WO2020057403A1 - 吲哚衍生物及其在医药上的应用 - Google Patents

吲哚衍生物及其在医药上的应用 Download PDF

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WO2020057403A1
WO2020057403A1 PCT/CN2019/105271 CN2019105271W WO2020057403A1 WO 2020057403 A1 WO2020057403 A1 WO 2020057403A1 CN 2019105271 W CN2019105271 W CN 2019105271W WO 2020057403 A1 WO2020057403 A1 WO 2020057403A1
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alkyl
cancer
aryl
methyl
heteroaryl
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PCT/CN2019/105271
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English (en)
French (fr)
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段茂圣
田世鸿
刘佳乐
熊艳林
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北京越之康泰生物医药科技有限公司
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Priority to CN201980060963.1A priority Critical patent/CN112996784B/zh
Publication of WO2020057403A1 publication Critical patent/WO2020057403A1/zh

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the invention relates to an indole derivative, a preparation method and a pharmaceutical composition containing the indole derivative, and use of the indole derivative as a vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, in particular to preparing treatment and vascular endothelial growth factor Use of drugs for receptor kinase dysfunction-related diseases such as cancer.
  • VEGFR vascular endothelial growth factor receptor
  • Angiogenesis is a tightly regulated, multi-step process that involves the interaction of multiple growth factors (including VEGFs, bFGF, and PDGFs) with their receptors.
  • multiple growth factors including VEGFs, bFGF, and PDGFs
  • Vascular endothelial growth factor (vascular endothelial growth factor, VEGF) is a heparin-binding growth factor specific to vascular endothelial cells. VEGF induces the formation of new blood vessels in vivo by binding to vascular endothelial growth factor receptor (VEGFR). This process stimulates physiological or pathological angiogenesis, while also regulating vascular permeability. Therefore, the expression of VEGFR and its activity are closely related to the density of tissue microvessels and the number of new blood vessels.
  • the VEGFR family includes VEGFR-1, VEGFR-2 and VEGFR-3.
  • Neovascularization plays a very important role in the growth, development and metastasis of tumors.
  • the neovascularization of the tumor provides oxygen and nutrients for solid malignant tumors, promotes the further growth of the tumor, and provides a way for the metastasis and spread of the tumor. Therefore, inhibiting the formation of tumor neovascularization has become an effective method for treating various cancers.
  • VEGFR kinase inhibitors Although several small molecule VEGFR kinase inhibitors have been used clinically, either they are multi-target drugs (such as sorafenib, regorafenib), or they have obvious side effects and patients' compliance is affected to some extent. Therefore, the continued development of highly active and selective novel VEGFR kinase inhibitors still has a wide range of needs and prospects in clinical applications.
  • the inventors After intensive research, the inventors have designed and synthesized a series of indole derivatives, which show the inhibitory activity of VEGFR kinase, and can be developed as drugs for treating diseases related to VEGFR kinase activity.
  • an object of the present invention is to provide a compound represented by the general formula (I),
  • X is CH or N
  • R 1 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further selected from One or more of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Group replacement
  • R 2 is selected from nitrogen-containing heterocyclic groups, which is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl , Heterocyclyl, aryl, heteroaryl substituted with one or more groups;
  • R 3 is selected from hydrogen, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkane Group, heterocyclyl, aryl, and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, and cycloalkane Substituted with one or more groups of aryl, heterocyclyl, aryl, heteroaryl;
  • R 4 is selected from hydrogen, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkane Group, heterocyclyl, aryl, and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, and cycloalkane Substituted with one or more groups of aryl, heterocyclyl, aryl, heteroaryl;
  • R 5 is selected from hydrogen, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkane Group, heterocyclyl, aryl, and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, and cycloalkane Substituted with one or more groups of aryl, heterocyclyl, aryl, heteroaryl;
  • R 6 is selected from hydrogen, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkane Group, heterocyclyl, aryl, and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, and cycloalkane Group, heterocyclyl, aryl, heteroaryl.
  • R 1 is selected from alkyl, preferably C 1 -C 6 alkyl, said alkyl further being selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkoxy , Cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • R 2 is selected from 4- to 10-membered nitrogen-containing heterocyclic groups, preferably 4- to 10-membered monocyclic nitrogen-containing heterocyclic groups, nitrogen-containing spiro heterocyclic groups, nitrogen-containing fused heterocyclic groups or nitrogen-containing bridged heterocyclic groups;
  • the nitrogen-containing heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclic , Aryl, heteroaryl substituted with one or more groups.
  • R 2 is selected from the group:
  • Y is selected from CH 2, NH, O, or S, S (O) y;
  • R a is selected from amino, hydroxy, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • i 0, 1 or 2;
  • j 0, 1, or 2;
  • n 0, 1 or 2;
  • y is 1 or 2;
  • the A ring is a C 3 -C 6 saturated or unsaturated ring.
  • R 2 is selected from the group:
  • the compound represented by the general formula (I) according to the present invention wherein R 3 is selected from hydrogen or halogen.
  • the compound represented by the general formula (I) according to the present invention wherein R 4 is selected from hydrogen or halogen.
  • the compound represented by the general formula (I) according to the present invention wherein R 5 is selected from hydrogen or halogen.
  • the compound represented by the general formula (I) according to the present invention wherein R 6 is selected from an alkyl group, preferably a C 1 -C 6 alkyl group.
  • Typical compounds of the invention include, but are not limited to, the following compounds:
  • the present invention further provides a method for preparing a compound represented by the general formula (I) according to the present invention, which comprises the following steps:
  • Compound Ij is subjected to a condensation reaction with an acid chloride compound in a basic medium to obtain a compound of general formula (I);
  • the base is preferably K 2 CO 3 and the solvent is preferably DMF;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X are as defined in claim 1.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the general formula (I) according to the present invention, and a pharmaceutically acceptable carrier or excipient.
  • the present invention further provides the use of a compound represented by the general formula (I) or a pharmaceutical composition comprising the same according to the present invention in the preparation of a vascular endothelial growth factor receptor kinase inhibitor.
  • the present invention further provides the use of a compound represented by the general formula (I) or a pharmaceutical composition containing the same according to the present invention in the manufacture of a medicament for treating a disease associated with dysfunction of a vascular endothelial growth factor receptor kinase, said
  • the disease is preferably bladder cancer, breast cancer, cervical cancer, rectal cancer, colon cancer, stomach cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer Skin cancer, brain cancer, bone cancer, soft tissue cancer, leukemia, and lymphoma, more preferably brain cancer, thyroid cancer, liver cancer, lung cancer, kidney cancer, breast cancer, gastric cancer, and rectal colon cancer.
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid according to a conventional method in the field to which the present invention belongs.
  • the acids include inorganic and organic acids, and particularly preferred are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid. , Trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable basic addition salt with a base.
  • the base includes an inorganic base and an organic base.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucosamine, triethanolamine, tromethamine, and the like.
  • Acceptable inorganic bases include aluminum hydroxide, hydroxide. Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, dragees, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives, To provide pleasing and delicious medicinal preparations. Tablets contain the active ingredients and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets can be uncoated or they can be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period.
  • water-soluble taste-masking substances such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or prolonged substances, such as ethyl cellulose, cellulose acetate butyrate, can be used.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil
  • Soft gelatin capsules are provided as an oral preparation.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which can be natural Produced phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecylethyleneoxy whale Heptadecaethyleneoxy cetanol, or the condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with fatty acids and hexitol Condensation products of anhydride-derived partial esters, such as polyethylene oxide
  • the aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more colorants, one or more flavoring agents, and one or more sweeteners.
  • preservatives such as ethyl paraben or n-propyl paraben
  • colorants such as ethyl paraben or n-propyl paraben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the sweeteners and flavoring agents described above can be added to provide a palatable formulation. These compositions can be preserved by the addition of an antioxidant such as fenoxyfen or alpha-tocopherol.
  • dispersible powders and granules suitable for use in the preparation of aqueous suspensions can provide active ingredients and dispersing or wetting agents, suspending agents or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents are described above. Other excipients such as sweeteners, flavors and colorants can also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
  • the pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of the partial ester and ethylene oxide Products such as polyethylene oxide sorbitol monooleate.
  • Emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerol to form a microemulsion.
  • Injections or microemulsions can be injected into a patient's bloodstream by local, large injections.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of a compound of the invention. To maintain this constant concentration, continuous intravenous drug delivery devices can be used.
  • the pharmaceutical composition of the present invention may be in the form of a sterile injectable water or oil suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol.
  • a sterile fixed oil can be conveniently used as a solvent or suspension medium.
  • any blended fixing oil including synthetic mono- or diesters can be used.
  • fatty acids such as oleic acid can also be prepared for injection.
  • the compounds of the invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus will dissolve in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of a drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the patient's health, the patient's behavior, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.
  • the optimal treatment such as the mode of treatment, the daily dosage of the compound of the general formula, or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment scheme.
  • the present invention may contain a compound represented by the general formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into clinically acceptable dosage forms.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not cause other adverse effects, such as allergic reactions and the like.
  • the compound of the present invention can be used as the sole active ingredient, and can also be used in combination with other drugs for treating diseases related to VEGF activity. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately, or sequentially.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably containing 1 to 6 carbons Atomic alkyl.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 2,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhex
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Methyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkane Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or formate.
  • alkenyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl and the like. Alkenyl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, and the like.
  • the alkynyl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group that shares one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings have complete conjugation. ⁇ electronic system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spirocycloalkyl is divided into monospirocycloalkyl, bisspirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings, preferably monospirocycloalkyl and bisspirocycloalkyl.
  • spirocycloalkyl More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, or 5 yuan / 6 yuan monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to a 5- to 20-membered, each ring in the system that shares an adjacent pair of carbon atoms with other rings in the system.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl.
  • fused cycloalkyl include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a complete Conjugate ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthalene Radical, benzocycloheptyl and the like.
  • a cycloalkyl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or formate.
  • groups which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) A heteroatom of m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 4 to 10 ring atoms, of which 1 to 3 are heteroatoms; and most preferably contains 5 to 7 ring atoms, of which 1 to Two or one to three are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, and preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O ) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • Spiroheterocyclyl is divided into monospiroheterocyclyl, bisspiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the rings, preferably monospiroheterocyclyl and bisspiroheterocyclyl. More preferred are 4-membered / 4-membered, 4-membered-5-membered, 4-membered-6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bonds, but none of the rings have a completely conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2), and the remaining rings Atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • fused heterocyclyl include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a complete A y-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bridged heterocyclyls include:
  • the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or formate.
  • aryl refers to a 6 to 14 membered, all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 members, such as benzene And naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • an aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or formate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine Oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidyl, thiazolyl; Pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the
  • Heteroaryl may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl, or formate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl, or formate.
  • groups which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heter
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2.
  • mercapto refers to -SH.
  • ester group refers to -C (O) O (alkyl) or -C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to a compound containing a -C (O) R group, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • an heterocyclic group optionally substituted with an alkyl group means that the alkyl group may but need not exist, and this description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted refers to one or more hydrogen atoms in a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiological / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.
  • the present invention uses the following synthetic scheme to prepare the compound of the general formula (I) of the present invention.
  • Step 1 ⁇ -acyl ethyl acetate (Ib) undergoes a substitution reaction with o-nitrofluorobenzene (Ia) under the action of a base to form a substituted nitrobenzene intermediate (Ic);
  • the base is preferably potassium tert-butoxide,
  • the solvent is preferably THF;
  • Step 2 The substituted nitrobenzene intermediate (Ic) is hydrolyzed under acidic conditions, and an asymmetric ketone intermediate (Id) is formed along with the decarboxylation reaction;
  • the acid is preferably acetic acid and concentrated sulfuric acid;
  • Step 3 The fluorine substituent on the phenyl group of the asymmetric ketone intermediate (Id) is hydrolyzed in an alkaline medium to form a p-nitrophenol intermediate (Ie); the base is preferably NaOAc;
  • Step 4 The p-nitrophenol intermediate (Ie) reduces the nitro group to an amino group under the action of a reducing agent, and simultaneously performs an intramolecular cyclization reaction in an acidic medium to form an indole intermediate (If);
  • the reducing agent is preferably Is iron powder, the acid is preferably acetic acid;
  • Step 5 Introduce R 4 at the 3 position of the indole through an electrophilic substitution reaction to form a substituted indole intermediate (Ig); for example, when R 4 is chloro, then the indole intermediate (If) is used for affinity with NCS Electrical substitution reaction introduces chlorine to the 3-position;
  • Step 6 Substitution reaction of indole intermediate (Ig) with chloroquinazoline (Ih) or chloroquinoline (Ih ') under basic conditions to form intermediate (Ii), the base is preferably 2, 6-dimethylpyridine, the catalyst is preferably DMAP;
  • Step 7 Catalytic hydrogenation of the intermediate (Ii) to remove the benzyl protecting group to form a 7-hydroxyquinoline or quinazoline intermediate (Ij).
  • the catalyst is preferably palladium / carbon;
  • Step 8 The 7-hydroxyquinoline or quinazoline intermediate (Ij) is condensed with a carbamoyl chloride in a basic medium to obtain a compound of the general formula (I); the base is preferably K 2 CO 3 , and the solvent is preferably DMF.
  • Chloroquinazoline (Ih) or chloroquinoline (Ih ') are synthesized by the following schemes 2 and 3, respectively:
  • Step 1 Chlorination of dichlorosulfoxide with 4-hydroxy-7-alkoxyquinazolin-6-yl acetate (Ih1) to form 4-chloro-7-alkoxyquinazolin-6- Methyl acetate intermediate (Ih2);
  • Step 2 The 4-chloro-7-alkoxyquinazolin-6-yl acetate intermediate (Ih2) is deacetylated first under the action of a base, and the free 4-chloro-6-hydroxy- 7-alkoxyquinazoline is then reacted with benzyl bromide to form 4-chloro-6-benzyloxy-7-alkoxyquinazoline intermediate (Ih), the base is preferably K 2 CO 3 , The solvent is preferably acetone.
  • Step 1 The p-nitrophenol intermediate (Ih'1) and acetyl chloride acetylate the phenolic hydroxyl group in an alkaline medium to form a 1-acetoxy-2-alkoxy-4-nitrobenzene intermediate (Ih ' 2), the base is preferably pyridine;
  • Step 2 Catalytic hydrogenation of 1-acetyl-2-alkoxy-4-nitrobenzene intermediate (Ih'2) to form 1-acetoxy-2-alkoxy-4-aminobenzene intermediate (Ih '3), the catalyst is preferably Pd / C, and the solvent is preferably ethanol;
  • Step 3 1-acetoxy-2-alkoxy-4-aminobenzene intermediate (Ih'3) and 5- (ethoxymethylene) -2,2-dimethyl-1,3- Dioxane-4,6-dione undergoes an addition-condensation reaction by means of a Michelal addition reaction to form 4-(((2,2-dimethyl-4,6-dioxo-1,3-di Oxane-5-methylene) amino) -2-alkoxyphenylacetate intermediate (Ih'4);
  • Step 4 4-(((2,2-Dimethyl-4,6-dioxo-1,3-dioxane-5-methylene) amino) -2-alkoxyphenylacetic acid
  • the ester intermediate (Ih'4) undergoes decarboxylation and intramolecular cyclization at high temperature to form 6-acetoxy-7-alkoxy-4-oxo-1,4-dihydroquinoline intermediate (Ih '5)
  • the high temperature reaction solvent is preferably diphenyl ether and biphenyl;
  • Step 5 6-acetoxy-7-alkoxy-4-oxo-1,4-dihydroquinoline intermediate (Ih'5) interacts with POCl 3 to form 4-chloro-6-acetoxy- 7-alkoxyquinoline intermediate (Ih'6);
  • Step 6 Basic hydrolysis of 4-chloro-6-acetoxy-7-alkoxyquinoline intermediate (Ih'6) to form 4-chloro-6-hydroxy-7-alkoxyquinoline intermediate (Ih'7), the base is preferably NaOH;
  • Step 7 4-Chloro-6-hydroxy-7-alkoxyquinoline intermediate (Ih'7) reacts with benzyl bromide under the action of a base to form 4-chloro-6-benzyloxy-7-alkoxy
  • the quinoline intermediate (Ih ') the base is preferably K 2 CO 3 , and the solvent is preferably DMF.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and X are as defined in the general formula (I).
  • FIG. 1 is a tumor growth curve of a human-derived xenograft breast cancer MDA-MB-231 model after the treatment in Experimental Example 2.
  • FIG. 2 is a curve of body weight changes of experimental animals after the treatment is started in Test Example 2.
  • the compounds of the present invention are prepared using convenient starting materials and general preparation steps.
  • the present invention gives typical or preferred reaction conditions such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions can also be adopted. Optimization conditions may vary with the use of specific reactants or solvents, but in general, reaction optimization steps and conditions can be determined.
  • protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions.
  • Protective groups suitable for various functional groups and their protection or deprotection conditions have been widely known to those skilled in the art. For example, T.W.Greene and G.M.Wuts' “Protective Groups in Organic Preparations” (3rd edition, Wiley, New York, 1999 and references cited in the book) describe in detail the protection or deprotection of a large number of protective groups.
  • Isolation and purification of compounds and intermediates adopt appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer plate chromatography, preparative high performance liquid chromatography, or a combination of the above methods.
  • the specific usage method can refer to the examples described in the present invention. Of course, other similar separation and purification methods can also be used. It can be characterized using conventional methods, including physical constants and spectral data.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts are given in units of 10 -6 (ppm). NMR was measured using a Brukerdps 400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl. Silane (TMS).
  • the MS was measured using an ACQUITY H-Class UPLC mass spectrometer (QDa Detector) (manufacturer: Waters).
  • the liquid phase was prepared using Waters 2545 high performance liquid chromatography (Waters 2489 UV / visual detector, 2767 sample MGR, single C18, 5 ⁇ m 20 mm x 250 mm) (manufacturer: Waters).
  • the microwave reaction used an initiator + EU type microwave reactor (manufacturer: Biotage).
  • the thin layer chromatography silica gel plate uses Qingdao Ocean Chemical Co., Ltd. GF254 silica gel plate.
  • the thin layer chromatography (TLC) silica gel plate uses a size of 0.15 mm to 0.2 mm.
  • the thin layer chromatography purification product uses a size of 0.4 mm to 0.5. mm.
  • the known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from Net Mall, Beijing Coupling, Sigma, Braunwell, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai BIDER and other companies.
  • reaction can be performed under an argon atmosphere or a nitrogen atmosphere.
  • An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Reaction solvents organic solvents or inert solvents are each expressed as the solvent used does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , Dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine and the like.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • chloroform Dichloromethane
  • ether ether
  • NMP nitrogen-methylpyrrolidone
  • pyridine pyridine
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction temperature is between -78 ° C and 200 ° C.
  • the reaction time and conditions are, for example, under one atmosphere of pressure, between -78 ° C and 200 ° C, and are completed in about 1 to 24 hours. If reacted overnight, the reaction time is generally 16 hours.
  • the reaction temperature is room temperature, which is 20 ° C to 30 ° C.
  • the monitoring of the reaction progress in the examples uses thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing systems used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • the eluent system for column chromatography and the eluent system for thin layer chromatography used to purify compounds include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate
  • A dichloromethane and methanol system
  • B n-hexane and ethyl acetate system
  • C petroleum ether and ethyl acetate
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • Step 1 Preparation of 3- (2,3-difluoro-6-nitrophenyl) -1-ethoxypentane-2,4-dione (a1)
  • Step 5 Preparation of ethyl 2- (3-chloro-5-methoxy-2-nitrophenyl) -3-oxobutanoate (e5)
  • Step 1 Preparation of 4-chloro-6-acetyl-7-methoxyquinazolin-6-yl acetate (f1)
  • Step 3 4-(((2,2-Dimethyl-4,6-dioxo-1,3-dioxane-5-methylene) amino) -2-methoxyphenylacetic acid Preparation of ester (n3)
  • reaction solution is cooled to 0 ° C, a solid is precipitated, filtered, and the precipitate is washed with ethanol (100 mL x 3) and dried to obtain 4-(((2,2-dimethyl-4,6-dioxo- 1,3-Dioxane-5-methylene) amino) -2-methoxyphenylacetate (n3) (54.7 g, yellow solid, yield: 66.6%).
  • Step 4 Preparation of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-yl acetate (n4)
  • Step 5 Preparation of 4-chloro-7-methoxyquinolin-6-yl acetate (n5)
  • a reaction flask containing acetic acid 500 mL was charged with 1,2-diethoxybenzene (100 g, 0.27 mol). After being dissolved, the solution was cooled to 0 ° C with an ice water bath, and 65% concentrated nitric acid (58 g) was slowly added dropwise. After the dropwise addition was completed, the reaction mixture was warmed to room temperature and stirred for 1 hour, at which time a large amount of solids precipitated.
  • Step 1 Preparation of 6- (benzyloxy) -4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinoline (q1)
  • Step 2 Preparation of 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q)
  • Step 1 Preparation of N-benzyl-N- (1-(((benzyloxy) carbonyl) amino) cyclopropane-1-carbonyl) glycine ethyl ester (ii1)
  • reaction solution was cooled to 0 ° C, and triphosgene (148 mg, 0.5 mmol) was added in portions. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 6 hours.
  • Step 1 Preparation of 1- (7-benzyl-4,7-diazaspiro [2.5] oct-4-yl) -2,2,2-trifluoroethane-1-one (jj1)
  • Step 2 Preparation of 2,2,2-trifluoro-1- (4,7-diazaspiro [2.5] oct-4-ylethyl-1-one hydrochloride (jj2)
  • Step 3 Preparation of 4- (2,2,2-trifluoroacetyl) -4,7-diazaspiro [2.5] octane-7-carbonyl chloride (jj)
  • Example 1 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl 2,4-dimethylpiperazine Preparation of oxazine-1-formate (1)
  • Step 1 Preparation of 6- (benzyloxy) -4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazoline (1a)
  • Step 2 Preparation of 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy 6-hydroxy-quinazoline (1b)
  • Step 3 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl 2,4-dimethylpiperazine Preparation of -1-formate (1)
  • the method was the same as that in Example 1, except that 4-fluoro-2-methyl-1H-indole-5 was replaced with 3-chloro-4-fluoro-2-methyl-1H-indole-5-ol (b).
  • 5-alcohol (a) and (R) -2,4-dimethylpiperazine-1-formyl chloride (j) were substituted for 2,4-dimethylpiperazine-1-formyl chloride (g) to obtain 4-((3-chloro-4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -2,4- Dimethylpiperazine-1-carboxylate (6) (8 mg, white solid, 10% yield in three steps).
  • the method was the same as that in Example 1, except that 7-fluoro-2-methyl-1H-indole-5-ol (c) was used instead of 4-fluoro-2-methyl-1H-indole-5-ol ( a) and substituting (R) -2,4-dimethylpiperazine-1-formyl chloride (j) for 2,4-dimethylpiperazine-1-formyl chloride (g) to obtain 4-(( 7-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -2,4-dimethylpiperazine-1- Formate (7) (18 mg, white solid, 13% yield over three steps).
  • the method was the same as that in Example 1, except that 7-chloro-2-methyl-1H-indole-5-ol (e) was used instead of 4-fluoro-2-methyl-1H-indole-5-ol ( a) and substituting (R) -2,4-dimethylpiperazine-1-formyl chloride (j) for 2,4-dimethylpiperazine-1-formyl chloride (g) to obtain 4-(( 7-chloro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -2,4-dimethylpiperazine-1- Formate (8) (15 mg, white solid, 15% yield over three steps).
  • the method was the same as that in Example 1, except that 4,7-difluoro-2-methyl-1H-indole-5-ol (d) was used instead of 4-fluoro-2-methyl-1H-indole-5 -Alcohol (a) and (R) -2,4-dimethylpiperazine-1-formyl chloride (j) in place of 2,4-dimethylpiperazine-1-formyl chloride (g) to obtain 4 -((4,7-difluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-yl (R) -2,4-dimethylpiperazine- 1-formate (9) (12 mg, white solid, three-step yield 8%).
  • Step 1 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-hydroxy-quinazolin-6-yl (R) -2,4-dimethyl Of piperazine-1-formate (10a)
  • Step 2 7-Ethoxy-4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinazolin-6-yl (R) -2,4dimethyl Of Benzylpiperazine-1-carboxylate (10)
  • reaction solution was diluted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by preparative HPLC (C18, acetonitrile / water (0.1% formic acid): 30% to 100%) to give 7-ethoxy-4-((4-fluoro-2-methyl-1H-indole- 5-yl) oxy) quinazolin-6-yl (R) -2,4dimethylpiperazine-1-carboxylate (10) (8.8 mg, white solid, yield 41.5%).
  • Step 1 4- (tert-butyl) -1- (4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinoline-6- ) (R) -2-methylpiperazine-1,4-dicarboxylate (12a)
  • Step 2 4-((4-Fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -2-methylpiperazine Preparation of -1-formate (12)
  • the method was the same as that in Example 11, except that 7-ethoxy-4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (r ) Instead of 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (S) -2 1,4-dimethylpiperazine-1-formyl chloride (k) instead of (R) -2,4-dimethylpiperazine-1-formyl chloride (j) to obtain 7-ethoxy-4- ( (4-Fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -2,4-dimethylpiperazine-1-carboxylic acid ester (17) (15 mg, white solid, yield 13.5%).
  • the preparation method was similar to that in Example 11, except that 7-ethoxy-4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (r ) Instead of 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (S) -3 1,4-dimethylpiperazine-1-formyl chloride (x) instead of (R) -2,4-dimethylpiperazine-1-formyl chloride (j) to obtain 7-ethoxy-4- ( (4-Fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -3,4-dimethylpiperazine-1-carboxylic acid ester (23) (50 mg, white solid, yield 39.8%).
  • the method was the same as that in Example 11, except that 7-ethoxy-4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (r ) Instead of 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (R) -3 1,4-dimethylpiperazine-1-formyl chloride (y) instead of (R) -2,4-dimethylpiperazine-1-formyl chloride (j) to obtain 7-ethoxy-4- ( (4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -3,4-dimethylpiperazine-1-carboxylic acid ester (25) (31 mg, white solid, 27.5% yield).
  • the method was the same as that in Example 11, except that 7-ethoxy-4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (r ) Instead of 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (R) -3 -Methylmorpholine-4-formyl chloride (l) in place of (R) -2,4-dimethylpiperazine-1-formyl chloride (j) to obtain 7-ethoxy-4-((4- Fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -3-methylmorpholine-4-formate (27) (40 mg, white solid, Yield: 36%).
  • the method was the same as that in Example 11, except that 7-ethoxy-4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (r ) Instead of 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (S) -3 -Methylmorpholine-4-formyl chloride (s) instead of (R) -2,4-dimethylpiperazine-1-formyl chloride (j) to obtain 7-ethoxy-4-((4- Fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -3-methylmorpholine-4-formate (29) (40 mg, white solid, Yield: 36%).
  • the method was the same as that in Example 11, except that 7-ethoxy-4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (r ) Instead of 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (S) -2 -Methylmorpholine-4-formyl chloride (gg) replacing (R) -2,4-dimethylpiperazine-1-formyl chloride (j) to obtain 4-((4-fluoro-2-methyl -1H-indole-5-yl) oxy) -7-ethoxyquinolin-6-yl (S) -2-methylmorpholine-4-formate (31) (40 mg, white solid, Yield: 36%).
  • the method was the same as that in Example 11, except that 7-ethoxy-4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (r ) Instead of 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (R) -2 -Methylmorpholine-4-formyl chloride (hh) replaces (R) -2,4-dimethylpiperazine-1-formyl chloride (j) to obtain 7-ethoxy-4-((4- Fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -2-methylmorpholine-4-formate (33) (14 mg, white solid, Yield: 36%).
  • Example 34 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (1S, 4S) -5-methyl Of aryl-2,5-diazabicyclo [2.2.1] heptane-2-formate (34)
  • Example 35 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (1S, 4S) -2,5 -Preparation of diazabicyclo [2.2.1] heptane-2-formate (35)
  • Example 38 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-ethoxyquinolin-6-yl (3S, 5R) -3,5 Of dimethylpiperazine-1-carboxylate (38)
  • Step 1 4-((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl 4-benzyl-4,7-di Preparation of Azaspiro [2.5] octane-7-carboxylic acid ester (43a)
  • Test Example 1 Evaluation of the inhibition of the enzyme activity (IC 50 ) of the compounds of the present invention on the kinases FLT1 (VEGFR1), FLT4 (VEGFR3) and KDR (VEGFR2)
  • the mobility change method (Mobility shift assay) was used to test the inhibitory activity of the compounds at the ATP concentrations of the corresponding kinases Km.
  • the control was staurosporine.
  • Test compound concentrations start at 10 ⁇ M and are diluted 10-fold.
  • Test results (IC 50) is the mean of two independent experiments.
  • Kinase FLT1 Invitrogen, Cat. No. PR6731B, Lot. No. 33924Q
  • Kinase FLT4 Invitrogen, Cat. No. PV4129, Lot. No. 38454G
  • Kinase KDR Carna, Cat. No. 08-191, Lot No.07CBS-0540
  • substrate peptide FAM-P22 GL Biochem, Cat. No 112393, Lot. No. P130408-ZB112393
  • substrate peptide FAM-P30 GL Biochem, Cat. No. 263631, Lot. No .P141015-XF263631
  • ATP Sigma, Cat. No. A7699-1G, CAS No.
  • Buffer preparation 50mM HEPES, pH7.5, 0.00015% Brij-35.
  • Sorafenib, anlotinib and the compound of the embodiment of the present invention were formulated into a gradient concentration in 100% DMSO, and diluted with the above buffer solution to 10% DMSO was added to a 384-well plate. For example, if the starting concentration of the compound is 10uM, use 100% DMSO to make 500uM, and then dilute 10 concentrations, and then dilute 10 times with a buffer solution to prepare a compound dilution containing 10% DMSO. Transfer 5ul to a 384-well plate. .
  • Inhibition rate (%) (DMSO control value-sample conversion rate / (DMSO control value-background value) * 100%.
  • the compound of the present invention exhibited a higher inhibitory effect on KDR (VEFGR2) and FLT4 (VEGFR3) kinase activity compared to the two positive control drugs.
  • Test Example 2 In vivo pharmacodynamic evaluation of a compound of the present invention on a human xenograft breast cancer MDA-MB-231 model
  • MDA-MB-231 cells purchased from ATCC, serial number: HTB-26; BALB / c nude mice: purchased from Speyway (Beijing) Biotechnology Co., Ltd .; Sorafenib: purchased from Shanghai Hongye Biological Technology Co., Ltd .; Cremophor: purchased from Beijing Solarbio Science & Technology Co., Ltd; solutol HS-15: purchased from Beijing Coupling Technology Co., Ltd.
  • MDA-MB-231 cells were inoculated subcutaneously on the right anterior flank of female BALB / c nude mice, and the tumors were administered in groups when the tumor grew to an average volume of about 150 mm 3 (day 10). It is divided into 4 groups of 5 animals each: vehicle control group, low-dose group of the compound of Example 11 (6mg / kg), high-dose group of the compound of Example 11 (25mg / kg), and Sorafenib positive control group (50mg / kg). kg).
  • the vehicle was a 10% solutol HS-15 aqueous solution.
  • the compound of Example 11 was dissolved in the vehicle to make a 0.6 mg / ml solution, and then administered orally by group, once a day for 21 consecutive days.
  • the positive control drug Sorafenib was dissolved in Cremophor / 95% ethanol / H 2 O (12.5% / 12.5% / 75%) to make a 5mg / ml solution, and then administered orally, once a day for 21 consecutive days.
  • the tumor volume and body weight were measured twice a week, and the relationship between the changes in body weight and tumor volume of tumor-bearing mice and the administration time was recorded. After the experiment, the mice in each group were euthanized, the tumor tissue was stripped, and they were placed neatly and photographed after weighing.
  • TGI% (1-T / C) ⁇ 100%.
  • T / C% is the relative tumor appreciation rate, that is, the percentage of tumor volume in the treatment group and control group at the end of the experiment.
  • T and C are the relative tumor volume (RTV) of the treatment group and the control group at the end of the experiment, respectively.
  • the tumor volume of the low- and high-dose compounds of the compound of Example 11 and the Sorafenib positive drug control group were significantly reduced (p ⁇ 0.01), and the tumor suppression rates of each treatment group were 99.4%. , 103.1% and 105.4%; there was no significant difference in tumor volume between the high and low dose groups of the compound of Example 11 and the Sorafenib positive drug control group (p> 0.05) (see Figure 1).
  • mice in each treatment group remained basically stable.
  • the high-dose group of the compound of Example 11 and the Sorafenib positive drug control group slightly decreased, but all mice were generally in good condition, with no discontinuation and no other abnormal performance.
  • the end of the experiment due to the huge tumor-bearing mice in the vehicle group, their body weights were significantly higher than those in the treatment groups (p ⁇ 0.01) (see Figure 2).
  • the compound of the present invention has a significant antitumor effect on the human xenograft breast cancer MDA-MB-231 model, effectively inhibits tumor growth, and has a certain dose-response relationship trend; high dose (25mg / kg) and low dose ( 6 mg / kg) has the same tumor suppressive effect as the positive drug Sorafenib at a dose of 50 mg / kg; tumor-bearing mice show good tolerance to the experimental amount of the compound of Example 11.

Abstract

公开了通式(I)所示的化合物、制备方法以及含有该化合物的药物组合物，及其用作血管内皮生长因子受体激酶抑制剂的用途，特别是用于治疗与血管内皮生长因子受体激酶功能失调相关的疾病如癌症的用途。其中通式(I)中的各取代基的定义与说明书中的定义相同。

Description

吲哚衍生物及其在医药上的应用 技术领域
本发明涉及一种吲哚衍生物、其制备方法及含有其的药物组合物，以及用作血管内皮生长因子受体(VEGFR)激酶抑制剂的用途，特别是用于制备治疗与血管内皮生长因子受体激酶功能失调相关的疾病如癌症的药物的用途。
背景技术
血管生成是一个严格调控的多步骤过程，涉及多种生长因子(包括VEGFs、bFGF和PDGFs)与其受体相互作用。
血管内皮生长因子(vascular endothelial growth factor，VEGF)是血管内皮细胞特异性的肝素结合生长因子，VEGF通过与血管内皮生长因子受体(VEGFR)结合在体内诱导新生血管的形成。这一过程刺激生理或病理性血管生成，同时也调节血管通透性。因此，VEGFR的表达及其活性与组织微血管的密度和新生血管的数量密切相关。VEGFR家族包括VEGFR-1、VEGFR-2和VEGFR-3。
新生血管生成在肿瘤的生长、发展和转移过程中起到非常重要的作用。肿瘤的新生血管为实体恶性肿瘤提供氧和营养素，促进肿瘤的进一步增长，并为肿瘤的转移扩散提供传播的途径。因此，抑制肿瘤新生血管的形成成为治疗多种癌症的有效方法。
虽然有几个小分子VEGFR激酶抑制剂在临床上被应用，但要么是多靶点药物(如索拉非尼、瑞戈非尼)，要么是副作用明显，患者的依从性受到一定影响。因此，继续开发高活性、高选择性的新型VEGFR激酶抑制剂在临床应用上依然有着广泛的需求和前景。
发明内容
本发明人经过潜心研究，设计合成了一系列吲哚衍生物，其显示出VEGFR激酶的抑制活性，可以被开发为治疗与VEGFR激酶活性相关的疾病的药物。
因此，本发明的目的是提供一种通式(I)所示的化合物，
Figure PCTCN2019105271-appb-000001
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用盐，
其中：
X为CH或N；
R 1选自氢、烷基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
R 2选自含氮杂环基，其任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
R 3选自氢、卤素、羟基、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
R 4选自氢、卤素、羟基、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
R 5选自氢、卤素、羟基、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
R 6选自氢、卤素、羟基、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。
在本发明一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中，
R 1选自烷基，优选C 1-C 6烷基，所述烷基进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中，
R 2选自4至10元含氮杂环基，优选4至10元单环含氮杂环基、含氮螺杂环基、含氮稠杂环基或含氮桥杂环基；
所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中，
R 2选自基团：
Figure PCTCN2019105271-appb-000002
其任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
其中：
Y选自CH 2、NH、O、或S、S(O) y；
R a选自、氨基、羟基、酯基、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基；
i为0、1或2；
j为0、1或2；
m为0、1或2；
y为1或2；
A环为C 3-C 6饱和或不饱和环。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中，
R 2选自基团：
Figure PCTCN2019105271-appb-000003
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中，R 3选自氢或卤素。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中，R 4选自氢或卤素。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中，R 5选自氢或卤素。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中，R 6选自烷基，优选C 1-C 6烷基。
本发明典型的化合物包括但不限于以下化合物：
Figure PCTCN2019105271-appb-000004
Figure PCTCN2019105271-appb-000005
Figure PCTCN2019105271-appb-000006
Figure PCTCN2019105271-appb-000007
Figure PCTCN2019105271-appb-000008
Figure PCTCN2019105271-appb-000009
Figure PCTCN2019105271-appb-000010
Figure PCTCN2019105271-appb-000011
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用盐。
本发明进一步提供一种制备根据本发明所述的通式(I)所示的化合物的方法，其包括以下步骤：
Figure PCTCN2019105271-appb-000012
化合物Ij与酰氯化合物在碱性介质中进行缩合反应，得到通式化合物(I)；
其中，所述碱优选为K 2CO 3，溶剂优选为DMF；
R 1、R 2、R 3、R 4、R 5、R 6、X如权利要求1所定义。
本发明进一步提供一种药物组合物，其包含根据本发明所述的通式(I)所示的化合物，以及药学上可接受的载体或赋形剂。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或包含其的药物组合物在制备血管内皮生长因子受体激酶抑制剂中的用途。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或包含其的药物组合物在制备治疗与血管内皮生长因子受体激酶功能失调相关的疾病的药物中的用途，所述疾病优选膀胱癌、乳腺癌、***、直结肠癌、肠癌、胃癌、头颈癌、肾癌、肝癌、肺癌、卵巢癌、***癌、睾丸癌、食道癌、胆囊癌、胰腺癌、甲状腺癌、皮肤癌、脑癌、骨癌、软组织癌、白血病和淋巴癌，更优选脑癌、甲状腺癌、肝癌、肺癌、肾癌、乳腺癌、胃癌和直结肠癌。
按照本发明所属领域的常规方法，本发明通式(I)所示的化合物可以与酸生成药学上可接受的酸式加成盐。所述酸包括无机酸和有机酸，特别优选盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
按照本发明所属领域的常规方法，本发明通式(I)所示的化合物可以与碱生成药学上可接受的碱式加成盐。所述碱包括无机碱和有机碱，可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等，可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或***胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、 聚乙烯吡咯烷酮和***胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。
通过加入水，适用于制备水混悬液的可分散粉末和颗粒可以提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂如上所述。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如在1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温 度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、***的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
本发明可以含有通式(I)所示的化合物，及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活性成分，也可以与其它治疗与VEGF活性相关的疾病的药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代， 所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或甲酸酯基。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2019105271-appb-000013
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2019105271-appb-000014
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2019105271-appb-000015
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或甲酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含4至10个环原子，其中1～3个是杂原子；最优选包含5至7个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2019105271-appb-000016
术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2019105271-appb-000017
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2019105271-appb-000018
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2019105271-appb-000019
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或甲酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2019105271-appb-000020
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或甲酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2019105271-appb-000021
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或甲酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或甲酸酯基。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指＝O。
术语“羧基”指-C(O)OH。
术语“巯基”指-SH。
术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。
术语“酰基”指含有-C(O)R基团的化合物，其中R为烷基、环烷基、杂环基、芳基、杂芳基。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下合成方案制备本发明的通式(I)化合物。
Figure PCTCN2019105271-appb-000022
步骤1：β-酰基乙酸乙酯(Ib)在碱的作用下与邻硝基氟苯(Ia)发生取代反应形成取代硝基苯中间体(Ic)；所述碱优选为叔丁醇钾，溶剂优选为THF；
步骤2：取代硝基苯中间体(Ic)在酸性条件下水解，同时伴随脱羧反应形成不对称酮中间体(Id)；所述的酸优选为醋酸和浓硫酸；
步骤3：不对称酮中间体(Id)苯基上的氟取代基在碱性介质中水解，形成对硝基苯酚中间体(Ie)；所述碱优选为NaOAc；
步骤4：对硝基苯酚中间体(Ie)在还原剂的作用下将硝基还原成氨基，同时在酸性介质中进行分子内环化反应形成吲哚中间体(If)；所述还原剂优选为铁粉，酸优选为醋酸；
步骤5：通过亲电取代反应在吲哚的3位引入R 4，形成取代的吲哚中间体(Ig)；例如当R 4为氯时，则通过吲哚中间体(If)与NCS进行亲电取代反应引入氯到3位；
步骤6：吲哚中间体(Ig)与氯代喹唑啉(Ih)或氯代喹啉(Ih’)在碱性条件下发生取代反应形成中间体(Ii)，所述碱优选为2,6-二甲基吡啶，催化剂优选为DMAP；
步骤7：催化氢化中间体(Ii)除去苄基保护基，形成7-羟基喹啉或喹唑啉中间体(Ij)，所述催化剂优选为钯/碳；
步骤8：7-羟基喹啉或喹唑啉中间体(Ij)与胺基甲酰氯在碱性介质中缩合，得到通式化合物(I)；所述碱优选为K 2CO 3，溶剂优选为DMF。
氯代喹唑啉(Ih)或氯代喹啉(Ih’)分别通过以下方案2和3合成制备：
Figure PCTCN2019105271-appb-000023
步骤1：二氯亚砜与4-羟基-7-烷氧基喹唑啉-6-基乙酸酯(Ih1)发生氯代反应形成4-氯-7-烷氧基喹唑啉-6-基乙酸酯中间体(Ih2)；
步骤2：4-氯-7-烷氧基喹唑啉-6-基乙酸酯中间体(Ih2)在碱的作用下，先脱去乙酰基，游离出来的4-氯-6-羟基-7-烷氧基喹唑啉紧接着与苄溴反应，形成4-氯-6-苄氧基-7-烷氧基喹唑啉中间体(Ih)，所述碱优选为K 2CO 3，溶剂优选为丙酮。
Figure PCTCN2019105271-appb-000024
步骤1：对硝基苯酚中间体(Ih’1)与乙酰氯在碱性介质中乙酰化酚羟基，形成1-乙酰氧基-2-烷氧基-4-硝基苯中间体(Ih’2)，所述碱优选为吡啶；
步骤2：催化氢化1-乙酰基-2-烷氧基-4-硝基苯中间体(Ih’2)，形成1-乙酰氧基-2-烷氧基-4-氨基苯中间体(Ih’3)，所述催化剂优选为Pd/C，溶剂优选为乙醇；
步骤3：1-乙酰氧基-2-烷氧基-4-氨基苯中间体(Ih’3)与5-(乙氧基亚甲基)-2,2-二甲基-1,3-二噁烷-4,6-二酮通过Micheal加成反应的方式进行加成-缩合反应形成4-(((2,2-二甲基-4,6-二氧代-1,3-二噁烷-5-亚甲基)氨基)-2-烷氧基苯基乙酸酯中间体(Ih’4)；
步骤4：4-(((2,2-二甲基-4,6-二氧代-1,3-二噁烷-5-亚甲基)氨基)-2-烷氧基苯基乙酸酯中间体(Ih’4)在高温下进行脱羧和分子内环化反应，形成6-乙酰氧基-7-烷氧基-4-氧代-1,4-二氢喹啉中间体(Ih’5)，所述高温反应溶剂优选为二苯醚和联苯；
步骤5：6-乙酰氧基-7-烷氧基-4-氧代-1,4-二氢喹啉中间体(Ih’5)与POCl 3作用形成4-氯-6-乙酰氧基-7-烷氧基喹啉中间体(Ih’6)；
步骤6：对4-氯-6-乙酰氧基-7-烷氧基喹啉中间体(Ih’6)进行碱性水解，形成4-氯-6-羟基-7-烷氧基喹啉中间体(Ih’7)，所述碱优选为NaOH；
步骤7：4-氯-6-羟基-7-烷氧基喹啉中间体(Ih’7)在碱作用下与苄溴反应，形成4-氯-6-苄氧基-7-烷氧基喹啉中间体(Ih’)，所述碱优选为K 2CO 3,溶剂优选为DMF。
R 1、R 2、R 3、R 4、R 5、R 6、X如通式(I)所定义。
附图说明
图1为试验例2中治疗开始后人源异种移植乳腺癌MDA-MB-231模型中肿瘤的生长曲线。
图2为试验例2中治疗开始后实验动物体重变化曲线。
具体实施方式
进一步通过实施例来理解本发明的化合物及其制备，这些实施例说明了一些制备或使用所述化合物的方法。然而，要理解的是，这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和要求保护的本发明范围之内。
本发明化合物是利用便利的起始原料和通用的制备步骤来完成制备的。本发明给出了典型的或倾向性的反应条件，诸如反应温度、时间、溶剂、压力、反应物的摩尔比。但是除非特殊说明，其他反应条件也能采纳。优化条件可能随着具体的反应物或溶剂的使用而改变，但在通常情况下，反应优化步骤和条件都能得到确定。
另外，本发明中可能用到了一些保护基团来保护某些官能团避免不必要的反应。适宜于各种官能团的保护基以及它们的保护或脱保护条件已经为本领域技术人员广泛熟知。例如T.W.Greene和G.M.Wuts的《有机制备中的保护基团》(第3版,Wiley,New York,1999和书中的引用文献)详细描述了大量的保护基团的保护或脱保护。
化合物和中间体的分离和纯化依据具体的需求采取适当的方法和步骤，例如过滤、萃取、蒸馏、结晶、柱层析、制备薄层板色谱、制备高效液相色谱或上述方法的混合使用。其具体使用方法可参阅本发明描述的实例。当然，其他类似的分离和纯化手段也是可以采用的。可以使用常规方法(包括物理常数和波谱数据)对其进行表征。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10 -6(ppm)的单位给出。NMR的测定是用Brukerdps 400型核磁仪，测定溶剂为氘 代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用ACQUITY H-Class UPLC质谱仪(QDa Detector)(生产商：Waters)。
制备液相使用Waters 2545高效液相色谱仪(Waters 2489 UV/可视检测器,2767样品MGR,单一C18,5μm 20mm x250mm)(生产商：Waters)。
微波反应使用引发剂+EU型微波反应器(生产商：Biotage)。
薄层层析硅胶板使用青岛海洋化工GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用青岛海洋硅胶100～200目、200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、北京偶合、Sigma、百灵威、易世明、上海书亚、上海伊诺凯、安耐吉化学、上海毕得等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
反应溶剂，有机溶剂或惰性溶剂各自表述为使用的该溶剂在所描述的反应条件下不参与反应，包括，如苯、甲苯、乙腈、四氢呋喃(THF)、二甲基甲酰胺(DMF)、氯仿、二氯甲烷、***、甲醇、氮-甲基吡咯碄酮(NMP)、吡啶等。实施例中无特殊说明，溶液是指水溶液。
本发明中所描述的化学反应一般在常压下进行。反应温度在-78℃至200℃之间。反应时间和条件为，例如，一个大气压下，-78℃至200℃之间，大约1至24小时内完成。如果反应过夜，则反应时间一般为16小时。实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。
制备实施例1：4-氟-2-甲基-1H-吲哚-5-醇(a)的制备
Figure PCTCN2019105271-appb-000025
步骤1：3-(2,3-二氟-6-硝基苯基)-1-乙氧基戊烷-2,4-二酮(a1)的制备
于0℃，将叔丁醇钾(39.6g，353mmol)加入含有150mL无水四氢呋喃的圆底烧瓶中，缓慢滴加3-氧代丁酸乙酯(41g，318mmol)。于0℃，将反应液搅拌0.5小时，继续加入1,2,3-三氟-4-硝基苯(25g，141mmol)。加毕，反应液升至室温搅拌过夜。反应完成后，过滤，滤液减压浓缩，加入乙酸乙酯(100mL)稀释，有机相用1N盐酸溶液洗涤至pH值<5，再用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品3-(2,3-二氟-6-硝基苯基)-1-乙氧基戊烷-2,4-二酮(a1)(40g)。
LC-MS(ESI)：m/z 301.1[M+H +]。
步骤2：1-(2,3-二氟-6-硝基苯基)丙-2-酮(a2)的制备
于室温，在含有乙酸(400mL)和硫酸(50mL)的反应瓶中加入3-(2,3-二氟-6-硝基苯基)-1-乙氧基戊烷-2,4-二酮(a1)(40g，132.78mmol)，反应液加热至回流过夜。反应完成后，冷却至室温，将反应液浓缩，加入饱和碳酸氢钠溶液淬灭，乙酸乙酯(100mL)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝5:1)，得到1-(2,3-二氟-6-硝基苯基)丙-2-酮(a2)(23g，黄色油状物，收率71％)。
LC-MS(ESI)：m/z 216.0[M+H +]。
步骤3：1-(2-氟-3-羟基-6-硝基苯基)丙-2-酮(a3)的制备
于室温，在含有DMF(200mL)的反应瓶中加入1-(2,3-二氟-6-硝基苯基)丙-2-酮(a2)(23g，107mmol)和乙酸钠(9.6g，118mmol)，反应液加热至100℃搅拌过夜。反应完成后，冷却至室温，加入乙酸乙酯(100mL)稀释，有机相用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝2:1)，得到1-(2-氟-3-羟基-6-硝基苯基)丙-2-酮(a3)(13g，黄色固体，收率57％)。
LC-MS(ESI)：m/z 214.0[M+H +]。
步骤4：4-氟-2-甲基-1H-吲哚-5-醇(a)的制备
于室温，在含有乙酸(10mL)的反应瓶中加入1-(2-氟-3-羟基-6-硝基苯基)丙-2-酮(1.0g，4.67mmol)和铁粉(15.7g，28mmol)，反应液加热至70℃搅拌6小时，反应完成后，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝2:1)，得到4-氟-2-甲基-1H-吲哚-5-醇(a)(700mg，灰色固体，收率90％)。
LC-MS(ESI)：m/z 166.0[M+H +]。
制备实施例2：3-氯-4-氟-2-甲基-1H-吲哚-5-醇(b)的制备
Figure PCTCN2019105271-appb-000026
于室温，在含有二氯甲烷(2mL)的反应瓶中加入4-氟-2-甲基-1H-吲哚-5-醇(a)(100mg，0.60mmol)和N-氯代丁二酰亚胺(80mg，0.60mmol)。于室温，将反应液搅拌过夜。反应完成后，减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝2:1)，得到3-氯-4-氟-2-甲基-1H-吲哚-5-醇(b)(40mg，灰色固体，收率33％)。
LC-MS(ESI)：m/z 200.0/202.0[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.23(s,1H),9.02(s,1H),6.91(d,J＝8.7Hz,1H),6.72(t,J＝8.4Hz,1H),2.29(s,3H)。
制备实施例3：7-氟-2-甲基-1H-吲哚-5-醇(c)的制备
Figure PCTCN2019105271-appb-000027
与制备中间体(a)的方法相似，除了用1,3,5-三氟-2-硝基苯替代1,2,3-三氟-4-硝基苯，制得7-氟-2-甲基-1H-吲哚-5-醇(c)(50mg，灰色固体，四步收率20％)。
LC-MS(ESI)：m/z 166.08[M+H +]。
制备实施例4：4,7-二氟-2-甲基-1H-吲哚-5-醇(d)的制备
Figure PCTCN2019105271-appb-000028
与制备中间体a的方法相似，除了用1,2,3,5-四氟-4-硝基苯替代1,2,3-三氟-4-硝基苯，制得4,7-二氟-2-甲基-1H-吲哚-5-醇(d)(270mg，灰色固体，四步收率10％)。
LC-MS(ESI)：m/z 184.1[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.28(s,1H),6.50(dd,J＝11.6,6.4Hz,1H),6.12(s,1H),2.34(s,3H)。
制备实施例5：7-氯-2-甲基-1H-吲哚-5-醇(e)的制备
Figure PCTCN2019105271-appb-000029
步骤1：3,5-二氟-4-硝基苯酚(e1)的制备
将3,5-二氟苯酚(13g，99.9mmol)溶于含有DCM(250mL)的反应瓶中。将反应液冷却至0℃后，滴加硝酸(7mL，70％)。加毕，将混合物升至室温搅拌30分钟，用冰水(500mL)淬灭，静置分层，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝5:1)，得到3,5-二氟-4-硝基苯酚(e1)(6.5g，白色固体，收率：37.3％)。
LC-MS(ESI)：m/z 174.16[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ6.76(d,J＝1.8Hz,1H),6.72(d,J＝1.7Hz, 1H),5.76(s,1H)。
步骤2：1,3-二氟-5-甲氧基-2-硝基苯(e2)的制备
在含有DMF(42mL)的反应瓶中，分别加入3,5-二氟-4-硝基苯酚(e1)(6.5g，37.1mmol)、碘甲烷(7.9g，55.6mmol)和碳酸钾(10.23g，74.2mmol)。于室温，将反应混合物搅拌过夜后，用乙酸乙酯稀释，有机相依次用水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝5:2)，得到1,3-二氟-5-甲氧基-2-硝基苯(e2)(4.0g，黄色的油状物，收率：56.9％)。
步骤3：3-氟-5-甲氧基-2-硝基苯胺(e3)的制备
在预先置入氨的甲醇溶液(60mL，7.0M)的反应瓶中加入1,3-二氟-5-甲氧基-2-硝基苯(4.0g，21.15mmol)。于室温，将反应混合物密封搅拌过夜后，减压浓缩，得到3-氟-5-甲氧基-2-硝基苯胺(e3)粗产物，直接用于下一步反应。
LC-MS(ESI)：m/z 187.02[M+H +]。
步骤4：1-氯-3-氟-5-甲氧基-2-硝基苯(e4)的制备
将亚硝酸特丁酯(575mg，5.6mmol)和氯化铜(750mg，5.6mmol)加入到含有乙腈(5mL)的反应瓶中。将反应液冷却至0℃后，滴加3-氟-5-甲氧基-2-硝基苯胺(e3)(520mg，2.8mmol)的乙腈溶液(10mL)。加毕，该混合物升至室温并搅拌2小时，用水淬灭。将反应混合物用乙酸乙酯萃取(3x50mL)，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝10:1)，得到1-氯-3-氟-5-甲氧基-2-硝基苯(e4)(400mg，黄色固体，收率：69.7％)。
步骤5：2-(3-氯-5-甲氧基-2-硝基苯基)-3-氧代丁酸乙酯(e5)的制备
在含有无水四氢呋喃(8mL)的反应瓶中加入叔丁醇钾(326mg，2.91mmol)、乙酰乙酸乙酯(378mg，1.5mmol)和1-氯-3-氟-5-甲氧基-2-硝基苯(e4)(400mg，1.95mmol)。反应混合液加热回流24小时。待反应完成后，用乙酸乙酯稀释，所得混合物依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝5:2)，得到2-(3-氯-5-甲氧基-2-硝基苯基)-3-氧代丁酸乙酯(e5)(410mg，黄色的油状物，收率：66.7％)。
LC-MS(ESI)：m/z 316.00[M+H +]。
步骤6：1-(3-氯-5-甲氧基-2-硝基苯基)丙-2-酮(e6)的制备
于室温，在含有乙酸(40mL)和硫酸(24mL)的反应瓶中加入2-(3-氯-5-甲氧基-2-硝基苯基)-3-氧代丁酸乙酯(e5)(4.0g，12.7mmol)。反应液加热至回流过夜。反应完成后，冷却至室温，将反应液浓缩，加入饱和碳酸氢钠溶液淬灭，并用乙酸乙酯(2x 100mL)萃取，合并的有机相用食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝5:2)，得到1-(3-氯-5-甲氧基-2-硝基苯基)丙-2-酮(e6)(1.5g，黄色油状物，收率48.7％)。
步骤7：7-氯-5-甲氧基-2-甲基-1H-吲哚(e7)的制备
于室温，在含有乙酸(20mL)的反应瓶中加入1-(3-氯-5-甲氧基-2-硝基苯基)丙-2-酮(e6)(1.5g，6.16mmol)和铁粉(2.06g，36.9mmol)。反应液加热至100℃搅拌1小时，反应完成后，过滤，滤液减压浓缩。残余物用乙酸乙酯(100mL)稀释，有机相依次用水、饱和碳酸氢钠溶液、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝10:3)，得到7-氯-5-甲氧基-2-甲基-1H-吲哚(e7)(1.0g，黄色油状物，收率83.3％)。
LC-MS(ESI)：m/z 196.06,198,01[M+H +]。
步骤8：7-氯-2-甲基-1H-吲哚-5-醇(e)的制备
在含DCM(30mL)的反应瓶中加入7-氯-5-甲氧基-2-甲基-1H-吲哚(e7)(1.0g，5.11mmol)。将混合液冷至-78℃，滴加三溴化硼(12.8mL，25.6mmol,2M在四氢呋喃溶液中)。滴加完毕后，将反应液缓慢升温至-10℃搅拌4小时。待反应完成后，用二氯甲烷(80mL)稀释，有机相用水、饱和碳酸氢钠溶液、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝10:3)，得到7-氯-2-甲基-1H-吲哚-5-醇(e)(800mg，黄色固体，收率82.1％)。
LC-MS(ESI)：m/z 182.03,184.14[M+H +]。
制备实施例6：6-(苄氧基)-4-氯-7-甲氧基喹唑啉(f)的制备
Figure PCTCN2019105271-appb-000030
步骤1：4-氯-6-乙酰基-7-甲氧基喹唑啉-6-基乙酸酯(f1)的制备
于室温，在含有二氯亚砜(100mL)的反应瓶中加入4-羟基-7-甲氧基喹唑啉-6-基乙酸酯(安耐吉化学)(10g，4.26mmol)和DMF(0.25mL)，反应液加热至回流2小时。冷却至室温后，加入20mL***，过滤得到粗产品4-氯-7-甲氧基喹唑啉-6-基乙酸酯(f1)(10g，灰色固体)。
LC-MS(ESI)：m/z 253.0/255.2[M+H +]。
步骤2：6-(苄氧基)-4-氯-7-甲氧基喹唑啉(f)的制备
于室温，在含有丙酮(15mL)的反应瓶中加入4-氯-7-甲氧基喹唑啉-6-基乙酸酯(f1)(1.0g，4.75mmol)、溴苄(975mg，5.70mmol)和碳酸钾(1.3g，9.5 mmol)。于室温，将反应液搅拌过夜。反应完成后，加入乙酸乙酯(20mL)稀释，有机相用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝2:1)，得到6-(苄氧基)-4-氯-7-甲氧基喹唑啉(f)(600mg，白色固体，收率42％)。
LC-MS(ESI)：m/z 301.1/303.1[M+H +]。
制备实施例7：2,4-二甲基哌嗪-1-甲酰氯(g)的制备
Figure PCTCN2019105271-appb-000031
步骤1：2,4-二甲基哌嗪-1-甲酸叔丁酯(g1)的制备
于室温，在含有二氯甲烷100(mL)的反应瓶中加入2-甲基哌嗪-1-甲酸叔丁酯(5.0g，24.97mmol)、甲醛水溶液(2.6mL，37.45mmol)和三乙酰氧基硼氢化钠(8.0g，37.45mmol)。于室温，将反应液搅拌过夜。反应完成后，加入饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取(3x50mL)，合并有机相用水和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗产物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝2:1)，得到2,4-二甲基哌嗪-1-甲酸叔丁酯(g1)(5.0g，无色液体，收率94％)。
LC-MS(ESI)：m/z 215.2[M+H +]。
步骤2：1,3-二甲基哌嗪盐酸盐(g2)的制备
于室温，在含有二氯甲烷(50mL)的反应瓶中加入2,4-二甲基哌嗪-1-甲酸叔丁酯(g1)(5.0g，23.23mmol)和盐酸二氧六环溶液(10mL，4M二氧六环溶液)。于室温，将反应液在搅拌2小时。反应完成后，减压浓缩，得到粗产品1,3-二甲基哌嗪盐酸盐(g2)(5.0g，白色固体)。
LC-MS(ESI)：m/z 115.1[M+H +]。
步骤3：2,4-二甲基哌嗪-1-碳酰氯(g)的制备
于室温，在含有无水二氯甲烷(20mL)的反应瓶中加入1,3-二甲基哌嗪盐酸盐(810mg，4.38mmol)和碳酸氢钠(1.5g，17.52mmol)。将反应液冷却至0℃，分批加入三光气(650mg，2.19mmol)，加毕升至室温搅拌6小时。反应完成后，减压浓缩，得到2,4-二甲基哌嗪-1-碳酰氯(g)(1.5g，白色固体)。
LC-MS(ESI)：m/z 177.1/179.2[M+H +]。
制备实施例8：3,4-二甲基哌嗪-1-甲酰氯(h)的制备
Figure PCTCN2019105271-appb-000032
于室温，在含有无水二氯甲烷(20mL)的反应瓶中加入1,2-二甲基哌嗪(500mg，4.38mmol)和碳酸氢钠(1.5g，17.52mmol)。将反应液冷却至0℃，分批加入三光气(650mg，2.19mmol)，加毕升至室温搅拌6小时。反应完成后，减压浓缩得到3,4-二甲基哌嗪-1-甲酰氯(h)(1.5g，白色固体)。
LC-MS(ESI)：m/z 177.1/179.2[M+H +]。
制备实施例9：(1R,4R)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酰氯(i)的制备
Figure PCTCN2019105271-appb-000033
与中间体g的制备方法相同，除了用(1R,4R)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯替代2-甲基哌嗪-1-甲酸叔丁酯，制得(1R,4R)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酰氯(i)(1.5g，白色固体)。
LC-MS(ESI)：m/z 175.1/177.1[M+H +]。
制备实施例10：(R)-2,4-二甲基哌嗪-1-甲酰氯(j)的制备
Figure PCTCN2019105271-appb-000034
与中间体g的制备方法相同，除了用(R)-2-甲基哌嗪-1-甲酸叔丁酯替代2-甲基哌嗪-1-甲酸叔丁酯，制得(R)-2,4-二甲基哌嗪-1-甲酰氯(j)(1.5g，白色固体)。
LC-MS(ESI)：m/z 177.1/179.1[M+H +]。
制备实施例11：(S)-2,4-二甲基哌嗪-1-甲酰氯(k)的制备
Figure PCTCN2019105271-appb-000035
与中间体g的制备方法相同，除了用(S)-2-甲基哌嗪-1-甲酸叔丁酯替代2-甲基哌嗪-1-甲酸叔丁酯，制得(S)-2,4-二甲基哌嗪-1-甲酰氯(k)(1.5g，白色固体)。
LC-MS(ESI)：m/z 177.1/179.1[M+H +]。
制备实施例12：(R)-3-甲基吗啉-4-甲酰氯(l)的制备
Figure PCTCN2019105271-appb-000036
与中间体h的制备方法相同，除了用(R)-3-甲基吗啉替代1,2-二甲基哌嗪，制得(R)-3-甲基吗啉-4-甲酰氯(l)(1.5g，白色固体)。
LC-MS(ESI)：m/z 164.0/162.0[M+H +]。
制备实施例13：5-(乙氧基亚甲基)-2,2-二甲基-1,3-二噁烷-4,6-二酮(m)的制备
Figure PCTCN2019105271-appb-000037
于室温，在250mL的反应瓶中加入丙二酸环(亚)异丙酯(25g，0.17mmol)和原甲酸三乙酯(77g，0.51mmol)。反应混合物于80℃搅拌3小时。待反应完成后，反应液减压浓缩，得到5-(乙氧基亚甲基)-2,2-二甲基-1,3-二噁烷-4,6-二酮(m)(34g，红色油状物)。
制备实施例14：6-(苄氧基)-4-氯-7-甲氧基喹啉(n)的制备
Figure PCTCN2019105271-appb-000038
Figure PCTCN2019105271-appb-000039
步骤1：2-甲氧基-4-硝基苯基乙酸酯(n1)的制备
于室温，在含有无水DCM(450mL)的反应瓶中加入2-甲氧基-4-硝基苯酚(45g，0.27mol)和吡啶(25.3g，0.32mol)。反应混合物冷至0℃，滴加乙酰氯(25.1g，0.32mmol)，滴加完毕，升至室温搅拌30分钟。待反应完成后，反应液用水洗涤，水相用二氯甲烷萃取3次，合并有机相，并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到2-甲氧基-4-硝基苯基乙酸酯(n1)(50.7g，黄色固体，收率：90.2％)。
步骤2：4-氨基-2-甲氧基苯基乙酸酯(n2)的制备
于室温，在含有乙醇(500mL)的反应瓶中加入2-甲氧基-4-硝基苯基乙酸酯(n1)(50.7g，0.24mol)和10％钯碳(55％的水)(2.5g)。反应液用氢气置换三次后于氢气氛围下搅拌过夜。待反应完成后，过滤，滤液减压浓缩，得到4-氨基-2-甲氧基苯基乙酸酯(n2)(44.4g，黑色油状物)。
LC-MS(ESI)：m/z 182.1[M+H +]。
步骤3：4-(((2,2-二甲基-4,6-二氧代-1,3-二噁烷-5-亚甲基)氨基)-2-甲氧基苯基乙酸酯(n3)的制备
于室温，在含有乙醇(800mL)的反应瓶中加入4-氨基-2-甲氧基苯基乙酸酯(n2)(44.4g，0.25mol)和5-(乙氧基亚甲基)-2,2-二甲基-1,3-二噁烷-4,6-二酮(m)(66g，0.33mol)。反应液加热至回流搅拌3小时。待反应完成后，反应液冷却至0℃，析出固体，过滤，沉淀用乙醇(100mLx3)洗涤，烘干，得到4-(((2,2-二甲基-4,6-二氧代-1,3-二噁烷-5-亚甲基)氨基)-2-甲氧基苯基乙酸酯(n3)(54.7g,黄色固体，收率：66.6％)。
LC-MS(ESI)：m/z 336.2[M+H +]。
1H NMR(400MHz,Chloroform-d)δ11.26(d,J＝14.3Hz,1H),8.59(d,J＝14.3Hz,1H),7.09(d,J＝8.4Hz,1H),6.85-6.79(m,2H),3.88(s,3H),2.32(s,3H),1.76(s,6H)。
步骤4：7-甲氧基-4-氧代-1,4-二氢喹啉-6-基乙酸酯(n4)的制备
于室温，在含有二苯醚(219g)和联苯(96g)的反应瓶中加入4-(((2,2-二甲基-4,6-二氧代-1,3-二噁烷-5-亚甲基)氨基)-2-甲氧基苯基乙酸酯(n3)(21.9g，65.3mmol)。反应液于190℃搅拌1.5小时。反应完成后，冷却至60℃，将反应液倒入石油醚(1.2 L)中，析出固体，过滤，沉淀用石油醚(200mL)洗涤，烘干，得到7-甲氧基-4-氧代-1,4-二氢喹啉-6-基乙酸酯(n4)(13g，黄色固体，收率：85.4％)。
LC-MS(ESI)：m/z 234.1[M+H +]。
步骤5：4-氯-7-甲氧基喹啉-6-基乙酸酯(n5)的制备
于室温，在含有氯仿(60mL)的反应瓶中加入7-甲氧基-4-氧代-1,4-二氢喹啉-6-基乙酸酯(n4)(5.5g，23.6mmol)和***(11.8mL，118mmol)。反应液加热至回流搅拌6小时。待反应完成后，反应液减压浓缩，残余物用乙酸乙酯稀释，有机相依次用水、饱和的碳酸氢钠溶液和饱和的食盐水洗涤。无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝2:1)，得到4-氯-7-甲氧基喹啉-6-基乙酸酯(n5)(4.3g，黄色固体，收率：72.4％)。
LC-MS(ESI)：m/z 252.13[M+H +]。
步骤6：4-氯-7-甲氧基-6-羟基喹啉(n6)的制备
于0℃，在含有乙醇(30mL)和水(5mL)的反应瓶中加入4-氯-7-甲氧基喹啉-6-基乙酸酯(n5)(3.5g，13.9mmol)和氢氧化钠(612mg，15.3mmol)。反应液继续搅拌1小时。待反应完成后，反应液减压浓缩，得到粗品4-氯-7-甲氧基-6-羟基喹啉(n6)。直接用于下一步反应。
LC-MS(ESI)：m/z 210.1[M+H +]。
步骤7：6-(苄氧基)-4-氯-7-甲氧基喹啉(n)的制备
在含有DMF(30mL)的反应瓶中加入4-氯-7-甲氧基-6-羟基喹啉(n6)(2.8g，13.4mmol)、碳酸钾(3.7g，26.8mmol)和溴化苄(3.4g，20.1mmol)。反应液于室温搅拌6小时。待反应完成后，加水(100mL)稀释并用乙酸乙酯萃取(30mL×3)，合并有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/2:1)，得到6-(苄氧基)-4-氯-7-甲氧基喹啉(n)(3.3g，黄色固体，收率：82.5％)。
LC-MS(ESI)：m/z 300.1[M+H +]。
制备实施例15：2-乙氧基-4-硝基苯酚(o)的制备
Figure PCTCN2019105271-appb-000040
步骤1：1,2-二乙氧基-4-硝基苯(o1)的制备
于室温，在含有乙酸(500mL)的反应瓶中加入1,2-二乙氧基苯(100g，0.27mol)。待溶解后，用冰水浴冷却至0℃，缓慢滴加65％的浓硝酸(58g)。滴加完毕 后，将反应混合物升至室温搅拌1小时，此时有大量固体析出。将反应液倒入冷水(1500mL)，过滤，沉淀用水(500mLx3)洗涤，烘干，得到1,2-二乙氧基-4-硝基苯(o1)(123.7g，黄色固体，收率：97.4％)。
1H NMR(400MHz,Chloroform-d)δ7.88(dd,J＝8.9,2.7Hz,1H),7.74(d,J＝2.6Hz,1H),6.89(d,J＝8.9Hz,1H),4.18(dq,J＝9.8,7.0Hz,4H),1.55–1.48(m,6H)。
步骤2：2-乙氧基-4-硝基苯酚(o)的制备
于室温，在含有乙二醇单***(500mL)和水(1L)的反应瓶中加入1,2-二乙氧基-4-硝基苯(107g，0.5mol)和氢氧化钾(112g，2mol)。加毕，反应混合物加热至回流搅拌72小时，待反应完成后，冷却至室温，反应液倒入冷水中，用浓盐酸调节pH呈酸性，有大量沉淀析出，过滤，沉淀用水(500mLx3)洗涤，烘干，得到2-乙氧基-4-硝基苯酚(o)(85g，黄色固体，收率：87.6％)。
1H NMR(400MHz,Chloroform-d)δ7.87(dd,J＝8.8,2.5Hz,1H),7.74(d,J＝2.5Hz,1H),6.98(d,J＝8.8Hz,1H),6.25(s,1H),4.26–4.20(m,2H),1.51(t,J＝7.0Hz,3H)。
制备实施例16：6-(苄氧基)-4-氯-7-乙氧基喹啉(p)的制备
Figure PCTCN2019105271-appb-000041
采用与制备实施例14相同的方法，除了用2-乙氧基-4-硝基苯酚(o)代替2-甲氧基-4-硝基苯酚，制得6-(苄氧基)-4-氯-7-乙氧基喹啉(p)(黄色固体，收率：8％)。
LC-MS(ESI)：m/z314.1,316.1[M+H +]。
制备实施例17：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)的制备
Figure PCTCN2019105271-appb-000042
步骤1：6-(苄氧基)-4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-7-甲氧基喹啉(q1)的制备
于室温，在含有2,6-二甲基吡啶(20mL)的反应瓶中加入6-(苄氧基)-4-氯-7-甲 氧基喹啉(n)(1.7g，5.7mmol)、4-氟-2-甲基-1H-吲哚-5-醇(a)(1.04g，6.3mmol)和4-二甲氨基吡啶(696mg，5.7mmol)。反应液加热至回流搅拌12小时。待反应完成后，反应混合物减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为DCM:MeOH＝10；1)，得到6-(苄氧基)-4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-7-甲氧基喹啉(q1)(1.5g，黄色固体，收率62.5％)。
LC-MS(ESI)：m/z 429.3[M+H +]。
步骤2：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)的制备
于室温，在含有甲醇(30mL)的反应瓶中加6-(苄氧基)-4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-7-甲氧基喹啉(q1)(1.5g,3.5mmol)和10％钯碳(55％的水)(300mg)。反应液用氢气置换三次后于氢气氛围下搅拌过夜。反应完成后，将反应液过滤，滤液减压浓缩，得到4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)(黄色固体)。
LC-MS(ESI)：m/z 339.2[M+H +]。
制备实施例18：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)的制备
Figure PCTCN2019105271-appb-000043
采用与制备实施例17相同的方法，除了用6-(苄氧基)-4-氯-7-乙氧基喹啉(p)代替6-(苄氧基)-4-氯-7-甲氧基喹啉(n)，制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)(2.0g,黄色固体，两步收率：57.7％)。
LC-MS(ESI)：m/z 353.2[M+H +]。
制备实施例19：(S)-3-甲基吗啉-4-甲酰氯(s)的制备
Figure PCTCN2019105271-appb-000044
于室温下，在含有无水二氯甲烷(20mL)的反应瓶中加入(S)-3-甲基吗啉(200mg,1.97mmol)和碳酸钾(2.2g,15.76mmol)。将反应液冷却至0℃，分批加入三光气(290.8mg,0.98mmol)。加毕，反应液升至室温搅拌6小时。反应完成后，过滤， 用二氯甲烷(20mL)洗涤，滤液减压浓缩，得到粗产品(S)-3-甲基吗啉-4-甲酰氯(s)(白色固体)。直接用于下一步反应。
LC-MS(ESI)：m/z 164.1/166.1[M+H +]。
制备实施例20：2-甲基吗啉-4-甲酰氯(t)的制备
Figure PCTCN2019105271-appb-000045
采用与制备实施例19相同的方法，除了用2-甲基吗啉代替3-(S)-3-甲基吗啉，制得2-甲基吗啉-4-甲酰氯(t)。
LC-MS(ESI)：m/z 164.1/166.1[M+H +]。
制备实施例21：(S)-六氢吡咯并[1,2-a]吡嗪-2(1H)-甲酰氯(u)的制备
Figure PCTCN2019105271-appb-000046
采用与制备实施例19相同的方法，除了用(S)-八氢吡咯并[1,2-a]吡嗪代替3-(S)-3-甲基吗啉，制得(S)-六氢吡咯并[1,2-a]吡嗪-2(1H)-甲酰氯(u)。
LC-MS(ESI)：m/z 188.17/120.20[M+H +]。
制备实施例22：(R)-六氢吡咯并[1,2-a]吡嗪-2(1H)-甲酰氯(v)的制备
Figure PCTCN2019105271-appb-000047
采用与制备实施例19相同的方法，除了用(R)-八氢吡咯并[1,2-a]代替3-(S)-3-甲基吗啉，制得(R)-六氢吡咯并[1,2-a]吡嗪-2(1H)-甲酰氯(v)。
LC-MS(ESI)：m/z 188.17/120.20[M+H +]。
制备实施例23：(2R,6S)-2,6-二甲基吗啉-4-甲酰氯(w)的制备
Figure PCTCN2019105271-appb-000048
采用与制备实施例19相同的方法，除了用(2R，6S)-2,6-二甲基吗啉代替3-(S)-3-甲基吗啉，制得(2R,6S)-2,6-二甲基吗啉-4-甲酰氯(w)。
LC-MS(ESI)：m/z 177.1/1179.1[M+H +]。
制备实施例24：(S)-3,4-二甲基哌嗪-1-甲酰氯(x)的制备
Figure PCTCN2019105271-appb-000049
采用与制备实施例7相同的方法，除了用(S)-3-甲基哌嗪-1-甲酸叔丁酯代替2-甲基哌嗪-1-甲酸叔丁酯，制得(S)-3,4-二甲基哌嗪-1-甲酰氯(x)。
LC-MS(ESI)：m/z 177.1/179.1[M+H +]。
制备实施例25：(R)-3,4-二甲基哌嗪-1-甲酰氯(y)的制备
Figure PCTCN2019105271-appb-000050
采用与制备实施例7相同的方法，除了用(R)-3-甲基哌嗪-1-甲酸叔丁酯代替2-甲基哌嗪-1-甲酸叔丁酯，制得(R)-3,4-二甲基哌嗪-1-甲酰氯(y)。
LC-MS(ESI)：m/z 177.1/179.1[M+H +]。
制备实施例26：(R)-4-(氯甲酰基)-2-甲基哌嗪-1-甲酸叔丁酯(z)的制备
Figure PCTCN2019105271-appb-000051
采用与制备实施例19相同的方法，除了用(R)-2-甲基哌嗪-1-甲酸叔丁酯代替3-(S)-3-甲基吗啉，制得(R)-4-(氯甲酰基)-2-甲基哌嗪-1-甲酸叔丁酯(z)。
LC-MS(ESI)：m/z 262.1/264.1[M+H +]。
制备实施例27：(S)-4-(氯甲酰基)-2-甲基哌嗪-1-甲酸叔丁酯(aa)的制备
Figure PCTCN2019105271-appb-000052
采用与制备实施例19相同的方法，除了用(S)-2-甲基哌嗪-1-甲酸叔丁酯代替3-(S)-3-甲基吗啉，制得(S)-4-(氯甲酰基)-2-甲基哌嗪-1-甲酸叔丁酯(aa)。
LC-MS(ESI)：m/z 262.1/264.1[M+H +]。
制备实施例28：(R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)的制备
Figure PCTCN2019105271-appb-000053
采用与制备实施例19相同的方法，除了用(R)-3-甲基哌嗪-1-甲酸叔丁酯代替3-(S)-3-甲基吗啉，制得(R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)。
LC-MS(ESI)：m/z 262.1/264.1[M+H +]。
制备实施例29：(S)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(cc)的制备
Figure PCTCN2019105271-appb-000054
采用与制备实施例19相同的方法，除了用(S)-3-甲基哌嗪-1-甲酸叔丁酯代替3-(S)-3-甲基吗啉，制得(S)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(cc)。
LC-MS(ESI)：m/z 262.1/264.1[M+H +]。
制备实施例30：(1R,4R)-5-(氯甲酰基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(dd)的制备
Figure PCTCN2019105271-appb-000055
用与制备实施例19相同的方法，除了用(1R,4R)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯代替3-(S)-3-甲基吗啉，制得(1R,4R)-5-(氯甲酰基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(dd)。
LC-MS(ESI)：m/z 260.1/262.1[M+H +]。
制备实施例31：硫代吗啉-4-甲酰氯(ee)的制备
Figure PCTCN2019105271-appb-000056
采用与制备实施例19相同的方法，除了用硫代吗啉代替3-(S)-3-甲基吗啉，制得硫代吗啉-4-甲酰氯(ee)。
LC-MS(ESI)：m/z 166.1/168.1[M+H +]。
制备实施例32：(2R,6S)-4-(氯甲酰基)-2,6-二甲基哌嗪-1-甲酸叔丁酯(ff)的制备
Figure PCTCN2019105271-appb-000057
采用与制备实施例19相同的方法，除了用(2R,6S)-2,6-二甲基哌嗪-1-甲酸叔丁酯代替3-(S)-3-甲基吗啉，制得(2R,6S)-4-(氯甲酰基)-2,6-二甲基哌嗪-1-甲酸叔丁酯(ff)。
制备实施例33：(S)-2-甲基吗啉-4-甲酰氯(gg)的制备
Figure PCTCN2019105271-appb-000058
采用与制备实施例19相同的方法，除了用(S)-2-甲基吗啉代替(S)-3-甲基吗啉，制得(S)-2-甲基吗啉-4-甲酰氯(gg)。
LC-MS(ESI)：m/z 164.0/166.0[M+H +]。
制备实施例34：(R)-2-甲基吗啉-4-甲酰氯(hh)的制备
Figure PCTCN2019105271-appb-000059
采用与制备实施例19相同的方法，除了用(R)-2-甲基吗啉代替(S)-3-甲基吗啉，制得(R)-2-甲基吗啉-4-甲酰氯(hh)。
LC-MS(ESI)：m/z 164.1/166.1[M+H +]。
制备实施例35：4-苄基-4,7-二氮杂螺[2.5]辛烷-7-碳酰氯(ii)的制备
Figure PCTCN2019105271-appb-000060
步骤1：N-苄基-N-(1-(((苄氧基)羰基)氨基)环丙烷-1-羰基)甘氨酸乙酯(ii1)的制备
于0℃，在含有DCM(120mL)的反应瓶中加入N-苄基甘氨酸乙酯(8.1g，42mmol)、1-(苄氧羰基氨基)环丙烷羧酸(9.9g，42mmol)、EDCI(12g，63mmol)和HOBT(8.5g，63mmol)。反应液升至室温搅拌12小时。然后加入饱和的碳酸氢钠水溶液淬灭，用二氯甲烷萃取(120mLx3)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA＝1:1)得到N-苄基-N-(1-(((苄氧基)羰基)氨基)环丙烷-1-羰基)甘氨酸乙酯(ii1)(10g，黄色固体，收率：58.2％)。
LC-MS(ESI)：m/z 411.3[M+H +]。
步骤2：7-苄基-4,7-二氮杂螺[2.5]辛烷-5,8-二酮(ii2)的制备
在含有乙醇(100mL)的圆底烧瓶中加N-苄基-N-(1-(((苄氧基)羰基)氨基)环丙烷-1-羰基)甘氨酸乙酯(9.5g,23.1mmol)和Pd/C(1g，10％)。密封，氢气置换三次，反应液在氢气氛围下室温搅拌2小时后，过滤。滤液减压浓缩，得到7-苄基-4,7-二氮杂螺[2.5]辛烷-5,8-二酮(ii2)(5g，黄色固体，收率94％)。
LC-MS(ESI)：m/z 231.2[M+H +]。
步骤3：7-苄基-4,7-二氮杂螺[2.5]辛烷(ii3)的制备
在含有THF(100mL)的反应瓶中加入7-苄基-4,7-二氮杂螺[2.5]辛烷-5,8-二酮(3.6g，15.6mmol)。该反应混合物冷至0℃后分批加入LiAlH 4(1.8g，46.8mmol)，继续搅拌2小时，待反应完成后，依次加入水(1.8g)和15％的氢氧化钠水溶液(1.8g)淬灭，搅拌30分钟后，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH＝10:1)得到7-苄基-4,7-二氮杂螺[2.5]辛烷(ii3)(2.5g，黄色油状物，收率：79％)。
LC-MS(ESI)：m/z 203.2[M+H +]。
步骤4：4-苄基-4,7-二氮杂螺[2.5]辛烷-7-碳酰氯(ii)的制备
于室温下，在含有无水二氯甲烷(20mL)的反应瓶中加入7-苄基-4,7-二氮杂螺[2.5]辛烷(ii3)(200mg,0.98mmol)和碳酸钾(1g,7.84mmol)。将反应液冷却至0℃，分批加入三光气(148mg,0.5mmol)。加毕，反应液升至室温搅拌6小时。反应完成后，过滤，用二氯甲烷(20mL)洗涤，滤液减压浓缩，得到粗产品4-苄基-4,7-二氮杂螺[2.5]辛烷-7-碳酰氯(ii)(白色固体)。直接用于下一步反应。
制备实施例36：4-(2,2,2-三氟乙酰基)-4,7-二氮杂螺[2.5]辛烷-7-碳酰氯(jj)的制备
Figure PCTCN2019105271-appb-000061
步骤1：1-(7-苄基-4,7-二氮杂螺[2.5]辛-4-基)-2,2,2-三氟乙烷-1-酮(jj1)的制备
于0℃，在含有DCM(10mL)的反应瓶中加入7-苄基-4,7-二氮杂螺[2.5]辛烷(ii3)(390mg,1.93mmol)、三乙胺(779mg，7.72mmol)和三氟乙酸酐(609mg，2.9mmol)。反应液搅拌1小时。然后加入饱和的碳酸氢钠水溶液淬灭，用二氯甲烷萃取(20mLx3)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA＝1:1)得到1-(7-苄基-4,7-二氮杂螺[2.5]辛-4-基)-2,2,2-三氟乙烷-1-酮(jj1)(430mg，黄色固体，收率：75％)。
LC-MS(ESI)：m/z 299.2[M+H +]。
步骤2：2,2,2-三氟-1-(4,7-二氮杂螺[2.5]辛-4-基乙-1-酮盐酸盐(jj2)的制备
在含有乙醇(10mL)的圆底烧瓶中加1-(7-苄基-4,7-二氮杂螺[2.5]辛-4-基)-2,2,2-三氟乙烷-1-酮(jj1)(430mg,1.45mmol)、Pd/C(100mg，10％)和浓盐酸(80mg)。密封，氢气置换三次，反应液在氢气氛围下室温搅拌2小时后，过滤。滤液减压浓缩，得到2,2,2-三氟-1-(4,7-二氮杂螺[2.5]辛-4-基乙-1-酮盐酸盐(jj2)(330mg，黄色固体，收率92％)。
LC-MS(ESI)：m/z 209.1[M+H +]。
步骤3：4-(2,2,2-三氟乙酰基)-4,7-二氮杂螺[2.5]辛烷-7-碳酰氯(jj)的制备
于室温下，在含有无水二氯甲烷(10mL)的反应瓶中加入2,2,2-三氟-1-(4,7-二氮杂螺[2.5]辛-4-基乙-1-酮盐酸盐(jj2)(150mg,0.62mmol)和碳酸钾(855mg,6.2mmol)。将反应液冷却至0℃，分批加入三光气(90mg，0.3mmol)。加毕，反应液升至室温搅拌6小时。反应完成后，过滤，用二氯甲烷(20mL)洗涤，滤液减压浓缩，得到粗产品4-(2,2,2-三氟乙酰基)-4,7-二氮杂螺[2.5]辛烷-7-碳酰氯(jj)(白色固体)。直接用于下一步反应。
实施例1：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基2,4-二甲基哌嗪-1-甲酸酯(1)的制备
Figure PCTCN2019105271-appb-000062
步骤1：6-(苄氧基)-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉(1a)的制备
于室温，在含有DMF(20mL)的反应瓶中加入6-(苄氧基)-4-氯-7-甲氧基喹唑啉(f)(1.0g，3.33mmol)、4-氟-2-甲基-1H-吲哚-5-醇(a)(660mg，3.99mmol)和碳酸钾(920mg，6.66mmol)，反应液加热至90℃搅拌过夜。反应完成后，加入乙酸乙酯(20mL)稀释，有机相用水和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为PE:EA＝1:1)，得到6-(苄氧基)-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉(1.0g，白色固体，收率59％)。
LC-MS(ESI)：m/z 430.2[M+H +]。
步骤2：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基6-羟基-喹唑啉(1b)的制备
于室温，在含有甲醇(10mL)的反应瓶中加入6-(苄氧基)-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉(1.0g，2.32mmol)和Pd/C(200mg)，反应液用氢气置换三次后，在氢气氛下搅拌1小时。反应完成后，过滤，滤液减压浓缩，得到粗产品4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基6-羟基-喹唑啉(1b)(1.0g，白色固体)。
LC-MS(ESI)：m/z 340.2[M+H +]。
步骤3：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基2,4-二甲基哌嗪-1-甲酸酯(1)的制备
于室温，在含有DMF(2mL)的反应瓶中加入4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-醇(50mg，0.147mmol)、2,4-二甲基哌嗪-1-甲酰氯(g)(200mg，Crude)和碳酸钾(41mg，0.294mmol)。反应液在于室温搅拌过夜。反应完成后，加入乙酸乙酯(5mL)稀释，有机相用水和食盐水洗涤，无水硫酸 钠干燥，过滤，滤液减压浓缩。残余物通过制备HPLC纯化(C18，乙腈/水(0.1％甲酸)：30％～100％)，得到4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基2,4-二甲基哌嗪-1-甲酸酯(15mg，白色固体，收率21％)。
LC-MS(ESI)：m/z 480.23[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.36(d,J＝2.4Hz,1H),8.62(s,1H),8.07(s,1H),7.54(s,1H),7.16(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.3Hz,1H),6.25(dt,J＝2.1,1.0Hz,1H),4.00(s,3H),3.33(m,3H),2.82–2.64(m,2H),2.41(d,J＝0.9Hz,3H),2.20(s,3H),2.03(dd,J＝71.6,10.3Hz,2H),1.34(s,3H)。
实施例2：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(1R,4R)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸酯(2)的制备
Figure PCTCN2019105271-appb-000063
与实施例1的制备方法相同，除了用(1R,4R)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酰氯(i)替代2,4-二甲基哌嗪-1-甲酰氯(g)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(1R,4R)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸酯(2)(15mg，白色固体，三步收率11％)。
LC-MS(ESI)：m/z 478.2[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.35(s,1H),8.62(s,1H),8.09(d,J＝5.2Hz,1H),7.54(s,1H),7.16(d,J＝8.6Hz,1H),7.00(dd,J＝8.6,7.3Hz,1H),6.32–6.18(m,1H),4.01(s,3H),3.47(s,2H),2.90–2.76(m,2H),2.54(s,2H),2.47–2.19(m,6H),1.91–1.75(m,2H)。
实施例3：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(3)的制备
Figure PCTCN2019105271-appb-000064
与实施例1的制备方法相同，除了用(R)-2,4-二甲基哌嗪-1-甲酰氯(j)替代2,4-二甲基哌嗪-1-甲酰氯(g)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(2)(12mg，白色固体，三步收率9％)。
LC-MS(ESI)：m/z 480.3[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ10.83(s,1H),8.20(s,1H),7.70(s,1H),7.25(s, 1H),6.86(d,J＝8.5Hz,1H),6.63(t,J＝8.4Hz,1H),6.03(p,J＝1.0Hz,1H),3.91(s,3H),2.78(s,2H),2.70–2.61(m,2H),2.44–2.39(m,2H),2.33(d,J＝0.9Hz,3H),2.20(d,J＝3.9Hz,7H)。
实施例4：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(S)-2,4-二甲基哌嗪-1-甲酸酯(4)的制备
Figure PCTCN2019105271-appb-000065
与实施例1的制备方法相同，除了用(S)-2,4-二甲基哌嗪-1-甲酰氯(k)替代2,4-二甲基哌嗪-1-甲酰氯(g)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(S)-2,4-二甲基哌嗪-1-甲酸酯(3)(15mg，白色固体，三步收率12％)。
LC-MS(ESI)：m/z 480.3[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ10.83(s,1H),8.20(s,1H),7.70(s,1H),7.25(s,1H),6.86(d,J＝8.5Hz,1H),6.63(t,J＝8.4Hz,1H),6.03(p,J＝1.0Hz,1H),3.91(s,3H),2.78(s,2H),2.70–2.61(m,2H),2.44–2.39(m,2H),2.33(d,J＝0.9Hz,3H),2.20(d,J＝3.9Hz,7H)。
实施例5：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(R)-3-甲基吗啉-4-甲酸酯(5)的制备
Figure PCTCN2019105271-appb-000066
与实施例1的制备方法相同，除了用(R)-3-甲基吗啉-4-甲酰氯(l)替代2,4-二甲基哌嗪-1-甲酰氯(g)。制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(R)-3-甲基吗啉-4-甲酸酯(5)(16mg，白色固体，三步收率12％)。
LC-MS(ESI)：m/z 467.2[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.37(d,J＝2.4Hz,1H),8.63(s,1H),8.10(s,1H),7.55(s,1H),7.17(d,J＝8.6Hz,1H),7.00(dd,J＝8.6,7.3Hz,1H),6.27–6.22(m,1H),4.01(s,3H),3.93–3.83(m,2H),3.71–3.57(m,3H),3.47(dd,J＝12.9,9.9Hz,2H),2.5(S,3H),2.41(d,J＝1.0Hz,3H)。
实施例6：4-((3-氯-4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(6)的制备
Figure PCTCN2019105271-appb-000067
与实施例1的制备方法相同，除了用3-氯-4-氟-2-甲基-1H-吲哚-5-醇(b)替代4-氟-2-甲基-1H-吲哚-5-醇(a)和用(R)-2,4-二甲基哌嗪-1-甲酰氯(j)替代2,4-二甲基哌嗪-1-甲酰氯(g)，制得4-((3-氯-4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(6)(8mg，白色固体，三步收率10％)。
LC-MS(ESI)：m/z 514.3/516.4[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.74(s,1H),8.64(s,1H),8.08(s,1H),7.55(s,1H),7.22(d,J＝8.7Hz,1H),7.11(dd,J＝8.7,7.2Hz,1H),4.01(s,3H),3.32(m,2H),2.81–2.64(m,2H),2.5(s,3H)2.38(s,3H),2.20(s,3H),2.12(d,J＝10.9Hz,1H),2.04–1.85(m,2H)。
实施例7：4-((7-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(7)的制备
Figure PCTCN2019105271-appb-000068
与实施例1的制备方法相同，除了用7-氟-2-甲基-1H-吲哚-5-醇(c)替代4-氟-2-甲基-1H-吲哚-5-醇(a)和用(R)-2,4-二甲基哌嗪-1-甲酰氯(j)替代2,4-二甲基哌嗪-1-甲酰氯(g)，制得4-((7-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(7)(18mg，白色固体，三步收率13％)。
LC-MS(ESI)：m/z 480.2[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.51(d,J＝2.0Hz,1H),8.62(s,1H),8.02(s,1H),7.51(s,1H),7.17(d,J＝1.9Hz,1H),6.90(dd,J＝11.5,2.0Hz,1H),6.24(s,1H),3.99(s,3H),3.26(s,2H),2.73(dd,J＝49.3,11.3Hz,3H),2.5(s,3H),2.41(s,3H),2.20(s,3H),2.12(d,J＝10.6Hz,2H)。
实施例8：4-((7-氯-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(8)的制备
Figure PCTCN2019105271-appb-000069
与实施例1的制备方法相同，除了用7-氯-2-甲基-1H-吲哚-5-醇(e)替代4-氟-2-甲基-1H-吲哚-5-醇(a)和用(R)-2,4-二甲基哌嗪-1-甲酰氯(j)替代2,4-二甲基哌嗪-1-甲酰氯(g)，制得4-((7-氯-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹唑啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(8)(15mg，白色固体，三步收率15％)。
LC-MS(ESI)：m/z 496.2/498.2[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.36(t,j＝2.4Hz,1H),8.62(s,1H),8.02(s,1H),7.51(s,1H),7.31(d,J＝2.0Hz,1H),7.10(d,J＝2.0Hz,1H),6.26(dd,J＝2.1,1.1Hz,1H),3.99(s,3H),3.32(m,3H),2.73(ddt,J＝50.3,11.2,1.9Hz,2H),2.43(d,J＝0.9Hz,3H),2.20(s,3H),2.03(dd,J＝71.8,11.5Hz,2H),1.33(s,3H)。
实施例9：4-((4,7-二氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-基(R)-2,4二甲基哌嗪-1-甲酸酯(9)的制备
Figure PCTCN2019105271-appb-000070
与实施例1的制备方法相同，除了用4,7-二氟-2-甲基-1H-吲哚-5-醇(d)替4-氟-2-甲基-1H-吲哚-5-醇(a)和用(R)-2,4-二甲基哌嗪-1-甲酰氯(j)替代2,4-二甲基哌嗪-1-甲酰氯(g)，制得4-((4,7-二氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-基(R)-2,4二甲基哌嗪-1-甲酸酯(9)(12mg，白色固体，三步收率8％)。
LC-MS(ESI)：m/z 498.3[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.84(t,J＝2.2Hz,1H),8.65(s,1H),8.06(s,1H),7.54(s,1H),7.06(dd,J＝10.6,5.5Hz,1H),6.35(s,1H),4.00(s,3H),3.4(m,2H),2.81–2.55(m,3H),2.5(s,3H),2.43(s,3H),2.20(s,3H),2.16–1.93(m,2H)。
实施例10：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹唑啉-6-基(R)-2,4二甲基哌嗪-1-甲酸酯(10)的制备
Figure PCTCN2019105271-appb-000071
步骤1：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-羟基-喹唑啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(10a)的制备
于室温，在含有无水DCM(2mL)的反应瓶中加入4-((4,7-二氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-基(R)-2,4二甲基哌嗪-1-甲酸酯(9)(50mg，0.1mmol)。将反应混合物冷却至-78℃，滴加三溴化硼四氢呋喃溶液(0.25mL,2M)。加毕，反应混合物升温至0℃搅拌1小时，待反应完成后，用饱和的碳酸氢钠溶液淬灭，并用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为DCM:MeOH＝10:1)，得到4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-羟基喹唑啉-6-基(R)-2,4-二甲基哌嗪-1-羧酸酯(10a)(22mg,白色固体，收率41.2％)。
LC-MS(ESI)：m/z 466.28[M+H +]。
步骤2：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹唑啉-6-基(R)-2,4二甲基哌嗪-1-甲酸酯(10)的制备
于室温，在含有丙酮(2mL)的反应瓶中加入4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-羟基喹唑啉-6-基(R)-2,4-二甲基哌嗪-1-羧酸酯(10a)(20mg,0.04mmol)、溴乙烷(6.5mg,0.06mmol)和碳酸钾(11mg，0.08mmol)。反应混合物加热至60℃搅拌2小时。待反应完成后，反应液用乙酸乙酯稀释，有机相用水和饱和的食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过制备HPLC纯化(C18，乙腈/水(0.1％甲酸)：30％～100％)，得到7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹唑啉-6-基(R)-2,4二甲基哌嗪-1-甲酸酯(10)(8.8mg，白色固体，收率41.5％)。
LC-MS(ESI)：m/z 494.2[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.38(s,1H),δ8.61(s,1H),8.05(s,1H),7.50(s,1H),7.16(d,J＝8.6Hz,1H),6.99(dd,J＝8.6,7.4Hz,1H),6.25(s,1H),4.27(dq,J＝6.2,3.6Hz,2H),3.87(s,1H),3.37(m,2H),2.80(d,J＝11.3Hz,1H),2.68(d,J＝11.1Hz,1H),2.41(s,3H),2.20(s,3H),2.11(d,J＝10.9Hz,1H),1.93(s,1H),1.40(t,J＝6.9Hz,3H),1.35(s,3H)。
实施例11：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(11)的制备
Figure PCTCN2019105271-appb-000072
于室温，在含有DMF(4mL)的反应瓶中加入4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基-喹啉(q)(100mg,0.29mmol)、(R)-2,4-二甲基哌嗪-1-甲酰氯(j)(204mg,1.16mmol)和碳酸钾(320mg,2.32mmol)。反应液在室温搅拌6小时。待反应完成后，加入乙酸乙酯(20mL)稀释，有机相用水和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过制备HPLC纯化(C18，乙腈/水(0.1％甲酸)：30％～100％)，得到4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(11)(80mg,白色固体，收率56.7％)。
LC-MS(ESI)：m/z 479.25[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.56(d,J＝5.3Hz,1H),7.99(s,1H),7.53(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.4,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.22(d,J＝70.6Hz,1H),3.96(s,3H),3.92(s,1H),3.37(s,1H),2.83–2.76(m,1H),2.67(dt,J＝11.5,1.8Hz,1H),2.42(d,J＝1.0Hz,3H),2.20(s,3H),2.12(d,J＝10.0Hz,1H),1.93(t,J＝11.7Hz,1H),1.34(s,3H)。
实施例12：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(R)-2-甲基哌嗪-1-甲酸酯(12)的制备
Figure PCTCN2019105271-appb-000073
步骤1：4-(叔丁基)-1-(4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基)(R)-2-甲基哌嗪-1,4-二甲酸酯(12a)的制备
于室温下，在含有DMF(6mL)的反应瓶中加入4-((4-氟-2-甲基-1H-吲哚-5-基) 氧基)-7-甲氧基-6-羟基-喹啉(q)(200mg,0.58mmol)、(R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)(310mg,1.16mmol)和碳酸钾(640mg,4.64mmol)。反应液在室温搅拌6小时。待反应完成后，加入乙酸乙酯(20mL)稀释，有机相用水和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM＝1:20)，得到4-(叔丁基)-1-(4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基)(R)-2-甲基哌嗪-1,4-二甲酸酯(12a)(240mg,黄色固体，收率72％)。
LC-MS(ESI)：m/z 565.3[M+H +]。
步骤2：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(R)-2-甲基哌嗪-1-甲酸酯(12)的制备
在含有DCM(4mL)的反应瓶中加入4-(叔丁基)-1-(4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基)(R)-2-甲基哌嗪-1,4-二甲酸酯(12a)(100mg，0.18mmol)和盐酸的1,4-二氧六环溶液(1mL，4M)。将混合物于室温搅拌6小时后，减压浓缩。残余物通过制备HPLC纯化(C18，乙腈/水(0.1％甲酸)：10％～100％)，得到4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(R)-2-甲基哌嗪-1-甲酸酯(12)(40mg，白色固体，48.6％)。
LC-MS(ESI)：m/z 465.35[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.45(d,J＝2.3Hz,1H),8.56(d,J＝5.3Hz,1H),7.99(s,1H),7.53(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),3.96(s,3H),3.80(d,J＝21.7Hz,2H),3.19(s,1H),2.98(d,J＝12.2Hz,1H),2.90–2.83(m,2H),2.69(d,J＝11.9Hz,1H),2.42(d,J＝1.0Hz,3H),1.33(s,3H)。
实施例13：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-2,4-二甲基哌嗪-1-甲酸酯(13)的制备
Figure PCTCN2019105271-appb-000074
与实施例11的制备方法相同，除了用(S)-2,4-二甲基哌嗪-1-甲酰氯(k)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)。制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-2,4-二甲基哌嗪-1-甲酸酯(13)(61mg,白色固体，收率43.6％)。
LC-MS(ESI)：m/z 479.25[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.56(d,J＝5.3Hz,1H),7.99(s,1H),7.53(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.4,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.22(d,J＝70.6Hz,1H),3.96(s,3H),3.92(s,1H),3.37(s,1H),2.83–2.76(m,1H),2.67(dt,J＝11.5,1.8Hz,1H),2.42 (d,J＝1.0Hz,3H),2.20(s,3H),2.12(d,J＝10.0Hz,1H),1.93(t,J＝11.7Hz,1H),1.34(s,3H)。
实施例14：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-2-甲基哌嗪-1-甲酸酯(14)的制备
Figure PCTCN2019105271-appb-000075
与实施例12的制备方法相同，除了用(S)-4-(氯甲酰基)-2-甲基哌嗪-1-甲酸叔丁酯(cc)替代(R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)。制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-2-甲基哌嗪-1-甲酸酯(14)(35mg，白色固体，收率53％)。
LC-MS(ESI)：m/z 465.32[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.45(s,1H),8.56(d,J＝5.3Hz,1H),8.01(s,1H),7.53(s,1H),7.22(d,J＝8.6Hz,1H),7.00(t,J＝8.1Hz,1H),6.37(dd,J＝5.3,1.0Hz,1H),6.28(s,1H),4.08(s,1H),3.96(s,3H),3.87(s,1H),3.09(s,1H),2.96(d,J＝12.7Hz,1H),2.77(d,J＝11.4Hz,3H),2.42(s,3H),1.04(d,J＝5.8Hz,3H)。
实施例15：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(15)的制备
Figure PCTCN2019105271-appb-000076
与实施例11的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)。制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(R)-2,4-二甲基哌嗪-1-甲酸酯(15)(40mg,白色固体，收率36％)。
LC-MS(ESI)：m/z 493.32[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),δ8.55(d,J＝5.3Hz,1H),7.98(s,1H),7.50(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.4,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.33(s,1H),4.21(qd,J＝7.0,2.8Hz,2H),3.89(s,1H),3.26(s,1H,2.80(d,J＝11.8Hz,1H),2.71–2.64(m,1H),2.42(d,J＝1.0Hz,3H),2.20(s,3H),2.11(d,J＝10.8Hz,1H),1.92(s,1H),1.40(t,J＝6.9Hz,3H),1.34(s,3H)。
实施例16：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(R)-2-甲基哌嗪-1-甲酸酯(16)的制备
Figure PCTCN2019105271-appb-000077
与实施例12的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r))替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)。制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(R)-2-甲基哌嗪-1-甲酸酯(16)(35mg,白色固体，收率53％)。
LC-MS(ESI)：m/z 479.37[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.55(dd,J＝5.3,3.1Hz,1H),7.98(s,1H),7.51(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.2,1.1Hz,1H),6.28(dt,J＝2.0,1.0Hz,1H),4.22(dq,J＝7.0,3.9,3.3Hz,2H),3.84(s,2H),3.18(s,1H),2.98(d,J＝11.9Hz,1H),2.86(d,J＝8.3Hz,2H),2.67(d,J＝10.2Hz,1H),2.42(d,J＝1.0Hz,3H),2.18(d,J＝14.7Hz,1H),1.43–1.38(m,3H),1.34(s,3H)。
实施例17：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(S)-2,4-二甲基哌嗪-1-甲酸酯(17)的制备
Figure PCTCN2019105271-appb-000078
与实施例11的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(S)-2,4-二甲基哌嗪-1-甲酰氯(k)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(S)-2,4-二甲基哌嗪-1-甲酸酯(17)(15mg,白色固体，收率13.5％)。
LC-MS(ESI)：m/z 493.32[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),δ8.55(d,J＝5.2Hz,1H),7.98(s,1H),7.50(s,1H),7.22(d,J＝8.6Hz,1H),7.00(t,J＝8.1Hz,1H),6.37(dd,J＝5.2,1.1Hz,1H),6.31–6.25(m,1H),4.33(s,1H),4.22(qt,J＝7.1,3.3Hz,2H),3.89(s,1H),3.26(s,1H),2.80(d,J＝11.3Hz,1H),2.67(d,J＝11.4Hz,1H),2.42(s,3H),2.20(s,3H),2.11(d,J＝10.9Hz,1H),1.94(d,J＝13.6Hz,1H),1.40(t,J＝6.9Hz,3H),1.34(s,3H)。
实施例18：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(S)-2-甲基哌嗪-1-甲酸酯(18)的制备
Figure PCTCN2019105271-appb-000079
与实施例12的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(S)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(cc)替代(R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)，制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(S)-2-甲基哌嗪-1-甲酸酯(18)(10mg，白色固体，收率49％)。
LC-MS(ESI)：m/z 479.31[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.55(d,J＝5.3Hz,1H),7.97(s,1H),7.50(s,1H),7.22(d,J＝8.6Hz,1H),7.00(t,J＝8.1Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dd,J＝2.2,1.2Hz,1H),4.22(dq,J＝6.7,3.2Hz,2H),3.83(s,2H),3.15(s,1H),2.95(s,1H),2.83(d,J＝6.7Hz,2H),2.64(s,1H),2.44–2.36(m,3H),2.18(d,J＝14.6Hz,1H),1.40(t,J＝6.9Hz,3H),1.33(s,3H)。
实施例19：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-3,4-二甲基哌嗪-1-甲酸酯(19)的制备
Figure PCTCN2019105271-appb-000080
与实施例11的制备方法相同，除了用(S)-3,4-二甲基哌嗪-1-甲酰氯(x)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-3,4-二甲基哌嗪-1-甲酸酯(19)(31.2mg,白色固体，收率36.8％)。
LC-MS(ESI)：m/z 479.35[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.56(d,J＝5.2Hz,1H),8.00(s,1H),7.53(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.02(d,J＝19.9Hz,1H),3.96(s,3H),3.79(s,1H),3.35(m,1H),3.10(d,J＝12.8Hz,1H),2.91(s,1H),2.75(t,J＝14.3Hz,1H),2.42(d,J＝1.0Hz,3H),2.23(s,3H),2.15(s,1H),1.03(s,3H)。
实施例20：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-3-甲基哌嗪-1-甲酸酯(20)的制备
Figure PCTCN2019105271-appb-000081
与实施例12的制备方法相同，除了用(S)-4-(氯甲酰基)-2-甲基哌嗪-1-甲酸叔丁酯(aa)替代(R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-3-甲基哌嗪-1-甲酸酯(20)(12mg，白色固体，收率48％)。
LC-MS(ESI)：m/z 465.33[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.56(d,J＝5.3Hz,1H),8.02(s,1H),7.53(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.2,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.08(d,J＝12.9Hz,1H),3.96(s,3H),3.87(d,J＝12.3Hz,1H),3.12(s,1H),3.00(d,J＝12.6Hz,1H),2.81(s,2H),2.59(d,J＝13.1Hz,1H),2.42(d,J＝1.0Hz,3H),1.05(s,3H)。
实施例21：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(R)-3,4-二甲基哌嗪-1-甲酸酯(21)的制备
Figure PCTCN2019105271-appb-000082
与实施例11的制备方法相同，除了用(R)-3,4-二甲基哌嗪-1-甲酰氯(y)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(R)-3,4-二甲基哌嗪-1-甲酸酯(21)(44mg,白色固体，收率31.2％)。
LC-MS(ESI)：m/z 479.42[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.56(d,J＝5.2Hz,1H),8.00(s,1H),7.53(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.02(d,J＝19.9Hz,1H),3.96(s,3H),3.79(s,1H),3.35(m,1H),3.10(d,J＝12.8Hz,1H),2.91(s,1H),2.75(t,J＝14.3Hz,1H),2.42(d,J＝1.0Hz,3H),2.23(s,3H),2.15(s,1H),1.03(s,3H)。
实施例22：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-乙氧基喹啉-6-基(R)-3-甲基哌嗪-1-甲酸酯(22)的制备
Figure PCTCN2019105271-appb-000083
与实施例12的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(R)-4-(氯甲酰基)-2-甲基哌嗪-1-甲酸叔丁酯(z)替代(R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-乙氧基喹啉-6-基(R)-3-甲基哌嗪-1-甲酸酯(22)(22mg,白色固体，收率64％)。
LC-MS(ESI)：m/z 479.33[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.55(d,J＝5.3Hz,1H),7.99(s,1H),7.50(s,1H),7.22(d,J＝8.6Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.30–6.27(m,1H),4.23(t,J＝6.9Hz,2H),4.09(s,1H),3.88(s,2H),3.12(s,1H),3.01(d,J＝12.4Hz,2H),2.80(s,2H),2.42(d,J＝1.0Hz,3H),1.41(d,J＝6.9Hz,3H),1.06(d,J＝6.0Hz,3H)。
实施例23：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(S)-3,4-二甲基哌嗪-1-甲酸酯(23)的制备
Figure PCTCN2019105271-appb-000084
与实施例11的制备方法相似，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(S)-3,4-二甲基哌嗪-1-甲酰氯(x)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(S)-3,4-二甲基哌嗪-1-甲酸酯(23)(50mg,白色固体，收率39.8％)。
LC-MS(ESI)：m/z 493.42[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.45(s,1H),8.55(d,J＝5.3Hz,1H),7.98(s,1H),7.50(s,1H),7.22(d,J＝8.6Hz,1H),7.00(t,J＝8.1Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.32–6.24(m,1H),4.22(q,J＝6.9Hz,2H),4.00(d,J＝17.8Hz,1H),3.79(d,J＝17.4Hz,1H),3.09(s,1H),2.90(s,1H),2.76(t,J＝16.9Hz,2H),2.42(s,3H),2.23(s,3H),2.15(s,1H),1.41(t,J＝6.9Hz,3H),1.04(d,J＝6.1Hz,3H)。
实施例24：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(S)-3-甲基哌嗪-1-甲酸酯(24)的制备
Figure PCTCN2019105271-appb-000085
与实施例12的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(S)-4-(氯甲酰基)-2-甲基哌嗪-1-甲酸叔丁酯(aa)替代(R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(S)-3-甲基哌嗪-1-甲酸酯(24)(22mg,白色固体，收率64％)。
LC-MS(ESI)：m/z 479.35[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(t,J＝2.2Hz,1H),8.55(d,J＝5.3Hz,1H),7.99(s,1H),7.50(s,1H),7.22(dd,J＝8.5,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.0Hz,1H),6.28(dt,J＝2.0,1.0Hz,1H),4.21(t,J＝7.0Hz,2H),4.08(s,1H),3.89(s,1H),3.10(s,1H),2.99(d,J＝12.3Hz,1H),2.78(s,2H),2.58(m,1H),2.42(d,J＝1.0Hz,3H),1.40(t,J＝7.0Hz,3H),1.05(d,J＝6.0Hz,3H)。
实施例25：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(R)-3,4-二甲基哌嗪-1-甲酸酯(25)的制备
Figure PCTCN2019105271-appb-000086
与实施例11的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(R)-3,4-二甲基哌嗪-1-甲酰氯(y)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(R)-3,4-二甲基哌嗪-1-甲酸酯(25)(31mg,白色固体，收率27.5％)。
LC-MS(ESI)：m/z 493.37[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.55(d,J＝5.3Hz,1H),7.98(s,1H),7.50(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.2,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.22(q,J＝6.9Hz,2H),4.02(s,1H),3.79(d,J＝17.4Hz,1H),3.27(s,1H),3.09(s,1H),2.95–2.74(m,2H),2.42(d,J＝1.0Hz,3H),2.23(s,3H),2.15(s,1H),1.41(t,J＝6.9Hz,3H),1.04(d,J＝6.0Hz,3H)。
实施例26：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(R)-3-甲基吗啉-4-甲酸酯(26)的制备
Figure PCTCN2019105271-appb-000087
与实施例11的制备方法相同，除了用(R)-3-甲基吗啉-4-甲酰氯(l)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(R)-3-甲基吗啉-4-甲酸酯(26)(50mg,白色固体，收率36％)。
LC-MS(ESI)：m/z 466.23[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.56(d,J＝5.3Hz,1H),8.02(s,1H),7.54(s,1H),7.22(dd,J＝8.5,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.38(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.15(s,1H),3.97(s,3H),3.88(dd,J＝11.2,3.4Hz,1H),3.72–3.59(m,2H),3.47(dd,J＝13.0,10.1Hz,3H),2.42(d,J＝1.0Hz,3H),1.33(s,3H)。
实施例27：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(R)-3-甲基吗啉-4-甲酸酯(27)的制备
Figure PCTCN2019105271-appb-000088
与实施例11的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(R)-3-甲基吗啉-4-甲酰氯(l)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(R)-3-甲基吗啉-4-甲酸酯(27)(40mg,白色固体，收率36％)。
LC-MS(ESI)：m/z480.33[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.55(d,J＝5.3Hz,1H),8.00(s,1H),7.51(s,1H),7.25–7.19(m,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.22(qt,J＝6.8,3.4Hz,3H),3.95–3.73(m,2H),3.72–3.61(m,2H),3.60–3.39(m,2H),2.42(d,J＝1.0Hz,3H),1.45–1.28(m,6H)。
实施例28：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-3-甲基吗啉-4-甲酸酯(28)的制备
Figure PCTCN2019105271-appb-000089
与实施例11的制备方法相同，除了用(S)-3-甲基吗啉-4-甲酰氯(s)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-3-甲基吗啉-4-甲酸酯(28)(40mg,白色固体，收率36％)。
LC-MS(ESI)：m/z 466.32[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.56(d,J＝5.3Hz,1H),8.02(s,1H),7.54(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.38(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,0.9Hz,1H),3.97(s,3H),3.88(dd,J＝11.4,3.5Hz,1H),3.70–3.61(m,2H),3.47(t,J＝11.5Hz,1H),2.42(d,J＝1.0Hz,3H),2.07(s,3H),1.33(s,3H)。
实施例29：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(S)-3-甲基吗啉-4-甲酸酯(29)的制备
Figure PCTCN2019105271-appb-000090
与实施例11的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(S)-3-甲基吗啉-4-甲酰氯(s)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(S)-3-甲基吗啉-4-甲酸酯(29)(40mg，白色固体，收率36％)。
LC-MS(ESI)：m/z 480.32[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.45(s,1H),8.55(d,J＝5.3Hz,1H),8.00(s,1H),7.51(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.0,1.0Hz,1H),4.22(qt,J＝6.8,3.4Hz,3H),3.89(dd,J＝11.4,3.5Hz,1H),3.84–3.73(m,1H),3.69(d,J＝11.5Hz,1H),3.61(dd,J＝11.6,3.2Hz,1H),3.46(t,J＝11.2Hz,2H),2.42(d,J＝0.9Hz,3H),1.40(t,J＝6.9Hz,3H),1.34(s,3H)。
实施例30：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基硫代吗啉-4-甲酸酯(30)的制备
Figure PCTCN2019105271-appb-000091
与实施例11的制备方法相同，除了用硫代吗啉-4-甲酰氯(ee)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基硫代吗啉-4-甲酸酯(30)(25mg，白色固体，收率44％)。
LC-MS(ESI)：m/z 482.29[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.43(s,1H),8.55(d,J＝5.3Hz,1H),8.02(s,1H),7.52(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,1.1Hz,1H),4.24(q,J＝6.9Hz,2H),3.72(s,2H),2.77(s,4H),2.42(d,J＝1.0Hz,3H),1.43(t,J＝6.9Hz,3H)。
实施例31：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-乙氧基喹啉-6-基(S)-2-甲基吗啉-4-甲酸酯(31)的制备
Figure PCTCN2019105271-appb-000092
与实施例11的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(S)-2-甲基吗啉-4-甲酰氯(gg)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-乙氧基喹啉-6-基(S)-2-甲基吗啉-4-甲酸酯(31)(40mg，白色固体，收率36％)。
LC-MS(ESI)：m/z 480.33[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.55(d,J＝5.3Hz,1H),8.01(s,1H),7.51(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.0,1.0Hz,1H),4.23(q,J＝6.9Hz,2H),4.09(s,1H),3.94–3.80(m,2H),3.56(s,2H),3.02(s,1H),2.71(d,J＝14.2Hz,1H),2.42(d,J＝1.0Hz,3H),1.41(t,J＝6.9Hz,3H),1.14(d,J＝6.2Hz,3H)。
实施例32：7-甲氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基2-甲基吗啉-4-甲酸酯(32)的制备
Figure PCTCN2019105271-appb-000093
与实施例11的制备方法相同，除了用(S)-2-甲基吗啉-4-甲酰氯(gg)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得7-甲氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基2-甲基吗啉-4-甲酸酯(32)(15mg，白色固体，收率36％)。
LC-MS(ESI)：m/z 465.25[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.56(d,J＝5.3Hz,1H),8.03(s,1H),7.54(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.38(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.05(dd,J＝23.0,13.2Hz,1H),3.97(s,3H),3.91–3.79(m,2H),3.56(s,2H),2.89(s,2H),2.42(d,J＝0.9Hz,3H),1.14(d,J＝6.2Hz,3H)。
实施例33：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(R)-2-甲基吗啉-4-甲酸酯(33)的制备
Figure PCTCN2019105271-appb-000094
与实施例11的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(R)-2-甲基吗啉-4-甲酰氯(hh)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(R)-2-甲基吗啉-4-甲酸酯(33)(14mg，白色固体，收率36％)。
LC-MS(ESI)：m/z 480.33[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.55(d,J＝5.2Hz,1H),8.01(s,1H),7.51(s,1H),7.22(d,J＝8.6Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,1.1Hz,1H),4.23(q,J＝6.9Hz,2H),4.06(s,1H),3.89(dd,J＝11.3,3.5Hz,2H),3.56(s,2H),2.95(d,J＝54.8Hz,1H),2.70(s,1H),2.42(d,J＝1.0Hz,3H),1.41(t,J＝6.9Hz,3H),1.14(d,J＝6.2Hz,3H)。
实施例34：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸酯(34)的制备
Figure PCTCN2019105271-appb-000095
与实施例11的制备方法相同，除了用(1R,4R)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酰氯(i)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得4-((4-氟-2-甲基-1H-吲哚 -5-基)氧基)-7-甲氧基喹啉-6-基(1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸酯(34)(13.3mg,白色固体，收率59％)。
LC-MS(ESI)：m/z 476.25[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.43(s,1H),8.56(d,J＝5.2Hz,1H),8.00(d,J＝3.6Hz,1H),7.53(s,1H),7.22(d,J＝8.6Hz,1H),7.11–6.92(m,1H),6.37(dd,J＝5.3,1.0Hz,1H),6.32–6.24(m,1H),3.96(s,3H),3.23(dd,J＝10.2,2.1Hz,1H),2.92–2.75(m,2H),2.60(d,J＝9.7Hz,1H),2.47–2.28(m,6H),2.08–1.91(m,1H),1.81(dd,J＝30.2,12.1Hz,2H)。
实施例35：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(1S，4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸酯(35)的制备
Figure PCTCN2019105271-appb-000096
与实施例12的制备方法相同，用(1R,4R)-5-(氯甲酰基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(dd)替代(R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸酯(35)(45mg，白色固体，收率64％)。
LC-MS(ESI)：m/z 463.33[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.45(s,1H),8.57(dd,J＝5.2,1.6Hz,1H),8.02(d,J＝3.5Hz,1H),7.54(d,J＝4.0Hz,1H),7.22(d,J＝8.6Hz,1H),7.00(t,J＝8.1Hz,1H),6.38(d,J＝5.3Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),3.97(d,J＝3.9Hz,5H),3.61(s,1H),3.40-3.431(m,1H),3.27(d,J＝10.2Hz,1H),3.13–3.01(m,2H),2.42(s,3H),2.01–1.92(m,1H),1.81–1.72(m,1H)。
实施例36：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸酯(36)的制备
Figure PCTCN2019105271-appb-000097
与实施例12的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(1R,4R)-5-(氯甲酰基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(dd)替代(R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)，制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸酯(36)(22mg, 白色固体，收率64％)。
LC-MS(ESI)：m/z 477.31[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.45(d,J＝2.7Hz,1H),8.55(dd,J＝5.3,1.8Hz,1H),8.00(d,J＝2.3Hz,1H),7.51(d,J＝4.3Hz,1H),7.22(d,J＝8.6Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(d,J＝5.3Hz,1H),6.28(q,J＝1.2Hz,1H),4.21-4.24(m,2H),3.95(d,J＝13.3Hz,1H),3.59(s,1H),3.39(d,J＝8.3Hz,2H),3.25(s,1H),3.07(dt,J＝15.3,7.8Hz,2H),2.42(d,J＝1.0Hz,3H),1.93(s,1H),1.41(td,J＝7.0,3.7Hz,3H)。
实施例37：7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸酯(37)的制备
Figure PCTCN2019105271-appb-000098
与实施例11的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(1R,4R)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酰氯(i)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)喹啉-6-基(1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸酯(37)(40mg,白色固体，收率35.9％)。
LC-MS(ESI)：m/z 491.34[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.55(d,J＝5.3Hz,1H),7.98(d,J＝3.6Hz,1H),7.50(s,1H),7.22(d,J＝8.6Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(d,J＝5.2Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.27–4.19(m,2H),3.77(m,1H),3.54–3.47(m,2H),3.22(dd,J＝10.2,2.1Hz,1H),2.93–2.75(m,2H),2.43–2.40(m,3H),2.38(d,J＝7.3Hz,3H),1.91–1.72(m,2H),1.46–1.35(m,3H)。
实施例38：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-乙氧基喹啉-6-基(3S,5R)-3,5-二甲基哌嗪-1-甲酸酯(38)的制备
Figure PCTCN2019105271-appb-000099
与实施例12的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(2R,6S)-4-(氯甲酰基)-2,6-二甲基哌嗪-1-甲酸叔丁酯(ff)替代 (R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(3S,5R)-3,5-二甲基哌嗪-1-甲酸酯(38)(29mg,白色固体，收率64％)。
LC-MS(ESI)：m/z 493.36[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(t,J＝2.4Hz,1H),8.55(d,J＝5.3Hz,1H),8.17(s,1H),7.99(s,1H),7.50(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.22(q,J＝6.9Hz,2H),4.14(d,J＝12.8Hz,1H),3.92(d,J＝12.7Hz,1H),2.89(d,J＝32.8Hz,2H),2.74–2.62(m,2H),2.42(d,J＝1.0Hz,3H),1.40(t,J＝6.9Hz,3H),1.06(d,J＝6.1Hz,6H)。
实施例39：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-乙氧基喹啉-6-基(2S,6R)-2,6-二甲基吗啉-4-甲酸酯(39)的制备
Figure PCTCN2019105271-appb-000100
与实施例11的制备方法相同，除了用7-乙氧基-4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-羟基喹啉(r)替代4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基喹啉(q)，并且用(2R,6S)-2,6-二甲基吗啉-4-甲酰氯(w)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-乙氧基喹啉-6-基(2S,6R)-2,6-二甲基吗啉-4-甲酸酯(39)(12mg，白色固体，收率36％)。
LC-MS(ESI)：m/z 494.29[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ8.55(d,J＝5.3Hz,1H),8.01(s,1H),7.51(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.02–6.96(m,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.22(q,J＝6.9Hz,2H),4.11(d,J＝13.2Hz,1H),3.90(d,J＝13.1Hz,1H),3.63(d,J＝18.7Hz,2H),2.79(t,J＝12.0Hz,1H),2.68–2.57(m,1H),2.42(d,J＝1.0Hz,3H),1.40(t,J＝6.9Hz,3H),1.14(d,J＝6.1Hz,6H)。
实施例40：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-2-甲基哌嗪-1-甲酸酯(40)的制备
Figure PCTCN2019105271-appb-000101
与实施例12的制备方法相同，除了用(S)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁 酯(cc)替代(R)-4-(氯甲酰基)-3-甲基哌嗪-1-甲酸叔丁酯(bb)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-2-甲基哌嗪-1-甲酸酯(38)(38mg,白色固体，收率64％)。
LC-MS(ESI)：m/z 465.33[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.45(d,J＝2.3Hz,1H),8.56(d,J＝5.3Hz,1H),7.99(s,1H),7.53(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),3.96(s,3H),3.80(d,J＝21.7Hz,2H),3.19(s,1H),2.98(d,J＝12.2Hz,1H),2.90–2.83(m,2H),2.69(d,J＝11.9Hz,1H),2.42(d,J＝1.0Hz,3H),1.33(s,3H)。
实施例41：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(R)-六氢吡咯并[1,2-a]吡嗪-2(1H)-甲酸酯(41)的制备
Figure PCTCN2019105271-appb-000102
与实施例11的制备方法相似，除了用(R)-六氢吡咯并[1,2-a]吡嗪-2(1H)-甲酰氯(v)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(R)-六氢吡咯并[1,2-a]吡嗪-2(1H)-甲酸酯(41)。
LC-MS(ESI)：m/z 491.36[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(d,J＝2.6Hz,1H),8.56(d,J＝5.3Hz,1H),8.00(s,1H),7.53(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.2,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.31(d,J＝12.5Hz,1H),4.15(dd,J＝31.3,12.7Hz,1H),3.96(s,3H),3.02(d,J＝9.4Hz,2H),2.85(t,J＝11.8Hz,1H),2.65(d,J＝13.6Hz,1H),2.42(d,J＝1.0Hz,3H),2.10(q,J＝8.8Hz,2H),1.83(s,1H),1.71(q,J＝10.1,9.2Hz,2H),1.39–1.26(m,2H)。
实施例42：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-六氢吡咯并[1,2-a]吡嗪-2(1H)-甲酸酯(42)的制备
Figure PCTCN2019105271-appb-000103
与实施例11的制备方法相似，除了用(S)-六氢吡咯并[1,2-a]吡嗪-2(1H)-甲酰氯(u)替代(R)-2,4-二甲基哌嗪-1-甲酰氯(j)，制得4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基(S)-六氢吡咯并[1,2-a]吡嗪-2(1H)-甲酸酯(42)。
LC-MS(ESI)：m/z 491.36[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.44(d,J＝2.6Hz,1H),8.56(d,J＝5.3Hz,1H),8.00(s,1H),7.53(s,1H),7.22(dd,J＝8.6,0.8Hz,1H),7.00(dd,J＝8.6,7.6Hz,1H),6.37(dd,J＝5.2,1.1Hz,1H),6.28(dt,J＝2.1,1.0Hz,1H),4.31(d,J＝12.5Hz,1H),4.15(dd,J＝31.3,12.7Hz,1H),3.96(s,3H),3.02(d,J＝9.4Hz,2H),2.85(t,J＝11.8Hz,1H),2.65(d,J＝13.6Hz,1H),2.42(d,J＝1.0Hz,3H),2.10(q,J＝8.8Hz,2H),1.83(s,1H),1.71(q,J＝10.1,9.2Hz,2H),1.39–1.26(m,2H)。
实施例43：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基4,7-二氮杂螺[2.5]辛烷-7-羧酸酯(43)的制备
Figure PCTCN2019105271-appb-000104
步骤1：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基4-苄基-4,7-二氮杂螺[2.5]辛烷-7-羧酸酯(43a)的制备
于室温下，在含有DMF(6mL)的反应瓶中加入4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基-喹啉(q)(250mg,0.74mmol)、4-苄基-4,7-二氮杂螺[2.5]辛烷-7-碳酰氯(ii)(400mg,1.5mmol)和碳酸钾(814mg,5.9mmol)。反应液在室温搅拌6小时。待反应完成后，加入乙酸乙酯(20mL)稀释，有机相用水和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM＝1:20)，得到4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基4-苄基-4,7-二氮杂螺[2.5]辛烷-7-羧酸酯(43a)(310mg,黄色固体，收率74％)。
LC-MS(ESI)：m/z 567.3[M+H +]。
步骤2：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基4,7-二氮杂螺[2.5]辛烷-7-羧酸酯(43)的制备
在含有乙醇(10mL)的圆底烧瓶中加入4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-4-苄基-4,7-二氮杂螺[2.5]辛烷-7-羧酸酯(43a)(310mg,0.55mmol)、Pd/C(50mg，10％)和浓盐酸(50mg)。密封，氢气置换三次，反应液在氢气氛围下室温搅拌2小时后，过滤。滤液减压浓缩，残余物通过制备HPLC纯化(C18，乙腈/水(0.1％甲酸)：30％～100％)，得到4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基4,7-二氮杂螺[2.5]辛烷-7-羧酸酯(43)(160mg，黄色固体，收率61％)。
LC-MS(ESI)：m/z 477.24[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.45(t,J＝2.3Hz,1H),8.56(d,J＝5.3Hz,1H),8.27(s,1H),8.04(s,1H),7.54(s,1H),7.23(d,J＝8.6Hz,1H),7.01(dd,J＝8.6,7.6Hz,1H),6.38(dd,J＝5.3,1.1Hz,1H),6.29(dt,J＝2.2,1.1Hz,1H),3.98(s,3H), 2.92(s,2H),2.80(s,2H),2.44–2.38(m,3H),1.09(s,3H),0.87(s,3H)。
实施例44：4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基4,7-二氮杂螺[2.5]辛烷-4-羧酸酯(44)的制备
Figure PCTCN2019105271-appb-000105
于室温下，在含有DMF(6mL)的反应瓶中加入4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基-6-羟基-喹啉(q)(150mg,0.44mmol)、4-(2,2,2-三氟乙酰基)-4,7-二氮杂螺[2.5]辛烷-7-碳酰氯(jj)(238mg,0.88mmol)和碳酸钾(485mg,3.52mmol)。反应液在室温搅拌6小时后，升至50℃继续搅拌1小时，待反应完成后，加入乙酸乙酯(20mL)稀释，有机相用水和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过制备HPLC纯化(C18，乙腈/水(0.1％甲酸)：30％～100％)，，得到4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-7-甲氧基喹啉-6-基4,7-二氮杂螺[2.5]辛烷-4-羧酸酯(44)(41mg,白色固体，收率19％)。
LC-MS(ESI)：m/z 477.3[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ11.43(s,1H),8.56(d,J＝5.3Hz,1H),7.97(d,J＝16.7Hz,1H),7.53(s,1H),7.22(d,J＝8.6Hz,1H),7.00(t,J＝8.1Hz,1H),6.37(dd,J＝5.3,1.1Hz,1H),6.31–6.26(m,1H),3.96(s,3H),3.61(s,1H),3.49(s,2H),3.29(s,2H),2.83(d,J＝20.6Hz,2H),2.42(s,3H),0.63(s,1H),0.51(s,2H)。
生物学测试
试验例1：本发明化合物对激酶FLT1(VEGFR1)、FLT4(VEGFR3)和KDR(VEGFR2)的酶活性抑制(IC 50)的评价实验
本试验使用迁移率改变法(Mobility shift assay)，测试化合物在ATP浓度分别为相应激酶Km下的抑制活性。对照品为孢碱(staurosporine)。
测试化合物的浓度从10μM开始，10倍稀释。测试结果(IC 50)为两次独立实验的平均值。
试验材料：
激酶FLT1(Invitrogen,Cat.No.PR6731B,Lot.No.33924Q)，激酶FLT4(Invitrogen,Cat.No.PV4129,Lot.No.38454G)和激酶KDR(Carna,Cat.No.08-191,Lot.No.07CBS-0540)，底物肽FAM-P22(GL Biochem,Cat.No112393,Lot. No.P130408-ZB112393)，底物肽FAM-P30(GL Biochem,Cat.No.263631,Lot.No.P141015-XF263631)，ATP(Sigma,Cat.No.A7699-1G,CAS No.987-65-5)，DMSO(Sigma,Cat.No.D2650,Lot.No.474382)，EDTA(Sigma,Cat.No.E5134,CAS No.60-00-4)，HEPES(Sigma，Cat.No.V900477-500G，CAS No.7365-45-9，Lot.No.WXBC4716V)，DTT(Sigma，Cat.No.D0632-25g，CAS No.3483-12-3，Lot.No.SLBF3964V)，Brij-35(Sigma,Cat.No.B4184,Lot No.018K61251)，96孔板(Corning,Cat.No.3365,Lot.No.22008026)，384孔板(Corning,Cat.No.3573,Lot.No.12608008)，孢碱(MCE,Cat.No.HY-15141,Lot.No.21226)，对照品索拉菲尼(大连美仑生物技术有限公司，货号#MB1666，批号#F1209A)和安罗替尼(按照专利US 20160326138合成)。
试验步骤：
1)缓冲液配制：50mM HEPES，pH 7.5，0.00015％Brij-35。
2)对照品索拉菲尼、安罗替尼和测试样品配制：将索拉菲尼、安罗替尼和本发明实施例化合物在100％DMSO中配制成梯度浓度，并用上述缓冲液稀释成10％DMSO，加入384孔板。例如，化合物起始浓度为10uM，则用100％DMSO配制成500uM，并梯度稀释10个浓度，再用缓冲液稀释10倍，配成含10％DMSO的化合物稀释液，转移5ul至384孔板。
3)将激酶FLT1、FLT4和KDR分别用以下缓冲液稀释成最佳浓度：50mM HEPES，pH 7.5，0.00015％Brij-35，2mM DTT。转移10ul至384孔板中，与化合物共孵育10-15分钟。
4)将底物FAM-P22、FAM-P30用以下缓冲液稀释成最佳浓度：50mM HEPES，pH 7.5，0.00015％Brij-35，10mM MgCl 2，Km下的ATP。加入10ul至384孔板起始反应，并于28℃反应1小时。
试验中各试剂的反应浓度如下表1所示。
表1
Figure PCTCN2019105271-appb-000106
5)用Caliper Reader(Perkin Elmer)读取转化率，按以下公式计算抑制率，取两次测试平均值：
抑制率(％)＝(DMSO对照值-样品转化率/(DMSO对照值-本底值)*100％。
6)用XL-fit软件拟合IC 50。
本发明化合物对激酶FLT1(VEGFR1)、FLT4(VEGFR3)和KDR(VEGFR2)的酶 活性抑制IC 50值示于下表中。
表2本发明化合物对VEGFR1、2、3激酶的抑制IC 50值
Figure PCTCN2019105271-appb-000107
Figure PCTCN2019105271-appb-000108
如上表2所示，本发明化合物与两个阳性对照药物相比，对KDR(VEFGR2)和FLT4(VEGFR3)激酶活性展现出了更高的抑制作用。
试验例2：本发明化合物对人源异种移植乳腺癌MDA-MB-231模型的体内药效学评价
实验材料：
MDA-MB-231细胞：购自ATCC，编号为：HTB-26；BALB/c裸鼠：购自斯贝福(北京)生物技术有限公司；索拉非尼(Sorafenib)：购自上海宏叶生物科技有限公司；Cremophor：购自Beijing Solarbio Science&Technology Co.,Ltd；solutol HS-15：购自北京偶合科技有限公司。
实验方法：
将MDA-MB-231细胞接种于雌性BALB/c nude小鼠右侧前胁肋部皮下，待肿瘤生长至平均体积为150mm 3左右时(第10天)进行分组给药。共分4组，每组5只，分别为：溶媒对照组、实施例11化合物低剂量组(6mg/kg)、实施例11化合物高剂量组(25mg/kg)、Sorafenib阳性对照组(50mg/kg)。溶媒为10％solutol HS-15水溶液，将实施例11化合物溶于溶媒制成0.6mg/ml溶液后按组灌胃给药，一天一次，连续给药21天。阳性对照药Sorafenib溶于Cremophor/95％乙醇/H 2O(12.5％/12.5％/75％)制成5mg/ml溶液后灌胃给药，一天一次，连续给药21天。每周测量肿瘤体积及体重两次，记录荷瘤鼠体重和肿瘤体积的变化与给药时间的关系。实验结束后，各组小鼠安乐死，剥离肿瘤组织，称重后摆放整齐拍照。计算治疗组与对照组相对肿瘤体积增值率(T/C％)和相对肿瘤生长抑制率(TGI％)，并应用IBM SPSS Statistics 22.0统计学软件，应用One-Way ANOVA检验对肿瘤体积、肿瘤重量和小鼠体重进行组间统计学分析(p<0.05认为有显著性差异)。
相对肿瘤抑制率TGI(％)：TGI％＝(1-T/C)×100％。T/C％为相对肿瘤增值率，即在实验结束时，治疗组和对照组相对肿瘤体积的百分比值。T和C分别为治疗组和对照组在实验结束时的相对肿瘤体积(RTV)。计算公式如下：T/C％ ＝TRTV/CRTV×100％(TRTV：治疗组平均RTV；CRTV：溶媒对照组平均RTV；RTV＝Vt-V0，V0为分组时该动物的瘤体积，Vt为治疗后该动物的瘤体积)。
实验结果：
在实验结束时，和溶媒组相比，实施例11化合物的低、高剂量组和Sorafenib阳性药对照组肿瘤体积均显著减小(p<0.01)，各治疗组的肿瘤抑制率分别为99.4％、103.1％和105.4％；实施例11化合物的高、低剂量组与Sorafenib阳性药对照组的肿瘤体积不具有显著性差异(p>0.05)(见图1)。
在实验期间，各治疗组小鼠体重基本保持稳定，实施例11化合物的高剂量组和Sorafenib阳性药对照组略有下降，但所有小鼠一般状态良好，无停药、无其它异常表现。至实验结束时，由于溶媒组小鼠荷瘤巨大，其体重显著高于各治疗组(p<0.01)(见图2)。
结论：
本发明化合物对人源异种移植乳腺癌MDA-MB-231模型产生了显著的抗肿瘤作用，有效地抑制了肿瘤生长，具有一定的剂量反应关系趋势；高剂量(25mg/kg)和低剂量(6mg/kg)的抑瘤效果与阳性药Sorafenib 50mg/kg剂量的效果相当；荷瘤鼠对本实验治疗量的实施例11化合物表现出良好的耐受性。

Claims (13)

  1. 一种通式(I)所示的化合物：
    Figure PCTCN2019105271-appb-100001
    或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用盐，
    其中：
    X为CH或N；
    R 1选自氢、烷基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    R 2选自含氮杂环基，其任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    R 3选自氢、卤素、羟基、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    R 4选自氢、卤素、羟基、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    R 5选自氢、卤素、羟基、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    R 6选自氢、卤素、羟基、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。
  2. 根据权利要求1所述的通式(I)所示的化合物，
    其中，
    R 1选自烷基，优选C 1-C 6烷基，所述烷基进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。
  3. 根据权利要求1或2所述的通式(I)所示的化合物，
    其中，
    R 2选自4至10元含氮杂环基，优选4至10元单环含氮杂环基、含氮螺杂环基、含氮稠杂环基或含氮桥杂环基；
    所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物，
    其中，
    R 2选自基团：
    Figure PCTCN2019105271-appb-100002
    其任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    其中：
    Y选自CH 2、NR a、O、或S、S(O) y；
    R a选自氨基、羟基、酯基、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基；
    i为0、1或2；
    j为0、1或2；
    m为0、1或2；
    y为1或2；
    A环为C 3-C 6饱和或不饱和环。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物，
    其中，R 3选自氢或卤素。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物，
    其中，R 4选自氢或卤素。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物，
    其中，R 5选自氢或卤素。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物，
    其中，R 6选自烷基，优选C 1-C 6烷基。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物，其中，所述化合物选自：
    Figure PCTCN2019105271-appb-100003
    Figure PCTCN2019105271-appb-100004
    Figure PCTCN2019105271-appb-100005
  10. 一种制备根据权利要求1至9中任一项所述的通式(I)所示的化合物的方法，其包含以下步骤：
    Figure PCTCN2019105271-appb-100006
    化合物Ij与酰氯化合物在碱性介质中进行缩合反应，得到通式化合物(I)；
    其中，所述碱优选为K 2CO 3，溶剂优选为DMF；
    R 1、R 2、R 3、R 4、R 5、R 6、X如权利要求1所定义。
  11. 一种药物组合物，其包含根据权利要求1至9中任一项所述的通式(I)所示的化合物，以及药学上可接受的载体或赋形剂。
  12. 根据权利要求1至9中任一项所述的通式(I)所示的化合物，或根据权利要求11所述的药物组合物，在制备血管内皮生长因子受体激酶抑制剂中的用途。
  13. 根据权利要求1至9中任一项所述的通式(I)所示的化合物，或根据权利要求11所述的药物组合物，在制备治疗与血管内皮生长因子受体激酶功能失调相关的疾病的药物中的用途，所述疾病优选膀胱癌、乳腺癌、***、直结肠癌、肠癌、胃癌、头颈癌、肾癌、肝癌、肺癌、卵巢癌、***癌、睾丸癌、食道癌、胆囊癌、胰腺癌、甲状腺癌、皮肤癌、脑癌、骨癌、软组织癌、白血病和淋巴癌，更优选脑癌、甲状腺癌、肝癌、肺癌、肾癌、乳腺癌、胃癌和直结肠癌。
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