WO2020057403A1 - Dérivé d'indole et son application médicale - Google Patents

Dérivé d'indole et son application médicale 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)
Chinese (zh)
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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/fr

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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.

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Abstract

L'invention concerne un composé représenté par la formule générale (I), un procédé de préparation, une composition pharmaceutique comprenant le composé, et une utilisation de celui-ci en tant qu'inhibiteur de la kinase du récepteur du facteur de croissance endothéliale vasculaire, en particulier une utilisation dans le traitement d'une maladie liée à un dysfonctionnement de la kinase du récepteur du facteur de croissance endothéliale vasculaire, telle que le cancer. La définition de chaque substituant dans la formule générale (I) est la même que la définition dans la description.
PCT/CN2019/105271 2018-09-18 2019-09-11 Dérivé d'indole et son application médicale WO2020057403A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000047212A1 (fr) * 1999-02-10 2000-08-17 Astrazeneca Ab Derives de quinazoline utilises comme inhibiteurs de l'angiogenese
WO2003064413A1 (fr) * 2002-02-01 2003-08-07 Astrazeneca Ab Composes de quinazoline
WO2005014582A1 (fr) * 2003-08-06 2005-02-17 Astrazeneca Ab Derives de quinazoline en tant qu'inhibiteurs d'angiogenese
WO2008112407A1 (fr) * 2007-03-14 2008-09-18 Advenchen Laboratories, Llc Composés substitués de spiro comme inhibiteurs d'angiogenèse
WO2014130612A1 (fr) * 2013-02-20 2014-08-28 Kala Pharmaceuticals, Inc. Composés thérapeutiques et leurs utilisations
WO2014135876A1 (fr) * 2013-03-06 2014-09-12 Astrazeneca Ab Inhibiteurs quinazoline de l'activation des formes mutantes du récepteur de croissance épidermique (egfr)

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000047212A1 (fr) * 1999-02-10 2000-08-17 Astrazeneca Ab Derives de quinazoline utilises comme inhibiteurs de l'angiogenese
WO2003064413A1 (fr) * 2002-02-01 2003-08-07 Astrazeneca Ab Composes de quinazoline
WO2005014582A1 (fr) * 2003-08-06 2005-02-17 Astrazeneca Ab Derives de quinazoline en tant qu'inhibiteurs d'angiogenese
WO2008112407A1 (fr) * 2007-03-14 2008-09-18 Advenchen Laboratories, Llc Composés substitués de spiro comme inhibiteurs d'angiogenèse
WO2014130612A1 (fr) * 2013-02-20 2014-08-28 Kala Pharmaceuticals, Inc. Composés thérapeutiques et leurs utilisations
WO2014135876A1 (fr) * 2013-03-06 2014-09-12 Astrazeneca Ab Inhibiteurs quinazoline de l'activation des formes mutantes du récepteur de croissance épidermique (egfr)

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