDM(Iscove's Modified Dulbecco's Medium):Iscove(人名)改良的Dulbecco(人名)培养基。
室温：25℃。
附图说明
为了更清楚地说明本发明实施例和现有技术的技术方案，下面对实施例和现有技术中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，还可以根据这些附图获得其他的附图。
图1显示实施例5中式I化合物甲磺酸盐的X-射线粉末衍射(XRPD)谱图；
图2显示实施例5中式I化合物甲磺酸盐的差示扫描量热(DSC)图；
图3显示实施例5中式I化合物甲磺酸盐的热重(TGA)图；
图4显示实施例3中式I化合物单盐酸盐的X-射线粉末衍射(XRPD)谱图；
图5显示实施例3中式I化合物二盐酸盐的X-射线粉末衍射(XRPD)谱图；
图6显示实施例3中式I化合物磷酸盐的X-射线粉末衍射(XRPD)谱图；
图7显示实施例3中式I化合物马尿酸盐的X-射线粉末衍射(XRPD)谱图；
图8显示实施例3中式I化合物硫酸盐的X-射线粉末衍射(XRPD)谱图；
图9显示实施例3中式I化合物氢溴酸盐的X-射线粉末衍射(XRPD)谱图；
图10显示实施例3中式I化合物苯磺酸盐的X-射线粉末衍射(XRPD)谱图；
图11显示实施例3中式I化合物草酸盐的X-射线粉末衍射(XRPD)谱图；
图12显示实施例3中式I化合物富马酸盐的X-射线粉末衍射(XRPD)谱图；
图13显示实施例3中式I化合物柠檬酸盐的X-射线粉末衍射(XRPD)谱图；
图14显示实施例6中式I化合物的晶型A的X-射线粉末衍射(XRPD)谱图。
具体实施方式
下面通过实施例更详细地描述本发明。但这些具体描述仅用于说明本发明的技术方案，不对本发明构成任何限制。
各仪器测试条件如下：
(1)X-射线粉末衍射仪(X-ray Powder Diffraction，XRPD)
仪器型号：Bruker D2 Phaser 2 nd
Figure PCTCN2022134408-appb-000013
Figure PCTCN2022134408-appb-000014
(2)热重分析仪(Thermogravimetric，TGA)
仪器型号：TA Instruments TGA25
吹扫气：氮气
升温速率：10℃/min
升温范围：室温-300℃
方法：将样品置于铝盘中，再将铝盘置于铂盘中，敞口在氮气氛围中以10℃/min的速度从室温升温至设定的温度。
(3)差示扫描量热仪(Differential Scanning Calorimeter，DSC)
仪器型号：TA Instruments DSC25
吹扫气：氮气
升温速率：10℃/min
升温范围：20-300℃
方法：样品置于铝盘中，压盖后在氮气氛围中以10℃/min的速度从20℃升温至设定的温度。
(4)动态水分吸附(DVS)
仪器型号：Surface Measurement System(SMS)-DVS Intrinsic
Figure PCTCN2022134408-appb-000015
具体的仪器设定参数如下：
实施例1(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的制备
Figure PCTCN2022134408-appb-000016
a)2-碘-4-(甲氧基甲基)苯胺
在二氯甲烷(261mL)/水(135mL)的溶液中加入4-(甲氧基甲基)苯胺(9g)、碘(16.65g)和碳酸氢钠(16.53g)，22℃下搅拌16h。反应液用饱和硫代硫酸钠(10ml)在室温下下猝灭。所得混合物用二氯甲烷(3x 100mL)萃取，接着用饱和氯化钠水溶液(1x100mL)洗涤合并的有机层，有机层再用无水硫酸钠干燥。过滤后，滤液减压浓缩。残渣经硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1v/v)，得到标题产物(16g)。MS(ESI+):264.0(M+H).
b)(2-氨基-5-(甲氧基甲基)苯基)二甲基氧化膦
在氮气气氛下，向N,N-二甲基甲酰胺(224mL)中加入2-碘-4-(甲氧基甲基)苯胺(16g，60.82mmol，1.00当量)、磷酸钾(14.20g)、醋酸钯(0.68g)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(1.76g)的搅拌溶液中添加二甲基氧化膦(5.22g)，于120℃下搅拌反应2小时。将混合物冷却至室温。过滤所得混合物，用N,N-二甲基甲酰胺(3x5mL)洗涤滤饼。滤液减压浓缩。用硅胶柱层析(二氯甲烷/甲醇＝20/1v/v)纯化残余物得到标题产物(12.9g)。MS(ESI+):214.1(M+H).
c)(2-((2,5-二氯嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦
在室温下向N,N-二甲基甲酰胺(22mL)中加入(2-氨基-5-(甲氧基甲基)苯基)二甲基氧化膦(1.10g)、2,4,5-三氯嘧啶(1.23g)和N,N-二异丙基乙胺(2.00g)搅拌3h。所得混合物用二氯甲烷(30mL)稀释。在0℃下加水(10ml)使反应猝灭。所得混合物用二氯甲烷(3x 50mL)萃取。合并的有机层用饱和氯化钠(1x50mL)洗涤并用无水硫酸钠干燥。过滤后，滤液减压浓缩。用硅胶柱层析(二氯甲烷/甲醇＝20/1v/v)纯化残余物得到标题产物(1.28g)。
MS(ESI+):360.0(M+H).
d)(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦
向异丙醇(2mL)中加入(2-((2,5-二氯嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦(50.00mg)和(S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺(31.98mg)，然后加入氯化氢的1，4-二氧六环溶液(10滴，4M),130℃下用微波辐射3.5小时。然后混合物冷却到室温，减压浓缩。粗品经反相高效液相色谱法纯化(柱为YMC Actus Triart C18，30*150mm，粒径5μm，流动相A：水(10mmol/L碳酸氢铵)，流动相B:乙腈，流速：60mL/min，梯度：20％B至50％B，8min，波长：220nm，保留时间：6.83min，柱温：25℃)，得标题产物(20.2mg)。
1H NMR(400MHz,DMSO-d 6,ppm)：δ11.07(s,1H),9.26(s,1H),8.52(d,J＝4.6Hz,1H),8.17(s,1H),7.53(dd,J＝14.0,2.0Hz,1H),7.44(q,J＝3.1Hz,2H),7.26(dd,J＝8.1,2.3Hz,1H),6.97(d,J＝8.1Hz,1H),4.42(s,2H),3.31(s,3H),3.01–2.75(m,2H),2.55(s,5H),2.50(s,2H),1.84(s,2H),1.81(s,3H),1.77(s,3H),1.70(q,J＝3.6,3.2Hz,4H),1.54(s,2H).MS(ESI+):554.2(M+H).
实施例2 活性测定
实施例1制备的相关化合物进行相关的酶活、细胞、体内相关的活性
活性测试中所使用的阳性药1(BGB324)具体结构如下：
Figure PCTCN2022134408-appb-000017
阳性药2(TP0903)具体结构如下：
Figure PCTCN2022134408-appb-000018
以上化合物均从上海升泓生物科技有限公司购买。
(1)AXL激酶抑制活性
1.实验流程
a)AXL酶(Carna，08-107)配置及加入：用1×酶缓冲液(将200μL的Enzymatic buffer kinase 5X,10μL的500mM的MgCl 2，10μL的100mM的DTT，6.26μL的2500nM的SEB，加入773.75μL的H 2O，配置成1ml的1×酶缓冲液)将33.33ng/uL的AXL酶稀释到0.027ng/μL(1.67×，final conc.＝0.016ng/μL)，使用BioTek(MultiFlo FX)自动分液仪，化合物孔和阳性对照孔分别加6μL的1.67倍终浓度的酶溶液；在阴性对照孔中加6μL的1×Enzymatic buffer。
b)化合物配制及加入：使用DMSO将实施例中制备的化合物及阳性药从10mM稀释到100μM，用化合物滴定仪(Tecan，D300e)进行滴定，滴定仪自动喷入每孔所需浓度，第1个浓度为1μM，1/2log梯度稀释，共8个浓度。2500rpm离心30s，室温孵育15min。
c)ATP、底物配制及加入：ATP(Sigma，A7699)用1×酶缓冲液进行稀释，从10mM稀释到75μM(5×)，终浓度为15μM；底物TK Substrate 3-biotin(Cisbio，61TK0BLC)用1×酶缓冲液，从500μM稀释到5μM(5×)，终浓度为1μM,；ATP同底物等体积混合，使用BioTek自动分液仪4μL加入每孔；2500rpm离心30s，25℃反应45min。
d)检测试剂配制及加入：Streptavidin-XL665(Cisbio，610SAXLG)用HTRF KinEASE detection buffer(cisbio)从16.67μM稀释到250nM(4×)，终浓度为62.5nM；TK Antibody-Cryptate(Cisbio)用HTRF KinEASE detection buffer(cisbio)从100×稀释到5×，终浓度为1×；XL665同Antibody等体积混合，使用BioTek自动分液仪10μL加入每孔，2500rpm离心30s，25℃反应1小时。反应结束后，用多功能读板仪HTRF进行检测。
2.数据分析
使用GraphPad Prism 5软件log(inhibitor)vs.response-Variable slope拟合量效曲线，得到化合物对AXL激酶抑制的IC 50值。
抑制率计算公式如下：
Figure PCTCN2022134408-appb-000019
3.实验结果详见下表
表12化合物AXL抑制活性IC 50数据
Figure PCTCN2022134408-appb-000020
Figure PCTCN2022134408-appb-000021
(2)化合物对细胞增殖抑制检测
1.实验流程
MV-4-11(人髓性单核细胞白血病细胞株，培养基：IMDM+10％胎牛血清)购自南京科佰生物科技有限公司，置于37℃,5％CO 2的培养箱中培养。取对数生长期的细胞分别以8000个/孔、6000个/孔、5000个/孔、4000个/孔和3000个/孔的细胞密度铺在96孔板中，并同时设置空白对照组。
将待测化合物以及阳性药溶解在二甲基亚砜中以制备10mM的储液，并置于-80℃冰箱中长期保存。细胞铺板24h后，用二甲基亚砜稀释10mM的化合物储液得到200倍浓度的工作液(最高浓度200或2000μM，3倍梯度，共10个浓度)，每个浓度各取3μL加入到197μL的完全培养基中，稀释得到3倍浓度的工作液，然后取50μL加入到100μL的细胞培养液中(二甲基亚砜终浓度为0.5％,v/v)，每个浓度设置两个复孔。加药处理72h后，每孔加入50μl的
Figure PCTCN2022134408-appb-000022
(购自Promega)，按照说明书的操作流程在Envision(PerkinElmer)上测定荧光信号，使用GraphPad Prism 5软件log(inhibitor)vs.response-Variable slope拟合量效曲线，得到化合物对细胞增殖抑制的IC 50值。抑制率计算公式：
Figure PCTCN2022134408-appb-000023
其中：
受试物信号值：细胞+培养基+化合物组荧光信号均值；
空白组信号值：培养基组(含0.5％DMSO)荧光信号均值；
阴性对照组信号值：细胞+培养基组(含0.5％DMSO)荧光信号均值。
2.实验结果
实施例1的化合物MV4-11细胞的抗增殖活性的IC 50(MV4-11,nM)为6.97。
(3)化合物的MV4-11体内药效
测试化合物以及阳性药对人急性单核细胞白血病细胞MV-4-11裸鼠移植瘤模型肿瘤体内生长的抑制作用。
1.小鼠模型的构建
收取对数生长期MV-4-11细胞，细胞计数后重悬后，调整细胞浓度至7.0×10 7细胞/mL；注射到裸鼠前右侧腋窝皮下，每只动物接种200为L(14×10 6细胞/只)，建立MV-4-11移植瘤模型。待瘤体积达到100～300mm 3，挑选健康状况良好、肿瘤体积相近的荷瘤鼠。
2.化合物的配置
将化合物以及阳性药，用适当的溶剂涡旋振荡后超声使化合物完全溶解后缓慢加入适量体积柠檬酸缓冲液，涡旋振荡，使液体混合均匀，得到浓度为0.1、0.5、1mg mL -1的给药制剂。
溶剂对照组：PEG400&柠檬酸缓冲液(20:80，v:v)。
3.动物分组及给药
将建模的小鼠随机分组(n＝6)，于分组当天开始给予相关化合物和阳性药，21天后或溶剂对照组肿瘤体积达到2000mm 3结束实验(以先达到指标为准)，给药体积均为10mL·kg -1。化合物以及阳性药均采取灌胃方式给予，每天给予一次。实验开始后每周测量2次瘤径和动物体重，计算肿瘤体积。
4.数据分析
肿瘤体积(TV)计算公式为：肿瘤体积(mm 3)＝l×w 2/2，
其中，l表示肿瘤长径(mm)；w表示肿瘤短径(mm)。
相对肿瘤体积(RTV)的计算公式为：RTV＝TV t/TV initial
其中，TV initial为分组给药时测量到的肿瘤体积；TV t为给药期间每一次测量时的肿瘤体积。
肿瘤生长抑制率TGI(％)的计算公式为：TGI＝100％×[1－(TV t(T)－TV initial(T))/(TV t(C)－TV initial(C))]
其中，TV t(T)表示治疗组每次测量的肿瘤体积；TV initial(T)表示分组给药时治疗组的肿瘤体积；TV t(C)表示溶剂对照组每次测量的肿瘤体积；TV initial(C)表示分组给药时溶剂对照组的肿瘤体积。
相对肿瘤增殖率(％T/C)的计算公式为：％T/C＝100％×(RTV T/RTV C)
其中，RTV T表示治疗组RTV；RTV C表示溶剂对照组RTV。
试验数据用Microsoft Office Excel 2007软件进行计算和相关统计学处理。
5.实验结果如下详见下表：
表13化合物的体内药效
Figure PCTCN2022134408-appb-000024
备注：表中的实验数据为实验结束(实验结束定义为：21天后或溶剂对照组肿瘤体积达到2000mm 3结束实验(以先达到指标为准))时，获得的相关数据。
(4)化合物的ICR小鼠药代动力学研究
1.化合物的灌胃处方配置
将各化合物用DMSO配制成10mg/mL的储备液。
混合溶媒配制：Tween 80:PEG400:Water＝1:9:90(v/v/v)
分别准确吸取浓度为10mg/mL的化合物DMSO储备液450μl至玻璃瓶，加入适当体积的DMSO和混合溶媒，最终制剂中溶媒的比例为DMSO:混合溶媒(v/v)＝10:90，涡旋(或超声)，分散均匀，分别得浓度为1mg/mL的4.5mL给药试液。
2.试验方案
取雄性6～10周龄ICR小鼠(小鼠来源：维通利华实验动物技术有限公司)，每组6只，小鼠禁食过夜，给药后4小时喂食。实验当天，小鼠分别灌胃给予10mg kg- 1化合物试液。给药后小鼠在0、5min、15min、30min、1h、2h、4h、8h、24h，由眼眶采血约100μL，置于EDTA-K 2抗凝管中。将全血样品于1500～1600g离心10min，将分离得到的血浆保存于-40～-20℃冰箱中，用于生物样品分析。LC-MS/MS方法测定血药浓度。
3.数据分析及结果
采用Pharsight Phoenix 7.0中的非房室模型计算药代动力学参数，具体结果详见下表。
表14化合物的小鼠药代动力学结果
化合物 Cmax(ng/mL) Tmax(h) AUC0-24(ng.h/mL) T 1/2(h)
实施例1 324 2.17 1300 1.35
阳性药2(TP-0903) 26.8 0.25 52.2 1.20
实施例3(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦(式I化合物)的盐以及晶型的制备
分别取约50mg式I化合物，即式I化合物，和1.05当量的酸(盐酸同时设置酸与式I化合物摩尔比为2.10的情况)，加入1mL溶剂并在室温下搅拌2天。所得澄清液通过5℃搅拌和缓慢挥发的方法尝试结晶，固体通过离心分离，在40℃下，鼓风干燥或减压干燥2-5小时后用于XRPD表征。
表15式I化合物成盐结果
Figure PCTCN2022134408-appb-000025
Figure PCTCN2022134408-appb-000026
Figure PCTCN2022134408-appb-000027
图4-13分别为式I化合物盐酸盐、二盐酸盐、磷酸盐、马尿酸盐、硫酸盐、氢溴酸盐、苯磺酸盐、草酸盐、富马酸盐、柠檬酸盐的X-射线粉末衍射(XRPD)谱图。
实施例4(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦(式I化合物)甲磺酸盐的制备方法
向20-mL玻璃小瓶中先后添加(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基))嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦(50mg)、甲苯(1mL)和甲磺酸(10mg)，在室温下搅拌反应2小时，得到混悬液状态的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基))嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦甲磺酸盐晶型。
实施例5(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化磷(式I化合物)甲磺酸盐的制备方法
向20-mL玻璃小瓶中先后添加(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基))嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦(1g)、乙酸乙酯(20mL)和甲磺酸(172.8mg)，在室温下搅拌反应10分钟后加入实施例4制备的甲磺酸盐晶型为晶种(5mg)搅拌30分钟。向玻璃小瓶中先后加入乙酸乙酯(20mL)、丙酮(10mL)和实施例4制备的甲磺酸盐晶型晶种(100.mg)搅拌析晶20分钟。抽滤，湿滤饼在真空下于40℃下干燥20小时，得到淡黄色固体粉末状态的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基))嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦甲磺酸盐晶型。
1H NMR(400MHz,DMSO-d6):11.11(s,1H)；9.46(br,1H)；9.36(s,1H)；8.58-8.50(m,1H)；8.19(s,1H)；7.60-7.43,(m,3H)；7.37(dd,J＝8.2,2.2Hz,1H)；7.04(d,J＝8.2Hz,1H)；4.44(s,2H)；3.53-3.46(m,3H)；3.33(s,3H)；3.15(s,2H)；2.82-2.62(m,4H)；2.32-2.29(m,5H)；1.99(s,2H)；1.89-1.75(m,8H)；1.40(q,J＝12.3Hz,2H).
其XRPD图谱参见附图1，DSC图谱参见附图2，TGA图参见图3。
实施例6(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦(式I化合物)的晶型A的制备
于3mL玻璃瓶中先后加入200mg按照实施例1方法制备的S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦和2mL纯化水，常温磁力搅拌6小时后，将样品离心，取湿样置于40℃减压干燥21小时后得176mg的晶型A，收率88.0％,其XRPD图谱详见图14，X射线粉末衍射图数据详见表16。
表16游离碱晶型A的X射线粉末衍射图数据
2θ(°) 高度(counts) I/I 0(％)
4.1 45 15.4
5.6 42 14.3
7.6 109 36.9
10.2 107 36.4
10.9 13 4.4
12.6 59 20.1
13.0 44 14.8
15.2 18 6.2
17.6 246 83.4
19.7 85 28.9
20.3 184 62.5
20.9 294 100.0
22.2 60 20.5
23.2 22 7.5
24.6 19 6.6
27.0 40 13.6
28.8 14 4.6
37.0 6 2.1
37.7 12 4.1

Claims (12)

  1. 一种式I化合物的药学上可接受的盐，所述盐选自有机酸盐或无机酸盐，其中所述有机酸盐选自甲磺酸盐、苯磺酸盐、草酸盐、富马酸盐、柠檬酸盐和马尿酸盐中的一种，所述无机酸盐选自盐酸盐、氢溴酸盐、硫酸盐或磷酸盐中的一种，式I化合物结构如下：
    Figure PCTCN2022134408-appb-100001
  2. 根据权利要求1所述的式I化合物的药学上可接受的盐，所述有机酸盐为甲磺酸盐。
  3. 根据权利要求2所述的式I化合物的药学上可接受的盐，所述甲磺酸盐为水合物形式，进一步为二水合物形式。
  4. 根据权利要求1-3任一项所述的式I化合物的药学上可接受的盐，所述有机酸盐中式I化合物与有机酸的摩尔比为1：1。
  5. 根据权利要求1所述的式I化合物的药学上可接受的盐，所述无机酸盐中式I化合物与无机酸的摩尔比为1：1或1：2；进一步地，所述无机酸盐为盐酸盐，所述盐酸盐中式I化合物与氯化氢的摩尔比为1：1或1：2。
  6. 一种式I化合物的药学上可接受的盐的晶型，所述盐选自有机酸盐或无机酸盐，其中所述有机酸盐选自甲磺酸盐、苯磺酸盐、草酸盐、富马酸盐、柠檬酸盐和马尿酸盐，所述无机酸盐选自盐酸盐、氢溴酸盐或磷酸盐。
    Figure PCTCN2022134408-appb-100002
  7. 根据权利要求6所述的式I化合物的药学上可接受的盐的晶型，所述盐为甲磺酸盐，进一步地，所述式I化合物的甲磺酸盐晶型的X射线粉末衍射图如图1所示。
  8. 一种式I化合物的晶型，其X射线粉末衍射图在2θ为7.6°±0.2°、10.2°±0.2°、17.6°±0.2°、20.3°±0.2°和20.9°±0.2°处具有衍射峰；
    进一步地，X射线粉末衍射图在2θ为4.1°±0.2°、7.6°±0.2°、10.2°±0.2°、12.6°±0.2°、13.0°±0.2°、17.6°±0.2°、19.7°±0.2°、20.3°±0.2°、20.9°±0.2°和22.2°±0.2°处具有衍射峰；
    进一步地，其X射线粉末衍射图在2θ为4.1°±0.2°、5.6°±0.2°、7.6°±0.2°、10.2°±0.2°、10.9°±0.2°、12.6°±0.2°、13.0°±0.2°、15.2°±0.2°、17.6°±0.2°、19.7°±0.2°、20.3°±0.2°、20.9°±0.2°、22.2°±0.2°、23.2°±0.2°、24.6°±0.2°、27.0°±0.2°、28.8°±0.2°、37.0°±0.2°和37.7°±0.2°处具有衍射峰；
    进一步地，以2θ角度表示的X射线粉末衍射具有如图14所示的图谱。
  9. 权利要求1-5任一项所述的式I化合物的药学上可接受的盐或权利要求6-7任一项所述的式I化合物的药学上可接受的盐的晶型的制备方法，其包括将式I化合物与相应的酸成盐的步骤。
  10. 根据权利要求9所述的制备方法，所述药学上可接受的盐的晶型为甲磺酸盐晶型，所述甲磺酸盐晶型通过包括以下步骤的方法制备得到：
    S1：将式I化合物、甲磺酸与甲苯搅拌得到式I化合物的甲磺酸盐晶型的晶种；
    S2：将式(I)化合物、甲磺酸与乙酸乙酯搅拌反应后加入步骤S1得到的晶型继续搅拌；
    S3：加入乙酸乙酯、丙酮和权利要求8所述的式I化合物的晶型，搅拌析晶得到所述甲磺酸盐晶型。
  11. 药物组合物，其包括权利要求1-5任一项所述的式I化合物的药学上可接受的盐、权利要求6-7任一项所述的式I化合物的药学上可接受的盐的晶型、权利要求8所述的式I化合物的晶型或权利要求9-10任一项所述的方法制备得到的药学上可接受的盐或药学上可接受的盐的晶型与药学上可接受的载体。
  12. 权利要求1-5任一项所述的式I化合物的药学上可接受的盐、权利要求6-7任一项所述的式I化合物的药学上可接受的盐的晶型、权利要求8所述的式I化合物的晶型或权利要求9-10任一项所述的方法制备得到的药学上可接受的盐或药学上可接受的盐的晶型在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
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