WO2024094016A1 - 一种二噁烷并喹啉类化合物的盐、其晶型以及它们的制备方法及应用 - Google Patents

一种二噁烷并喹啉类化合物的盐、其晶型以及它们的制备方法及应用 Download PDF

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WO2024094016A1
WO2024094016A1 PCT/CN2023/128656 CN2023128656W WO2024094016A1 WO 2024094016 A1 WO2024094016 A1 WO 2024094016A1 CN 2023128656 W CN2023128656 W CN 2023128656W WO 2024094016 A1 WO2024094016 A1 WO 2024094016A1
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cancer
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water
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French (fr)
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张强
徐俊
计凌涛
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北京赛特明强医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/33—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to a salt of N-(3-fluoro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, a crystal form thereof, a preparation method thereof, and an application thereof in the preparation of a drug as a tyrosine kinase (e.g., VEGFR-2, c-MET, c-KIT, PDGFRa, RET, AXL, NTRK) inhibitor.
  • a tyrosine kinase e.g., VEGFR-2, c-MET, c-KIT, PDGFRa, RET, AXL, NTRK
  • Vascular endothelial growth factor receptor is a member of the receptor tyrosine kinase family. It binds to its ligand vascular endothelial growth factor (VEGF) to produce a series of biochemical and physiological processes, ultimately promoting the formation of new blood vessels.
  • VEGF vascular endothelial growth factor
  • the formation of tumor blood vessels and their permeability are mainly regulated by vascular endothelial growth factor (VEGF), which acts through at least two different receptors (VEGFR-1 and VEGFR-2).
  • VEGF is an important stimulator of normal and pathological angiogenesis and vascular permeability (Jakeman et al., 1993, Endocrinology 133: 848-859; Kolch et al., 1995, Breast Cancer Research and Treatment, 36: 139-155; Connolly et al., 1989, J. Biol. Chem. 264: 20017-20024).
  • Vascular endothelial growth factor induces angiogenesis phenotype by inducing endothelial cell proliferation, protease expression and migration, and subsequent formation of capillary cell organization. Therefore, the antagonism of VEGF produced by the chelation of VEGF by antibodies can lead to the inhibition of tumor growth (Kim et al., 1993, Nature 362: 841-844).
  • VEGFR-2 Since VEGFR-2 is mainly distributed in vascular endothelial cells, it can bind to VEGF-A, VEGF-C, VEGF-D, and VEGF-E. VEGF stimulates the proliferation of endothelial cells, increases vascular permeability, and the formation of new blood vessels mainly by binding to and activating VEGFR-2. If the activity of VEGFR-2 is blocked, tumor growth and metastasis can be inhibited through direct and indirect pathways, thereby achieving an ideal anti-tumor effect. Therefore, finding small molecule inhibitors with high activity and selectivity for VEGFR-2 has become a very promising tumor treatment strategy.
  • Hepatocyte growth factor receptor is a type of tyrosine kinase receptor, and its abnormal activation plays an important role in the occurrence and development of various malignant tumors, including lung cancer.
  • Hepatocyte growth factor (HGF) is a specific ligand of c-MET. After c-MET binds to HGF, it exerts biological effects through the HGF/c-MET signaling pathway.
  • the HGF/c-MET signaling pathway can induce a series of biological effects such as cell proliferation, dispersion, migration, organ morphogenesis, and angiogenesis.
  • Abnormal activation of c-MET can be manifested as receptor overexpression, gene mutation, amplification, ectopic, and rearrangement.
  • c-MET plays an important role in cell proliferation, metabolism, tumor generation, metastasis, and angiogenesis, and has become an important target for anti-tumor therapy.
  • Targeted therapy targeting c-MET has shown its importance in the treatment of various malignant tumors including lung cancer.
  • WO2019154133 (application number PCT/CN2019/073260, application date 2019.01.25) discloses a compound that can effectively inhibit VEGFR-2 and c-MET tyrosine kinases. The compound can also effectively inhibit the proliferation of tumor cells such as MHCC97H.
  • the compound structure is shown in formula (I):
  • the present invention provides pharmaceutically acceptable salts of the compound of formula (I), crystal forms thereof, and methods for preparing the same and their use in preparing drugs as tyrosine kinase (e.g., VEGFR-2, c-MET, c-KIT, PDGFRa, RET, AXL, NTRK) inhibitors.
  • tyrosine kinase e.g., VEGFR-2, c-MET, c-KIT, PDGFRa, RET, AXL, NTRK
  • the salt forms and crystal forms of the present invention have good physicochemical properties and biochemical activities.
  • the present invention provides a pharmaceutically acceptable salt of a compound represented by formula (I),
  • the pharmaceutically acceptable salt is selected from inorganic salts or organic salts, preferably p-toluenesulfonate, mucate, and phosphate.
  • the pharmaceutically acceptable salt of the present invention can be a salt of N-(3-fluoro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and p-toluenesulfonic acid in a chemical ratio of 1:1 or 1:2.
  • the present invention provides a method for preparing a pharmaceutically acceptable salt of a compound of formula (I), comprising the step of subjecting N-(3-fluoro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide to a salt-forming reaction with an inorganic acid or an organic acid, preferably a step of subjecting the salt-forming reaction with p-toluenesulfonic acid, mucic acid or phosphoric acid.
  • the salt-forming reaction is carried out in a solvent
  • the solvent is selected from water, alcohol solvents, halogenated hydrocarbon solvents, ketone solvents, ether solvents, nitrile solvents, ester solvents, amide solvents, aliphatic hydrocarbon solvents, alicyclic hydrocarbon solvents, aromatic hydrocarbon solvents, mixed solvents of alcohol solvents and water, mixed solvents of ketone solvents and water, mixed solvents of alcohol solvents and ether solvents, mixed solvents of halogenated hydrocarbon solvents and nitrile solvents, mixed solvents of amide solvents and water, or mixed solvents of nitrile solvents and water;
  • the ketone solvent is preferably acetone
  • the alcohol solvent is preferably methanol, ethanol or isopropanol
  • the ether solvent is preferably diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or dioxane, the
  • the present invention provides a method for preparing a p-toluenesulfonate salt of a compound of formula (I), comprising the step of salting N-(3-fluoro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and p-toluenesulfonic acid in a chemical ratio of 1:1 or 1:2.
  • the present invention further provides a method for preparing a p-toluenesulfonate salt of a compound of formula (I) in A-II crystalline form, comprising taking a certain amount of the compound of formula (I) and p-toluenesulfonic acid in a molar ratio of 1:1, suspending and stirring in a solvent for a period of time, and then drying.
  • the solvent may be acetone, dichloromethane or dioxane.
  • the present invention provides a method for preparing a mucic acid salt of a compound of formula (I), comprising taking a certain amount of the compound of formula (I) and mucic acid at a molar ratio of 0.5:1, suspending and stirring in a solvent for a period of time, and then vacuum drying. More specifically, the solvent may be acetone.
  • the present invention provides a method for preparing a phosphate of a compound of formula (I), comprising taking a certain amount of the compound of formula (I) and phosphoric acid at a molar ratio of 1:1, suspending and stirring in a solvent for a period of time, and then vacuum drying.
  • the solvent may be ethanol/water.
  • the present invention further provides a method for preparing a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I), comprising taking a certain amount of the compound of formula (I) and the inorganic acid or organic acid, preferably p-toluenesulfonic acid, mucic acid, phosphoric acid, in a certain molar ratio, suspending and stirring in a solvent for a period of time, and then drying.
  • the solvent is as described above.
  • the preparation method of the crystalline form of the present invention may also include methods such as anti-solvent addition, slow volatilization, slow cooling, room temperature or high temperature suspension stirring, cyclic heating and cooling, gas-solid permeation, gas-liquid diffusion, polymer induction, etc.
  • the present invention provides a mucic acid salt A-I crystal form of a compound of formula (I) N-(3-fluoro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, wherein in its X-ray powder diffraction spectrum, there are characteristic peaks at 2 ⁇ angles of 3.95, 5.54, 7.46, 10.87, and 16.58, wherein the error range of the 2 ⁇ angle of each characteristic peak is ⁇ 0.2;
  • characteristic peaks at 2 ⁇ angles of 3.47, 3.95, 5.54, 7.46, 8.46, 10.48, 10.87, 14.90, 15.28, 16.16, and 16.58, wherein the error range of the 2 ⁇ angle of each characteristic peak is ⁇ 0.2;
  • the 2 ⁇ angle is 3.47, 3.95, 5.54, 7.46, 8.46, 10.48, 10.87, 11.72, 14.08, 14.90, 15.28,
  • the present invention provides a p-toluenesulfonate salt of a compound of formula (I) N-(3-fluoro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide of A-II crystalline form, wherein in its X-ray powder diffraction spectrum, there are characteristic peaks at 2 ⁇ angles of 5.30, 6.54, 7.97, 8.78, 13.01, 15.86, 19.70, 19.94 and 20.62, wherein the error range of the 2 ⁇ angle of each characteristic peak is ⁇ 0.2;
  • characteristic peaks at 2 ⁇ angles of 5.30, 6.54, 7.97, 8.78, 10.52, 11.63, 11.81, 13.01, 15.86, 17.54, 19.34, 19.70, 19.94, 20.62, 22.50, and 25.95, wherein the error range of the 2 ⁇ angle of each characteristic peak is ⁇ 0.2;
  • the present invention provides a di-p-toluenesulfonate A-IV crystalline form of a compound of formula (I) N-(3-fluoro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, wherein in its X-ray powder diffraction spectrum, there are characteristic peaks at 2 ⁇ angles of 6.36, 13.60, and 19.20, wherein the error range of the 2 ⁇ angle of each characteristic peak is ⁇ 0.2;
  • characteristic peaks at 2 ⁇ angles of 6.36, 9.87, 11.50, 13.60, 16.00, 19.20, 20.26, 20.86, and 21.36, wherein the error range of the 2 ⁇ angle of each characteristic peak is ⁇ 0.2;
  • the present invention provides an A-V crystal form of a phosphate of a compound of formula (I) N-(3-fluoro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, wherein in its X-ray powder diffraction spectrum, there are characteristic peaks at 2 ⁇ angles of 5.68, 7.56, and 16.93, wherein the error range of the 2 ⁇ angle of each characteristic peak is ⁇ 0.2;
  • characteristic peaks at 2 ⁇ angles of 4.03, 5.68, 6.84, 7.56, 9.36, 11.30, 11.94, 16.93, 19.76, and 23.01, wherein the error range of the 2 ⁇ angle of each characteristic peak is ⁇ 0.2;
  • compositions which comprises a pharmaceutically acceptable salt of the compound of formula (I) described in the present application, preferably a p-toluenesulfonate, a mucate, a phosphate, or any one of the crystalline forms A-I of the mucate, A-II of the p-toluenesulfonate, A-IV of the di-p-toluenesulfonate, or A-V of the phosphate of the compound of formula (I), and one or more pharmaceutically acceptable carriers or excipients.
  • a pharmaceutically acceptable salt of the compound of formula (I) described in the present application preferably a p-toluenesulfonate, a mucate, a phosphate, or any one of the crystalline forms A-I of the mucate, A-II of the p-toluenesulfonate, A-IV of the di-p-toluenesulfonate, or A-V of the phosphat
  • the pharmaceutical composition of the present application may also contain one or more other therapeutic agents.
  • the present application also relates to the use of a pharmaceutically acceptable salt, crystal form or pharmaceutical composition of the compound of formula (I) in the preparation of drugs for treating diseases related to tyrosine kinases VEGFR-2, c-MET, c-KIT, PDGFRa, RET, AXL, NTRK (NTRK includes TRK family kinases such as TRK-A, TRK-B, TRK-C, etc.).
  • the disease is preferably cancer or an autoimmune disease, especially fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, Rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain tumor, B-cell and T-
  • the present invention also relates to a method for treating diseases or conditions mediated by kinases such as VEGFR-2, c-MET, c-KIT, PDGFRa, RET, AXL, NTRK, etc., which comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt, crystalline form or pharmaceutical composition of the compound of formula (I) described in the present application to a patient (human or other mammal, especially human) in need thereof, wherein the diseases or conditions mediated by kinases such as VEGFR-2, c-MET, c-KIT, PDGFRa, RET, AXL, NTRK, etc. include those mentioned above.
  • kinases such as VEGFR-2, c-MET, c-KIT, PDGFRa, RET, AXL, NTRK, etc.
  • FIG1 is an XRPD diagram of the mucic acid salt form A-I of the compound of formula (I);
  • FIG2 is a TGA diagram of the mucic acid salt form A-I of the compound of formula (I);
  • FIG3 is a DSC graph of the mucic acid salt form A-I of the compound of formula (I);
  • FIG4 is an XRPD diagram of the p-toluenesulfonate crystalline form A-II of the compound of formula (I);
  • FIG5 is a TGA diagram of the p-toluenesulfonate crystalline form A-II of the compound of formula (I);
  • FIG6 is a DSC graph of the p-toluenesulfonate crystalline form A-II of the compound of formula (I);
  • FIG7 is an XRPD diagram of the p-toluenesulfonate crystalline form B-III of the compound of formula (I);
  • FIG8 is a TGA diagram of the p-toluenesulfonate crystalline form B-III of the compound of formula (I);
  • FIG9 is a DSC graph of the p-toluenesulfonate crystalline form B-III of the compound of formula (I);
  • FIG10 is an XRPD diagram of the di-p-toluenesulfonate crystalline form A-IV of the compound of formula (I);
  • FIG11 is a TGA diagram of the di-p-toluenesulfonate crystalline form A-IV of the compound of formula (I);
  • FIG12 is a DSC graph of the di-p-toluenesulfonate crystalline form A-IV of the compound of formula (I);
  • Figure 13 is an XRPD diagram of phosphate crystal forms A-V of the compound of formula (I);
  • Figure 14 is a TGA graph of phosphate crystal forms A-V of the compound of formula (I);
  • Figure 15 is a DSC graph of phosphate crystal forms A-V of the compound of formula (I);
  • FIG16 is a graph showing changes in tumor volume in the free form of the compound of formula (I) and the negative control group
  • FIG17 is a graph showing changes in tumor volume in the administration of the mucic acid salt A-I crystalline form of the compound of formula (I) of Example 1 and the negative control group;
  • FIG18 is a graph showing changes in tumor volume in the p-toluenesulfonate A-II crystalline form of the compound of formula (I) of Example 2 and in the negative control group;
  • FIG19 is a graph showing changes in tumor volume in the administration group of the phosphate AV crystal form of the compound of formula (I) of Example 5 and the negative control group.
  • C1 - C6 alkyl means an alkyl portion containing 1 to 6 carbon atoms.
  • C1 - C3 alkyl means an alkyl portion containing 1 to 3 carbon atoms.
  • C1 - C6 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl, etc.
  • ether solvent refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include, but are not limited to, diethyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, propylene glycol methyl ether or methyl tert-butyl ether.
  • alcohol solvent refers to a group derived from one or more hydroxyl groups replacing one or more hydrogen atoms on a C 1 -C 6 alkyl group, and specific examples include but are not limited to methanol, ethanol, isopropanol, n-propanol, isopentanol or trifluoroethanol.
  • ester solvent refers to a combination of a lower organic acid containing 1 to 4 carbon atoms and a lower alcohol containing 1 to 6 carbon atoms, and specific examples include but are not limited to ethyl acetate, isopropyl acetate or butyl acetate.
  • ketoone solvent refers to a compound in which a carbon group (-CO-) is connected to two hydrocarbon groups. Depending on the hydrocarbon groups in the molecule, ketones can be divided into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones and unsaturated ketones. Specific examples include but are not limited to: acetone, acetophenone, methyl isobutyl ketone or methyl pyrrolidone.
  • nitrile solvent refers to a group derived from one or more cyano groups replacing one or more hydrogen atoms on a C 1 -C 6 alkyl group, and specific examples include, but are not limited to, acetonitrile or propionitrile.
  • aliphatic hydrocarbon solvent refers to chain hydrocarbons with 1 to 10 carbon atoms, such as saturated aliphatic hydrocarbons, including alkane solvents, and specific examples include but are not limited to: n-butane, n-pentane, n-hexane or n-heptane.
  • alicyclic hydrocarbon solvent refers to a hydrocarbon compound having a cyclic carbon skeleton and 1 to 8 ring atoms, and specific examples include but are not limited to cyclopentane or cyclohexane.
  • amide solvent refers to a compound containing a carbonylamino group (-CONH-) and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, N,N-dimethylformamide or N,N-dimethylacetamide.
  • aromatic hydrocarbon solvents refers to a general term for carbocyclic compounds and their derivatives having a closed cyclic conjugated system in the molecule and a ⁇ electron number that conforms to Huckel's rule. Specific examples include, but are not limited to, toluene, isopropylbenzene or xylene.
  • halogenated hydrocarbon solvent refers to a group derived from one or more halogen atoms replacing one or more hydrogen atoms on a C 1 -C 6 alkyl group, wherein the halogen atoms include fluorine, chlorine, bromine, iodine atoms, etc.
  • Specific examples of the "halogenated hydrocarbon solvent” include, but are not limited to, methyl chloride, dichloromethane, chloroform or carbon tetrachloride.
  • mixed solvent refers to a solvent formed by mixing one or more different types of organic solvents in a certain proportion, or a solvent formed by mixing an organic solvent and water in a certain proportion;
  • the mixed solvent is preferably a mixed solvent of one or more alcohol solvents, a mixed solvent of an alcohol solvent and an ether solvent, a mixed solvent of an alcohol solvent and an aliphatic hydrocarbon solvent, a mixed solvent of an ether solvent and an aliphatic hydrocarbon solvent, a mixed solvent of an alcohol solvent and water, a mixed solvent of a ketone solvent and water, a mixed solvent of a halogenated hydrocarbon solvent and a nitrile solvent, a mixed solvent of an amide solvent and water, or a mixed solvent of an ether solvent and water;
  • the alcohol solvent, ether solvent, aliphatic hydrocarbon solvent, halogenated hydrocarbon solvent, amide solvent and nitrile solvent are as defined above.
  • the term "pharmaceutically acceptable salt” refers to organic and inorganic salts of the compounds of the present invention, which are suitable for use in humans and lower animals without excessive toxicity, irritation, allergic response, etc., and have a reasonable benefit/risk ratio.
  • Amines, carboxylic acids, phosphonates, and other types of compounds Pharmaceutically acceptable salts are well known in the art.
  • the salts can be formed by reacting the compounds of the invention with a suitable free base or acid.
  • salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or by using methods well known in the art, such as ion exchange, to obtain these salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, per-3-phenylpropionate, phosphate, picrate, propionate,
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc.
  • Other pharmaceutically acceptable salts include appropriate non-toxic ammonium, quaternary ammonium, and amine cations formed using cations such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.
  • the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable salt of a compound of formula (I) described herein or a crystalline form thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer drug, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic or an additional active agent of an anti-angiogenic compound; and any pharmaceutically acceptable carrier, adjuvant or excipient.
  • a kinase inhibitor small molecule, polypeptide, antibody, etc.
  • an immunosuppressant an anticancer drug
  • an antiviral agent an anti-inflammatory agent
  • an antifungal agent an antibiotic or an additional active agent of an anti-angiogenic compound
  • any pharmaceutically acceptable carrier, adjuvant or excipient any pharmaceutically acceptable carrier, adjuvant or excipient.
  • the pharmaceutically acceptable salt of the compound of formula (I) of the present invention or its crystal form can be used alone or in combination with one or more other agents.
  • the therapeutic agent can be formulated to be administered simultaneously or sequentially at different times, or the therapeutic agent can be administered as a single composition.
  • the so-called "combination therapy" refers to the use of the compound of the present invention together with another agent, and the administration method is that each agent is co-administered at the same time or each agent is administered sequentially. In either case, the purpose is to achieve the best effect of the drug.
  • Co-administration includes simultaneous delivery of dosage forms, as well as separate dosage forms of each compound.
  • the administration of the compound of the present invention can be used simultaneously with other therapies known in the art, for example, in cancer treatment, radiotherapy or additional therapies such as cell growth inhibitors, cytotoxic agents, other anticancer agents, etc. are used to improve cancer symptoms.
  • additional therapies such as cell growth inhibitors, cytotoxic agents, other anticancer agents, etc. are used to improve cancer symptoms.
  • the present invention is not limited to the order of administration; the compound of the present invention can be administered previously, simultaneously, or after other anticancer agents or cytotoxic agents.
  • the pharmaceutically acceptable salt of the compound of formula (I) or its crystalline form as the active ingredient can be intimately mixed with a pharmaceutical carrier, which is carried out according to conventional pharmaceutical compounding techniques, wherein the carrier can be in a variety of forms according to the preparation form designed for different modes of administration (e.g., oral or parenteral administration).
  • a pharmaceutical carrier which is carried out according to conventional pharmaceutical compounding techniques, wherein the carrier can be in a variety of forms according to the preparation form designed for different modes of administration (e.g., oral or parenteral administration).
  • Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some such pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, which is jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.
  • the pharmaceutical composition of the present invention may be in the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injection such as transparent liquids, suspensions, emulsions; or for topical use such as ointments, creams; or as suppositories for rectal administration.
  • the pharmaceutical composition may also be in the form of a unit dose suitable for one-time administration of a precise dose.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a pharmaceutically acceptable salt or a crystalline form thereof of the compound as an active ingredient prepared according to the present invention, and may also include other medical or pharmaceutical preparations, carriers, adjuvants, and the like.
  • the therapeutic compound may also be administered to mammals other than humans.
  • the dosage of the drug administered to a mammal will depend on the species of the animal and the disease or disorder it is experiencing.
  • the therapeutic compound may be administered to the animal in the form of capsules, boluses, tablets or liquids.
  • the therapeutic compound may also be administered to the animal by injection or infusion.
  • These pharmaceutical forms are prepared in accordance with conventional methods consistent with standard veterinary practice.
  • the pharmaceutical composition may be administered to the animal in admixture with the animal feed, whereby a concentrated feed additive or premix may be prepared for admixture with ordinary animal feed.
  • the present invention also provides methods for preparing corresponding pharmaceutically acceptable salts and crystal forms.
  • a variety of methods can be used to prepare the salts and crystal forms described herein, including the following methods, or using other methods known in the chemical field. Those skilled in the art also understand the changes to these methods, and preferred methods include but are not limited to the following methods.
  • X-ray powder diffraction (XRPD): The measurement was carried out using an X'Pert3 X-ray powder diffraction analyzer produced by PANalytacal. The specific collection information is shown in Table 1 below.
  • TGA thermogravimetric analysis The test was carried out using a TA Q5000/5500 thermogravimetric analyzer with a heating rate of 10°C/min and a temperature range of room temperature to the set endpoint temperature (refer to the corresponding graph for details).
  • DSC Differential Scanning Calorimetry The test was carried out using TA Q200/Q2000/2500 differential scanning calorimeter with a heating rate of 10°C/min and a temperature range of 25°C to the set endpoint temperature (refer to the corresponding spectrum for details).
  • Dynamic moisture sorption The curves were collected on the DVS Intrinsic of SMS (Surface Measurement Systems). At 25°C, the humidity range was 0%RH-95%RH, the step was 10% (the last step was 5%), and the dm/dt was 0.002%/min.
  • HPLC High performance liquid chromatography/ion chromatography
  • HPLC was tested using Agilent 1260/1100 high performance liquid chromatograph (Agilent Eclipse Plus C18, 100 ⁇ 4.6mm, 3.5 ⁇ m, chromatographic column), and IC was tested using ThermoFisher ICS-1100 ion chromatograph (IonPac AS18 Analytical Column, 250*4mm, chromatographic column).
  • simulated fasting intestinal fluid FaSSIF
  • FaSSIF simulated fasting intestinal fluid
  • simulated fed intestinal fluid Take 0.41 mL of glacial acetic acid, 0.20 g of NaOH, and 0.59 g of NaCl into a 50-mL volumetric flask. Add about 48 mL of purified water to dissolve, and adjust the pH to 5.0 with 1 M hydrochloric acid or 1 M NaOH solution. Add purified water to make up to volume, and weigh in 0.56 g of SIF powder to dissolve.
  • Step 1) Dissolve 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxano[2,3-f]quinoline (251 mg, 1 mmol) in dichloromethane, dropwise add 1 mol/L boron tribromide dichloromethane solution (3 mL, 3 mmol), and stir until the reaction is complete. Concentrate to obtain 236 mg of a light yellow solid product (5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxano[2,3-f]quinoline), with a yield of 99%. MS: 238[M+H] + .
  • Step 2) The product obtained in step 1) (236 mg, 1 mmol) was dissolved in N, N-dimethylformamide, 4-(3-chloropropyl)morpholine (163 mg, 1 mmol) and potassium carbonate (414 mg, 3 mmol) were added, and the mixture was heated and stirred until the reaction was completed. Water and ethyl acetate were added for extraction, and the organic phase was concentrated and then column chromatography was performed to obtain 291 mg of an off-white solid (10-chloro-5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]-quinoline), with a yield of 80%.
  • Step 3) Add chlorobenzene (5 mL), 10-chloro-5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]quinoline (291 mg, 0.8 mmol), 2-fluoro-4-nitrophenol (125 mg, 0.8 mmol) and triethylamine (0.3 mL) into a reaction flask and reflux for 15-20 hours.
  • Step 5 A solution of 1-(4-fluorophenylcarbamoyl)cyclopropane-1-carboxylic acid (170 mg, 0.76 mmol) in dichlorothionyl (5 mL) was heated to reflux for reaction, and after clarification, the reflux reaction was continued for 1 hour, cooled, and concentrated to obtain a yellow solid product (1-(4-fluorophenylcarbamoyl)cyclopropane 1-carbonyl chloride) 180 mg, which was directly used in the next step;
  • Step 6) To a solution of 3-fluoro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy)aniline (340 mg, 0.75 mmol) in NMP (2 mL) were added a solution of 1-(4-fluorophenylcarbamoyl)cyclopropane 1-carbonyl chloride (180 mg, 0.75 mmol) in dichloromethane (1 mL) and Triethylamine (0.2 mL) was added, stirred at room temperature for 5 hours, quenched with water, washed with saturated sodium carbonate, extracted with dichloromethane, dried, concentrated, and purified by column chromatography to obtain the product (N-(3-fluoro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10
  • the crystal form was defined as Crystal Form A-I by X-ray powder diffraction detection, the XRPD diagram is shown in Figure 1, the characteristic peak positions are shown in Table 2 above, and the TGA and DSC spectra are shown in Figures 2 and 3.
  • the TGA/DSC results show that the sample loses 1.1% of its weight after being heated to 150°C, and has an endothermic peak at 207.3°C (peak temperature).
  • the crystal form was defined as Crystal Form A-II by X-ray powder diffraction detection, the XRPD diagram is shown in FIG4, the characteristic peak positions are shown in Table 3 below, and the TGA and DSC spectra are shown in FIG5 and FIG6.
  • the TGA/DSC results show that the sample loses 1.0% of its weight after being heated to 150°C, and has an endothermic peak at 156.2°C (peak temperature).
  • the crystal form was defined as crystal form B-III by X-ray powder diffraction detection, the XRPD pattern is shown in FIG7, the characteristic peak positions are shown in Table 4 above, and the TGA and DSC spectra are shown in FIG8 and FIG9.
  • the TGA/DSC results show that the sample loses 3.4% of its weight after being heated to 150°C, and has two endothermic peaks at 124.4 and 139.3°C (peak temperatures).
  • the crystal form was defined as Crystal Form A-IV by X-ray powder diffraction detection, the XRPD diagram is shown in FIG10, the characteristic peak positions are shown in Table 5, and the TGA and DSC spectra are shown in FIG11 and FIG12.
  • the TGA/DSC results show that the sample loses 1.3% of its weight after being heated to 150°C, and has an endothermic peak at 228.8°C (peak temperature).
  • the crystal form was defined as Crystal Form A-V by X-ray powder diffraction detection, the XRPD diagram is shown in FIG13, the characteristic peak positions are shown in Table 6 below, and the TGA and DSC spectra are shown in FIG14 and FIG15.
  • the TGA/DSC results show that the sample loses 7.1% of its weight after being heated to 150°C, and has two endothermic peaks at 90.5 and 148.2°C (peak temperatures).
  • the hygroscopicity of the free compound of formula (I), mucic acid salt form A-I, p-toluenesulfonate salt forms A-II and B-III, di-p-toluenesulfonate salt form A-IV and phosphate salt form A-V was evaluated by a dynamic moisture sorption instrument (DVS). Starting with 0% relative humidity (0% RH), the test collected the mass change percentage of the sample under a constant temperature of 25°C and the humidity changed (0% RH-95% RH-0% RH). The moisture adsorption of the 6 test samples at 25°C/80% RH is shown in Table 9 below.
  • the p-toluenesulfonate crystalline form A-II of the compound of formula (I) was placed at 25°C/60% RH for 6 months to investigate its long-term stability.
  • the test data are listed in Table 11 below. The results show that the p-toluenesulfonate crystalline form A-II of the compound of formula (I) did not undergo significant degradation after being placed at 25°C/60% RH for 6 months, had good physical and chemical stability, and the crystalline form did not change.
  • the present application studies the biological kinase activity of the p-toluenesulfonate salt form A-II of the free compound prepared in Example 2.
  • the study found that in addition to VEGFR-2 and c-MET, it can also effectively inhibit the activity of tyrosine kinases such as PDGFRa, RET, c-KIT, TRK-A, TRK-B, and AXL.
  • the experiment used the Mobility Shift Assay method.
  • the starting concentration of the test substance was 2.5 ⁇ M, 3-fold dilution, a total of 10 concentrations, and replicate testing.
  • the p-toluenesulfonate salt of the free compound prepared in Example 2 was used as the test compound.
  • the initial concentration of the test was 2.5 ⁇ M, and the concentration was 50 times higher, i.e., 125 ⁇ M.
  • 158 ⁇ l of 100% DMSO was added to the second well of the 96-well plate, and then 2 ⁇ l of 10 mM compound solution was added. 125 ⁇ M compound solution was prepared. 60 ⁇ l of 100% DMSO was added to the other wells. 30 ⁇ l of compound was taken from the second well and added to the third well. The dilution was performed 3 times in sequence, for a total of 10 concentrations.
  • Dilution instrument automatic microporous pipette (Precision PRC384U)
  • RPMI1640 ThermoFisher, catalog number C11875500BT
  • fetal bovine serum Hyclone, catalog number SV30087.03
  • trypsin-EDTA ThermoFisher, catalog number 25200072
  • penicillin-streptomycin Hyclone, catalog number SV30010
  • DSMO Life Science, catalog number 0231-500ML
  • Solutol Sigma, 70142-34-6-1kg
  • test compounds Preparation of test compounds: Weigh an appropriate amount of the test compound (including the free form of the compound of formula (I) and different salts of the compound prepared in Examples 1, 2 and 5), completely suspend/dissolve them in an appropriate volume of 0.1% sodium carboxymethyl cellulose, stir and vortex to obtain a uniform solution or suspension.
  • EBC-1 cells in the logarithmic growth phase were inoculated into immunodeficient nude mice (BALB/c nude, female, 6-8 weeks old, weight 18 ⁇ 2g), subcutaneously on the right back, cell inoculation amount of 5 ⁇ 10 6 /mouse, after the tumor grows to 150-200mm 3 , the animals are randomly divided into groups, 6/group.
  • the dose of each test substance is set to 15mg/kg and 7.5mg/kg (both are calculated as the concentration of the effective formula (I) compound), and the drug is administered once a day for about 3 weeks.
  • the test compounds are prepared freshly every day.
  • T and C represent the average tumor volume at a certain time point of the drug-treated group and the control group, respectively.
  • the compound of formula (I) in different salts and its free state compound showed a certain antitumor effect at a dose of 15 mg/kg and 7.5 mg/kg, and the effect was significantly enhanced at a dose of 15 mg/kg.
  • the three different salts showed better antitumor efficacy than the free state compound, especially the p-toluenesulfonate salt of the compound of formula (I) had a more significant effect.
  • Table 17 T/C (%) of the compounds in the examples of the present application in the human lung cancer EBC-1 nude mouse tumor model

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Abstract

本发明提供了一种二噁烷并喹啉类化合物的盐、其晶型以及它们的制备方法及其应用。具体地，涉及N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的盐、其晶型以及它们的制备方法及其在制备作为酪氨酸激酶(例如VEGFR-2和c-MET等)抑制剂的药物中的应用。式（I）。

Description

一种二噁烷并喹啉类化合物的盐、其晶型以及它们的制备方法及应用 技术领域
本发明涉及N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的盐、其晶型以及它们的制备方法及其在制备作为酪氨酸激酶(例如VEGFR-2、c-MET、c-KIT、PDGFRa、RET、AXL、NTRK)抑制剂的药物中的应用。
背景技术
血管内皮生长因子受体(vascular endothelial growth factor receptor，VEGFR)是受体酪氨酸激酶家族中的一种，通过与其配体血管内皮生长因子(vascular endothelial growth factor,VEGF)结合产生一系列生化和生理过程，最终促使新生血管形成。肿瘤血管的生成和它们的通透性主要通过血管内皮细胞生长因子(VEGF)调节，其通过至少两种不同的受体(VEGFR-1、VEGFR-2)发挥作用。根据Jakeman、Kolch、Connolly等的研究显示：VEGF是正常和病理性血管生成和血管渗透性的重要刺激物(Jakeman等，1993，Endocrinology 133：848-859；Kolch等，1995，Breast Cancer Research and Treatment，36：139-155；Connolly等，1989，J.Biol.Chem.264：20017-20024)。血管内皮细胞生长因子通过诱导内皮细胞增殖、蛋白酶表达和迁移及随后形成毛细管的细胞组织来诱发血管芽生表型。因此，通过抗体对VEGF的螯合作用产生的对VEGF的拮抗作用可导致肿瘤生长的抑制(Kim等，1993，Nature 362：841-844)。
由于VEGFR-2主要分布在血管内皮细胞内，可以与VEGF-A、VEGF-C、VEGF-D、VEGF-E结合。而VEGF刺激内皮细胞的增殖、增加血管的通透性和新血管的生成作用主要是通过结合和激活VEGFR-2来实现的。如果阻断VEGFR-2的活性，可以通过直接和间接途径抑制肿瘤的生长和转移，进而达到理想的抗肿瘤效果。因此，寻找对VEGFR-2具有高活性、高选择性的小分子抑制剂成为非常有前景的肿瘤治疗策略。
肝细胞生长因子受体(hepatocyte growth factor receptor，c-MET)是酪氨酸激酶受体的一种，其异常活化在多种恶性肿瘤包括肺癌的发生和发展中起着重要的作用。肝细胞生长因子(HGF)为c-MET的特异性配体，c-MET与HGF结合后通过HGF/c-MET信号通路发挥生物学作用。HGF/c-MET信号通路能诱导细胞增殖、分散、迁移、器官形态形成、血管发生等一系列生物效应。c-MET的异常活化可表现为受体过表达、基因突变、扩增、异位、重排等。这些变化可导致下游信号通路失调，如丝氨酸/苏氨酸蛋白激酶(AKT)、胞外信号激酶(ERK)、磷脂酰肌醇-3-羟基激酶、视网膜母细胞瘤抑制蛋白(Rb)通路等，介导肿瘤发生、侵袭和转移、血管新生、上皮间质转化等过程。c-MET在细胞的增殖、代谢以及肿瘤的产生、转移、血管生成中扮演着重要角色，已成为抗肿瘤治疗的重要靶点。以c-MET为靶点的靶向治疗已在包括肺癌在内的多种恶性肿瘤的治疗中显现出其重要意义。在使用抗肿瘤药物的治疗过程中，多个信号通路的相互作用会影响抗肿瘤药物的作用效果，如HFG/c-MET信号通路与其他通路的相互作用影响了抗肿瘤药物的治疗效果，产生药物耐药性。因此，多激酶靶点联合用药成为新的抗肿 瘤治疗手段。
WO2019154133(申请号PCT/CN2019/073260，申请日2019.01.25)中公开了一种能有效抑制VEGFR-2和c-MET酪氨酸激酶的化合物，该化合物也能有效抑制MHCC97H等肿瘤细胞的增殖，其化合物结构如式(I)所示：
但是，式(I)所示的化合物在水中的溶解度极低，在模拟肠胃液中的溶解度也不理想，大大影响药物在肠胃中的溶出并最终影响药物在人体中的吸收，进而影响药物的疗效，因此，改善式(I)所示化合物的各方面的物化性质(如溶解度、化学稳定性、药代动力学性能、生物利用度等)是很有必要的。
发明内容
本发明提供式(I)化合物的可药用的盐、其晶型，以及它们的制备方法及其在制备作为酪氨酸激酶(例如VEGFR-2、c-MET、c-KIT、PDGFRa、RET、AXL、NTRK)抑制剂的药物中的应用，本发明的盐型和晶型具备良好的物理化学性质和生化活性。
本发明提供一种式(I)所示化合物的可药用的盐，
所述可药用的盐选自无机盐或有机盐，优选对甲苯磺酸盐、黏酸盐、磷酸盐。
具体地，本发明的所述可药用的盐可以为N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺与对甲苯磺酸以1：1或者1：2的化学配比成的盐。
本发明提供一种制备式(I)化合物的可药用盐的制备方法，包括将N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺与无机酸或者有机酸进行成盐反应的步骤，优选与对甲苯磺酸、黏酸、磷酸进行成盐反应的步骤。
具体地，所述的成盐反应在溶剂中进行，所述溶剂选自水、醇类溶剂、卤代烃类溶剂、酮类溶剂、醚类溶剂、腈类溶剂、酯类溶剂、酰胺类溶剂、脂肪烃类溶剂、脂环烃类溶剂、芳香烃类溶剂、醇类溶剂与水的混合溶剂、酮类溶剂与水的混合溶剂、醇类溶剂与醚类溶剂的混合溶剂、卤代烃类溶剂与腈类溶剂的混合溶剂、酰胺类溶剂与水的混合溶剂或腈类溶剂与水的混合溶剂；所述酮类溶剂优选丙酮，所述醇类溶剂优选甲醇、乙醇或异丙醇，所述醚类溶剂优选乙醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃或二氧六环，所述卤代烃类溶剂优选二氯甲烷或三氯甲烷，所述腈类溶剂优选乙腈，所述酯类溶剂优选乙酸乙酯、乙酸异丙酯或乙酸丁酯，所述酰胺类溶剂优选N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，所述脂肪烃类溶剂优选正庚烷，所述脂环烃类溶剂优选环己烷，所述芳香烃类溶剂优选甲苯、二甲苯或异丙基苯，所述醇类溶剂与醚类溶剂的混合溶剂优选乙醚与甲醇的混合溶剂，所述卤代烃类溶剂与腈类溶剂的混合溶剂优选二氯甲烷与乙腈的混合溶剂，所述醇类溶剂与水的混合溶剂优选甲醇与水或乙醇与水的混合溶剂，所述酮类溶剂与水的混合溶剂优选丙酮与水的混合溶剂，所述酰胺类溶剂与水的混合溶剂优选N,N-二甲基甲酰胺与水的混合溶剂。
本发明提供一种制备式(I)化合物的对甲苯磺酸盐的方法，包括将N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺与对甲苯磺酸以1：1或者1：2的化学配比成盐的步骤。本发明进一步提供了制备式(I)化合物的对甲苯磺酸盐A-II晶型的方法：包括以摩尔比为1:1取一定量式(I)化合物与对甲苯磺酸，在溶剂中混悬搅拌一段时间，然后干燥。更具体地，所述溶剂可以为丙酮、二氯甲烷或者二氧六环。
本发明提供一种制备式(I)化合物的黏酸盐的方法，以摩尔比为0.5:1取一定量式(I)化合物与黏酸，在溶剂中混悬搅拌一段时间，然后真空干燥。更具体地，所述溶剂可以为丙酮。
本发明提供一种制备式(I)化合物的磷酸盐的方法，以摩尔比为1:1取一定量式(I)化合物与磷酸，在溶剂中混悬搅拌一段时间，然后真空干燥。更具体地，所述溶剂可以为乙醇/水。
本发明进一步提供了制备式(I)化合物的可药用盐的晶型的方法，包括以一定的摩尔比取一定量式(I)化合物与所述无机酸或者有机酸，优选对甲苯磺酸、黏酸、磷酸，在溶剂中混悬搅拌一段时间，然后干燥。所述溶剂如上所描述。本发明中晶型的制备方法还可以包括反溶剂添加、缓慢挥发、缓慢降温、室温或高温悬浮搅拌、循环升降温、气固渗透、气液扩散、高聚物诱导等方法。
本发明提供一种式(I)化合物N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的黏酸盐的A-I晶型，其中，其X-射线粉末衍射图谱中，在2θ角为3.95、5.54、7.46、10.87、16.58处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
优选地，在2θ角为3.47、3.95、5.54、7.46、8.46、10.48、10.87、14.90、15.28、16.16、16.58处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
更优选地，在2θ角为3.47、3.95、5.54、7.46、8.46、10.48、10.87、11.72、14.08、14.90、15.28、 16.16、16.58、17.90、20.29、21.65、22.35、23.37、24.53、25.45、27.35、32.58处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
本发明提供一种式(I)化合物N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的对甲苯磺酸盐的A-II晶型，其中，其X-射线粉末衍射图谱中，在2θ角为5.30、6.54、7.97、8.78、13.01、15.86、19.70、19.94、20.62处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
优选地，在2θ角为5.30、6.54、7.97、8.78、10.52、11.63、11.81、13.01、15.86、17.54、19.34、19.70、19.94、20.62、22.50、25.95处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
更优选地，在2θ角为5.30、6.54、7.97、8.78、10.52、11.63、11.81、13.01、13.54、14.33、14.52、15.06、15.86、16.46、17.54、18.02、18.25、18.75、19.34、19.70、19.94、20.62、21.06、21.46、22.50、23.67、24.02、24.35、25.12、25.95、26.45、27.20、27.87、29.20、30.15、30.87、31.83处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
本发明提供一种式(I)化合物N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的二对甲苯磺酸盐的A-IV晶型，其中，其X-射线粉末衍射图谱中，在2θ角为6.36、13.60、19.20处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
优选地，在2θ角为6.36、9.87、11.50、13.60、16.00、19.20、20.26、20.86、21.36处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
更优选地，在2θ角为6.36、9.45、9.87、11.50、12.88、13.60、14.40、16.00、19.20、20.26、20.86、21.36、22.59、23.76、26.73处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
本发明提供一种式(I)化合物N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的磷酸盐的A-V晶型，其中，其X-射线粉末衍射图谱中，在2θ角为5.68、7.56、16.93处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
优选地，在2θ角为4.03、5.68、6.84、7.56、9.36、11.30、11.94、16.93、19.76、23.01处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
更优选地，在2θ角为4.03、5.68、6.84、7.56、9.36、11.30、11.94、12.56、13.69、16.17、16.93、19.76、22.02、23.01、23.98、25.19处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
本申请的另一方面提供一种药物组合物，该药物组合物包含本申请所述式(I)化合物的可药用盐，优选对甲苯磺酸盐、黏酸盐、磷酸盐，或者包含所述式(I)化合物的黏酸盐的A-I晶型、对甲苯磺酸盐的A-II晶型、二对甲苯磺酸盐的A-IV晶型或者磷酸盐的A-V晶型中任一晶型，以及一种或多种药学上可接受的载体或赋形剂。
本申请的药物组合物还可以包含一种或多种其他治疗剂。
本申请还涉及所述式(I)化合物的可药用盐、晶型或者药物组合物在制备治疗与酪氨酸激酶VEGFR-2、c-MET、c-KIT、PDGFRa、RET、AXL、NTRK(NTRK包括TRK-A、TRK-B、TRK-C等TRK家族激酶)相关的疾病的药物中的应用。
所述疾病优选为癌症或者自身免疫疾病，尤其是眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、 类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
本发明还涉及一种治疗VEGFR-2、c-MET、c-KIT、PDGFRa、RET、AXL、NTRK等激酶介导的疾病或病症的方法，其包括对有需要的患者(人或其他哺乳动物，尤其是人)给药治疗有效量的本申请所述式(I)化合物的可药用盐、晶型或者药物组合物，所述VEGFR-2、c-MET、c-KIT、PDGFRa、RET、AXL、NTRK等激酶介导的疾病或病症包括前述提及的那些。
附图说明
从下面结合附图的详细描述中，将会更加清楚地理解本发明的上述及其他目的、特征和其他优点，其中，
图1为式(I)化合物的黏酸盐晶型A-I的XRPD图；
图2为式(I)化合物的黏酸盐晶型A-I的TGA图；
图3为式(I)化合物的黏酸盐晶型A-I的DSC图；
图4为式(I)化合物的对甲苯磺酸盐晶型A-II的XRPD图；
图5为式(I)化合物的对甲苯磺酸盐晶型A-II的TGA图；
图6为式(I)化合物的对甲苯磺酸盐晶型A-II的DSC图；
图7为式(I)化合物的对甲苯磺酸盐晶型B-III的XRPD图；
图8为式(I)化合物的对甲苯磺酸盐晶型B-III的TGA图；
图9为式(I)化合物的对甲苯磺酸盐晶型B-III的DSC图；
图10为式(I)化合物的二对甲苯磺酸盐晶型A-IV的XRPD图；
图11为式(I)化合物的二对甲苯磺酸盐晶型A-IV的TGA图；
图12为式(I)化合物的二对甲苯磺酸盐晶型A-IV的DSC图；
图13为式(I)化合物的磷酸盐晶型A-V的XRPD图；
图14为式(I)化合物的磷酸盐晶型A-V的TGA图；
图15为式(I)化合物的磷酸盐晶型A-V的DSC图；
图16为式(I)化合物的游离态给药与阴性对照组的肿瘤体积的变化图；
图17为实施例1的式(I)化合物的黏酸盐A-I晶型给药与阴性对照组的肿瘤体积的变化图；
图18为实施例2的式(I)化合物的对甲苯磺酸盐A-II晶型给药与阴性对照组的肿瘤体积的变化图；
图19为实施例5的式(I)化合物的磷酸盐A-V晶型给药与阴性对照组的肿瘤体积的变化图。
发明详述
除非另有说明，在本申请(包括说明书和权利要求书)中使用的以下术语具有下面给出的定义。在本申请中，除非另外说明，使用“或”或“和”意味着“和/或”。此外，术语“包括”以及其它形式的使用，例如“包含”、“含有”和“具有”，不是限制性的。本文使用的章节标题仅仅是为了组织的目的，而不应解释为对所述的主题的限制。
除非有特殊说明，术语“C1-C6烷基”表示含有1至6个碳原子的烷基部分，同理C1-C3烷基表示含有1至3个碳原子的烷基部分，比如，C1-C6烷基包括甲基、乙基、丙基、异丙基、n-丁基、异丁基、仲-丁基、叔-丁基、n-戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、n-己基、2-己基和2-甲基戊基等。
术语“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：乙醚、二氧六环、四氢呋喃、2-甲基四氢呋喃、丙二醇甲醚或甲基叔丁基醚。
术语“醇类溶剂”是指一个或多个羟基取代C1-C6烷基上的一个或多个氢原子所衍生的基团，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。
术语“酯类溶剂”是指含1至4个碳原子的低级有机酸与含1至6个碳原子的低级醇的结合物，具体实例包括但不限于：乙酸乙酯、乙酸异丙酯或乙酸丁酯。
术语“酮类溶剂”是指碳基(-CO-)与两个烃基相连的化合物，根据分子中烃基的不同，酮可分为脂肪酮、脂环酮、芳香酮、饱和酮和不饱和酮，具体实例包括但不限于：丙酮、苯乙酮、甲基异丁基甲酮或甲基吡咯烷酮。
术语“腈类溶剂”是指一个或多个氰基取代C1-C6烷基上的一个或多个氢原子所衍生的基团，具体实例包括但不限于：乙腈或丙腈。
术语“脂肪烃类溶剂”是指碳原子数为1-10个的链状碳氢化合物如饱和脂肪烃类，包括烷烃类溶剂，具体实例包括但不限于：正丁烷、正戊烷、正己烷或正庚烷。
术语“脂环烃类溶剂”是指具有环状碳骨架且环原子数为1-8个的烃类化合物，具体实例包括但不限于：环戊烷或环己烷。
术语“酰胺类溶剂”是指含有羰基氨基(-CONH-)且碳原子个数为1-10个的化合物，具体实例包括但不限于：N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
术语“芳香烃类溶剂”是指分子中具有闭合环状的共轭体系，π电子数符合休克尔规则的碳环化合物及其衍生物的总称，具体实例包括但不限于：甲苯、异丙基苯或二甲苯。
术语“卤代烃类溶剂”是指一个或多个卤素原子取代C1-C6烷基上的一个或多个氢原子所衍生的基团，所述卤素原子包括氟、氯、溴、碘原子等，所述“卤代烃类溶剂”具体实例包括但不限于：氯甲皖、二氯甲皖、三氯甲烷或四氯化碳。
术语“混合溶剂”是指一种或多种不同种类的有机溶剂按照一定比例混合而成的溶剂，或有机溶剂与水按照一定比例混合而成的溶剂；所述混合溶剂优选为一种或多种醇类溶剂的混合溶剂、醇类溶剂与醚类溶剂的混合溶剂、醇类溶剂与脂肪烃类溶剂的混合溶剂、醚类溶剂与脂肪烃类溶剂的混合溶剂、醇类溶剂与水的混合溶剂、酮类溶剂与水的混合溶剂、卤代烃类溶剂与腈类溶剂的混合溶剂、酰胺类溶剂与水的混合溶剂或醚类溶剂与水的混合溶剂；所述醇类溶剂、醚类溶剂、脂肪烃类溶剂、卤代烃类溶剂、酰胺类溶剂和腈类溶剂如前文所定义。
如本文所用，术语“可药用盐”是指本发明的化合物的有机盐及无机盐，此盐适用于人类和低等动物，无过度毒性、刺激性、过敏反应等，具有合理的利益/风险比。胺，羧酸，膦酸盐，和其它类型的化合物 的药学上可接受的盐在所属领域中是众所周知的。该盐可以由本发明的化合物与合适的游离碱或酸反应而成。包括但不限于，与无机酸如盐酸、氢溴酸、磷酸、硫酸、高氯酸或与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸形成的盐，或通过使用本领域熟知的方法，例如离子交换法，来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、过3-苯基丙酸盐、磷酸盐、苦味酸盐、丙酸盐、硬脂酸盐、硫酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。其他药学上可接受的盐包括适当的无毒的铵、季铵，和使用诸如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根，低级烷基磺酸盐和芳基磺酸盐形成的胺基阳离子。
本发明的药物组合物包含本文所述式(I)化合物的可药用盐或其晶型、激酶抑制剂(小分子，多肽，抗体等)、免疫抑制剂、抗癌药、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物的另外的活性剂；以及任何药学上可接受的载体、佐剂或赋形剂。
本发明式(I)化合物的可药用盐或其晶型可以作为单独使用，也可以与一种或多种其它药剂联合使用。当联合给药时，治疗剂可以配制成同时给药或顺序地在不同的时间给药，或者所述治疗剂可以作为单一组合物给药。所谓“组合疗法”，指的是使用本发明的化合物与另一种药剂一起使用，给药方式为每种药剂同时共同给药或每种药剂顺序给药，无论哪种情况，目的都是要达到药物的最佳效果。共同给药包括同时递送剂型，以及每种化合物分别的单独剂型。因此，本发明的化合物的给药可以与已知的本领域的其他疗法同时使用，例如，在癌症治疗中使用放射治疗或细胞生长抑制剂、细胞毒性剂、其它抗癌剂等附加疗法来改善癌症状。本发明并不限于给药的顺序；本发明的化合物可以先前施用，同时施用，或在其他抗癌剂或细胞毒性剂之后施用。
为了制备这一发明的药学成分，作为其活性成分的分子式(I)的化合物的可药用盐或其晶型可紧密的与药学载体混合在一起，这是根据传统的制药配料技术而进行的，其中的载体可根据按不同的给药方式(例如，口服或肠外给药)设计好的制备形式而采用多种多样的形式。适当的药学上可接受的载体在技术上是众所周知的。对一些这类药学可接受的载体的描述可以在《药学赋形剂手册》里找到，该书由美国药学会和英国药学社联合出版。
本发明药物组合物可以有以下形式，比如说，适合口服给药，例如药片，胶囊，药丸，药粉，持续释放的形式，溶液或悬浮液；用于胃肠外注射如透明液，悬浮液，乳状液；或者用于局部用药如膏，霜；亦或作为栓剂用于直肠给药。药学成分也可以单位剂量的形式适合用于精确剂量的一次性给药。该药学成分将包括一种传统的药学载体或赋形剂以及根据目前的发明制成的作为活性成分的化合物的可药用盐或其晶型，另外，也可以包括其他的医学或药学制剂，载体，辅助剂，等等。
治疗性化合物也可给于哺乳动物而非人类。给一个哺乳动物所用的药物剂量将取决于该动物的种类以及它的疾病状况或其所处的失调状态。治疗性化合物可以以胶囊，大丸药，药片药水的形式喂给动物。也可以通过注射或灌输的方式让治疗性化合物进入动物体内。我们根据符合兽医实践标准的传统的方式制备好这些药物形式。作为一种可选择的方式，药学合成药可以同动物饲料混合在一起喂给动物，因此，浓缩的饲料添加剂或预拌和料可以备以混合普通的动物饲料。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。下面提供的实施例可以更好的说明本发明，除非特别说明，所有的温度为℃。本申请部分化合物的命名根据chemdraw命名翻译得到。本发明还提供了制备相应可药用盐、晶型的方法，可以使用多种方法来制备本文所述的盐、晶型，包括下述方法，或者使用化学领域已知的其他方法，本领域技术人员也理解对这些方法的变化，优选方法包括但不限于下述方法。
实验所用仪器及其测试条件：
X射线粉末衍射(XRPD)：测定使用PANalytacal生产的X'Pert3X射线粉末衍射分析仪进行，具体采集信息如下表1所示。
表1、XRPD测试参数
TGA热重分析：检测采用TA Q5000/5500热重分析仪进行，升温速率10℃/min，温度范围为室温-设置终点温度(具体参照相应图谱)。
DSC差示扫描量热：检测采用TA Q200/Q2000/2500差示扫描量热仪进行，升温速率10℃/min，温度范围为25℃-设置终点温度(具体参照相应图谱)。
动态水分吸附(DVS)：曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃，湿度变化范围为0％RH-95％RH，步进为10％(最后一步为5％)，dm/dt：0.002％/min。
高效液相色谱/离子色谱(HPLC/IC)：HPLC采用安捷伦1260/1100高效液相色谱仪(Agilent Eclipse Plus C18,100×4.6mm,3.5μm，色谱柱)测试，IC采用ThermoFisher ICS-1100离子色谱仪(IonPac AS18 Analytical Column,250*4mm，色谱柱)测试。
生物溶媒的配置
1.模拟胃液的配制(SGF)：称取0.1g NaCl和0.05g曲纳通X-100至50-mL容量瓶中，加入纯化水溶清。 加入67.5μL浓盐酸(12M)，用1M的盐酸或1M的NaOH溶液调节pH至1.8。加纯化水定容。
2.模拟禁食状态肠液的配制(FaSSIF)：称取0.17g无水NaH2PO4,0.021g NaOH和0.31g NaCl至50-mL容量瓶中。加入约48mL纯化水溶清，用1M的盐酸或1M的NaOH溶液调节pH至6.5。加纯化水定容，并称入0.11g SIF粉末溶清。
3.模拟喂食状态肠液的配制(FeSSIF)：取0.41mL冰醋酸，0.20g NaOH和0.59g NaCl至50-mL容量瓶中。加入约48mL纯化水溶清，用1M的盐酸或1M的NaOH溶液调节pH至5.0。加纯化水定容，并称入0.56g SIF粉末溶清。
游离态式(I)的合成
N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的制备
其制备参见专利申请号WO2019154133的文件。
步骤1)：将10-氯-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉(251mg,1mmol)溶于二氯甲烷中，滴入1摩尔每升的三溴化硼的二氯甲烷溶液(3mL,3mmol)，搅拌至反应完毕。浓缩得浅黄色固体产品(5-羟基-10-氯-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉)236mg，产率99％。MS:238[M+H]+。
步骤2)：将步骤1)所得产品(236mg,1mmol)溶于N,N-二甲基甲酰胺，加入4-(3-氯丙基)吗啉(163mg,1mmol)和碳酸钾(414mg,3mmol)，加热搅拌至反应完毕。加入水和乙酸乙酯萃取，有机相浓缩后柱层析得类白色固体(10-氯-5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉)291mg，产率80％。1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝4.8Hz,1H),7.37(d,J＝4.8Hz,1H),7.10(s,1H),4.47-4.30(m,4H),4.17(t,J＝6.4Hz,2H),3.59(t,J＝4.6Hz,4H),2.45(t,J＝7.1Hz,2H),2.39(d,J＝4.5Hz,4H),1.97-1.95(m,2H).MS:365[M+H]+。
步骤3)：将氯苯(5mL)、10-氯-5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉(291mg,0.8mmol)、2-氟-4-硝基苯酚(125mg,0.8mmol)和三乙胺(0.3mL)加入反应瓶中回流反应15-20小时。冷却，浓缩，所得固体用碳酸钾水溶液洗涤得到黄色固体产物(10-(2-氟-4-硝基苯氧基)-5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉)370mg,96％收率,MS:486[M+H]+。
步骤4)：将步骤3)所得产品(370mg,0.76mmol)加入Pd/C的甲醇(10mL)溶液中，氢气置换后在氢气环境下室温搅拌反应10小时，过滤，浓缩得白色固体产物(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺)340mg,1H NMR(400MHz,DMSO-d6)δ8.37(d,J＝5.3Hz,1H),7.08-6.88(m,2H),6.60-6.49(m,1H),6.48-6.40(m,1H),6.32(d,J＝5.2Hz,1H),5.44(s,2H),4.37-4.39(m,4H),4.16(t,J＝6.4Hz,2H),3.59(t,J＝4.6Hz,4H),2.46(d,J＝7.0Hz,2H),2.39(s,4H),1.95-1.97(m,2H)；MS:456[M+H]+。
步骤5)：1-(4-氟苯基氨基甲酰基)环丙烷-1-羧酸(170mg,0.76mmol)的二氯亚砜(5mL)溶液加热回流反应，澄清后继续回流反应1小时，冷却，浓缩得到黄色固体产物(1-(4-氟苯基氨基甲酰基)环丙烷1-甲酰氯)180mg直接用于下一步；
步骤6)：向3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺(340mg,0.75mmol)的NMP(2mL)溶液中分别加入1-(4-氟苯基氨基甲酰基)环丙烷1-甲酰氯(180mg,0.75mmol)的二氯甲烷溶液(1mL)和三乙胺(0.2mL)，室温搅拌反应5小时，加水淬灭，饱和碳酸钠洗涤，二氯甲烷萃取，干燥，浓缩，柱层析纯化得到产物(N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺)260mg,1HNMR(400MHz,DMSO-d6)δ10.32(s,1H),10.00(s,1H),8.41(d,J＝5.2Hz,1H),7.98-7.79(m,1H),7.67-7.59(m,2H),7.53-7.39(m,1H),7.24(t,J＝9.0Hz,1H),7.18-7.11(m,2H),7.06(s,1H),6.43-6.34(m,1H),4.37-4.34(m,4H),4.17(t,J＝6.4Hz,2H),3.59(t,J＝4.6Hz,4H),2.46(t,J＝7.1Hz,2H),2.39(d,J＝4.6Hz,4H),2.08-1.79(m,2H),1.47(d,J＝2.3Hz,4H)；13C NMR(101MHz,DMSO-d6)δ168.7,168.4,160.9,151.8,149.6,146.6,138.2,133.8,129.8,127.7,123.4,122.9,115.6,115.4,107.9,102.2,67.1,66.7,64.4,63.97,55.2,53.8,32.3,26.2,15.7；MS:661[M+H]+。
实施例1.式(I)化合物的黏酸盐的晶型A-I的制备
表2、黏酸盐晶型A-I的特征峰
将式(I)化合物300mg与黏酸(酸碱摩尔比为0.5:1)在丙酮中室温下混悬搅拌4天后，再添加15mg式(I)化合物继续室温搅拌2天，然后室温真空干燥，制得产物。
1H NMR结果显示，样品中酸碱摩尔比为0.5:1。
1HNMR(400MHz,DMSO-d6)δ10.34(s,1H),10.02(s,1H),8.42-8.41(d,J＝4Hz,1H),7.88-7.84(m,1H),7.66-7.62(m,2H),7.47-7.44(m,1H),7.26-7.13(m,3H),7.07(s,1H),6.40-6.39(d,J＝4Hz,1H),4.35(s,4H),4.21(s,1H)，4.19-4.16(t,2H),3.77(s,1H),3.61-3.59(m,4H),2.43-2.41(m,6H),2.01-1.95(m,2H),1.49-1.44(m,4H)。
经X-射线粉末衍射检测，将该晶型定义为晶型A-I，XRPD图如图1所示，其特征峰位置如上表2所示，TGA和DSC谱图如图2和图3所示。TGA/DSC结果显示样品加热至150℃后失重1.1％，并在207.3℃(峰值温度)有1个吸热峰。
实施例2.式(I)化合物的对甲苯磺酸盐的晶型A-II的制备
将式(I)化合物300mg与对甲苯磺酸(酸碱摩尔比为1:1)在丙酮中室温下混悬搅拌1天后，室温真空干燥，制得产物。
1H NMR结果显示，样品中酸碱摩尔比为1.0:1。
1HNMR(400MHz,MeOD)δ8.43-8.42(d,J＝4Hz,1H),7.86-7.82(m,1H),7.70-7.68(m,2H),7.60-7.56(m,2H),7.43-7.40(m,1H),7.25-7.20(m,3H),7.12-7.07(m,3H),6.57-6.56(m,1H),4.44(s,4H),4.37-4.34(m,2H),3.97(m,4H),3.44-3.38(m,6H),2.42-2.39(m,2H),2.36(s,3H),1.66(s,4H)。(酰胺上的活泼氢不显示)
经X-射线粉末衍射检测，将该晶型定义为晶型A-II，XRPD图如图4所示，其特征峰位置如下表3所示，TGA和DSC谱图如图5和图6所示。TGA/DSC结果显示样品加热至150℃后失重1.0％，并在156.2℃(峰值温度)有1个吸热峰。
表3、对甲苯磺酸盐晶型A-II的特征峰

实施例3.式(I)化合物的对甲苯磺酸盐的晶型B-III的制备
表4、对甲苯磺酸盐的晶型B-III的特征峰
将约50mg对甲苯磺酸盐晶型A-II产品在水中50℃下悬浮搅拌1天，过滤后室温干燥制得。
1H NMR结果显示，样品中酸碱摩尔比为0.9:1。
1HNMR(400MHz,MeOD)δ8.43-8.42(d,J＝4Hz,1H),7.86-7.82(m,1H),7.70-7.68(m,2H),7.60-7.56(m,2H),7.43-7.40(m,1H),7.25-7.20(m,3H),7.12-7.07(m,3H),6.57-6.56(m,1H),4.44(s,4H),4.37-4.34(m,2H),3.97(m,4H),3.44-3.38(m,6H),2.42-2.39(m,2H),2.36(s,3H),1.66(s,4H)。(酰胺上的活泼氢 不显示)
经X-射线粉末衍射检测，将该晶型定义为晶型B-III，XRPD图如图7所示，其特征峰位置如上表4所示，TGA和DSC谱图如图8和图9所示。TGA/DSC结果显示样品加热至150℃后失重3.4％，并在124.4和139.3℃(峰值温度)有2个吸热峰。
实施例4.式(I)化合物的二对甲苯磺酸盐的晶型A-IV制备
将式(I)化合物300mg与对甲苯磺酸(酸碱摩尔比为2:1)在丙酮中室温下混悬搅拌1天后，室温真空干燥，制得产物。
1H NMR结果显示，样品中酸碱摩尔比为2.0:1。
1HNMR(400MHz,MeOD)δ8.60-8.58(d,J＝8Hz,1H),7.97-7.93(m,1H),7.66-7.64(m,4H),7.60-7.55(m,2H),7.53-7.50(m,1H),7.42-7.38(m,1H),7.19-7.17(m,4H),7.13-7.01(m,3H),6.86-6.84(m,1H),4.56-4.49(m,4H),4.45-4.42(m,2H),4.10(m,2H),3.91(m,2H),3.72(m,2H),3.53-3.49(m,2H),3.22(m,2H),2.46-2.43(m,2H),2.34(s,6H),1.61(s,4H)。(酰胺上的活泼氢不显示)
经X-射线粉末衍射检测，将该晶型定义为晶型A-IV，XRPD图如图10所示，其特征峰位置如下表5所示，TGA和DSC谱图如图11和图12所示。TGA/DSC结果显示样品加热至150℃后失重1.3％，并在228.8℃(峰值温度)有1个吸热峰。
表5、二对甲苯磺酸盐的晶型A-IV的特征峰
实施例5.式(I)化合物的磷酸盐的晶型A-V的制备
将式(I)化合物300mg与磷酸(酸碱摩尔比为1:1)在EtOH/H2O(19:1,v/v)中混合并添加25mg晶种(以50mg游离态式(I)化合物与等摩尔比的磷酸在EtOH/H2O(19:1,v/v)中室温搅拌5天，过滤室温干燥制得)，室温下混悬搅拌2天，后室温真空干燥，制得产物。HPLC/IC结果显示样品酸碱摩尔比为0.8:1。1HNMR(400MHz,MeOD)δ8.40-8.39(d,J＝4Hz,1H),7.84-7.83(d,J＝4Hz,1H),7.60-7.56(m,2H), 7.41-7.38(m,1H),7.23-7.18(t,1H),7.12-7.07(m,2H),6.52-6.50(m,2H),4.42(s,4H),4.32-4.29(t,2H),3.89-3.87(m,4H),3.09-3.02(m,6H),2.32-2.25(m,2H),1.66(s,4H)。(酰胺上的活泼氢不显示)
经X-射线粉末衍射检测，将该晶型定义为晶型A-V，XRPD图如图13所示，其特征峰位置如下表6所示，TGA和DSC谱图如图14和图15所示。TGA/DSC结果显示样品加热至150℃后失重7.1％，并在90.5和148.2℃(峰值温度)有2个吸热峰。
表6、磷酸盐的晶型A-V的特征峰
实验例1.本申请盐和晶型在水中的溶解度测定
对游离态式(I)化合物、黏酸盐晶型A-I、对甲苯磺酸盐晶型A-II、二对甲苯磺酸盐晶型A-IV和磷酸盐晶型A-V在水和三种生物溶媒中的动态溶解度进行了评估。
以10mg/mL的投料浓度(40mg物料投入4mL溶剂中)在37℃条件下利用旋转混合的方式(25rpm)测定各样品在水、SGF、FaSSIF和FeSSIF(1,2,4和24小时)四种溶剂体系的溶解度。每个时间点的样品经离心过滤后(0.45μm PTFE过滤头)，测定滤液的HPLC浓度和pH值。溶解度试验结果总结于表7中。结果显示在H2O和FaSSIF中，对甲苯磺酸盐晶型A-II、二对甲苯磺酸盐晶型A-IV和磷酸盐晶型A-V溶解度相比游离态提升明显；在SGF中，溶解度均较接近；在FeSSIF中，其余四种晶型均较游离态溶解度有较大提升。
表7动态溶解度测试结果总结

LOQ：0.60μg/mL；ND：未检出
同时对对甲苯磺酸盐晶型A-II和晶型B-III在水中的平衡溶解度进行了评估。称取～10/8mg物料于HPLC小瓶中，加入1.0/0.8mL水，在室温下悬浮搅拌24小时。对样品离心过滤，滤液测试HPLC。溶解度结果示于于表8，结果显示对甲苯磺酸盐晶型A-II溶解度高于晶型B-III。
表8.平衡溶解度结果总结
实验例2.本申请盐和晶型的引湿性研究
通过动态水分吸附仪(DVS)对游离态式(I)化合物、黏酸盐晶型A-I、对甲苯磺酸盐晶型A-II和B-III、二对甲苯磺酸盐晶型A-IV和磷酸盐晶型A-V进行引湿性评估。以0％相对湿度(0％RH)为起始，测试收集了25℃恒温条件下，随湿度变化(0％RH-95％RH-0％RH)时，样品的质量变化百分比。6种测试样品在25℃/80％RH时的水分吸附分别如下表9所示。结果显示式(I)化合物的游离态几乎无引湿性，其对甲苯磺酸盐晶型A-II略有引湿性，对甲苯磺酸盐晶型B-III、黏酸盐晶型A-I，二对甲苯磺酸盐晶型A-IV和磷酸盐晶型A-V有引湿性，各样品在DVS测试前后晶型均不变。
表9引湿性评估结果
实验例3.本申请盐和晶型的稳定性研究
将如下6种测试样品分别在25℃/60％RH和40℃/75％RH条件下放置1周后，通过XRPD和HPLC检测样品的物理和化学稳定性。测试数据列于下表10中。结果显示6种样品在25℃/60％RH和40℃/75％RH条件下放置1周后均未发生明显降解，化学稳定性良好，且晶型均未发生改变。
同时对对甲苯磺酸盐晶型A-II和晶型B-III固体分别在80℃下放置24小时后，通过XRPD和HPLC检测样品的物理和化学稳定性，结果显示对甲苯磺酸盐晶型A-II和晶型B-III在该高温条件下也未发生晶型变化或化学降解。
表10.固态稳定性评估总结

长期稳定性研究
将式(I)化合物的对甲苯磺酸盐晶型A-II在25℃/60％RH下放置6个月，考察其长期稳定性。测试数据列于下表11中。结果显示式(I)化合物的对甲苯磺酸盐晶型A-II在25℃/60％RH条件下放置6个月后均未发生明显降解，物理化学稳定性良好，且晶型未发生改变。
表11.式(I)化合物的对甲苯磺酸盐晶型A-II的长期稳定性评估总结
实验例4.本申请盐和晶型的激酶活性研究
本申请对实施例2制备的游离态化合物的对甲苯磺酸盐晶型A-II的生物激酶活性进行了研究，研究发现其除VEGFR-2和c-MET外，还能有效抑制PDGFRa、RET、c-KIT、TRK-A、TRK-B、AXL等酪氨酸激酶的活性。
实验采用Mobility Shift Assay方法，待测物的测试起始浓度为2.5μM，3倍稀释，共10个浓度，复孔测试。
表12.激酶活性测试试剂信息

表13.激酶活性测试仪器信息
实验方法
1.配制1倍的激酶缓冲液和终止液
1.1 1倍激酶缓冲液
50mM HEPES,pH 7.5
0.0015％Brij-35
1.2终止液
100mM HEPES,pH 7.5
0.015％Brij-35
0.2％Coating Reagent#3
50mM EDTA
2.化合物配制
1)化合物稀释
实施例2制备的游离态化合物的对甲苯磺酸盐为测试化合物，测试起始浓度为2.5μM，配制成50倍浓度，即125μM。在96孔板上第二个孔中加入158μl的100％DMSO，再加入2μl 10mM化合物溶 液，即配制成125μM化合物溶液。其他孔加入60μl的100％DMSO。从第二孔中取30μl化合物加入第三孔中，依次往下做3倍稀释，共稀释10个浓度。稀释仪器：自动微孔移液器(Precision PRC384U)
2)转移5倍化合物到反应板
①从50倍浓度化合物96孔板的每一孔取10μl到另一块96孔板中，加入90μl激酶缓冲液，配制成5倍浓度化合物。
②从5倍浓度化合物96孔板中取出5μl到一块384孔反应板。例如，96孔板的A1孔转移到384孔板的A1和A2孔中，96孔板的A2孔转移到384孔板的A3和A4孔中，以此类推。
3.激酶反应
1)配制2.5倍酶溶液
将激酶加入1倍激酶缓冲液，形成2.5倍酶溶液。
2)向384孔板中加入酶溶液
1. 384孔反应板中已有5μl的10％DMSO溶解的5倍化合物。
2.在384孔反应板中加入10μl的2.5倍酶溶液，阴性对照孔加入10μl激酶缓冲液。
3.室温下孵育10分钟。
3)配制2.5倍的底物溶液
将FAM标记的多肽和ATP(ATP浓度见附件)加入1倍激酶缓冲液，形成2.5倍底物溶液。
4)向384孔板中加入底物溶液，
在384孔反应板中加入10μl的2.5倍底物溶液，1000rpm离心1分钟。
5)激酶反应和终止
1. 28℃下孵育60分钟生化培养箱型号：SPX-100B-Z
2.向384孔反应板中加30μl终止液终止反应，1000rpm离心1分钟。
4.Caliper EZ ReaderⅡ读取数据
Caliper EZ ReaderⅡ上读取转化率数据。
5.抑制率计算
1)从Caliper EZ ReaderⅡ上复制转化率数据。
2)把转化率转化成抑制率数据。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。
Percent inhibition＝(max-conversion)/(max-min)*100.
3)用XLFit excel add-in version 5.4.0.8拟合IC50值.
拟合公式:Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)
表14.激酶测试条件

研究发现，被测物对以上各酪氨酸激酶抑制的IC50均小于或等于10.0nM。
实验例5.本申请不同盐和游离态化合物的小鼠荷瘤药效研究
本试验通过对人肺癌细胞EBC-1裸鼠荷瘤模型口服给予本申请游离态式(I)化合物、以及实施例1、2和5制备的该化合物的不同盐，研究它们对肿瘤生长的影响。
表15.小鼠荷瘤药效实验用仪器:
表16.实验动物和细胞:
试剂：RPMI1640(ThermoFisher，目录号C11875500BT)；胎牛血清(Hyclone，目录号SV30087.03)；0.25％胰蛋白酶-EDTA(ThermoFisher，目录号25200072)；青霉素-链霉素(Hyclone，目录号SV30010)；DSMO(Life Science，目录号0231-500ML)；Solutol(Sigma，70142-34-6-1kg)
受试化合物配制：称取适当重量的待测化合物(包括游离态式(I)化合物、以及实施例1、2和5制备的该化合物的不同盐)，分别完全混悬/溶解于适当体积的0.1％羧甲基纤维素钠,搅拌、涡旋混匀，得到均一溶液或混悬液。
方法：所有试验均经过动物福利委员会授权同意，取对数生长期的EBC-1接种免疫缺陷裸小鼠(BALB/c  nude，雌性，6-8周龄，体重18±2g)，右侧背部皮下，细胞接种量为5×106/只，待肿瘤生长至150-200mm3后将动物随机分组，6只/组。各受试物剂量均设为15mg/kg、7.5mg/kg(都以有效式(I)化合物浓度计)，每天给药一次，共3周左右，受试化合物均每天现用现配。实验过程中，每周2次测量荷瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝1/2×a×b2，其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：阴性对照组RTV。T和C分别表示给药组和对照组的某一时间点的平均瘤体积。结果：实验结果如表17及图16-19所示。不同盐的式(I)化合物以及其游离态化合物在15mg/kg、7.5mg/kg剂量时都表现出一定的抑瘤作用，15mg/kg剂量时效果明显增强，同时，三种不同的盐相比于游离态化合物，都表现出更好的抑瘤药效，尤其以式(I)化合物的对甲苯磺酸盐效果更为显著。
表17：本申请实施例化合物在人肺癌EBC-1裸鼠荷瘤模型中T/C(％)
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原则的前提下，本发明的实施方式还可以作出若干改进和修饰，这些改进和修饰也应视为本发明的保护范围。

Claims (13)

  1. 一种式(I)所示化合物N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的可药用的盐，
    所述可药用的盐选自无机盐或有机盐，优选对甲苯磺酸盐、黏酸盐、磷酸盐。
  2. 根据权利要求1所述的可药用盐，其中，该可药用的盐为N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺与对甲苯磺酸以1：1或者1：2的化学配比成的盐。
  3. 一种如权利要求1所述的可药用盐的制备方法，包括将N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺与无机酸或者有机酸进行成盐反应的步骤，优选与对甲苯磺酸、黏酸、磷酸进行成盐反应的步骤。
  4. 根据权利要求3所述的制备方法，其中，所述的成盐反应在溶剂中进行，所述溶剂选自水、醇类溶剂、卤代烃类溶剂、酮类溶剂、醚类溶剂、腈类溶剂、酯类溶剂、酰胺类溶剂、脂肪烃类溶剂、脂环烃类溶剂、芳香烃类溶剂、醇类溶剂与水的混合溶剂、酮类溶剂与水的混合溶剂、醇类溶剂与醚类溶剂的混合溶剂、卤代烃类溶剂与腈类溶剂的混合溶剂、酰胺类溶剂与水的混合溶剂或腈类溶剂与水的混合溶剂；所述酮类溶剂优选丙酮，所述醇类溶剂优选甲醇、乙醇或异丙醇，所述醚类溶剂优选乙醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃或二氧六环，所述卤代烃类溶剂优选二氯甲烷或三氯甲烷，所述腈类溶剂优选乙腈，所述酯类溶剂优选乙酸乙酯、乙酸异丙酯或乙酸丁酯，所述酰胺类溶剂优选N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，所述脂肪烃类溶剂优选正庚烷，所述脂环烃类溶剂优选环己烷，所述芳香烃类溶剂优选甲苯、二甲苯或异丙基苯，所述醇类溶剂与醚类溶剂的混合溶剂优选乙醚与甲醇的混合溶剂，所述卤代烃类溶剂与腈类溶剂的混合溶剂优选二氯甲烷与乙腈的混合溶剂，所述醇类溶剂与水的混合溶剂优选甲醇与水或乙醇与水的混合溶剂，所述酮类溶剂与水的混合溶剂优选丙酮与水的混合溶剂，所述酰胺类溶剂与水的混合溶剂优选N,N-二甲基甲酰胺与水的混合溶剂。
  5. 一种如权利要求3所述的可药用盐的制备方法，其中，包括将N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺与对甲苯磺酸以1：1或者1：2的化学配比成盐的步骤。
  6. 式(I)化合物N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的黏酸盐的A-I晶型，其中，其X-射线粉末衍射图谱中，在2θ角为3.95、5.54、7.46、10.87、16.58处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
    优选地，在2θ角为3.47、3.95、5.54、7.46、8.46、10.48、10.87、14.90、15.28、16.16、16.58处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
    更优选地，在2θ角为3.47、3.95、5.54、7.46、8.46、10.48、10.87、11.72、14.08、14.90、15.28、16.16、16.58、17.90、20.29、21.65、22.35、23.37、24.53、25.45、27.35、32.58处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
  7. 式(I)化合物N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的对甲苯磺酸盐的A-II晶型，其中，其X-射线粉末衍射图谱中，在2θ角为5.30、6.54、7.97、8.78、13.01、15.86、19.70、19.94、20.62处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
    优选地，在2θ角为5.30、6.54、7.97、8.78、10.52、11.63、11.81、13.01、15.86、17.54、19.34、19.70、19.94、20.62、22.50、25.95处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
    更优选地，在2θ角为5.30、6.54、7.97、8.78、10.52、11.63、11.81、13.01、13.54、14.33、14.52、15.06、15.86、16.46、17.54、18.02、18.25、18.75、19.34、19.70、19.94、20.62、21.06、21.46、22.50、23.67、24.02、24.35、25.12、25.95、26.45、27.20、27.87、29.20、30.15、30.87、31.83处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
  8. 式(I)化合物N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的二对甲苯磺酸盐的A-IV晶型，其中，其X-射线粉末衍射图谱中，在2θ角为6.36、13.60、19.20处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
    优选地，在2θ角为6.36、9.87、11.50、13.60、16.00、19.20、20.26、20.86、21.36处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
    更优选地，在2θ角为6.36、9.45、9.87、11.50、12.88、13.60、14.40、16.00、19.20、20.26、20.86、21.36、22.59、23.76、26.73处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
  9. 式(I)化合物N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的磷酸盐的A-V晶型，其中，其X-射线粉末衍射图谱中，在2θ角为5.68、7.56、16.93处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
    优选地，在2θ角为4.03、5.68、6.84、7.56、9.36、11.30、11.94、16.93、19.76、23.01处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2；
    更优选地，在2θ角为4.03、5.68、6.84、7.56、9.36、11.30、11.94、12.56、13.69、16.17、16.93、19.76、22.02、23.01、23.98、25.19处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
  10. 一种药物组合物，其包含权利要求1至2中任一项所述的可药用盐或权利要求6-9中任一项所述的晶型，以及一种或多种药学上可接受的载体或赋形剂。
  11. 根据权利要求10所述的药物组合物，其中，所述药物组合物还包含一种或多种其他治疗剂。
  12. 权利要求1至2中任一项所述的可药用盐或权利要求6-9中任一项所述的晶型或权利要求10-11所述的药物组合物在制备治疗与酪氨酸激酶VEGFR-2、c-MET、c-KIT、PDGFRa、RET、AXL、NTRK相关的疾病的药物中的应用。
  13. 根据权利要求12所述的应用，所述疾病为癌症或者自身免疫疾病，尤其是眼底疾病、干眼症、 银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
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CN108503650A (zh) * 2017-02-27 2018-09-07 北京赛特明强医药科技有限公司 二噁烷并喹唑啉类化合物或其药用盐或其水合物及其作为酪氨酸激酶抑制剂的应用
WO2019154133A1 (zh) * 2018-02-11 2019-08-15 北京赛特明强医药科技有限公司 二噁烷并喹啉类化合物及其制备方法与应用

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* Cited by examiner, † Cited by third party
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CN108503650A (zh) * 2017-02-27 2018-09-07 北京赛特明强医药科技有限公司 二噁烷并喹唑啉类化合物或其药用盐或其水合物及其作为酪氨酸激酶抑制剂的应用
WO2019154133A1 (zh) * 2018-02-11 2019-08-15 北京赛特明强医药科技有限公司 二噁烷并喹啉类化合物及其制备方法与应用

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